Contribution of pharmacists with expertise in infectious diseases to appropriate individualized vancomycin dosing.

BACKGROUND/AIM: Dose adjustment of vancomycin (VCM) is important in improving clinical outcomes and avoiding adverse effects such as nephrotoxicity. Although pharmacist-managed VCM therapy has been reported to optimize treatment, there are no studies focused on pharmacist expertise to date. In this study, we compared the contribution of pharmacists trained for infectious diseases and general pharmacists to dose adjustment of VCM. PATIENTS AND METHODS: We retrospectively investigated VCM trough concentration after dose adjustment by both trained (n = 67) and general (without special training for infectious diseases; n = 85) pharmacists. We also compared the incidence of nephrotoxicity during VCM treatment in both groups. RESULTS: The rate of achieving therapeutic VCM trough concentration (10-20 µg/mL) was higher in the trained group than in the control group (80.6 vs. 54.1%, p < 0.001). No significant differences in incidence of nephrotoxicity were observed between the two groups (p = 0.744). Trained pharmacists could contribute more successfully to the achievement of therapeutic VCM concentration ranges without increasing the risk of nephrotoxicity.

Comparative Analysis of Intrinsic Capacity Impairments, Determinants, and Clinical Consequences in Older Community-Dwellers in Japan and Taiwan: Longitudinal Studies Showing Shared Traits and Distinct Presentations.

OBJECTIVES: Despite the recognized impact of intrinsic capacity (IC) impairment on healthy aging, international comparisons in different sociocultural contexts are scarce. This study aimed to compare IC impairment among community-dwelling older adults in Japan and Taiwan to explore the context of healthy aging in different countries. DESIGN: Comparative observational study. SETTING: National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) in Japan and Longitudinal Aging Study of Taipei (LAST) in Taiwan. PARTICIPANTS: 794 individuals (age range, 60.0-86.5 years) from NILS-LSA and 1,358 (60.0-96.7 years) from LAST. MEASUREMENTS: IC impairment was evaluated across the domains of locomotion, cognition, vitality, sensory capacity, and psychological well-being. Participants were categorized as having impaired IC or healthy. We investigated associations between IC impairment, falls, and all-cause mortality. RESULTS: IC impairment was present in 54.9% and 37.3% of participants in the NILS-LSA and LAST cohorts, respectively. Male NILS-LSA participants with impaired IC (odds ratio [OR]:1.50, 95% confidence interval [CI]:1.03-2.20), with hearing loss (OR:1.98, 95% CI:1.00-3.90) were more likely to fall. In LAST, impaired locomotion (OR:2.14, 95% CI:1.46-3.14) increased the risk of falls. Men with impaired IC (hazard ratio [HR]; 2.14, 95% CI:1.10-4.15) and visual impairment (HR:2.21, 95% CI:1.15-4.25) and women with impaired psychological well-being (HR:4.94, 95% CI:1.28-18.97) in the NILS-LSA cohort had greater risk for all-cause mortality; however, this was not shown for LAST participants. CONCLUSION: The prevalence and distribution of IC impairment and associated biomarkers differed significantly between participants in Japan and Taiwan. However, the associations with adverse outcomes remained similar, emphasizing the need for tailored interventions for healthy aging.

Association between Reduction of Muscle Mass and Faster Declines in Global Cognition among Older People: A 4-Year Prospective Cohort Study.

OBJECTIVES: A few studies reported that both decrease and increase in body mass index (BMI) were associated with the development of dementia in later life. However, it is unclear what changes in body composition are associated with cognitive decline. This study investigated the longitudinal influences of changes in body composition on cognitive function among community-dwelling adults. DESIGN, SETTING AND PARTICIPANTS: This longitudinal study included older adults aged ≥60 years without cognitive impairment who participated in National Institute for Longevity Sciences - Longitudinal Study of Aging. MEASUREMENTS: Cognitive function was assessed using the MMSE. Body composition was measured by a dual-energy X-ray absorptiometry system. Then, BMI, fat mass index (FMI), fat-free mass index (FFMI), and muscle mass index (MMI) were calculated. The changes in body composition over 6 years (second wave to fifth wave) were calculated, and three groups were created: decreased group, decrease of >5%; stable group, change within 5%, and increased group, increase of >5%. In statistical analysis, a linear mixed model was applied by sex to investigate the influences of body composition changes on cognitive function over 4 years (fifth wave to seventh wave). RESULTS: This study analyzed 515 participants (mean age, 67.05 years; 53.4% men). Men with decreased group in FFMI and MMI exhibited faster declines in MMSE scores than those with stable group (ß [95% CI]: FFMI, -0.293 [-0.719 to -0.020]; MMI, -0.472 [-0.884 to -0.059]). In women, there was no significant association between body composition changes and cognitive functions. CONCLUSIONS: Decrease in fat-free mass and muscle mass is associated with faster cognitive declines in men. These results suggest the importance of continuous monitoring of muscle mass to prevent cognitive decline in later life.

Association of Dietary Intake with the Transitions of Frailty among JapaneseCommunity-Dwelling Older Adults.

BACKGROUND: Frailty is a dynamic process, with frequent transitions between frailty, prefrailty, and robust statuses over time. The effect of dietary intake on frailty transitions is unknown. OBJECTIVE: To examine the association between dietary intake and frailty transitions. DESIGN: Survey-based retrospective analysis of the National Institute for Longevity Sciences-Longitudinal Study of Aging data. SETTING: Areas neighboring the National Center for Geriatrics and Gerontology in Aichi Prefecture, Japan. PARTICIPANTS: We included 469 prefrail community dwellers aged 60-87 years who participated both in the baseline (2008-2010) and 2-year follow-up (2010-2012) surveys of the National Institute for Longevity Sciences-Longitudinal Study of Aging. MEASUREMENTS: Transitions of frailty were categorized by changes in status from baseline to follow-up: "deterioration (prefrail to frail)," "persistence (persistent prefrail)," and "reversal (prefrail to robust)." Estimated dietary (nutrients and food) intakes assessed by 3-day dietary records in each frailty transition were analyzed with a multivariate-adjusted general linear model after adjusting for sex, age, education, family income, smoking, and chronic disease. RESULTS: At the 2-year follow-up, 28%, 7%, and 65% of participants had robust, frail, and pre-frail status, respectively. Among 13 food groups, only milk and dairy product intake was positively associated with frailty reversal even after adjusting for all frailty criteria at baseline. Despite insignificant differences in the estimated mean intakes, the baseline intake of saturated fatty acids, potassium, and vitamin B1 tended to be the highest in the reversal group. The estimated mean (standard error) for milk and dairy product intake (g/day) was 79.1 (28.6), 129.3 (19.9), and 161.7 (21.7) for the deterioration, persistence, and reversal groups, respectively (P=0.0036, P-trend=0.0019). CONCLUSIONS: Daily consumption of dairy products may contribute to frailty reversal and frailty prevention among older community dwellers who consume small amounts of dairy products. Other food groups showed no association with frailty status transitions.

Low Amino Acid Score of Breakfast is Associated with the Incidence of Cognitive Impairment in Older Japanese Adults: A Community-Based Longitudinal Study.

BACKGROUND: The protein digestibility-corrected amino acid score (PDCAAS) represents the degree of utilizable dietary protein, namely the protein quality. The PDCAAS of a diet is required to be evaluated on a meal-by-meal basis, as food digestion and absorption occur with each meal intake. Although a positive association between protein intake and cognitive function has been reported, no study has investigated the association between PDCAAS of a diet and cognitive function. OBJECTIVES: To investigate the relationship between PDCAAS of a diet and cognitive impairment in older adults. DESIGN: Longitudinal epidemiological study. SETTING: Community-based setting. PARTICIPANTS: We analyzed 541 community-dwellers who participated in both baseline and follow-up survey. They were 60-83 years of age without cognitive impairment at baseline. MEASUREMENTS: Cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score ≤27. Individual PDCAASs were calculated for each of three regular meals from the 3-day dietary records at baseline. Participants were classified into two groups according to the sex-specific tertiles (T1-T3) of the PDCAAS for each meal (i.e., T1 as the low score group and T2-T3 as the medium and high score group). The dependent variable was cognitive impairment observed after 4 years, and the explanatory variables were the PDCAAS groups for each meal (the medium and high group as the reference) and covariates (sex, age, body mass index, education, depressive symptoms, medical history, protein intake at each meal, and the MMSE score at baseline). Multivariable logistic regression analysis was performed to evaluate the low PDCAAS group for cognitive impairment after 4 years. RESULTS: A significant association was observed only between a low PDCAAS of breakfast and the incidence of cognitive impairment (the adjusted odds ratios [95% confidence intervals] of low PDCAAS for cognitive impairment for breakfast, lunch, and dinner were 1.58 [1.00-2.50], 0.85 [0.54-1.34], and 1.08 [0.71-1.65], respectively). CONCLUSION: A lower PDCAAS of breakfast, i.e., a diet with poor quality of protein, was associated with the incidence of cognitive impairment in older adults of the community.

Relationship between Serum Fatty Acids and Components of Physical Frailty in Community-Dwelling Japanese Older Adults.

Polyunsaturated fatty acids help maintain insulin sensitivity, mitochondrial function, and anti-inflammation. It is well known that deterioration in these areas can cause frailty. However, little is known about the differences in serum polyunsaturated fatty acid levels among frailty components. We investigated the cross-sectional relationship between frailty and serum fatty acids in 1,033 community-dwelling older adults aged 60-88 years. Polyunsaturated fatty acid concentrations were measured from fasting blood samples. The modified phenotype criteria defined frailty. Polyunsaturated fatty acid levels were compared among each component using general linear modeling after controlling for sex, age, body mass index, smoking status, household income, and medical history. Lower polyunsaturated fatty acid levels were associated with the modified frailty criteria, including shrinking and weakness (p < 0.05). Our findings suggest that serum polyunsaturated fatty acid levels differ depending on the frailty status of older adults.

TRENDS IN THE PREVALENCE OF FRAILTY IN JAPAN: A META-ANALYSIS FROM THE ILSA-J.

OBJECTIVE: To examine whether age-specific prevalence of frailty in Japan changed between 2012 and 2017. DESIGN: This study performed meta-analyses of data collected from 2012 to 2017 using the Integrated Longitudinal Studies on Aging in Japan (ILSA-J), a collection of representative Japanese cohort studies. SETTING: The ILSA-J studies were conducted on community-living older adults. PARTICIPANTS: ILSA-J studies were considered eligible for analysis if they assessed physical frailty status and presence of frailty in the sample. Seven studies were analyzed for 2012 (±1 year; n = 10312) and eight studies were analyzed for 2017 (±1 year; n = 7010). Five studies were analyzed for both 2012 and 2017. MEASUREMENTS: The study assessed the prevalence of frailty and frailty status according to 5 criteria: slowness, weakness, low activity, exhaustion, and weight loss. RESULTS: The overall prevalence of physical frailty was 7.0% in 2012 and 5.3% in 2017. The prevalence of frailty, especially in people 70 years and older, tended to decrease in 2017 compared to 2012. Slight decreases were found in the prevalence of frailty subitems including weight loss, slowness, exhaustion, and low activity between 2012 and 2017, but change in the prevalence of weakness was weaker than other components. CONCLUSIONS: The prevalence of physical frailty decreased from 2012 to 2017. There are age- and gender-related variations in the decrease of each component of frailty.

The Association between Dietary Amino Acid Intake and Cognitive Decline 8 Years Later in Japanese Community-Dwelling Older Adults.

OBJECTIVES: Previous studies have reported a relationship between low protein intake and cognitive decline and have suggested that this association may be related to specific amino acid intake. However, the effects of amino acid intake on the maintenance of cognitive function have yet to be clarified. We examined the longitudinal association between dietary amino acid intake and cognitive function in community-dwelling older adults. DESIGN: Longitudinal epidemiological study. SETTING: Community-based setting. PARTICIPANTS: This study comprised 427 study participants aged 60-82 years with no cognitive decline, defined as a Mini-Mental State Examination (MMSE) score of >27 at baseline, who also participated in a follow-up. The average and standard deviation of the follow-up period was 8.2 ± 0.3 years. MEASUREMENTS: Dietary intake was assessed using three-day dietary records at baseline. Participants were classified into quartiles (Q1-Q4) based on the intake of 19 amino acids for males and females. Next, we classified participants into Q1 and Q2-Q4 groups. Cognitive function was assessed using the MMSE both at baseline and at follow-up. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between the Q1 group and cognitive decline (MMSE ≤27), using the Q2-Q4 group as a reference group. Covariates were age, sex, body mass index, years of education, severity of depressive symptoms, history of lifestyle diseases (hypertension, dyslipidemia, diabetes mellitus, stroke, and ischemic heart disease), energy intake (kcal/d), protein intake (g/d), and MMSE score at baseline. RESULTS: Cognitive decline was present in 133 (31.1%) participants. After adjustment for covariates, including total protein intake, the ORs (95% CIs) for cognitive decline were 2.40 (1.21-4.75) for lysine, 2.05 (1.02-4.09) for phenylalanine, 2.18 (1.09-4.34) for threonine, and 2.10 (1.06-4.15) for alanine. CONCLUSION: The results suggest that lysine, phenylalanine, threonine, and alanine intake is important for the maintenance of cognitive function in older people, independent of total protein intake.

The Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT): The Study Protocol for an 18-Month, Multicenter, Randomized, Controlled Trial.

BACKGROUND/OBJECTIVES: The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. DESIGN/SETTING: Eighteen-month, multi-centered, randomized controlled trial. PARTICIPANTS: We plan to recruit 500 older adults aged 65-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. INTERVENTION: The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. MEASUREMENTS: The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. CONCLUSIONS: This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention.

Association of Muscle Strength and Gait Speed with Cross-Sectional Muscle Area Determined by Mid-Thigh Computed Tomography - A Comparison with Skeletal Muscle Mass Measured by Dual-Energy X-Ray Absorptiometry.

BACKGROUND: Muscle mass is often mentioned not to reflect muscle strength. For muscle mass assessment skeletal muscle index (SMI) is often used. We have reported that dual-energy X-ray absorptiometry (DXA)-derived SMI does not change with age in women, whereas the cross-sectional muscle area (CSMA) derived from computed tomography (CT) does. OBJECTIVES: The present study aimed to compare CT and DXA for the assessment of muscle tissue. DESIGN AND SETTING: Cross-sectional study in the local residents. PARTICIPANTS: A total of 1818 subjects (age 40-89 years) randomly selected from community dwellers underwent CT examination of the right mid-thigh to measure the cross-sectional muscle area (CSMA). Skeletal muscle mass (SMM) was measured by DXA. The subjects performed physical function tests such as grip strength, knee extension strength, leg extension strength, and gait speed. The correlation between CT-derived CSMA and DXA-derived SMM along with their association with physical function was examined. RESULTS: After controlling for related factors, the partial correlation coefficient of muscle cross-sectional area (CSA) with physical function was larger than that of DXA-derived SMM for gait speed in men (p=0.002) and knee extension strength in women (p=0.03). The partial correlation coefficient of quadriceps (Qc) CSA with physical function was larger than that of DXA-derived SMM for leg extension power in both sexes (p=0.01), gait speed in men (p<0.001), and knee extension strength in women (p<0.001). CONCLUSION: Mid-thigh CT-derived CSMA, especially Qc CSA, showed significant associations with grip strength, knee extension strength, and leg extension power, which were equal to or stronger than those of DXA-derived SMM in community-dwelling middle-aged and older Japanese people. The mid-thigh CSMA may be a predictor of mobility disability, and is considered to be useful in the diagnosis of sarcopenia.

Dietary factors associated with the development of physical frailty in community-dwelling older adults.

OBJECTIVES: Nutrition plays an important role in the development of frailty, and the present study examined the association between energy, macronutrient, and food intake and the development of physical frailty. DESIGN: Prospective cohort study. SETTING: The National Institute for Longevity Sciences - Longitudinal Study of Aging (NILS-LSA), a community-based study. PARTICIPANTS: Participants included 166 men and 117 women aged 65-86 years without frailty components at baseline who participated in both the sixth (2008-2010) and seventh (2010-2012) waves of the NILS-LSA. MEASUREMENTS: Physical frailty was assessed using the modified criteria established by the Cardiovascular Health Study (2001). All participants were classified as "robust (number of frailty components: 0)," "prefrail (1-2)," or "frail (3-5)." Energy, macronutrient, and food intake was calculated based on 3-day dietary records during the sixth wave. Associations between dietary intake per day and the development of frailty 2 years later (from robust at the sixth wave to prefrail/frail at the seventh wave) were examined using multiple logistic regression analysis after adjusting for sex, baseline age, and other covariables. RESULTS: Among the participants included, 36% were classified as prefrail/frail 2 years later. Higher energy [1 standard deviation (SD), odds ratio (95% confidence interval): 362 kcal, 0.68 (0.49-0.94)], protein [16 g, 0.72 (0.53-0.97)], and fat [15 g, 0.69 (0.52-0.92)] intake was negatively associated with frailty development. Higher meat [38 g, 0.68 (0.51-0.92)] and dairy [114 g, 0.73 (0.55-0.96)] intake was negatively associated with frailty development. Higher energy intake was negatively associated with the development of weakness (low grip strength) and low activity, while higher protein intake was negatively associated with the development of low activity. CONCLUSION: Increased consumption of meat and dairy products may provide sufficient protein and fat necessary for achieving higher energy intake, thereby effectively preventing physical frailty among older Japanese individuals.

Men who were thin during early adulthood exhibited greater weight gain-associated visceral fat accumulation in a study of middle-aged Japanese men.

OBJECTIVE: This study aimed to assess the relationship between weight gain from early adulthood and visceral fat accumulation. METHODS: The participants were 549 men aged 42 to 64 years who were randomly selected from the local resident registry for the National Institute for Longevity Sciences' neighbourhood. They were asked to recall their weight at 18 years of age, and then, post-18 weight-change values were calculated for each participant (their current weight minus their weight at 18). The participants were divided according to their median body mass index (BMI) at 18 years of age (initial BMI) (<20.14 and ≥20.14 kg m-2). Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured on computed tomography scans. RESULTS: The participants with initial BMI of <20.14 kg m-2 exhibited greater post-18 weight changes than those with initial BMI of ≥20.14 kg m-2. The participants' post-18 weight-change values were negatively correlated with their initial BMI and positively correlated with both VFA and SFA. The slope of the regression line for the relationship between post-18 weight change and VFA was steeper in the participants with initial BMI of <20.14 kg m-2 (ß = 4.36) than in those with initial BMI of ≥20.14 kg m-2 (ß = 3.23). CONCLUSIONS: Visceral fat accumulation is affected not only by an individual's post-18 weight gain but also by their initial BMI. Men who were thin in early adulthood experienced greater weight gain-associated VFA increases, but the same was not true for SFA.

Age-Related 12-Year Changes in Dietary Diversity and Food Intakes among Community-Dwelling Japanese Aged 40 to 79 Years.

OBJECTIVES: This study describes trends in dietary diversity and food intake over 12 years according to age at first participation in the study. DESIGN: Prospective cohort study. SETTING: The National Institute for Longevity Sciences - Longitudinal Study of Aging, a community-based study. PARTICIPANTS: Participants included 922 men and 879 women who participated in the first study-wave (age, 40-79 years) and also participated in at least one study-wave from the second to seventh study-wave. Study-waves were conducted biennially. MEASUREMENTS: Dietary intake was calculated from 3-day dietary records with photographs. Dietary diversity was determined using the Quantitative Index for Dietary Diversity based on food intake. A mixed-effects model was used to estimate linear changes in dietary diversity and food intake over 12 years according to age at first study-wave. RESULTS: Mean (standard deviation (SD)) follow-up time and number of study-wave visits were 9.5 (3.7) years and 5.4 (1.8), respectively. Mean (SD, range) dietary diversity score was 0.86 (0.06, 0.52-0.96) in men and 0.88 (0.04, 0.66-0.96) in women, respectively. Fixed effects for interactions of age and time with dietary diversity score were statistically significant (p<0.05). The slope of dietary diversity among men aged 40 to 55 years increased (40-year-old slope = 0.00093/year, p<0.01; 55-year-old slope = 0.00035/year, p=0.04), with a decreasing trend started at 65 years old, although this trend was not significant (65-year-old slope = -0.00003/year, p=0.88; 79-year-old slope = -0.00057/year, p=0.21). The slope of dietary diversity among women aged 40 to 44 years increased (40-year-old slope = 0.00053/year, p=0.02; 44-year-old slope = 0.00038/year, p=0.04), whereas the slope of dietary diversity among women aged 63 to 79 years decreased (63-year-old slope = -0.00033/year, p=0.03; 79-year-old slope = -0.00092/year, p<0.001). Fruit, milk and dairy intake decreased in men around their 60s; milk and dairy intake decreased in women around their 50s; and beans and fruit intake decreased in women from their 70s. CONCLUSION: Twelve-year longitudinal data showed dietary diversity declined in women in their 60s. In terms of food intake, fruit, milk and dairy intake decreased in both sexes in their 50s and 60s; such declines would lower dietary diversity.

Age-related Changes in Energy Intake and Weight in Community-dwelling Middle-aged and Elderly Japanese.

OBJECTIVE: This study attempts to describe trends in energy intake and weight change over 12 years according to age at first participation in the study. DESIGN: Prospective cohort study. SETTING: The National Institute for Longevity Sciences - Longitudinal Study of Aging (NILS-LSA), a community-based study. PARTICIPANTS: Participants included 922 men and 879 women who participated in the first study-wave (age 40-79 years) and also participated in at least one study-wave from the second to seventh study-wave. Each study-wave was conducted biennially. For individuals, the entire follow-up period was 12 years. MEASUREMENTS: Energy intake was calculated from 3-day dietary records with photographs. Weight and height were measured under a fasting state. To estimate linear changes in energy intake and weight over 12 years according to age at first study-wave, we used the mixed-effects model. RESULTS: Mean (SD) follow-up time and number of study-wave visits were 9.5 (3.7) years and 5.4 (1.8) times, respectively. The fixed effect of the interaction of age and time in energy intake and weight was statistically or marginally statistically significant both in men (p<0.01) and in women (p<0.06). In men, when energy intake was estimated according to age, the rate of decrease in energy intake increased from -6.8 to -33.8 kcal/year for ages 40-79 years. In women, the rate of decrease in energy intake slightly increased in older age groups (-9.1 to -16.7 kcal/year for ages 40-79 years). Weight increased in males in their 40s (0.07 kg/year from age 40) and started to decline by age 53. In women, weight started to decline around age 47 (-0.04 kg/year). CONCLUSION: Twelve-year longitudinal data showed energy intake declined both in men and women in their 40s, and the rate of decrease increased in older males. Weight started to decline in men in their mid-50s and women in their late 40s. Further studies that focus on energy intake and weight reduction are needed to prevent weight loss or underweight in an increasingly aging society.

Pituitary-adrenocortical response to metoclopramide in patients with acromegaly and prolactinoma: a clinical evaluation of catecholamine-mediated adrenocorticotropin secretion.

We have demonstrated that metoclopramide stimulates cortisol secretion at least in part by a stress-mediated effect in normal men. To examine further the effect of the drug on the hypothalamo-pituitary adrenal system, we studied the cortisol response to 20 mg metoclopramide in patients with acromegaly, prolactinomas, and functional hyperprolactinemia and compared the results with the responses to insulin-induced hypoglycemia. In some patients, the effects of metoclopramide on CRH-induced ACTH and cortisol increase were studied to determine whether a change in dopaminergic (catecholaminergic) activity altered CRH stimulation of pituitary-adrenal function. No cortisol response to 20 mg metoclopramide occurred in 13 tests on 8 of 9 patients with prolactinoma or acromegaly with hyperprolactinemia, whereas both acromegalic patients without hyperprolactinemia had a response. All of the patients had a normal cortisol response to insulin-induced hypoglycemia. Pretreatment with metoclopramide enhanced the CRH-induced cortisol increase from 30-120 min after CRH in normal men, but only at 15 and 30 min in 5 agromegalic patients. The results suggest that metoclopramide acts in the hypothalamus to release ACTH through a dopamine antagonist-mediated (catecholaminergic) mechanism, and that metoclopramide may act additively with CRH to stimulate ACTH secretion in normal men. The absence of a metoclopramide-induced cortisol response in patients with acromegaly or prolactinomas and the absence of a normal cortisol response to metoclopramide-CRH in acromegalic patients could be due to endogenous catecholamine deficiency in these patients.

Complete genome sequence of an aerobic thermoacidophilic crenarchaeon, Sulfolobus tokodaii strain7.

The complete genomic sequence of an aerobic thermoacidophilic crenarchaeon, Sulfolobus tokodaii strain7 which optimally grows at 80 degrees C, at low pH, and under aerobic conditions, has been determined by the whole genome shotgun method with slight modifications. The genomic size was 2,694,756 bp long and the G + C content was 32.8%. The following RNA-coding genes were identified: a single 16S-23S rRNA cluster, one 5S rRNA gene and 46 tRNA genes (including 24 intron-containing tRNA genes). The repetitive sequences identified were SR-type repetitive sequences, long dispersed-type repetitive sequences and Tn-like repetitive elements. The genome contained 2826 potential protein-coding regions (open reading frames, ORFs). By similarity search against public databases, 911 (32.2%) ORFs were related to functional assigned genes, 921 (32.6%) were related to conserved ORFs of unknown function, 145 (5.1%) contained some motifs, and remaining 849 (30.0%) did not show any significant similarity to the registered sequences. The ORFs with functional assignments included the candidate genes involved in sulfide metabolism, the TCA cycle and the respiratory chain. Sequence comparison provided evidence suggesting the integration of plasmid, rearrangement of genomic structure, and duplication of genomic regions that may be responsible for the larger genomic size of the S. tokodaii strain7 genome. The genome contained eukaryote-type genes which were not identified in other archaea and lacked the CCA sequence in the tRNA genes. The result suggests that this strain is closer to eukaryotes among the archaea strains so far sequenced. The data presented in this paper are also available on the internet homepage (http://www.bio.nite.go.jp/E-home/genome_list-e.html/).

Complete sequence and gene organization of the genome of a hyper-thermophilic archaebacterium, Pyrococcus horikoshii OT3.

The complete sequence of the genome of a hyper-thermophilic archaebacterium, Pyrococcus horikoshii OT3, has been determined by assembling the sequences of the physical map-based contigs of fosmid clones and of long polymerase chain reaction (PCR) products which were used for gap-filling. The entire length of the genome was 1,738,505 bp. The authenticity of the entire genome sequence was supported by restriction analysis of long PCR products, which were directly amplified from the genomic DNA. As the potential protein-coding regions, a total of 2061 open reading frames (ORFs) were assigned, and by similarity search against public databases, 406 (19.7%) were related to genes with putative function and 453 (22.0%) to the sequences registered but with unknown function. The remaining 1202 ORFs (58.3%) did not show any significant similarity to the sequences in the databases. Sequence comparison among the assigned ORFs in the genome provided evidence that a considerable number of ORFs were generated by sequence duplication. By similarity search, 11 ORFs were assumed to contain the intein elements. The RNA genes identified were a single 16S-23S rRNA operon, two 5S rRNA genes and 46 tRNA genes including two with the intron structure. All the assigned ORFs and RNA coding regions occupied 91.25% of the whole genome. The data presented in this paper are available on the internet at http:@www.nite.go.jp.

CHox11L2, a Hox11 related gene, is expressed in the peripheral nervous system and subpopulation of the spinal cord during chick development.

cHox11L2, the chick counterpart of mouse Hox11L2, was isolated. cHox11L2 was expressed in the developing chick peripheral nervous system, i.e. sensory cranial nerves of placodal ectoderm origin, sympathetic ganglia, dorsal root ganglia and enteric ganglia as well as a limited regions of the spinal cord. In neuronal derivatives of the neural crest, cHox11L2 was expressed in the postmigratory cells and not in the migrating neural crest cells. Furthermore, intense signals of cHox11L2 mRNA were detected also in the spinal cord and the dorsal roots of 10-day embryos. No transcripts were detected in the spinal cord of the postnatal day-2 animals. These results suggest that cHox11L2 might play a role in neuronal differentiation during chick nervous system development.

Effect of indomethacin on Ca2+-stimulated adenosine triphosphatase in the microsomes of rat submandibular gland.

The effect of indomethacin, which is a nonsteroidal anti-inflammatory drug, on Ca2+-stimulated adenosine triphosphatase (Ca2+-ATPase) activity in the microsomes of rat submandibular gland was investigated. The effect of aspirin on Ca2+-ATPase activity was also studied.

Effects of head and body position on two- and three-dimensional configurations of the upper airway.

This study was carried out to test the hypothesis that changes in head/body position induce changes in upper-airway dimensions. Contiguous images were obtained by means of magnetic resonance imaging in normal awake subjects during nasal breathing. A statistical analysis was made on 5 consecutive slices, including the most constricted sites in both the retropalatal and retroglossal regions. Dimensional changes in the upper airway in association with changes in head/body position were evaluated. In the retropalatal region, there was a significant decrease in the lateral dimension in the lateral recumbent position compared with that in the supine position. The cross-sectional area in the retroglossal region was significantly increased in both the "supine with the head rotated" and "lateral recumbent" positions. This change was accompanied by significant volumetric changes in the retroglossal region. Thus, sleeping with the head rotated may be effective for improving upper-airway obstruction.