Comprehensive analyses of neurodevelopmental outcomes and quality of life of children with biliary atresia.

OBJECTIVES: To holistically evaluate neurodevelopmental outcomes and quality of life (QOL) of Japanese patients with biliary atresia (BA) and to investigate the factors associated with the outcomes. METHODS: This study enrolled patients with BA aged 5-18 years who visited Osaka University Hospital in 2021. Neurodevelopmental assessments were performed to evaluate intellectual ability, cognitive functions and adaptive skill levels. Furthermore, emotional and behavioral issues, characteristics of attention deficit hyperactivity disorder, and QOL were concomitantly assessed in the same cohort. Biochemical and social factors associated with the results were examined. RESULTS: Fifty-three patients, with a median age of 11.2 years were included in the analyses. Patients with BA had a significantly lower Full-Scale Intelligence Quotient or developmental quotient (FSIQ/DQ) score and Vineland Adaptive Behavior Scale (VABS) composite score than the general Japanese population. Household education level and short stature were associated with low and borderline FSIQ/DQ and VABS composite scores, respectively. Among patients with low and borderline FSIQ/DQ scores, those with average or high VABS composite scores received significantly less neuroeducational care than those with low and borderline VABS composite scores. Despite the low FSIQ/DQ and VABS composite scores, the total QOL scores were higher than those of the general population. CONCLUSION: Patients with BA had intellectual and behavioral impairments. Notably, patients with intellectual impairments are overlooked and not followed up, especially if adaptive skills are maintained.

Rationale and study design of the GOREISAN for heart failure (GOREISAN-HF) trial: A randomized clinical trial.

BACKGROUND: The decongestion strategy using loop diuretics is essential for improving signs and symptoms of heart failure (HF). However, chronic use of loop diuretics in HF has been linked to worsening renal function and adverse clinical outcomes in a dose-dependent manner. Goreisan, a traditional Japanese herbal medicine, has a long history of use in Japan for regulating body fluid homeostasis and has been recognized as causing less adverse outcomes such as dehydration in contrast to loop diuretics in clinical practice. Therefore, we designed the GOREISAN-HF trial to evaluate the long-term effects of a new decongestion strategy adding Goreisan to usual care in patients with HF and volume overload. METHODS: The GOREISAN-HF trial is an investigator-initiated, multicenter, pragmatic, randomized, comparative effectiveness trial in which we will enroll 2,192 patients hospitalized for HF at 68 hospitals in Japan. All study participants will be randomly assigned to either a decongestion strategy that adds Goreisan at a dose of 7.5 g daily on top of usual care or usual care alone. Investigators have the flexibility to change the existing diuretic regimen in both groups. The primary end point is the improvement rate of cardiac edema at 12-month follow-up, and the co-primary end point is a composite of all-cause death or hospitalization up to the end of the planned follow-up period. Secondary end points include longitudinal changes in patient-reported outcomes, loop diuretics dose, and renal function. CONCLUSIONS: The GOREISAN-HF is the first large-scale randomized pragmatic trial to assess the efficacy and safety of a new congestion control strategy adding Goreisan to usual care in patients with HF and volume overload. REGISTRATION NUMBER: NCT04691700.

Kampo medicine for the holistic approach to older adults with heart failure.

Heart failure (HF) is a leading cause of hospitalization, morbidity, and mortality in older adults and represents a significant clinical and economic burden on the health care system. However, there are many challenges in assessing and managing HF in elderly patients, who often have coexisting multimorbidity, frailty, and malnutrition. Therefore, it is often difficult to solve these problems with Western medicine alone, and a holistic approach, including Kampo medicine, can be helpful. In particular, managing volume control and frailty by adding Kampo formulas may help improve health-related quality of life and substantially impact prognosis in HF. This review article summarizes the role of Kampo medicine for older patients with HF and frailty.

Senna Versus Magnesium Oxide for the Treatment of Chronic Constipation: A Randomized, Placebo-Controlled Trial.

INTRODUCTION: This is the first prospective, double-blinded, randomized, placebo-controlled trial to evaluate the safety and efficacy of a stimulant laxative compared with an osmotic agent for the treatment of chronic idiopathic constipation. METHODS: Patients were randomly administered stimulant laxative (senna, 1.0 g), osmotic agent (magnesium oxide [MgO], 1.5 g), or placebo for 28 consecutive days. The primary endpoint was overall symptom improvement. Secondary endpoints were spontaneous bowel movement (SBM), complete SBM, and patient assessment of constipation quality of life (QOL). RESULTS: Ninety patients (mean age, 42 years; 93% women; mean duration of symptoms, 9.9 years) were enrolled; all completed the study. The response rate for overall improvement was 11.7% in the placebo group, 69.2% in the senna group, and 68.3% in the MgO group (P < 0.0001). Change in SBM was significantly greater in the senna and MgO groups than that in the placebo group (P < 0.001). Similarly, change in complete SBM was significantly greater in the senna and MgO groups than that in the placebo group (P < 0.01). On the patient assessment of constipation QOL, significant improvements were seen in the senna and MgO groups compared with those in the placebo group (senna, P < 0.05; MgO, P < 0.001). The frequency of severe treatment-related adverse events was 0%. DISCUSSION: Senna and MgO significantly improved the frequency of bowel movements and QOL score and seem to be effective in the treatment of constipation.

Use of plasma-free amino acids as biomarkers for detecting and predicting disease risk.

This paper reviews developments regarding the use of plasma-free amino acid (PFAA) profiles as biomarkers for detecting and predicting disease risk. This work was initiated and first published in 2006 and was subsequently developed by Ajinomoto Co., Inc. After commercialization in 2011, PFAA-based tests were adopted in over 1500 clinics and hospitals in Japan, and numerous clinician-led studies have been performed to validate these tests. Evidence is accumulating that PFAA profiles can be used for diabetes prediction and evaluation of frailty; in particular, decreased plasma essential amino acids could contribute to the pathophysiology of severe frailty. Integration of PFAA evaluation as a biomarker and effective essential amino acid supplementation, which improves physical and mental functions in the elderly, could facilitate the development of precision nutrition, including personalized solutions. This present review provides the background for the technology as well as more recent clinical findings, and offers future possibilities regarding the implementation of precision nutrition.

Reassessing the Ecology of Medical Care in Japan.

Studies on ecology of medical care can provide valuable information on how people seek healthcare in a specific geographic area. The objective of this study was to update a 2003 report on the ecology of medical care in Japan, identifying relevant changes in healthcare patterns. We collected information based on a prospective health diary recorded for a month in 2013 (n = 4548; 3787 adults and 797 children) using a population-weighted random sample from a nationally representative panel. We compared our overall and stratified findings with a similar study conducted in 2003. During a one-month period, per 1000 adults and children living in Japan, we estimated that 794 report at least one symptom, 447 use an over-the-counter (OTC) drug, 265 visit a physician's office, 117 seek help from a professional provider of complementary or alternative medicine (CAM), 70 visit a hospital outpatient clinic (60 community-based and 10 university-based), 6 are hospitalized, and 4 visit a hospital emergency department. After adjusting for demographic variables, we found that healthcare seeking behaviors were influenced by age, gender and area of living. Compared with the 2003 study, participants in this study had fewer symptoms, fewer physician and emergency room visits, and less OTC use, but reported higher frequency of CAM use (p < .01 for all). Compared with 2003, reported symptoms, physician visits and OTC use has decreased, while CAM use has increased. Our findings may be useful to policymakers in Japan in a context where healthcare expenditure and a rapidly aging population are two challenging issues.

Significance of electrocardiogram recording in high intercostal spaces in patients with early repolarization syndrome.

AIMS: Published reports regarding inferolateral early repolarization (ER) syndrome (ERS) before 2013 possibly included patients with Brugada-pattern electrocardiogram (BrP-ECG) recorded only in the high intercostal spaces (HICS). We investigated the significance of HICS ECG recording in ERS patients. METHODS AND RESULTS: Fifty-six patients showing inferolateral ER in the standard ECG and spontaneous ventricular fibrillation (VF) not linked to structural heart disease underwent drug provocation tests by sodium channel blockade with right precordial ECG (V1-V3) recording in the 2nd-4th intercostal spaces. The prevalence and long-term outcome of ERS patients with and without BrP-ECG in HICS were investigated. After 18 patients showing type 1 BrP-ECG in the standard ECG were excluded, 38 patients (34 males, mean age; 40.4 ± 13.6 years) were classified into four groups [group A (n = 6;16%):patients with ER and type 1 BrP-ECG only in HICS, group B (n = 5;13%):ERS with non-type 1 BrP-ECG only in HICS, group C (n = 8;21%):ERS with non-type 1 BrP-ECG in the standard ECG, and group D (n = 19;50%):ERS only, spontaneously or after drug provocation test]. During follow-up of 110.0 ± 55.4 months, the rate of VF recurrence including electrical storm was significantly higher in groups A (4/6:67%), B (4/5:80%), and C (4/8:50%) compared with D (2/19:11%) (A, B, and C vs. D, P < 0.05). CONCLUSIONS: Approximately 30% of the patients with ERS who had been diagnosed with the previous criteria showed BrP-ECG only in HICS. Ventricular fibrillation mostly recurred in patients showing BrP-ECG in any precordial lead including HICS; these comprised 50% of the ERS cohort.

Polaprezinc attenuates cyclophosphamide-induced cystitis and related bladder pain in mice.

Cav3.2 T-type Ca(2+) channels targeted by H2S, a gasotransmitter, participate in cyclophosphamide-induced cystitis and bladder pain. Given that zinc selectively inhibits Cav3.2 among T-channel isoforms and also exhibits antioxidant activity, we examined whether polaprezinc (zinc-l-carnosine), a medicine for peptic ulcer treatment and zinc supplementation, reveals preventive or therapeutic effects on bladder inflammation and/or pain in the mouse with cyclophosphamide-induced cystitis, a model for interstitial cystitis. Systemic administration of cyclophosphamide caused cystitis-related symptoms including increased bladder weight and vascular permeability, and histological signs of bladder edema, accompanied by bladder pain-like nociceptive behavior/referred hyperalgesia. All these symptoms were significantly attenuated by oral preadministration of polaprezinc at 400 mg/kg. The same dose of polaprezinc also prevented the increased malondialdehyde level, an indicator of lipid peroxidation, and protein upregulation of cystathionine-γ-lyase, an H2S-generating enzyme, but not occludin, a tight junction-related membrane protein, in the bladder tissue of cyclophosphamide-treated mice. Oral posttreatment with polaprezinc at 30-100 mg/kg reversed the nociceptive behavior/referred hyperalgesia in a dose-dependent manner without affecting the increased bladder weight. Together, our data show that zinc supplementation with polaprezinc prevents the cyclophosphamide-induced cystitis probably through the antioxidant activity, and, like T-channel blockers, reverses the established cystitis-related bladder pain in mice, suggesting novel therapeutic usefulness of polaprezinc.

Summary of workshop discussions on establishing upper limits for amino acids with specific attention to available data for the essential amino acids leucine and tryptophan.

The morning of the first day of the 8th Amino Acid Assessment Workshop was organized and co-sponsored by the International Council on Amino Acid Science (ICAAS) and the International Life Sciences Institute Research Foundation and was focused on the International Life Sciences Institute Research Foundation's approach to establishing upper limits of nutrients. The remainder of d 1 and all of d 2 were focused on the safety of leucine and tryptophan, with special emphasis on determining the upper level of the safe range of intake. It was recognized that some toxicological frameworks, mainly the key-events dose response framework, might be applicable to amino acids and provide appropriate assistance to regulators in establishing upper limits for amino acids as a group of nutrients used in dietary supplements. ICAAS-funded projects for determining the upper intake limits for the essential amino acid leucine provided the main pool of leucine data discussed at the workshop. The acute clinical study suggests 500 mg/(kg · d) as a possible upper limit for leucine in healthy humans, but the safety margin needed to widen this limit to the general population has not been determined. For tryptophan, the workshop participants found less ground for consensus. Older efficacy studies suggested that tryptophan at 8-15 g/d was well tolerated, but human research was abruptly terminated in the late 1980s and no new data are available. Animal results obtained in pigs and rodents were discussed and 2 possible strategies for applying those outcomes to humans were described.

A novel drug delivery system of oral curcumin markedly improves efficacy of treatment for heart failure after myocardial infarction in rats.

Curcumin is an inhibitor of p300 histone acetyltransferase activity, which is associated with the deterioration of heart failure. We reported that native curcumin, at a dosage of 50 mg/kg, prevented deterioration of the systolic function in rat models of heart failure. To achieve more efficient oral pharmacological therapy against heart failure by curcumin, we have developed a novel drug delivery system (DDS) which markedly increases plasma curcumin levels. At the dosage of 0.5 mg/kg, DDS curcumin but not native curcumin restored left ventricular fractional shortening in post-myocardial infarction rats. Thus, our DDS strategy will be applicable to the clinical setting in humans.

Excess dietary L-cysteine, but not L-cystine, is lethal for chicks but not for rats or pigs.

A comparative species investigation of the relative pharmacologic effects of sulfur amino acids was conducted using young chicks, rats, and pigs. Ingestion of excess Met, Cys, or Cys-Cys supplemented at 2.5-, 5.0-, 7.5-, or 10 times the dietary requirement in a corn-soybean meal diet depressed chick growth to varying degrees. Strikingly, ingestion of excess Cys at 30 g/kg Cys (7.5-times the dietary requirement) caused a chick mortality rate of 50% after only 5 d of feeding. Growth was restored and chick mortality was reduced by supplementing diets containing 25 g/kg excess Cys with KHCO3 at 10 g/kg. Additionally, mortality was prevented by supplementing the drinking water of chicks receiving 25 g/kg supplemental Cys with H2O2 (0.05% final concentration). After young rats and pigs consumed excess Cys or Cys-Cys up to 40 g/kg for 14 d, weight gain was severely depressed, but we observed no mortality. An excess of dietary Cys-Cys>or=48 g/kg caused some mortality in rats. Pigs exhibited rapid recovery from growth-depressing excesses of Cys or Cys-Cys. These results lend credence to the acute toxic effects associated with the ingestion of excess sulfur amino acids and highlight the potential for excess dietary cyst(e)ine to be more pernicious than Met in certain species.

Complementary appearance of glucose and lipid metabolism in cardiac sarcoidosis.

Sarcoidosis is a non-caseating granulomatous systemic disease of unknown pathogenesis, and cardiac involvement is the most important prognostic factor. We have evaluated the value of the combined study of F-18 fluoro-2-deoxyglucose positron emission tomography and iodine-123 labeled 15-(p-iodophenyl)-3R,S-methylpentadecanoic acid single-photon emission tomography for the assessment of cardiac involvement of sarcoidosis, by comparing the findings with gadolinium magnetic resonance in a patient with histologically-proven cardiac sarcoidosis.

Prolonged oral treatment with an essential amino acid L-leucine does not affect female reproductive function and embryo-fetal development in rats.

L-leucine, an essential amino acid, is one of the most popular ingredients in dietary supplements. To investigate a possibility of its embryo-fetal toxicity in rats, 11- to 12-week old dams were orally administered an aqueous solution of L-leucine at doses of 300 or 1000 mg/kg body weight on gestational days 7-17. Body weight and feed intake was evaluated throughout the whole course of pregnancy (days 0-20). L-Leucine did not influence body weight, but at a dose of 1000 mg/kg, slightly enhanced feed intake on days 14 and 18 of pregnancy. Caesarean section (day 20) revealed no influences on the litter size and weight of live-born fetuses, the number of corpora lutea, implantation index or the quality of placenta, and the minor increase in feed intake was considered irrelevant to the pregnancy outcomes. Fetuses were evaluated in a battery of external, visceral and skeletal examinations. No effects of L-leucine on gender ratio and external abnormalities, and no significant treatment-related variations in visceral and skeletal pathologies were observed. These results suggested that L-leucine, administered orally during organogenesis at doses up to 1000 mg/kg body weight, did not affect the outcome of pregnancy and did not cause fetotoxicity in rats.

Thirteen-week oral toxicity study of L-arginine in rats.

The amino acid L-arginine (Arg) has been used extensively in dietary and pharmacological products. This study evaluated toxicological and behavioral effects of Arg produced by Ajinomoto Co. (Tokyo, Japan) during a dosing study with male and female Sprague-Dawley rats. The amino acid was incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% (w/w). A control group of rats received only a standard diet. All diets were administered ad libitum for 13 continuous weeks. To examine recoverability of any potential effects, the administration period was followed by a 5-week-long recovery, during which only a standard diet was provided. In male and female rats in each concentration group, treatment-related changes were not observed for clinical signs, body weights, diet consumption, ophthalmology, gross pathology, organ weight, or histopathology. An elevated level of plasma glucose was detected in some male rats (5.0%, w/w) during the analysis conducted in the fifth week of administration; however, the degree of the change was within the physiological range, and no changes were observed at the end of the administration period. In the same group, an increase in hemoglobin, together with a tendency toward an increase in the red blood cell counts, was found, but the change was considered toxicologically insignificant. The no-observed-adverse-effect level (NOAEL) for Arg was estimated at 5.0% (w/w) for both genders (males, 3.3 +/- 0.1 g/kg/day; females, 3.9 +/- 0.2 g/kg/day).

Thirteen-week oral toxicity study of L-glutamine in rats.

L-Glutamine (Gln) is a semiessential amino acid used in enteral feeding in critically ill patients, and is contained in numerous dietary supplements available to the general public. This study evaluated toxicological effects of Gln in male and female Sprague-Dawley rats. Gln produced by Ajinomoto Co. (Tokyo, Japan) was incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% (w/w), respectively. A control group of rats received only a standard diet. All diets were administered ad libitum for 13 consecutive weeks. To examine recoverability of any potential effects, the administration period was followed by a 5-week recovery period, during which only the standard diet was provided to all animals. Throughout the administration and recovery periods, no deaths were observed, and no changes in diet consumption, ophthalmologic findings, gross pathology, and histopathology were detected. Several changes in urine parameters (total protein, urine pH, and a positive incidence (+/-) of ketone bodies) were observed in the 2.5% and 5.0% groups at the end of the administration period. Minor increases were found in hematology parameters for the 5.0% group (platelet count, gamma-globulin, lactate dehydrogenase [LDH]), but all changes were within physiological range. No effects of administration were observed in the 1.25% group. The no-observed-adverse-effect level (NOAEL) for Gln was estimated at 1.25% for both genders (males 0.83 +/- 0.01 g/kg/day; females, 0.96 +/- 0.06 g/kg/day).

Thirteen-week oral toxicity study of L-lysine hydrochloride in rats.

L-Lysine hydrochloride (Lys) is an essential amino acid in humans and animals, and it is used in animal feeds, in prevention of herpes simplex recurrence, and cereal fortification in some developing countries. This study evaluated toxicological and behavioral effects of Lys during a dosing study with male and female Sprague-Dawley rats. The amino acid was incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% (w/w). A control group of rats received a standard diet. All diets were administered ad libitum for 13 consecutive weeks. To examine stability of any potential effects, the administration period was followed by a 5-week recovery period, during which only the standard diet was provided to all animals. In male and female rats in each concentration group, treatment-related changes were not observed in the clinical signs, body weights, diet consumption, water intake, ophthalmology, gross pathology, organ weights, or histology. A Lys-related drop in serum concentration and an increase in urine excretion of chlorides was a compensatory reaction to the ingested hydrochloride. No functional, biochemical, or histological changes in renal function were found. The no-observed-adverse-effect level (NOAEL) for Lys was estimated at 5.0% for both genders (male, 3.36 +/- 0.12 g/kg/day; female, 3.99 +/- 0.28 g/kg/day).

Thirteen-week oral toxicity study of branched-chain amino acids in rats.

Branched-chain amino acids (L-isoleucine, L-valine, and L-leucine) are being increasingly used in sport supplements. This study evaluated toxicological and behavioral effects of L-isoleucine (Ile), L-valine (Val), and L-leucine (Leu) during a dosing study with male and female Sprague-Dawley rats. The amino acids were incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% (w/w). A control group of rats received a standard diet. All diets were administered ad libitum for 13 consecutive weeks. To examine stability of any potential effects, the administration period was followed by a 5-week recovery period, during which only the standard diet was provided to all animals. No significant, dose-related effects on body weight were found in rats fed a Leu- and Ile-supplemented diet. Val mixed into a diet at 5.0% (w/w) decreased slightly, but significantly body weight gain in females, but not males. Ile (5.0% w/w) affected the urine electrolytes, protein, ketone bodies, urine glucose, and urobilinogen in both genders, yet the observed changes remained mostly within the range observed in controls. The random findings in hepatology and ophthalmology at the 13-week sacrifice were not considered toxicologically relevant to effects of the tested amino acids. No significant changes in organ weights were recorded. We estimate the no-observed-adverse-effect level (NOAEL) for Ile at 2.5% for both genders (male, 1.565 +/- 0.060 g/kg/day; females, 1.646 +/- 0.095 g/kg/day), Val at 5.0% for males (3.225 +/- 0.135 g/kg/day) and 2.5% for females (1.853 +/- 0.060 g/kg/day), and Leu at 5.0% for both genders (males, 3.333 +/- 0.101 g/kg/day: females, 3.835 +/- 0.257 g/kg/day).