Five-year changes in ovarian function restoration in premenopausal patients with breast cancer taking tamoxifen after chemotherapy: An ASTRRA study report.

BACKGROUND: Adding ovarian function suppression (OFS) after chemotherapy improves survival in young women with moderate- and high-risk breast cancer. Assessment of ovarian function restoration after chemotherapy becomes critical for subsequent endocrine treatment and addressing fertility issues. PATIENTS AND METHODS: In the adding OFS after chemotherapy trial, patients who resumed ovarian function up to 2 years after chemotherapy were randomised to receive either 5 years of tamoxifen or adding 2 years of OFS with tamoxifen. Ovarian function was evaluated from enrolment to randomisation, and patients who did not randomise because of amenorrhoea for 2 years received tamoxifen and were followed up for 5 years. Prospectively collected consecutive hormone levels (proportion of patients with premenopausal follicle-stimulating hormone [FSH] levels <30 mIU/mL and oestradiol [E2] levels ≥40 pg/mL) and history of menstruation were available for 1067 patients with breast cancer. RESULTS: Over 5 years of tamoxifen treatment, 69% of patients resumed menstruation and 98% and 74% of patients satisfied predefined ovarian function restoration as per serum FSH and E2 levels, respectively. Menstruation was restored in 91% of patients younger than 35 years at baseline, but in only 33% of 45-year-old patients over 5 years. Among these patients, 41% experienced menstruation restoration within 2 years after chemotherapy and 28% slowly restored menstruation after 2-5 years. Younger age (<35 years) at baseline, anthracycline without taxanes and ≤90 days of chemotherapy were predictors of menstruation restoration. CONCLUSIONS: During 5 years of tamoxifen treatment after chemotherapy, two-thirds of the patients experienced menstruation restoration, especially patients younger than 35 years. Young age, Adriamycin without taxanes and short duration of chemotherapy appeared to have a positive effect on ovarian reserves in the long term. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00912548.

Acotiamide improves stress-induced impaired gastric accommodation.

BACKGROUND: Gastric accommodation is a reflex reaction related to gastric reservoir function. Psychological stress, such as anxiety, inhibits gastric accommodation in humans. Acotiamide enhances the effect of acetylcholine in the enteric nervous system, enhances gastric contractility, and accelerates delayed gastric emptying. However, the effect of acotiamide on stress-induced impaired gastric accommodation remains unclear. Therefore, we examined the effect of acotiamide on gastric accommodation and stress-induced impaired gastric accommodation using a conscious guinea pig model. METHODS: A polyethylene bag was inserted through the distal region of the gastric body into the proximal stomach of 5-week-old male Hartley guinea pigs. Gastric accommodation was evaluated by measuring the intrabag pressure in the proximal stomach after oral administration of a liquid meal. In the stress model, animals were subjected to water-avoidance stress. Acotiamide (Z-338) or nizatidine was administered subcutaneously. Fecal output was determined as the number of fecal pellets. KEY RESULTS: Administration of the liquid meal significantly decreased intrabag pressure, indicating induction of gastric accommodation. Acotiamide treatment prolonged liquid meal-induced gastric accommodation and significantly increased the number of fecal pellets compared to controls. Water-avoidance stress significantly inhibited liquid meal-induced gastric accommodation. Pretreatment with acotiamide significantly improved stress-induced impaired gastric accommodation. The number of fecal pellets in the acotiamide group increased significantly compared to controls. Acotiamide, but not nizatidine, significantly decreased gastric emptying. CONCLUSIONS & INFERENCES: Acotiamide prolongs gastric accommodation and improves stress-induced impaired gastric accommodation, indicating a potential role for acotiamide in the treatment of functional dyspepsia through its effects on gastric accommodation reactions.

The absence of somatotroph proliferation during continuous stress is a result of the lack of extracellular signal-regulated kinase 1/2 activation.

The integrity of homeostasis can be affected by chronic stress, and hyposomatotropism is evident in chronic stress-associated illnesses. In the present study, we demonstrated that a continuous stress (CS) severely affected somatotrophs among hormone-secreting cells in the anterior lobe (AL) of the pituitary by using a rat CS model. Among AL cells, the proliferation of somatotrophs was almost entirely suppressed in rats that had 3-5 days of CS (5dCS), although other hormone-secreting cells continued to proliferate. The cell size of somatotrophs was reduced at 5dCS (P<0.01), the number of secretory granules was increased at 3dCS (P<0.01) and serum growth hormone (GH) was on declining trend during 1 to 5dCS, suggesting that GH release was inhibited. GH-releasing hormone (GHRH) mRNA level in the arcuate nucleus was transiently decreased, whereas its receptor expression in the AL was significantly increased in CS rats. When 5dCS rats were injected with GHRH, transient GH secretion was observed, whereas proliferation of somatotrophs did not occur. The GHRH administration failed to stimulate extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and the nuclear translocation of ERK in somatotrophs. These results suggest that somatotrophs of 5dCS rats expressed sufficient GHRH receptor, which could transfer a signal for GH release. However, the GHRH-induced proliferation signal was blocked somewhere between the receptor and ERK1/2. Because significant increase of corticosterone in the initial stage (the 1-3dCS) was observed in this model, the corticosterone may affect the signalling. Although the mechanism underlying the blockage of the proliferation signal in somatotrophs under CS remains unclear, these somatotrophic disorder, suggesting that the present animal model may be useful for understanding the molecular mechanisms of chronic stress-associated illnesses.

Association between visceral obesity and sarcopenia and vitamin D deficiency in older Koreans: the Ansan Geriatric Study.

OBJECTIVES: To investigate whether vitamin D levels are independently associated with visceral obesity, sarcopenia, or sarcopenic obesity. DESIGN: Cross-sectional. SETTING: Population-based sample of elderly adults living in Ansan, Korea. PARTICIPANTS: Two hundred sixteen men and 268 women aged 65 and older. MEASUREMENTS: Serum 25-hydroxyvitamin D (25(OH)D) levels, visceral fat area (VFA) according to abdominal computed tomography scanning, and body composition (body fat percentage, appendicular skeletal muscle mass (ASM)) using dual-energy X-ray absorptiometry. Visceral obesity was defined as VFA of 100 cm(2) or greater and sarcopenia as ASM/height(2) more than 1 standard deviation (SD) below the sex-specific mean of a young reference group. RESULTS: The adjusted 25(OH)D level for men was negatively associated with systolic blood pressure, VFA, and body fat percentage but positively associated with ASM. In women, waist circumference, triglyceride levels, and VFA were negatively correlated with 25(OH)D levels. In the joint regression model, VFA and ASM were independently associated with 25(OH)D levels (ß = -0.078, P = .01 and ß = 0.087, P = .02, respectively) per 1SD difference in VFA and ASM in men but not women. When participants were categorized according to four visceral obesity and sarcopenia categories, adjusted mean 25(OH)D level was lower in men with visceral obesity than in men without but was not affected by the presence or absence of sarcopenia. CONCLUSION: Greater visceral fat and lower muscle mass were associated with lower 25(OH)D levels in elderly Korean men, suggesting that screening for vitamin D deficiency may be appropriate in older Koreans with visceral obesity or sarcopenia. Sarcopenic obesity as defined according to prespecified criteria did not have an additive association with 25(OH)D levels.

Disturbance of rapid eye movement sleep in senescence-accelerated mouse prone/8 mice is improved by retinoic acid receptor agonist Am80 (Tamibarotene).

Senescence-accelerated mouse prone/8 (SAMP8) mice are known to exhibit age-related deterioration in sleep-wake architecture compared with senescence-accelerated mouse resistant/1 (SAMR1) mice. We investigated whether treatment with Am80 (Tamibarotene), a retinoic acid receptor agonist, would improve sleep in 9-10-month-old SAMP8 mice. One week of Am80 administration improved the decrease in rapid eye movement (REM) sleep shown by SAMP8 mice. Real-time RT-PCR analysis demonstrated an impairment in the hippocampal retinoid cascade (retinoic acid receptor alpha and transthyretin) in SAMP8 in comparison to SAMR1 mice. Am80 treatment induced an increase in mRNA expression in the vesicular acetylcholine transporter in the brainstem and transthyretin in the hippocampus. Furthermore, decreased cortical acetylcholine content in SAMP8 was improved by Am80 administration. Decreased non-REM sleep and delta oscillation were also observed in SAMP8 mice; however, this was not improved by Am80 administration. These results partially support the hypothesis that the effects of aging on sleep-wake architecture are improved by the activation of retinoic acid receptors. The improvement may be induced by the activation of the cholinergic pathway.

Korean translation and validation of the functional assessment of cancer therapy-breast (FACT-B) scale version 4.

We undertook to translate and cross-culturally adapt the Functional Assessment of Cancer Therapy-Breast (FACT-B) scale into Korean and to evaluate its reliability and validity. The translation procedure followed the standard Functional Assessment of Chronic Illness Therapy translation methodology. A total of 201 breast cancer patients (mean age, 43.87 years) were studied for psychometric properties of the FACT-B scale. A pre-test of 20 Korean breast cancer patients indicated that the Korean FACT-B scale provided good content coverage and overall comprehensibility. Our results indicated high internal consistency of the FACT-B scale, with Cronbach's alpha coefficients ranging from 0.79 to 0.90. The only exception was the Breast Cancer Scale (BCS), which had a Cronbach's alpha coefficient of 0.67. We can consider that most of the patients in this study had not resumed sexual activity after surgery and found it difficult to comment on this aspect. We also considered that contents of the BCS may have been somewhat heterogeneous. After performing a factor analysis of the BCS data from this study, we identified three factors, accounting 58.8%: psychological distress (5 items, with explained variances of 27.5%), feminine satisfaction (2 items, with explained variances of 17.1%), and physical complaints (2 items, with explained variances of 14.2%). The FACT-B scale also demonstrated good convergent and divergent validity when correlated with the shortened forms of the Profile of Mood States and the Functional Living Index-Cancer (FLIC). We can now evaluate the Quality of Life (QoL) of Korean breast cancer patients using this reliable and valid instrument. Nevertheless our study has the limitation that it did not evaluate the sensitivity to the changes of the patients' QoL in the long term follow-up, and we will supplement it in our further study.

Tyramine-immunoreactive neuronal structures in the rat brain: abundance in the median eminence of the mediobasal hypothalamus.

Immunoreactivity to p-tyramine, one of the natural trace amines, was studied in the rat brain by an anti-p-tyramine antibody. Immunoreactivity to this amine is very weak in the nigrostriatal dopaminergic neurons and terminals, and weak in the locus coeruleus noradrenergic ones. It was intensified in these structures after monoamine oxidase inhibition. On the other hand, this amine was highly concentrated in the median eminence of the mediobasal hypothalamus, in which its physiological function on prolactin release has been demonstrated.

Increase of hippocampal acetylcholine release at the onset of dark phase is suppressed in a mutant mice model of evening-type individuals.

We have previously reported that clock mutant mice on Jcl:ICR background show about 2-h delayed circadian profiles in body temperature, spontaneous activity and sleep-wake rhythm, and that they appear to be useful as a model of evening-type of individual. Hippocampal acetylcholine (ACh) release which is positively correlated with attention, learning and memory shows a circadian variation. In this study, changes in hippocampal ACh release in transitional phase from light (rest) to dark (active) period in clock mutant mice were monitored using an in vivo microdialysis method. Compared with wild mice, the increase in hippocampal ACh in the first 2 h of the active period in the mutant mice was suppressed in parallel with peak frequency in electroencephalogram theta rhythm. The molecular basis of the circadian system appears to have a strong effect on hippocampal cholinergic function, and is probably associating with individual temporal differences in voluntary behavior, cognition, learning and/or memory performance.

Influence of sleep disturbance on steroid 5alpha-reductase mRNA levels in rat brain.

Sleep deprivation has been shown to affect the production of steroid hormones in peripheral steroidogenic organs, but little is known about the influence of sleep disturbance on the metabolism of steroid hormones in the brain. To elucidate a possible association of the sleep-wake cycle with brain neurosteroid metabolism, the influence of short-term sleep disturbance on the expression of mRNA encoding steroid 5alpha-reductase, the enzyme converting progesterone and other steroid hormones to their neuroactive 5alpha-reduced metabolites, was investigated. Rats were first subjected to non-selective disturbance of the sleep-wake cycle, and the expression of steroid 5alpha-reductase mRNA in rat hippocampus and brainstem was determined using a semi-quantitative one-step RT-PCR technique. Non-selective disturbance of the sleep-wake cycle resulted in the elevation of 5alpha-reductase mRNA levels in the brainstem, but not in the hippocampus, and the elevated mRNA expression returned to the basal levels after a short period of the sleep recovery. Further studies showed that selective REM sleep deprivation significantly elevated 5alpha-reductase mRNA levels in both hippocampus and brainstem, thus proposing the possibility that REM sleep reduction may largely contribute to the elevation of steroid 5alpha-reductase mRNA levels observed during short-term disturbance of the sleep-wake cycle. Since the enhancement of steroid 5alpha-reductase gene expression may result in the elevation of neuroactive 5alpha-reduced steroid production in the brainstem, the findings presented here provide further evidence for suggesting that neuroactive steroids may play a physiologically important role in the neuronal network for REM sleep initiation and maintenance.

Mouse model for morningness/eveningness.

Human morning/evening preferences has recently been reported to be associated with polymorphism of the 3' flanking region of the Clock gene, which was the first identified mammalian circadian clock gene. We recorded body temperature, spontaneous activity, electroencephalogram and electromyogram for 48 h in mice with Jcl:ICR genetic background and homozygous for the Clock mutation (Cl/Cl on Jcl:ICR). In both wild-type and Cl/Cl on Jcl:ICR, body temperature, activity, wake and sleep were completely entrained to LD cycle. However, phases of the rhythm for body temperature, activity and wake duration in the Cl/Cl on Jcl:ICR were about 2 h delayed in comparison with the wild-type. This study has provided further evidence on the close relationship between human morning/evening preference and the molecular basis of circadian clock system, and has suggested that Cl/Cl on Jcl:ICR is useful for an animal model for human morning/evening preference.

Semi-quantitative RT-PCR analysis of environmental influence on P450scc and PNMT mRNA expression in rat adrenal glands.

Environmental influence on brain function, particularly spatial learning and memory, has been extensively investigated, but little is known about the influence of environmental conditions on the functions of peripheral organs. In the present study, the effects of different housing conditions on the steady-state levels of mRNAs encoding cholesterol side-chain cleavage enzyme (cytochrome P450scc) and phenylethanolamine N-methyltransferase (PNMT) in adrenal glands was examined to investigate the environmental influence on both adrenocortical and adrenomedullary functions. Behavioral changes of the animals housed in different conditions were first examined to assess the relevance of environmental manipulation used. In consistent with previous findings, housing of the animals in enriched conditions resulted in the significant reduction of spontaneous motor activity (locomotor activity and rearing) in comparison with housing in isolated conditions, thus indicating the relevance of housing conditions used in this work for investigating the environmental influence on adrenal function. Then, the effects of these housing conditions on P450scc and PNMT mRNA levels in adrenal glands were examined using semi-quantitative RT-PCR method. In comparison with the isolated group, the enriched group showed significantly higher levels of P450scc mRNA. In contrast, PNMT mRNA levels in the enriched group were significantly lower than those in the isolated group. These results propose the possibility that the environmental conditions may cause differential alterations in adrenocortical and adrenomedullary functions, although their possible association with behavioral changes still remains to be elucidated.

Differential effect of short-term REM sleep deprivation on NGF and BDNF protein levels in the rat brain.

It is well known that REM sleep is associated with memory consolidation, especially, procedural skill learning. Neurotrophic factors are known to be involved in synaptic plasticity. We therefore investigated the effects of selective REM sleep deprivation (RSD) on NGF and BDNF proteins in the hippocampus, cerebellum and brainstem in the rat. NGF and BDNF were detected by an ELISA. Our findings show that 6 h RSD affected the NGF and BDNF protein levels in different manner. In the cerebellum and brainstem, BDNF was significantly decreased, while NGF was not changed. Conversely, in the hippocampus, NGF was significantly decreased while BDNF was not changed. This study indicates that REM sleep may be associated with the secretion of neurotrophic factors and thus contribute to the memory functions.

Sympathetic activity in alexithymics with mother's low care.

This study examines the relationships between alexithymic characteristics and their psychological factors (i.e., maternal closeness) and the sympathetic system in a sample of male college students. At the resting period, low frequency (LF)/ high frequency (HF) ratio, as an index of sympathetic activity, was significantly higher for students with high scores on global alexithymia or its alexithymia factor (difficulty describing feelings) than those with low scores, suggesting that alexithymic students tend to indicate high sympathetic activity during the resting period. During stress, the increase of LF/HF ratio was higher for students with low scores on alexithymia than those with high scores. Although no significant differences were noted, one may speculate that the differences in stress-related activation of LF/HF are due to higher levels of LH/HF in high alexithymics prior to stress. Our findings indicate that significant association between alexithymia and sympathetic activity during the resting period was controlled for the level of mother's care, suggesting that maternal attachment in infancy and/or childhood may play an important role in the development of alexithymic characteristics and/or sympathetic activity during the resting period.

Why does arterial blood pressure rise actively during REM sleep?

A large fluctuation in autonomic function is one of the most important characteristics of REM sleep. Arterial blood pressure (AP) increases during the transition from non-REM to REM sleep, showing phasic surges during REM sleep. REM-associated AP changes involve 1) a long-term recovery process after surgery, 2) circadian rhythm, 3) relationships with ambient temperature. REM-associated AP changes are mediated by sympathetic nerves, buffered by baroreflex, abolished in decerebrated cats, and related to hippocampal theta activity in rats. Furthermore, the midbrain dopaminergic system has been recently found to be involved in increases in REM-associated AP.

The N400 event-related potential in aphasia.

Although the N400 component of event-related potentials (ERPs) is suggested to reflect language processing, exactly which language processing functions N400 is sensitive to is not clear. We investigated this component in aphasic patients with some impairments of language processing. Meaningful and meaningless words in Kana (Japanese characters) were used as stimuli under a visual oddball paradigm. Increases in N400 latency and amplitude in the aphasic group were significant in comparison with the control group. In the aphasic group, N400 latency correlated significantly with the performance intelligence quotient employed besides language quotients. Moreover, the N400 effects were seen more clearly in the left hemisphere than in the right hemisphere for both groups. We propose that the abnormal variations in amplitude or latency of N400 in the aphasic group reflect language processing functions (controlled processing and automatic processing) that are different between slight and severe cases of aphasia. Moreover, N400 effects are sensitive to intellectual abilities besides language ability. We also suggest that N400 effects in the left hemisphere for the aphasic group are a reflection of active language processing as the substitution function.

Sino-aortic denervation augments the increase in blood pressure seen during paradoxical sleep in the rat.

Using a computer assisted telemetric system, we have re-examined the effect of sino-aortic denervation (SAD) on the changes in arterial blood pressure (AP) and heart rate (HR) during sleep in the rat suitably recovered from the operation. Eight 1 hourly polygraphic recordings were performed 4 weeks after the initial SAD surgery. In the SAD rats, the increase in AP during paradoxical sleep (PS) was much larger than that in sham-operated rats. HR in the SAD rats increased on-going from slow-wave sleep to PS, but it showed no change in sham-operated rats. The present study suggests that chronic SAD causes the enhanced AP increase during PS concomitantly with the persistent hypertension and tachycardia across sleep-wake states.

Spontaneous activity, sleep, and body temperature in rats lacking the CCK-A receptor.

Because of a genetic mutation, the Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat, a model for human non-insulin-dependent diabetes mellitus (NIDDM), shows no expression of the CCK-A receptor gene. We investigated the spontaneous physical activity, sleep, and body temperature in young OLETF rats that had not yet developed diabetes mellitus, and compared these data with age-matched control LETO (non-diabetic strain, Long-Evans-Tokushima-Otsuka) rats. The amount of large movements during the dark phase for the OLETF rats was significantly less than that of control rats. Thus, the amounts of total daily large movement and the ratio of dark-to-light phase movement in the OLETF rats were less than those of control rats, although the amount of small movement was similar for both groups. The diurnal rhythm of body temperature was similar for both groups. In addition, the amount of and circadian rhythm for each vigilance state and slow-wave activity were similar for the two groups. This study demonstrates that the CCK-A receptor might play a role in affecting the level of motor activity, adding hyperphagia, and the circadian rhythm of large movement in these rats prior to the manifestation of NIDDM. In contrast, a CCK-A receptor deficiency does not appear to affect sleep or body temperature in these rats.

Injection of 6-hydroxydopamine into the ventral tegmental area suppresses the increase in arterial pressure during REM sleep in the rat.

We have examined the effect of injection of 6-hydroxydopamine (6-OHDA) into the ventral tegmental area (VTA) on the changes in arterial blood pressure (AP) and heart rate (HR) during the transition from non-rapid eye movement (NREM) sleep to REM sleep. The 6-OHDA-treated rats showed suppression of the increase of AP and HR during REM sleep and of theta frequency in the cortical electroencephalogram (EEG) during wakefulness (W) and REM sleep. It is suggested that midbrain dopaminergic neurons are involved in the control of AP and HR during REM sleep and in the EEG theta activity.

Influence of cedar essence on spontaneous activity and sleep of rats and human daytime nap.

We investigated whether exposure to the odor of extracted cedar essence (CE) has (i) an influence on spontaneous activity and sleep-wake states of rats and (ii) a sleep-promoting effect on human daytime nap after taking an ordinary night's sleep. In rats exposed to CE, spontaneous activities and amount of wake were significantly decreased, while the amount of non-rapid eye movement (NREM) sleep was significantly increased. In human daytime nap, NREM sleep stage 2 latency was significantly shortened after exposure to CE.

The effects of acetazolamide on arterial pressure variability during REM sleep in the rat.

During rapid eye movement (REM) sleep, the arterial pressure (AP) undergoes large fluctuations in the rat, cat, and other mammals, including humans, and it has been suggested that this effect originates in the forebrain. In addition, acetazolamide (ACTZ), a carbonic anhydrase inhibitor, is known to be effective in the treatment of central sleep apnea or epilepsy. The aim of the present study was to analyze the effects of ACTZ on EEG theta rhythm and AP variability during REM sleep in rats. Treatment consisted of intraperitoneal injection of 5 mg of ACTZ in 0.5 mL of saline (n = 6) or 0.5 mL of vehicle alone (n = 6). We then recorded and analyzed the mean AP (MAP) variations during different sleep phases, using a telemetric system. Our results show: 1) Significant decreases in the coefficient of variation of MAP, in the very-low frequency (0.025 - 0.225 Hz) component of the power spectral density of the AP and in theta frequency in the electroencephalogram, were seen in the ACTZ-treated group during REM sleep compared with controls, whereas no significant difference was found between the two groups in non-REM sleep. There was no significant difference in sleep duration, average MAP, and heart rate between the groups. Our data suggest that ACTZ may act as a stabilizing factor preventing AP fluctuations during REM sleep.