Human plasma concentration-time profiles of troglitazone and troglitazone sulfate simulated by in vivo experiments with chimeric mice with humanized livers and semi-physiological pharmacokinetic modeling.

Troglitazone and its major metabolite troglitazone sulfate were intravenously administered to chimeric mice with different ratios of liver replacement by human hepatocytes. Total clearances were converted to hepatic intrinsic clearances normalized to their liver weight, with the assumption that extra-hepatic elimination of these compounds was negligible. These values were plotted against the replacement indices, and postulated values for virtual 100% chimeric mice were assumed to be equivalent to those in humans. Metabolic formation ratio was estimated by comparing AUCs of troglitazone sulfate after separate administration of troglitazone and troglitazone sulfate. Liver to plasma concentration ratios were obtained from direct measurement. These parameters were extrapolated to 100% chimeric mice and subjected to semi-physiological pharmacokinetic modeling using pharmacokinetic parameters for oral administration taken from literature. Our simulated plasma concentration-time profile of troglitazone agreed well with observed values obtained in clinical study. However, the profile of troglitazone sulfate was far below the reported values. Although the possible reasons for this discrepancy remains unsolved, the combination of chimeric mice with semi-physiological PK modeling proved to be a useful tool in understanding the function of each PK parameter in human pharmacokinetics of troglitazone and its conjugated metabolite.

Effect of preoperative sedentary behavior on clinical recovery after total knee arthroplasty: a prospective cohort study.

OBJECTIVES: Prolonged sedentary behavior (SB) may affect clinical improvements following total knee arthroplasty (TKA). We aim to assess preoperative SB effect on improvements in clinical outcomes after TKA. We hypothesized that patients with high proportion of preoperative SB have small improvements in clinical outcomes after TKA. METHODS: We recruited 115 adults with knee osteoarthritis (OA), planning to undergo TKA. Knee-specific functional outcomes were assessed using the new knee society score (KSS), including total score, symptoms, patient satisfaction, patient expectations, and functional activities. Gait function was assessed using the timed up and go (TUG) test. SB was measured using a triaxial accelerometer. Multiple linear regression analysis was performed to investigate preoperative SB effect on improvements in clinical outcomes 6 months postoperatively by adjusting for several factors as potential confounders. RESULTS: Of 115 patients, 82 were included. High proportion of preoperative SB had a significant negative effect on recovery at 6 months in the new KSS total score [ß, -0.83, 95% confidence interval (CI), -1.53 to -0.12; p = 0.02], symptoms (-0.15, -0.28 to -0.02; p = 0.03), patient satisfaction (-0.22, -0.42 to -0.02; p = 0.03), and functional activities (-0.40, -0.76 to -0.04; p = 0.03) after adjusting for potential confounders. CONCLUSIONS: A high proportion of preoperative SB was a risk factor for reduced improvements in knee-specific functional outcomes after TKA. To prevent poor functional recovery after TKA, it is essential to understand the preoperative lifestyle factors and intervene proactively during acute postoperative phase in patients with high SB proportion.Key Points• Preoperative high proportion of SB had a negative effect on improvement in new KSS total scores, symptoms, patient satisfaction, and functional activities.• When considering clinical outcomes after TKA, clinicians should closely monitor patients with high proportions of preoperative SB to prevent poor functional recovery.

Adult onset of Immunoglobulin A vasculitis - A case report.

Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, primarily occurs during childhood between the ages of 3 and 15 years and is the most common form of systemic vasculitis in children ; its occurrence in adults has been rarely reported. Such low incidence could be attributable to either under-diagnosis or misdiagnosis. Thus, not only pediatricians but also physicians should be able to diagnose IgAV accurately to manage the patients appropriately and avoid its associated complications. In addition, treatment of adult onset IgAV with renal involvement has not been fully established yet. We describe here a case of adult onset IgAV complicated by proteinuria and pharyngitis, which was cured by no specific treatment. J. Med. Invest. 66 : 344-346, August, 2019.

Evaluation of Maltose-Induced Chemical Degradation at the Interface of Bilayer Tablets.

Fixed dose combination tablets consisting of mirabegron (MB) and solifenacin succinate (SS) were developed and formulated into bilayer tablets in the current study. The results of a chemical stability study showed that the original formulation for the tablets led to a significant increase of unknown degradants in the SS layer. Two compatibility studies were conducted to simulate the interface between the MB and SS layers, and the results revealed that the degradants only formed in the presence of both active pharmaceutical ingredients (APIs), and that the presence of maltose in the SS layer was critical to inducing degradation. High resolution mass spectroscopy coupled with high performance liquid chromatography was used to determine the chemical structures of the degradants, which were identified to MB derivatives bearing one or two sugar units. These findings therefore suggested that the degradation of the API could be attributed to the addition of sugar units from maltose to MB under the acidic conditions caused by SS. With this in mind, we developed a new formulation by replacing maltose with hydroxypropyl cellulose as a polymer-type binder. The results showed that this formulation suppressed the formation of the degradants. The results of this study have shown that chemical degradation can occur at the interface of bilayer tablets and that an alternative strategy is available to formulate more stable MB/SS bilayer tablets.

Effect of glutamine supplementation on neutrophil function in male judoists.

Glutamine is an important amino acid for immune function. Though high intensity and prolonged exercise decreases plasma glutamine concentration and causes immune suppression, the relationship between neutrophil functions and glutamine has not yet been found. The purpose of this study was to investigate the impacts of glutamine supplementation on neutrophil function. Twenty-six male university judoists were recruited. Subjects were classified into glutamine and control groups. The glutamine group ingested 3000 mg of glutamine per day and the control group ingested placebo for 2 weeks. Examinations were performed at the start of preunified loading exercise (pre-ULE), then 1 and 2 weeks after ULE (post-ULE). Reactive oxygen species (ROS) production, phagocytic activity, serum opsonic activity and serum myogenic enzymes were measured. Differences between the levels obtained in pre-ULE and post-ULE for the two groups were compared. In the glutamine group, ROS production activity increased 1 week after ULE, whereas it was not observed in the control group (P < 0.001). Though myogenic enzymes increased significantly after ULE (P < 0.001), the glutamine group remained unchanged by supplementation during ULE. Glutamine supplementation has prevented excessive muscle damage and suppression of neutrophil function, especially in ROS production activity, even during an intensive training period.

Influence of a 3-month training program on muscular damage and neutrophil function in male university freshman judoists.

We studied the effects of a high intensity and high frequency 3-month training program on muscle damage and neutrophil function in male judoists. The study included 15 male judoists who started intensive judo training program after a 6-month break. Creatine kinase (CK), neutrophil counts and reactive oxygen species (ROS) production capability as well as phagocytic activity (PA) of neutrophils were measured at 2 stages; entering university (pre-training) and after 3-month training (post-training). At both points, we investigated parameters three times: just before, immediately after and 24 h after a 2-h practice session. Practice-mediated change in CK was lower at post-training than at pre-training. Neutrophil count significantly increased after 2-h practice but recovered 24 h later whereas it showed no subsequent and further increased at 24 h post-practice. Although neutrophil ROS production capability and PA both decreased (breakdown) after practice session, ROS production capability increased and PA decreased (well-adapted) at the post-training. Long-term training strengthened muscular function and improved neutrophil reaction against practice-mediated stress.

Characteristics of patients with brain metastases from lung cancer in a palliative care center.

PURPOSE AND METHODS: Patients with brain metastases present severe symptoms owing to the tumor growth or treatment side effects, and supportive measures are often critical for the patients and their families. However, there is currently a lack of palliative care and end-of-life (EoL) provision for patients affected by advanced brain tumors. We performed a retrospective analysis of the characteristics of patients with brain metastases from lung cancer between August 1998 and December 2008 in our palliative care center. RESULTS: During this period, 55 such patients died. The male/female ratio was 0.86, and the mean age was 60.7 years. The duration of the last stay before death varied between 2 and 196 days (mean, 42.6 days). Death appeared predictable as the consequence of end-stage disease in all cases. The most frequent general clinical complaints were pain (64.8%), general fatigue (46.2%), and dyspnea (31.4%). The most frequent symptoms related to the brain tumors were consciousness deterioration (33%), headache (26%), cranial nerve palsy (19%), and delirium (19%). The symptoms in patients with carcinomatous meningitis were headache (63.6%), cranial nerve palsy (45.4%), epilepsy (27.2%), and nausea and vomiting (27.2%). The therapy tools used were chemotherapy in 9% and steroids and glycerol in 32.7%. Four patients who had leptomeningeal carcinomatosis suffered from hydrocephalus, and treatments for vasogenic edema or antalgics were less effective. In such cases, cerebrospinal fluid drainage may be effective if there are no space-occupying lesions. One patient had cortical atrophy with cognitive impairment and another had a cerebral infarction during admission. CONCLUSION: Optimization of the quality of life in its final stages requires efficient palliative care, which involves considerable psychological, sociological, technical, and financial burdens. Palliative management of brain metastases requires a multidisciplinary approach performed by a well-trained neuro-oncology team, and it is important to avoid any treatment that is harmful or has a poor toxicity/efficacy ratio to avoid inappropriate prolongation of dying.

Effects of intense exercise on the physiological and mental condition of female university judoists during a training camp.

To clarify the physical and mental fatigue caused by intense exercise and the relationship between the two types of fatigue, we examined changes in anthropometric and biochemical variables, neutrophil function, and the Profile of Mood States (POMS) questionnaire in 13 female university judoists attending a one-week training camp. Blood glucose, total cholesterol, haemoglobin, leukocyte count, IgG, and phagocytic activity all decreased after the training camp compared with baseline (P < or = 0.046). Aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and neutrophil oxidative burst activity increased after the training camp (P < or = 0.007). Of the POMS scores, that for Fatigue increased after the training camp (P = 0.041) and that for Vigour decreased (P = 0.042). The changes in several POMS scores correlated with the changes in blood biochemical variables. In particular, the change in Total mood disturbance was negatively associated with changes in myogenic enzymes (P < or = 0.032). Our results suggest that intense exercise during training camps for female judoists leads to the appearance and accumulation of mental and physical fatigue, which are related to each other.

Measuring neutrophil functions might be a good predictive marker of overtraining in athletes.

In order to develop a predictive marker of overtraining in athletes, we examined the changes in neutrophil function [reactive oxygen species (ROS) production capability and phagocytic activity (PA)] for 10 male and 13 female judoists attending a training camp. Measurements were taken four times in total--immediately before and after a 2 h unified exercise loading (UEL) performed 1 day before (Pre-Camp) and the day after the 7 day training camp (Post-Camp). UEL-mediated aspartate aminotransferase was higher at Post-Camp than at Pre-Camp in females but not in males. Post-Camp leukocyte/neutrophil counts after the UEL significantly increased in females but not in males. The rate of change in C4 was significantly smaller in females than in males at Post-Camp. Only ROS significantly decreased without any compensation (increase in PA) being made at Post-Camp in females. In conclusion, this finding, namely that ROS significantly decreased only at Post-Camp without any compensatory mechanism (increase in PA), would suggest that the training camp imposed greater loading on females than males. This consideration was supported by the atypical aspartate aminotransferase, leukocyte/neutrophil counts and C4 findings which were seen at Post-Camp only in females. Therefore, regularly examining neutrophil functions such as ROS and PA might be a good preventative measure against overtraining in athletes participating in training camps.

The effects of a two-hour judo training session on the neutrophil immune functions in university judoists.

The present study examined the effects of judo training on neutrophil and related functions. We measured and studied changes in the neutrophil and its related functions in 22 male university judoists immediately before (Pre values) and immediately after (Post values) a 2 h training session: reactive oxygen species (ROS) production capability, phagocytic activities (PA) and serum opsonic activity (SOA). Neutrophil count in whole blood, myogenic enzymes (creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase), immunoglobulins (IgG, IgA and IgM) and complements (C3 and C4) in serum were also measured. The Post values of the neutrophil count, myogenic enzymes and IgG increased significantly compared with the Pre values. ROS production capability and SOA also significantly increased following training, although PA showed a slight decrease (but not statistically significant). Taking the findings of our previous studies into consideration, three major neutrophil or related functions, namely ROS production capability, PA and SOA, might compensate for each other to maintain the overall integrity of the neutrophil immune function, in that ROS and SOA increased to compensate for the slight decrease in PA, or PA slightly decreased to compensate for the increase in ROA and SOA after exercise.

Clinicopathological evaluation of biological behavior of submucosal invasive gastric carcinomas: relationship among lymph node metastasis, mucin phenotype and proliferative activity.

BACKGROUND: Gastric carcinomas have been classified into the differentiated and undifferentiated type, on the basis of its tendency to gland formation. As a result of recent advances in mucin histochemistry, mucin phenotypes of gastric carcinomas have been investigated. However, no consensus on the evaluation of the grade of malignancy of early gastric carcinomas regarding mucin phenotype expression has developed. To address this issue, we evaluated the lymph node metastasis rate and proliferative activity of a submucosal invasive (sm) gastric carcinoma according to mucin phenotype expression. METHODS: In resected surgical specimens from 108 patients with a single sm gastric carcinoma, the association between clinicopathological factors and lymph node metastasis was evaluated. In all cases, immunohistochemical staining with human gastric mucin, Muc-2, and CD10 and mucin histochemical staining by paradoxical concanavalin A staining were performed. The mucin phenotypes were classified into gastric-type (G-type), intestinal-type (I-type), mixed gastric and intestinal type (M-type), or a lack of mucin (LOM), using these as markers. To evaluate the cell proliferative activity of the gastric carcinoma, proliferating cell nuclear antigen (PCNA) staining was also performed. RESULTS: The rate of lymph node metastasis was higher for G-type sm carcinomas. A multivariate analysis showed that the G-type and lymphatic invasion were independent factors of lymph node metastasis. However, the PCNA-labeling index (PCNA-LI) was low for G-type carcinomas irrespective of the presence or absence of lymph node metastasis. In I-type carcinomas, PCNA-LI was significantly higher in cases that were positive for lymph node metastasis than in negative cases. CONCLUSION: G-type and lymphatic invasion are independent risk factors for lymph node metastasis of an sm gastric carcinoma, and proliferative activity may be a significant parameter for lymph node metastasis in cases with I-type carcinomas.

Change in the capability of reactive oxygen species production by neutrophils following weight reduction in female judoists.

OBJECTIVE: Athletes undergoing weight reduction are recognised as being more prone to infection. Few studies exist for athletes on the weight reduction-mediated changes in neutrophil function and related activities such as reactive oxygen species (ROS) production capability, phagocytic activity (PA) and serum opsonic activity (SOA). METHODS: 16 Japanese female university judoists were examined in the early morning of the first day (pre-values) and the last day (post-values) of a 20-day pre-competition training period. Of the 16 subjects, 8 needed to reduce weight (WR group) and the other 8 did not (control group). The parameters assessed were the neutrophil count, serum immunoglobulins and complements, myogenic enzymes, ROS production capability, PA and SOA. RESULTS: Comparing the post-values with the pre-values, ROS production significantly increased in both groups (p<0.01 for both). PA significantly decreased in the WR group (p<0.05); it also decreased in the control group but the decrease was not significant. SOA significantly increased in the control group (p<0.05), but showed no significant change in the WR group. CONCLUSIONS: The changes in the WR group were probably a direct consequence of the weight-reduction regimen coupled with the exercise regimen, suggesting that neutrophil parameters (ROS production, PA and SOA) had tended to deviate from their typical compensatory changes to maintain immune system homoeostasis.

The main neutrophil and neutrophil-related functions may compensate for each other following exercise-a finding from training in university judoists.

In order to clarify the relationship between exercise and neutrophil function, we measured three major neutrophil and neutrophil-related functions, viz. the reactive oxygen species (ROS) production capability and phagocytic activity (PA) of neutrophils and serum opsonic activity (SOA), simultaneously before and after a unified loading exercise under three different sets of conditions. Thirteen female collegiate judoists were examined with a unified exercise loading (2 h) immediately before and after a 64 day training period. Immediately thereafter, the athletes took part in a 6 day intensified training camp, following which the same exercise loading was repeated. Responses from circulating neutrophils were estimated by comparing the two sets of values obtained before and after the two instances of exercise loading. The parameters assessed included neutrophil count, SOA, PA and ROS production capability. ROS production increased after the exercise loading performed immediately before and after the 64 day training period just before the camp, (p < 0.01) but decreased following the exercise loading performed after the camp (p < 0.05). This suggested depressed bacteriocidal capability of the circulating neutrophils. PA decreased after the exercise loading sessions imposed prior to and after the 64 day training period (p < 0.01) but did not change in the loading session after the camp. No changes were seen in SOA produced with the loading exercise either before the 64 day exercise period or before the camp, but increased significantly following the post-camp session (p < 0.05). In conclusion, athletic training-induced changes in immune functional activities of neutrophils, such as ROS production and PA, and neutrophil-related factors, such as SOA, may compensate for each other to maintain the overall integrity of the neutrophil immune function.

Differences in fat-free mass and muscle thicknesses at various sites according to performance level among judo athletes.

The purpose of this study was to investigate differences in fat-free mass and thicknesses of various muscles among judo athletes of different performance levels. The subjects were 69 male judo athletes of 3 different performance levels. Group A was composed of athletes who participated in the Olympic Games or Asian Games (n = 13). Groups B (n = 21) and C (n = 35) were composed of judo athletes at a university who did or did not participate in intercollegiate competitions (including qualifying matches), respectively. Muscle and fat thicknesses were measured by B-mode ultrasound at 9 sites. Fat percentage was calculated from fat thicknesses using a previously reported equation. Fat-free mass was calculated from fat percentage and body weight. Muscles thicknesses were normalized to the height of the individual. Group A had significantly larger fat-free mass than Group C (p < 0.05). The normalized thicknesses of the elbow extensor and flexor muscles were significantly larger in Group A than in Group C. The normalized thickness of the elbow flexor muscle was significantly larger in Group A than in Group B. The results of this study showed that judo athletes with low performance levels such as those in Group C had lower fat-free mass, and the degree of development of the brachialis muscles differed according to performance level.

Effect of 6 months' training on the reactive oxygen species production capacity of neutrophils and serum opsonic activity in judoists.

The effects of long-term training on the production of reactive oxygen species (ROS) from neutrophils and serum opsonic activity (SOA) remain to date unknown. The aim of this study was to evaluate the effect of 6 months training on ROS production and SOA in judoists. Fifty-six judoists were enrolled this study. White blood cell counts, serum creatine kinase (CK), asparate aminotransferase (ASAT), alanine aminotransferase (ALAT), lactate dehydrogenase (LDH) and ROS production from neutrophils, and serum opsonic activity (SOA) using the lucigenin and luminol probes, were measured before and after daily judo exercise (2 h) in March and September. The subjects started their training from March after no exercise for three months, and continued it for 6 months (until September). In March, myogenic enzymes such as CK, ASAT, LDH and neutrophil counts increased and immunoglobulins, complements and SOA decreased after daily judo exercise. Such significant changes were not seen in September. On the other hand, ROS significantly increased after daily judo exercise in both March and September, with no significant difference in the rates of change. In conclusion, 6 month training minimized the changes in SOA as well as muscle enzymes, neutrophil counts, serum immunoglobulins and complements. This could be categorized as a long-term training effect. However, no such change was seen in ROS.

[Effects of gender-related weight reduction on the physical condition of male and female college judoists].

OBJECTIVE: In order to study the gender-related effects of weight reduction on the physical condition of male and female college judoists during weight reduction periods, we examined changes in anthropometric, nutritional intake and biochemical parameters in 43 male and female college judoists 20 days (pre-weight reduction) before and one day (post-weight reduction) before the game. METHODS: Subjects were divided into two groups. Thirty subjects (22 males, 8 females) who required weight reduction were defined as the weight reduction (WR) group, and the remaining 13 subjects (5 males, 8 females) were defined as the non-reduction (non-WR) group. RESULTS: In both WR groups, anthropometric parameters and nutritional intake significantly decreased after weight reduction compared to the pre-values. The change ratios of nutritional intake during the weight reduction period in the female WR group were higher than those in the male WR group. Serum lipids and electrolytes significantly decreased after the weight reduction compared to the pre-values in both WR groups. In the female WR group, Cr and UA significantly increased after the weight reduction compared to the pre-values. Although it was not significant, Ht increased after the weight reduction compared to the pre-values only in the female WR group. TP, Cr, UA, BUN, CK, LDH and IgA significantly increased after the weight reduction compared to the pre-values in the weight reduction compared to the pre-values in the male WR group. In contrast, in both non-WR groups, these parameters did not change significantly during the research period. CONCLUSIONS: Our findings suggest that nutritional exhaustion and dehydration may be the major effects brought about by energy and fluid restriction in female college judoists during a weight reduction period. On the other hand, in male college judoists undergoing weight reduction, the data suggest that muscle damage and myogenic protein catabolism may be caused chiefly by exercise. These differences may be due to the difference in the method of weight reduction for the different genders, namely, mainly exercise in males and mainly energy and fluid restriction in females.

Pulmonary inflammatory pseudotumor with rapid growth and serum carcinoembryonic antigen elevation.

Inflammatory pseudotumors consist of chronic inflammatory cells, predominantly plasma cells. We report a rare case of pulmonary inflammatory pseudotumor associated with rapid growth and elevated serum carcinoembryonic antigen (CEA). A 75-year-old man referred for bloody sputum was found in chest computed tomography (CT) to have a round circumscribed tumor with a cavity located in the periphery of the right lower pulmonary lobe. Cytological examination of a biopsy specimen obtained by CT-guided transthoracic fine needle aspiration showed no malignancy. Two months later, the tumor had noticeably grown, accompanied by a notable rise in serum CEA. We conducted right lower pulmonary lobectomy with regional lymph node dissection, since malignancy could not be ruled out by frozen-section examination. Histological examination of the resected specimen showed an inflammatory pseudotumor with CEA production.