Effect of whey protein-derived decapeptide on mood status and blood variables in healthy adults: a randomized, double-blind, placebo-controlled cross-over trial.

PURPOSE: The importance of maintaining good mental health with overall well-being has recently drawn attention from various fields. Functional peptides found from various protein sources reportedly reduce mental health problems. We found a new decapeptide (AJI-801) from whey proteins, which can possibly improve mood status and increase blood acetyl-L-carnitine (ALC) and fibroblast growth factor 21 (FGF21) levels. In this study, we assessed the effects of a single intake of whey protein hydrolysate containing a high amount of AJI-801 (WPH) on blood variables and mood status. METHODS: A randomized, double-blind, placebo-controlled cross-over trial of two doses of WPH (100 and 500 mg) was conducted. Participants, aged between 20 and 59 years with fatigue were allocated to two groups based on the WPH doses received, and set first test food in each study. The blood ALC and FGF21 levels at baseline and after 60, 120, and 180 min of test food intake were analyzed and the responses to the questionnaire items for mood status were obtained at baseline and after 60 and 180 min of test food intake. RESULTS: There were no significant differences in the blood ALC and FGF21 levels between the two groups. As mood status, intake of 500-mg WPH (including 2.5-mg AJI-801) showed significant improvement in Depression/Dejection of the Profile of Mood States Questionnaire second edition and visual analog scale score for depression, as compared to the placebo. CONCLUSIONS: Intake of AJI-801 500-mg WPH (including 2.5-mg AJI-801) contributes to the improvement of feeling down in healthy persons with fatigue. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN 000046829).

A short-term intervention of ingesting iron along with methionine and threonine leads to a higher hemoglobin level than that with iron alone in young healthy women: a randomized, double-blind, parallel-group, comparative study.

PURPOSE: Enhancing iron absorption and utilization is important for amelioration iron status faster and thereby, for improving quality of life. Dietary protein and amino acids, including methionine and threonine, have been reported to facilitate the absorption and utilization of dietary iron. Here, we investigated the effect of combined ingestion of methionine, threonine, and iron on the improvement of iron status during a short-term intervention, by comparing that with iron ingestion alone in healthy young women. METHODS: This was a randomized, double-blind, parallel-group, comparative study with 45 participants (aged 20-39) randomly assigned to three groups (n = 15 each): one group was administered 200 mg methionine, 400 mg threonine, and 6 mg iron once daily (FEMT); another ingested 6 mg iron alone (FE); and the third group ingested a placebo (PCG). Blood samples and dietary nutrient data were collected before the intervention (week 0) and after 2, 4, and 6 weeks. Serum iron, hemoglobin, transferrin, and ferritin levels were measured. RESULTS: Blood hemoglobin levels were significantly higher in the FEMT than in the FE group (P < 0.05) at week 4. Serum iron, transferrin, and ferritin levels were not changed across groups. In addition, our analyses showed that the observed increase in hemoglobin levels was affected by the intervention rather than changes in dietary nutrient intake. CONCLUSIONS: Ingestion of methionine and threonine with low doses of iron leads to a higher hemoglobin levels than that with iron alone in a short period of 4 weeks. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN000046621).

The additive effects of exercise and essential amino acid on muscle mass and strength in community-dwelling older Japanese women with muscle mass decline, but not weakness and slowness: a randomized controlled and placebo trial.

BACKGROUND: Exercise and essential amino acid supplementation have been separately shown to improve muscle mass in elderly people, however, the combined, added effects of both interventions have yielded inconsistent results on muscle mass, strength, and physical function improvement. AIMS: To investigate the additive effects of exercise and essential amino acid supplementation on muscle mass, strength, and walking ability in older Japanese women with muscle mass decline, but not weakness and slowness. METHODS: One hundred thirty women over 65 years of age were defined as having muscle decline and randomly assigned into two groups; exercise and amino acid supplementation (n = 65) or exercise and placebo supplementation (n = 65). The exercise group attended a 60-min comprehensive training program once a week and were encouraged to perform a home-based exercise program. The amino acid or placebo group ingested a 3 g supplement daily for 3-month. Body composition was determined by bioelectrical impedance analysis. Interview data and functional fitness measurements, such as muscle strength and walking ability were collected at baseline and after the 3-month intervention. RESULTS: There were no significant group × time interactions in primary outcomes such as muscle mass and strength. However, interactions were observed in the degree of low back discomfort (P = 0.014). Percent change of low back discomfort was significantly greater in exercise + amino acid group compared with exercise + placebo group. CONCLUSIONS: The combination of exercise and amino acid supplementation had a beneficial effect on low back discomfort. However, additional effects were not observed in primary outcomes including muscle mass and strength in this population.

Role of CXC chemokine receptor type 4 as a lactoferrin receptor.

Lactoferrin exerts its biological activities by interacting with receptors on target cells, including LDL receptor-related protein-1 (LRP-1/CD91), intelectin-1 (omentin-1), and Toll-like receptor 4 (TLR4). However, the effects mediated by these receptors are not sufficient to fully explain the many functions of lactoferrin. C-X-C-motif cytokine receptor 4 (CXCR4) is a ubiquitously expressed G-protein coupled receptor for stromal cell-derived factor-1 (SDF-1/CXCL12). Lactoferrin was found to be as capable as SDF-1 in blocking infection by an HIV variant that uses CXCR4 as a co-receptor (X4-tropic HIV), suggesting that lactoferrin interacts with CXCR4. We addressed whether CXCR4 acts as a lactoferrin receptor using HaCaT human keratinocytes and Caco-2 human intestinal cells. We found that bovine lactoferrin interacted with CXCR4-containing lipoparticles, and that this interaction was not antagonized by SDF-1. In addition, activation of Akt in response to lactoferrin was abrogated by AMD3100, a small molecule inhibitor of CXCR4, or by a CXCR4-neutralizing antibody, suggesting that CXCR4 functions as a lactoferrin receptor able to mediate activation of the PI3K-Akt signaling pathway. Lactoferrin stimulation mimicked many aspects of SDF-1-induced CXCR4 activity, including receptor dimerization, tyrosine phosphorylation, and ubiquitination. Cycloheximide chase assays indicated that turnover of CXCR4 was accelerated in response to lactoferrin. These results indicate that CXCR4 is a potent lactoferrin receptor that mediates lactoferrin-induced activation of Akt signaling.

Promoting effect of lactoferrin on barrier function and epithelial differentiation of human keratinocytes.

The purpose of this study was to elucidate the effects of bovine lactoferrin on keratinocyte differentiation and barrier function. Addition of bovine lactoferrin to differentiating HaCaT human keratinocytes led to increased transepithelial electrical resistance (TER), a marker of epithelial barrier function. This elevation was followed by upregulation of two differentiation markers, involucrin and filaggrin. The expression level of sterol regulatory element-binding protein-1 was also enhanced by bovine lactoferrin. The lactoferrin-induced upregulation of involucrin and filaggrin expression were confirmed in normal human epidermal keratinocytes (NHEK). Treatment with SB203580, a p38 mitogen-activated protein kinase (MAPK) α inhibitor, impaired the upregulation of involucrin and filaggrin expression in response to lactoferrin. The elevation of p38 MAPK phosphorylation was further enhanced by lactoferrin in the initial stage of differentiation of HaCaT keratinocytes. The findings suggest that bovine lactoferrin promotes epithelial differentiation by a p38-MAPK-dependent mechanism.

The use of a temperature-responsive column for the direct analysis of drugs in serum by two-dimensional heart-cutting liquid chromatography.

A novel pretreatment method, which was performed using a two-dimensional high-performance liquid chromatography (2D-HPLC) system, was proposed for the direct analysis of drugs in human serum. A temperature-responsive column was used as a pretreatment column. The stationary phase of the temperature-responsive column exhibits temperature-regulated hydrophilic/hydrophobic characteristics. Controlling the ionic strength of the eluent enables human serum albumin (HSA) to pass through the column without retention. When serum samples containing barbiturates or benzodiazepines were injected into the temperature-responsive column using 10 mM of ammonium acetate (pH 6.5) as the mobile phase and in the temperature range of 10-40 °C, HSA was eluted from the column near the dead time, followed by the individual drugs. When the column temperature was changed, the retention times of the drugs were altered owing to surface property changes within the pretreatment column. These closely eluted compounds were subsequently introduced into the analytical column using a column-switching valve, with a minimal gap time to avoid foreign substance contamination. This new 2D-HPLC method afforded high-quality chromatograms of multiple drugs without unwanted peaks from foreign substances. The present technique could be an attractive choice in selecting the analytical method for drug analysis.

Hepatocyte nuclear factor 4α is a critical factor for the production of complement components in the liver.

The complement system plays an important role in biological defense as an effector to eliminate microorganisms that invade an organism and it is composed of more than 50 proteins, most of which are produced in the liver. Of these proteins, the mRNA expression of C3 and Cfb is known to be positively regulated by the nuclear receptor HNF4α. To investigate whether HNF4α regulates the complement system, we analyzed the hepatic expression of genes involved in the complement activation pathway and membrane attack complex (MAC) formation within the complement system using liver-specific Hnf4a-null mice (Hnf4aΔHep mice) and tamoxifen-induced liver-specific Hnf4a-null mice (Hnf4af/f;AlbERT2cre mice). We found that hepatic expression of many complement genes including C8a, C8b, C8g, and C9 that are involved in formation of the MAC was markedly decreased in Hnf4aΔHep mice and Hnf4af/f;AlbERT2cre mice. Furthermore, expression of C8A, C8B, and C8G was also decreased in human hepatoma cell lines in which the expression of HNF4α was suppressed, and expression of C8G and C9 was induced in a human immortalized hepatocyte cell line with forced expression of HNF4α. Transactivation of C8g and C9 was dependent on HNF4α expression of HNF4α binding sites, indicating that C8g and C9 are novel target genes of HNF4α. The results suggest that hepatic HNF4α plays an important role in regulation of the complement system, mainly MAC formation.

Combination of poly-γ-glutamic acid and galactooligosaccharide improves intestinal microbiota, defecation status, and relaxed mood in humans: a randomized, double-blind, parallel-group comparison trial.

The genus Bifidobacterium comprises beneficial intestinal bacteria that play a crucial role in the regulation of human health. Traditional prebiotics are known to increase intestinal bifidobacteria by supplying a carbon source necessary for their growth. However, intestinal bifidobacteria need not only a carbon source but also a nitrogen source for growth. Moreover, the growth of bifidobacteria is known to be inhibited in a culture medium that does not contain glutamic acid. Based on these reports, we hypothesized that the combined intake of traditional prebiotics and glutamic acid would be beneficial for growth of bifidobacteria in the gut. In this study, we investigated the effects of the combination of galactooligosaccharide (GOS; traditional prebiotic material) and poly-γ-glutamic acid (γ-PGA; source of glutamic acid) and only GOS on the intestinal microbiota and health conditions (including intestinal regulation, mood status, gastrointestinal condition, skin condition, and sleep quality) in a randomized, double-blind, parallel-group comparison trial in healthy subjects. The combined intake of GOS and γ-PGA significantly increased the prevalence of B. longum compared to the intake of GOS alone. A minimum effective dose of 2.0 g GOS and 0.3 g γ-PGA improved defecation and mood status. We revealed the combined effects of GOS and γ-PGA on intestinal microbiota as well as physical condition and concluded that the delivery of glutamic acid to the large intestine with traditional prebiotics is useful as an advanced prebiotic.

A retrospective study comparing interventions by oncology and non-oncology pharmacists in outpatient chemotherapy.

BACKGROUND: The differences in the clinical pharmacy services (CPS) provided by oncology and non-oncology pharmacists have not been sufficiently explained. AIM: This study aimed to demonstrate the differences in direct CPS provided by oncology and non-oncology pharmacists for patients and physicians, and to assess the potential impact of these services on medical costs. METHODS: We retrospectively examined CPS provided by oncology and non-oncology pharmacists for outpatients who underwent chemotherapy between January and December 2016. RESULTS: In total, 1177 and 1050 CPS provided by oncology and non-oncology pharmacists, respectively, were investigated. The rates of interventions performed by oncology and non-oncology pharmacists for physicians-determined treatment were 18.5% and 11.3%, respectively (p < .001). The rates of oncology and non-oncology pharmacist interventions accepted by physicians were 84.6 and 78.8%, respectively (p = .12). Level 4 and Level 5 interventions accounted for 64.6% of all oncology pharmacist interventions and 53.0% of all non-oncology pharmacist interventions (p = .03). The rates of improvement in symptoms from adverse drug reactions among patients resulting from interventions by oncology and non-oncology pharmacists were 89.4 and 72.1%, respectively (p = .02). Conservative assessments of medical cost impact showed that a single intervention by an oncology and by a non-oncology pharmacist saved ¥6355 and ¥3604, respectively. CONCLUSION: The results of the present study suggested that CPS by oncology pharmacists enable safer and more effective therapy for patients with cancer and indirectly contribute to reducing health care fees.

Functional Movements in Japanese Mini-Basketball Players.

Functional movement screen (FMS) has been used to establish normative data and determine potential injury risk for young adults and athletes, but there are few data in elementary school-age children. The purpose of this study was to establish fundamental values for the FMS in elementary school-age mini-basketball players. Secondary purposes were to examine relationships between functional movement patterns and age, peak height velocity (PHV), and body mass index (BMI), and to compare functional movement patterns between boys and girls and between individuals with and without a history of injury. The mean composite FMS score was 16.5 ± 2.2 (16.5 ± 2.4 for boys, 16.5 ± 1.7 for girls). The composite FMS score was positively correlated with age (r = .312) and negatively correlated with the BMI (r = - .371). However, the FMS score was not correlated with PHV or with PHV age. The FMS score was not different between boys and girls or between individuals who reported a previous injury and those who did not. However, boys in the mini-basketball teams performed better than girls on the trunk stability push-up and rotary stability tests. Age and the body mass index were significantly associated with better and poorer functional movement, respectively.

Injuries in Japanese Junior Soccer Players During Games and Practices.

CONTEXT: Soccer is the most popular junior sport in the world. In junior sports, injury analysis and injury-prevention measures for players, especially those under 12 years of age, are urgently needed. OBJECTIVE: To prospectively study the incidence, sites, types, and mechanisms of injuries in elementary school-aged junior soccer players during games and practices. DESIGN: Descriptive epidemiology study. SETTING: Elementary school-aged junior soccer teams in Nagoya, Japan. PATIENTS OR OTHER PARTICIPANTS: Eighty-nine players in 5 community-based club teams of junior soccer (U-12, age range = 11-12 years; U-11, age range = 10-11 years; U-10, age ≤10 years). MAIN OUTCOME MEASURE(S): Data on all game and practice injuries for the 2013-2014 season were collected using an injury report form. Injury rates were calculated according to injury site, type, and mechanism. RESULTS: The overall injury rate was 2.59/1000 athlete-hours (AHs). The game injury rate (GIR; 6.43/1000 AHs) was higher than the practice injury rate (PIR; 1.49/1000 AHs; P < .05). The most common anatomical areas of injury during games and practices were the lower limbs (62.5% and 4.02/1000 AHs versus 38.5% and 0.57/1000 AHs, respectively). Contusions (27.6%, n = 8) were the most frequent type of overall injuries. Most game injuries resulted from body contact (43.8%, 2.81/1000 AHs), whereas most practice injuries resulted from other types of contact (53.8%, 0.83/1000 AHs). CONCLUSIONS: The GIRs were higher than the PIRs in Japanese junior soccer players. A lower overall PIR suggested that players in the U-12 age group practiced under appropriate conditions. However, the higher GIR in this age category needs to be decreased.

Hyperbaric oxygen in addition to antibiotic therapy is effective for bisphosphonate-induced osteonecrosis of the jaw in a patient with multiple myeloma.

A 60-year-old man with multiple myeloma (MM) (IgG-kappa, stage IIIA) had been treated with minodronate at 6 mg orally as a phase 1 clinical trial for myeloma bone disease for 13 months (total dose, 4032 mg). Then he received incadronate at 10mg intravenously every 1 to 4 weeks (total dose, 350 mg). In July 2005, he complained of mild right mandibular pain, and bone scintigram showed a hot spot at the right side of the mandible. Panoramic radiograph showed osteonecrosis of the jaw (ONJ) and axial and 3-dimensional computed tomography confirmed ONJ. Oral examination showed massive gingival swelling of the right side of the mandible without exposed necrotic bone. He was given clarithromycin in addition to levofloxacin, followed by hyperbaric oxygen (HBO) therapy, which resulted in the complete disappearance of the pain. This is a first reported case of ONJ induced by incadronate. The present case suggests that early detection of ONJ by regular dental check-ups is important in the management of patients with MM who have received bisphosphonate therapy, and HBO in combination with antibiotic therapy is effective in the early stage of ONJ.

Injuries in Japanese Mini-Basketball Players During Practices and Games.

CONTEXT: Mini-basketball is one of the most popular junior sports in Japan. Mini-basketball-related injuries may increase because of early specialization. However, no reports have been published to date concerning basketball injuries in children younger than 12 years of age. OBJECTIVE: To prospectively study the incidence, sites, types, and mechanisms of injuries in mini-basketball teams. DESIGN: Descriptive epidemiology study. SETTING: Mini-basketball teams in Kobe, Japan. PATIENTS OR OTHER PARTICIPANTS: A total of 95 players in 7 community-based mini-basketball club teams (age range, 9 through 12 years). MAIN OUTCOME MEASURE(S): Data on all practice and game injuries for the 2013-2014 season were collected using an injury report form. Injury rates were calculated according to site, type, and mechanism. RESULTS: The overall injury rate was 3.83 per 1000 athlete-hours (AHs). The game injury rate ( 12.92/1000 AHs) was higher than the practice injury rate (3.13/1000 AHs; P < .05). The most common anatomical areas of injury during games and practices were the head and neck (36.4%, 4.70/1000 AHs) and the upper limbs (47.8%, 1.50/1000 AHs). Sprains (42.9%, n = 39) were the most common type of injuries overall, followed by contusions (29.7%, n = 27). Most game injuries resulted from body contact (45.5%, 5.87/1000 AHs), whereas most practice injuries resulted from other contact (56.5%, 1.77/1000 AHs). CONCLUSIONS: Game injury rates were higher than practice injury rates in Japanese mini-basketball players. The high practice injury rate in this study may be due to specific factors related to growth, such as individual differences in height, or to skills, such as inexperience in ball handling.

Combination therapy with thalidomide, incadronate, and dexamethasone for relapsed or refractory multiple myeloma.

The feasibility and efficacy of a combination of thalidomide, incadronate, and dexamethasone (TID) were studied in 12 patients with relapsed or refractory multiple myeloma. The protocol, consisting of 300 mg/day of thalidomide administered orally, intravenous incadronate (10 mg/day) administered weekly, and 12 mg/day dexamethasone for 4 days, was repeated every 3 weeks. Evaluations of efficacy and toxicity were carried out every 3 weeks and were continued for 3 cycles. Three patients were excluded during the study because of apnea, severe somnolence, and pancytopenia. Of 9 evaluated patients, the partial responses achieved in 3 patients and the minor responses achieved in 4 patients corresponded to a response rate of 78% according to the criteria of the European Group for Blood and Marrow Transplantation. In addition, painful osteolytic symptoms improved rapidly after 1 cycle of TID therapy in the 10 patients evaluated. These data suggest that TID is a feasible and promising therapeutic approach for refractory and relapsed multiple myeloma.

Plasmacytoma of the urinary bladder in a renal transplant recipient.

A 28-year-old woman underwent renal transplantation in 1993. Eight years later, she experienced macroscopic hematuria, and Epstein-Barr virus-negative solitary extramedullary plasmacytoma (EMP) of the urinary bladder was diagnosed. After the reduction of immunosuppressive therapy, she received combined chemotherapy, resulting in complete tumor disappearance. However, 10 months later, she relapsed with aggressive multiple EMP and died of disease progression in 2003. This report is the first of a case of solitary EMP of the urinary bladder appearing as posttransplantation plasma cell dyscrasias after renal transplantation.

Unique three-way translocation, t(3;14;18)(q27;q32;q21), in follicular lymphoma.

A 43-year-old woman was diagnosed as having stage IV follicular lymphoma. Phenotypically, the lymphoma cells were CD5(-), CD10(+), CD19(+), CD20(+), CD23(-), HLA-DR(+), and IgM-lambda(+). Conventional chromosomal analysis showed a three-way t(3;14;18)(q27;q32;q21) in the lymphoma cells, which was confirmed by spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH). Immunohistochemistry revealed that both BCL2 and BCL6 proteins were expressed in the lymphoma cells, whereas only the BCL6 gene, and not the BCL2 gene, was rearranged by Southern blotting. The patient received combination chemotherapy and has been well for 3 years. This is the first reported case showing a three-way translocation involving 2 major lymphoma-specific abnormalities, 3q27 and t(14;18)(q32;q21).

Malignant lymphoma presenting as a cardiac tumor and superior vena caval syndrome successfully treated by haploidentical stem cell transplantation.

A 16 year-old male with B-cell non-Hodgkin's lymphoma presenting as a cardiac tumor and superior vena caval (SVC) syndrome received a haploidentical stem cell transplant (SCT) from his mother after conventional and salvage chemotherapy. He received additional radiation therapy for the residual tumor and is alive and well on day 640 after transplantation. Malignant lymphoma presenting as a cardiac tumor, including primary cardiac lymphoma, is rare. Although many reports have shown the poor prognosis of cardiac lymphoma, our case suggests that allogeneic haploidentical SCT might be useful for the treatment of aggressive cardiac lymphoma.

Nitrogen-containing bisphosphonate incadronate augments the inhibitory effect of farnesyl transferase inhibitor tipifarnib on the growth of fresh and cloned myeloma cells in vitro.

RAS gene mutations occur in 30 - 40% of multiple myeloma (MM) patients. Farnesylation is the first step in the post-translational modification of RAS proteins. Tipifarnib is a potent farnesyl transferase inhibitor, and incadronate prevents post-translational prenylation of GTP-binding proteins such as RAS proteins. We examined the effect of tipifarnib in combination with incadronate on the growth of fresh and cloned myeloma cells in vitro. Tipifarnib inhibited the growth of myeloma cells, and this inhibition was intensified when tipifarnib was combined with incadronate. Tipifarnib, in combination with incadronate, may have some benefits in MM patients.

Withdrawal of Continuous Positive Airway Pressure Therapy after Malar Advancement and Le Fort II Distraction in a Case of Apert Syndrome with Obstructive Sleep Apnea.

Apert syndrome is a congenital syndrome characterized by craniosynostosis and craniofacial dysostosis, among other features, and is reported to cause obstructive sleep apnea (OSA) because of upper airway narrowing associated with midfacial dysplasia. We recently encountered a case involving a patient with Apert syndrome complicated by OSA who began to receive continuous positive airway pressure (CPAP) therapy at the age of 4. OSA resolved after maxillofacial surgery performed at the age of 11, and CPAP was eventually withdrawn. In pediatric patients with maxillofacial dysplasia complicated by OSA, a long-term treatment plan including CPAP in addition to maxillofacial plastic and reconstructive surgery should be considered in view of the effects of OSA on growth.

Disseminated infection due to Scedosporium apiospermum in a patient with acute myelogenous leukemia.

A 62-year-old man diagnosed with acute myelogenous leukemia which had developed from myelodysplastic syndrome received cytarabine and idarubicine as an induction therapy. The patient developed pneumonia and bacterial sepsis during profound neutropenia. Fever and sepsis improved by using many anti-bacterials and anti-fungals but he became febrile again and complained of severe lumbar pain. 67Ga scintigram showed abnormal uptake in the lumbar vertebra and left sternoclavicular joint, suggesting a diagnosis of discitis and osteomyelitis in the lumbar vertebra and sternoclavicular arthritis. We biopsied the site several times but culture of the biopsy specimen could not isolate any pathogens, and high fever persisted for about 10 months despite administration of various anti-bacterials and anti-fungals. Finally we inserted a catheter into the abscess at the iliopsoas muscle and Scedosporium apiospermum was isolated in the bloody pus obtained from the catheter. Itraconazole and amphotericin B were restarted, and the high fever and lumbar pain improved rapidly. The findings of S. apiospermum infection in this patient emphasizes the importance of being aware of this pathogen in patients with hematologic malignancy during the neutropenic phase.