Fermented milk retains beneficial effects on skeletal muscle protein anabolism after processing by centrifugation and supernatant removal.

Lactobacillus-fermented milk can stimulate anabolic effects in skeletal muscle. Fermented milk containing Lactobacillus produces aqueous molecules, such as free AA and lactate. This study aimed to investigate how processing fermented milk by centrifugation and removal of supernatant affects AA absorption and postprandial skeletal muscle protein synthesis (MPS) when mice are fed fermented milk. We gavaged male Sprague-Dawley rats with skim milk (S), fermented milk (F), or processed fermented milk (P), and examined the total AA content in portal vein blood (reflecting AA absorption) and plantaris muscle MPS at 30, 60, and 90 min following administration. Relative to fasted rats, at 30 min the total AA concentration in portal vein blood from rats in the P groups was significantly higher, followed by F and S, respectively. The MPS rates were higher for the F or P groups compared with the S group. Phosphorylation levels of p70S6 kinase in the P and F groups were significantly higher than those for the S group 30 min after administration, although the level of Akt phosphorylation was similar among the groups. These results suggested that fermentation improves AA absorption that in turn enhances postprandial MPS via Akt-independent mechanisms, and that processed fermented milk retains these favorable effects on MPS.

A case of nivolumab-induced acute-onset type 1 diabetes mellitus in melanoma.

Nivolumab, an anti-PD-1 antibody, is now considered an important therapeutic agent in several advanced malignancies. However, immune-related adverse events such as endocrinopathies have been reported with its use. Thyroid disorder and isolated adrenocorticotropic hormone deficiency have frequently been reported as nivolumab-induced immune-related adverse events. Another endocrinopathy is nivolumab-induced type 1 diabetes mellitus (t1dm), described as diabetes mellitus with rapid onset and complete insulin insufficiency, at times leading to fulminant t1dm. We report the case of a 68-year-old woman who developed pancreatic islet-related autoantibody-negative t1dm, possibly induced by nivolumab, under continuous glucocorticoid administration. She was treated with nivolumab for advanced malignant melanoma, concomitant with 10 mg prednisolone daily for thrombophlebitis tapered to 5 mg after 13 courses of nivolumab therapy. At approximately the 27th course of nivolumab therapy, she showed elevated plasma glucose levels despite preserved insulin secretion. A month later, she developed diabetic ketoacidosis. Her insulin secretion decreased and finally was exhausted. She was diagnosed with acute-onset rather than fulminant t1dm because of a rapidly progressive course to diabetic ketoacidosis during just more than 1 week. She is currently receiving insulin replacement. There has been no recurrence of the melanoma. Thus, nivolumab might induce autoimmune diabetes mellitus, with patients having t1dm-sensitive human leucocyte antigen being more susceptible even when receiving glucocorticoids. Physicians should be aware that nivolumab could potentially induce t1dm as a critical immune-related adverse event.

Effects of Low-Dose Dairy Protein Plus Micronutrient Supplementation during Resistance Exercise on Muscle Mass and Physical Performance in Older Adults: A Randomized, Controlled Trial.

OBJECTIVES: To investigate whether supplementation with low-dose dairy protein plus micronutrients augments the effects of resistance exercise (RE) on muscle mass and physical performance compared with RE alone among older adults. DESIGN: Randomized controlled trial. SETTING: Tokyo, Japan. PARTICIPANTS: Eighty-two community-dwelling older adults (mean age, 73.5 years) were randomly allocated to an RE plus dairy protein and micronutrient supplementation group or an RE only group (n = 41 each). INTERVENTION: The RE plus supplementation group participants ingested supplements with dairy protein (10.5 g/day) and micronutrients (8.0 mg zinc, 12 µg vitamin B12, 200 µg folic acid, 200 IU vitamin D, and others/day). Both groups performed the same twice-weekly RE program for 12 weeks. MEASUREMENTS: Whole-body, appendicular, and leg lean soft-tissue mass (WBLM, ALM, and LLM, respectively) with dual-energy X-ray absorptiometry, physical performance, biochemical characteristics, nutritional intake, and physical activity were measured before and after the intervention. Data were analyzed by using linear mixed-effects models. RESULTS: The groups exhibited similar significant improvements in maximum gait speed, Timed Up-and-Go, and 5-repetition and 30-s chair stand tests. As compared with RE only, RE plus supplementation significantly increased WBLM (0.63 kg, 95% confidence interval [CI]: 0.31-0.95), ALM (0.37 kg, 95% CI: 0.16-0.58), LLM (0.27 kg, 95% CI: 0.10-0.46), and serum concentrations of 25-hydroxyvitamin D (4.7 ng/mL, 95% CI: 1.6-7.9), vitamin B12 (72.4 pg/mL, 95% CI: 12.9-131.9), and folic acid (12.9 ng/mL, 95% CI: 10.3-15.5) (all P < 0.05 for group-by-time interactions). Changes over time in physical activity and nutritional intake excluding the supplemented nutrients were similar between groups. CONCLUSION: Low-dose dairy protein plus micronutrient supplementation during RE significantly increased muscle mass in older adults but did not further improve physical performance.

Randomised clinical trial: vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the healing of erosive oesophagitis.

BACKGROUND: Vonoprazan is a novel potassium-competitive acid blocker which may provide clinical benefit in acid-related disorders. AIM: To verify the non-inferiority of vonoprazan vs. lansoprazole in patients with erosive oesophagitis (EE), and to establish its long-term safety and efficacy as maintenance therapy. METHODS: In this multicentre, randomised, double-blind, parallel-group comparison study, patients with endoscopically confirmed EE (LA Classification Grades A-D) were randomly allocated to receive vonoprazan 20 mg or lansoprazole 30 mg once daily after breakfast. The primary endpoint was the proportion of patients with healed EE confirmed by endoscopy up to week 8. In addition, subjects who achieved healed EE in the comparison study were re-randomised into a long-term study to investigate the safety and efficacy of vonoprazan 10 or 20 mg as maintenance therapy for 52 weeks. RESULTS: Of the 409 eligible subjects randomised, 401 completed the comparison study, and 305 entered the long-term maintenance study. The proportion of patients with healed EE up to week 8 was 99.0% for vonoprazan (203/205) and 95.5% for lansoprazole (190/199), thus verifying the non-inferiority of vonoprazan (P < 0.0001). Vonoprazan was also effective in patients with more severe EE (LA Classification Grades C/D) and CYP2C19 extensive metabolisers. In the long-term maintenance study, there were few recurrences (<10%) of EE in patients treated with vonoprazan 10 or 20 mg. Overall, vonoprazan was well-tolerated. CONCLUSIONS: The non-inferiority of vonoprazan to lansoprazole in EE was verified in the comparison study, and vonoprazan was well-tolerated and effective during the long-term maintenance study.

Randomised clinical trial: a dose-ranging study of vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the treatment of erosive oesophagitis.

BACKGROUND: The potassium-competitive acid blocker vonoprazan (VPZ) has potent acid-inhibitory effects and may offer clinical advantages over conventional therapy for acid-related disorders. AIM: To investigate the efficacy and safety of VPZ in patients with erosive oesophagitis (EO). METHODS: In this multicentre, randomised, double-blind, parallel-group, dose-ranging study, patients ≥20 years with endoscopically confirmed EO [Los Angeles (LA) grades A-D] received VPZ 5, 10, 20 or 40 mg, or lansoprazole (LPZ) 30 mg once daily for 8 weeks. The primary endpoint was the proportion of healed EO subjects as shown by endoscopy at week 4. RESULTS: A total of 732 subjects received VPZ or LPZ. The proportion of healed EO subjects at week 4 was 92.3%, 92.5%, 94.4%, 97.0% and 93.2%, respectively, with VPZ 5, 10, 20 and 40 mg and LPZ 30 mg. All VPZ doses were non-inferior to LPZ when adjusted for baseline LA grades A/B and C/D. Among those with LA grades C/D, the proportions of healed EO subjects were 87.3%, 86.4%, 100%, 96.0% and 87.0%, respectively, with VPZ 5, 10, 20 and 40 mg and LPZ 30 mg. The incidence of adverse events was similar across the groups. CONCLUSIONS: Vonoprazan was effective and non-inferior to LPZ in healing EO. VPZ 20 mg or higher was highly efficacious for severe EO (LA grades C/D). VPZ was associated with no safety concern during this 8-week study, while there was a dose-dependent increase in serum gastrin. Once-daily VPZ 20 mg is the recommended clinical dose for treating EO.

Randomised clinical trial: safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a novel potassium-competitive acid blocker, in healthy male subjects.

BACKGROUND: TAK-438 (vonoprazan) is a potassium-competitive acid blocker that reversibly inhibits gastric H(+) , K(+) -ATPase. AIM: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-438 in healthy Japanese and non-Japanese men. METHODS: In two Phase I, randomised, double-blind, placebo-controlled studies, healthy men (Japan N = 60; UK N = 48) received TAK-438 10-40 mg once daily at a fixed dose level for 7 consecutive days. Assessments included safety, tolerability, pharmacokinetics and pharmacodynamics (intragastric pH). RESULTS: Plasma concentration-time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax ≤2 h). Mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional, with no apparent time-dependent inhibition of metabolism. There was no important difference between the two studies in AUC0-tau on Day 7. TAK-438 caused dose-dependent acid suppression. On Day 7, mean 24-h intragastric pH>4 holding time ratio (HTR) with 40 mg TAK-438 was 100% (Japan) and 93.2% (UK), and mean night-time pH>4 HTR was 100% (Japan) and 90.4% (UK). TAK-438 was well tolerated. The frequency of adverse events was similar at all dose levels and there were no serious adverse events. There were no important increases in serum alanine transaminase activity. Serum gastrin and pepsinogen I and II concentrations increased with TAK-438 dose. CONCLUSIONS: TAK-438 in multiple rising oral dose levels of 10-40 mg once daily for 7 days was safe and well tolerated in healthy men and caused rapid, profound and sustained suppression of gastric acid secretion throughout each 24-h dosing interval. Clinicaltrials.gov identifiers: NCT02123953 and NCT02141711.

Randomised clinical trial: efficacy of the addition of a prokinetic, mosapride citrate, to omeprazole in the treatment of patients with non-erosive reflux disease - a double-blind, placebo-controlled study.

BACKGROUND: Proton pump inhibitors (PPIs) are less effective in non-erosive reflux disease (NERD) patients than in reflux oesophagitis patients. Whether the addition of prokinetics to PPIs improves NERD patients' symptoms remains unknown. AIM: To evaluate the efficacy of mosapride in NERD patients when used with PPI. METHODS: A total of 200 NERD patients were randomised to one of two arms: omeprazole (10 mg once daily) plus mosapride citrate (5 mg three times a day) (treatment arm) and omeprazole plus placebo (placebo arm). The primary endpoint was the rate of responders [visual analogue scale (VAS) was zero or <1 cm] after 4 weeks of treatment. The secondary endpoints were changes in the VAS score and the safety profile. RESULTS: There was no significant difference between the rates of responders in both arms in intent-to-treat (ITT) and per-protocol (PP) analysis. The change in the VAS score in treatment arm was significantly better than placebo arm in PP analysis (-4.0 ± 0.2 and -3.3 ± 0.2, mean ± S.E.M.) (N.S. in ITT analysis). The rate of adverse events was similar in both groups. CONCLUSION: The addition of mosapride to omeprazole was not more effective than omeprazole alone.

Randomised clinical trial: a multicentre, double-blind, placebo-controlled study on the efficacy and safety of rabeprazole 5 mg or 10 mg once daily in patients with non-erosive reflux disease.

BACKGROUND: The efficacy of rabeprazole 5 mg/day for patients with non-erosive reflux disease (NERD) has not been reported in the literature. AIM: To evaluate the efficacy of rabeprazole 5 mg and 10 mg/day in Japanese NERD patients. The influence of baseline characteristics as well as genetic background on efficacy was also analysed. METHODS: Subjects were grade M (minimal changes) NERD patients. Two hundred and eighty-eight of these subjects, who were nonresponders to open label antacid therapy, entered in a 4-week, double-blind treatment (placebo, rabeprazole 5 mg or 10 mg/day). RESULTS: Complete heartburn relief rates were 21% in placebo, 34% in rabeprazole 5 mg and 44% in rabeprazole 10 mg (5 mg vs. placebo P = 0.074, 10 mg vs. placebo P = 0.001). Rabeprazole 5 mg was significantly more effective than placebo in elderly patients and in patients with low heartburn frequency or without hiatal hernia. The efficacy of rabeprazole 10 mg was not influenced by age, BMI, hiatal hernia, Helicobacter pylori infection, frequency and severity of heartburn or CYP2C19 genotypes. CONCLUSIONS: Rabeprazole 5 mg was effective in a subgroup of Japanese NERD patients. Rabeprazole 10 mg provided more potent heartburn relief than 5 mg and was less fragile to baseline characteristics.

Influence of long-term cigarette smoking on immunoglobulin E-mediated allergy, pulmonary function, and high-resolution computed tomography lung densitometry in elderly patients with asthma.

BACKGROUND: Smoking is the most important cause of chronic obstructive pulmonary disease (COPD). However, the influence of cigarette smoking on the pathogenesis of asthma in the elderly remains controversial. This study attempted to clarify the influence of cigarette smoking on elderly asthmatics. METHODS: Forty-eight asthmatics over 70 years old (25 ex-smokers and 23 never-smokers) and 20 patients with COPD over 70 years old (all ex-smokers) were studied to determine the influence of cigarette smoking on IgE-mediated allergy (total IgE, IgE antibodies against inhalant allergens, bronchial hyper-responsiveness (BHR), generation of leukotriene (LT) B4 and C4), pulmonary function, and the relative area of lung showing attenuation values less than -950 Hounsfield units (RA950) on high-resolution computed tomography scans. RESULTS: The incidence of positive IgE antibodies against inhalant allergens, BHR, and the generation of leukotriene B4 (LTB4) by leucocytes were significantly increased in patients with a history of smoking compared with those without. Residual volume (%RV) was significantly increased, and diffusing capacity for carbon monoxide was significantly decreased in ex-smokers with asthma and COPD compared with never-smokers with asthma. Inspiratory RA950 and ratio of expiratory RA950 to inspiratory RA950 were significantly larger in asthmatics with a smoking history than in those without, and in COPD patients than in asthmatics. CONCLUSION: Cigarette smoking enhances the production of IgE antibodies, BHR, and generation of LTB4 by leucocytes in elderly asthmatics. Increased hyper-inflation or emphysematous changes of the lungs expressed by increased RA950, closely related to %RV, was more frequently observed in ex-smokers compared with never-smokers.

Decreased computed tomographic lung density during exacerbation of asthma.

Recently, it was shown that both mean lung density (MLD) and the relative lung area with an attenuation of <-950 HU (RA950) are related to severity of asthma in nonsmoking asthmatics. The aim of the present study was to examine whether reduced computed tomography (CT) lung density during exacerbation could change after treatment. A cross-sectional study was performed to compare CT lung density in 30 stable asthmatics, 30 unstable asthmatics and 25 control subjects. In order to investigate longitudinally the effect of treatment on decreased CT lung density, 17 asthmatics with an exacerbation were followed at the initiation of treatment and 2 months after relief. The MLD was significantly lower and the RA950 significantly higher in unstable asthmatics than in controls and stable asthmatics. Both MLD and RA950 changed significantly with administration of systemic glucocorticoid therapy. The changes in forced expiratory volume in one second correlated significantly with those in both MLD and RA950. The changes in residual volume also correlated significantly with those in both MLD and RA950. It was concluded that decreased computed tomographic lung density during an asthma exacerbation is at least partially reversible, and changes in mean lung density and the relative lung area with a radiation attenuation of <-950 HU are related to the change in forced expiratory volume in one second and residual volume.

Vertebral fracture and cortical bone changes in corticosteroid-induced osteoporosis.

Despite an intriguing understanding of trabecular bone dynamics, little is known about corticosteroid-induced cortical bone loss and fractures. Recently, we verified a steroid-induced decrease in cortical bone volume and density using peripheral quantitative computed tomography (pQCT) in adult asthmatic patients given oral corticosteroids. Subsequently, the pQCT parameters and presence of vertebral fractures were investigated to further clarify the role of cortical bone quality in fractures in 86 postmenopausal (>5 years after menopause) asthmatic patients on high-dose oral steroid (>10 g cumulative oral prednisolone) (steroid group) and 194 age-matched controls (control group). Cortical and trabecular bone was subjected to measurement of various parameters using pQCT (Stratec XCT960). Relative Cortical Volume (RCV) was calculated by dividing the cortical area by the total bone area. Strength Strain Index (SSI) was determined in the radius based on the density distribution around the axis. Spinal fracture was assessed on lateral radiographs. Patients treated with high doses of oral steroid (>10 g cumulative oral prednisolone) were found to have an increased risk of fracture compared with control women receiving no steroid medication (odds ratio, 8.85; 95% CI, 4.21-18.60) after adjustment was made for years since menopause, body mass index and RCV. In both groups, the diagnostic and predictive ability of the pQCT parameters for vertebral fracture was assessed by the areas under their receiver operating characteristic (ROC) curves. All parameters were found to be significant predictors ( p<0.0001) in the control group. In the steroid group, however, the cortical bone mineral density (BMD) ( p = 0.001), RCV ( p<0.0001) and SSI ( p = 0.001) were found to be significant predictors, but not trabecular BMD ( p = 0.176). For comparison between the two groups, thresholds of all parameters for vertebral fracture were also calculated by the point of coincidence of sensitivity with specificity in ROC testing and the 90th percentile value. Although a rise in fracture threshold in the steroid group was suggested, considerable difference in the values obtained by the two methods of calculation precluded any conclusion. High-dose oral steroid administration was associated with an increased risk of fracture. Cortical bone parameters obtained by pQCT could play a role as good predictors of future corticosteroid-induced vertebral fractures.

Influence of age and disease severity on high resolution CT lung densitometry in asthma.

BACKGROUND: Low attenuation areas (LAA) on computed tomographic (CT) scans have been shown to represent emphysematous changes in patients with chronic obstructive pulmonary disease (COPD). However, the significance of LAA is still controversial in patients with asthma. This study was undertaken to assess the usefulness of lung CT densitometry in the detection of airspace enlargement in association with asthma severity. METHODS: Forty five asthmatic subjects and 15 non-smoking controls were studied to determine the influence of age, pulmonary function, and asthma severity on mean lung density (MLD) and the relative area of the lung showing attenuation values less than -950 HU (RA(950)) on high resolution CT (HRCT) scans. RESULTS: In asthmatic patients both MLD and RA(950) correlated with parameters of airflow limitation (%FEV(1), FEV(1)/FVC, %FEF(25-75)) and lung volume (%TLC, %FRC, %RV), but not with lung transfer factor (%TLCO, %TLCO/VA). The results of HRCT lung densitometry also correlated with patient age and severity of asthma. CONCLUSIONS: Decreased CT lung density in non-smoking asthmatics is related to airflow limitation, hyperinflation and aging, but not with lung transfer factor.

Hypoperfusion following encephalitis: SPECT with acetazolamide.

At 4 weeks and 8 months following initial symptoms, we performed single-photon emission computed tomography (SPECT) with acetazolamide (ACZ) testing in a patient recovering from acute encephalitis, possibly acute disseminated encephalomyelitis (ADEM). Both regional hypoperfusion at baseline and diminished cerebrovascular reserve were seen after focal hyperintensities had disappeared in magnetic resonance imaging (MRI). The time course of SPECT abnormalities reflected the clinical course more closely than the time course of MRI abnormalities. Thus, persistent cerebral circulatory impairment probably contributed to cognitive and language deficits observed at the subacute stage.

Low-attenuation areas of the lungs on high-resolution computed tomography in asthma.

To investigate the low-attenuation areas of the lungs (LAA) in asthma, we compared the mean lung density (MLD) and the LAA in 22 asthmatics (12 ex-smokers and 10 nonsmokers) and 13 patients with chronic obstructive pulmonary disease (COPD) by high-resolution computed tomography. The MLD and the relative area of the lung with attenuation values lower than -950 Hounsfield Units at full inspiration (inspiratory RA950) were significantly different in nonsmoking asthmatics compared to patients with COPD and asthmatics with a smoking history. The MLD and the RA950 correlated significantly with the FEV1 in all groups and with the DL(CO) in patients with COPD and asthmatics with a smoking history but not in nonsmoking asthmatics. We concluded that the LAA in asthmatics with a smoking history indicates the presence of emphysema, but in nonsmoking asthmatics it reflects hyperinflation and nonemphysematous expiratory airflow limitation rather than emphysematous lesions.

The formation of capsule and septum in human hepatocellular carcinoma.

The formation of fibrous capsule around the cancer nodule and of the septum in the tumor is frequently observed with the development of hepatocellular carcinoma (HCC). We aimed to clarify how the capsule and septum were formed during the growth of HCC. Liver samples surgically resected from 25 patients with HCC were studied with in situ hybridization for type-I, -III, and -IV procollagen. Type-I and -III procollagen-expressing cells, mostly alpha-smooth muscle actin (SMA)-positive, were increased in the fibrous capsule and in the septum between HCC nodules. These cells were also found at the invasion front of HCC and around the necrotic cancer tissues. Type-IV procollagen gene expression was mainly observed in mesenchymal cells localized in both HCCs and non-cancerous liver. Cancer cells or hepatocytes did not express any of these procollagen genes. The present study reveals that the capsule and septum are mainly formed by alpha-SMA-positive mesenchymal cells at the interface between two different tissues (e.g., cancer nodule vs non-cancerous liver or another cancer nodule). The wound healing occurs even in HCC. The capsule formation may result from interaction between tumor and host liver and interfere the growth and invasion of HCC.

Oral glucocorticoid-induced fall in cortical bone volume and density in postmenopausal asthmatic patients.

Despite a deepening understanding of the influence of glucocorticoids (GC) on trabecular bone, little is known about GC-induced cortical bone loss. To elucidate the mechanism of GC-induced loss of cortical bone strength with particular reference to cortical bone loss, changes in cortical density, relative cortical volume, and the Strength Strain Index (SSI) based on biomechanical analyses of the geographic distribution of cortical bone material were measured. These parameters were compared, using peripheral quantitative computed tomography (pQCT), among the following age-matched groups: 68 postmenopausal asthmatic patients receiving high-dose oral GC in addition to inhaled GC (oral GC group), 68 postmenopausal asthmatic patients receiving only inhaled GC (inhaled GC group) and 69 postmenopausal controls without asthma or GC therapy (control group). Cortical bone mineral density (BMD) was measured, relative cortical volume was obtained by dividing the cortical area by the total bone area using pQCT (Stratec XCT960), and the Strength Strain Index (SSI) was calculated in the radius based on the density distribution around the axis. Spinal fracture was assessed on lateral radiographs. The number of vertebral fractures per patient correlated highly with cortical BMD, relative cortical volume and SSI values at the radius. The number of vertebral fractures per patient and the number of patients with fracture were similar between the control and inhaled GC group, both being significantly lower than those in the oral GC group. Total BMD, trabecular BMD, cortical BMD, relative cortical volume and SSI were similar between the first two, being significantly higher than in the last group. The slopes of cortical volume-density relationship, however, were identical among the three groups, indicating the persistence of cortical bone remodeling and a similar degree of calcification regardless of GC administration.