Expression of metallothionein in colorectal cancers and synchronous liver metastases.

The aim of this study is to clarify whether the expression of metallothionein (MT) is related with the malignant potential in primary colorectal cancer and/or synchronous liver metastasis. Immunohistochemical staining for MT was performed on the specimens of adenocarcinoma of the colon and rectum and its liver metastases in 34 patients treated with curative surgery, respectively. Expression of MT was compared with clinicopathological variables and patient survival. In patients with primary colorectal cancer, positive expression was found in 7 of 34 (20.6%) patients, but MT was not detected in any of the cases of liver metastases (0%; p = 0.0111). In the primary tumor, positive MT expression was significantly associated with a higher degree of lymph node involvement (mean +/- SD: 48.4 +/- 33.8 vs. 18.6 +/- 24.4% in MT-positive and MT-negative tumors, respectively; p = 0.0122). The survival rate in the patients with MT-negative tumors was significantly better than that in those with MT-positive tumors as primary sites (p = 0.0198). MT expression in colorectal cancer may be a potential marker affecting lymph node metastases and may be a predictor of a poor prognosis, particularly in patients with synchronous liver metastases.

Diminished melatonin secretion in the elderly caused by insufficient environmental illumination.

The pineal hormone melatonin has some circadian regulatory effects and is assumed to have a close relation with sleep initiation and maintenance. Many previous reports have described age-related decreases in melatonin levels, especially in elderly insomniacs (EIs), which may act as causal or exacerbating factors in sleep disturbances in the elderly. Ten elderly residents with psychophysiological insomnia (mean age, 74.2 yr), 10 healthy residents of the same home [elderly control (EC) group; mean age, 72.7 yr], and 10 healthy young control subjects (mean age, 20.9 yr) living at home participated in this study. The elderly persons, especially the EIs, were exposed to significantly less environmental light and simultaneously suffered from significantly diminished nocturnal melatonin secretion. Supplementary exposure to 4 h (1000 to 1200 h, 1400 to 1600 h) of midday bright light in the EI group significantly increased melatonin secretion to levels similar to those in the young control group without circadian phase-shifting. There was a tendency for the magnitude of the increase in nocturnal melatonin secretion stimulated by bright light to parallel amelioration of sleep disturbances in these subjects. The present findings suggest that we need to pay attention to elderly individuals who suffer under conditions of poor environmental light resulting in disorganized circadian rhythms, including the sleep-wake cycle.

Supplementary administration of artificial bright light and melatonin as potent treatment for disorganized circadian rest-activity and dysfunctional autonomic and neuroendocrine systems in institutionalized demented elderly persons.

Increased daytime napping, early morning awakening, frequent nocturnal sleep interruptions, and lowered amplitude and phase advance of the circadian sleep-wake rhythm are characteristic features of sleep-waking and chronobiological changes associated with aging. Especially in elderly patients with dementia, severely fragmented sleep-waking patterns are observed frequently and are associated with disorganized circadian rhythm of various physiological functions. Functional and/or organic deterioration of the suprachiasmatic nucleus (SCN), decreased exposure to time cues such as insufficient social interaction and reduced environmental light, lowered sensitivity of sensory organs to time cues, and reduced ability of peripheral effector organs to express circadian rhythms may cause these chronobiological changes. In many cases of dementia, the usual treatments for insomnia do not work well, and the development of an effective therapy is an important concern for health care practitioner and researchers. Recent therapeutical trials of supplementary administration of artificial bright light and the pineal hormone melatonin, a potent synchronizer for mammalian circadian rhythm, have indicated that these treatments are useful tools for demented elderly insomniacs. Both bright light and melatonin simultaneously ameliorate disorganized thermoregulatory and neuroendocrine systems associated with disrupted sleep-waking times, suggesting a new, potent therapeutic means for insomnia in the demented elderly. Future studies should address the most effective therapeutic design and the most suitable types of symptoms for treatment and investigate the use of these tools in preventive applications in persons in early stages of dementia.

Concurrent expressions of metallothionein, glutathione S-transferase-pi, and P-glycoprotein in colorectal cancers.

PURPOSE: Because the status of the inherent drug-resistance of colorectal cancers remains obscure, human colorectal cancers with no neoadjuvant therapy were retrospectively investigated regarding the expression of three drug-resistant proteins: metallothionein, glutathione S-transferase-pi, and P-glycoprotein. METHODS: Paraffin-embedded tissues of 130 colorectal cancers (Dukes A, 20; B, 49; C, 41; D, 20) obtained by surgical resections from 1982 to 1989 were used. The three proteins were immunostained by the streptavidin-biotin complex method. The immunostaining was judged to be positive if more than 5 percent of cells showed positive staining by use of cell analysis system. The data were compared with clinicopathologic features (Dukes A-D) and patients' prognosis (Dukes AC). RESULTS: Metallothionein, glutathione S-transferase-pi, and P-glycoprotein were positively expressed in 91 (70 percent), 30 (23 percent), and 98 (75 percent), respectively. A total of 120 (86 percent) expressed at least one drug-resistant protein. No intergroup differences were observed between positive and negative expressions of the proteins and their clinicopathologic features except tumor location. Rectal cancers positively expressed P-glycoprotein and three proteins more frequently. Twenty-six (20 percent), 65 (50 percent), and 21 (16 percent) cancers positively expressed one, two, and three proteins, respectively. The disease-free survival rates of patients with Dukes A through C cancer with positive staining for one, two, and three proteins were 100, 94, and 83 percent (at 1 year); 100, 72, and 51 percent (at 3 years); and 94, 66, and 38 percent (at 5 years), respectively (Kaplan-Meier with log-rank test; P = 0.016). In the multivariate Cox analysis, age, Dukes stage, tumor size, and glutathione S-transferase-pi were independent prognostic factors. CONCLUSIONS: The patients with concurrent expression of drug-resistant proteins in their cancers had worse prognoses. Examining drug-resistant proteins in colorectal cancers may be useful in selecting adjuvant chemotherapy and in predicting prognosis more accurately.

Effects of repeated selective serotonin reuptake inhibitor paroxetine treatments on mouse forced swimming.

Studies were performed in the mouse forced swimming model, a well known experimental depression model, in order to detect the mechanism of the antidepressive effects induced by repeated serotonin reuptake inhibitor (SSRI) dosing. Five-day repeat dosing of a typical SSRI, paroxetine, increased climbing, a distinctive antidepressive behavior, 1 h after but not 1 h before treatment. The coinjection of paroxetine and serum in mice treated with four repeated doses of paroxetine distinctively increased the behavior, but the coinjection of paroxetine and serum in mice without paroxetine did not. These results indicate that repeated dosing of paroxetine produces a serum substance related to the antidepressive effects induced by serotonin neuron activities. Furthermore, the behavior induced by 5-day repeated dosing of paroxetine was decreased by 100 and 10 micrograms/kg of ketanserin (5-HT2 antagonist) and 100 micrograms/kg of LY-278584 (5-HT3 antagonist). The present findings strongly suggest that repeated dosing of paroxetine produces a serum substance stimulating the antidepressive neuronal pathway sensitively mediated by 5-HT2 and 5-HT3 receptor activity.

Randomized, dim light controlled, crossover test of morning bright light therapy for rest-activity rhythm disorders in patients with vascular dementia and dementia of Alzheimer's type.

The authors compared the therapeutic effect of morning bright and dim light exposure on rest-activity (R-A) rhythm disorders in patients with vascular dementia (VD) and patients with dementia of Alzheimer's type (DAT). Participants in this study were 12 patients with VD (M/F = 5/7; average age = 81 years) and 10 patients with DAT (M/F = 4/6; average age = 78 years). They were exposed to 2 weeks of bright light (BL; 5000-8000 lux) and 2 weeks of dim light (DL; 300 lux) in the morning (09:00-11:00) in a randomized crossover design in which the 2-week treatment period took place between pretreatment (1 week) and posttreatment (1 week) periods. Continuous R-A monitoring was performed at 1-minute intervals throughout the study using an actigraph around the nondominant wrist. The BL exposure for 2 weeks induced a significant reduction in both nighttime activity and percentages of nighttime activity to total activity compared with the pretreatment period, as well as compared with the DL condition in the VD group, but not in the DAT group. These findings support the assumption that the therapeutic efficacies of morning BL exposure are prominent in VD patients and are mainly due to its photic effect rather than nonphotic effects such as the intensification of social interaction accompanying light therapy.

Marked suppression of cortical auditory evoked response shortly before the onset of REM sleep.

In 10 of 12 subjects examined, the amplitude of N300, a component of the cortical auditory evoked potential, was evidently smaller in rapid eye movement (REM) sleep than in non-REM sleep. The start of the reduction associated with the onset of the first episode of REM sleep was examined in these 10 subjects. In five of these, a marked reduction of N300 amplitude occurred 0.5-2.5 min before the appearance of muscle atonia of REM sleep. In two subjects, a similarly marked reduction of the N300 amplitude occurred 0.5-1.0 min before the disappearance of sleep spindles or K-complexes. This suggests that a suppression of the synchronizing mechanism in the cerebrum sometimes occurs briefly prior to the occurrence of other physiological phenomena associated with REM sleep.

Favorable effect of transcranial electrostimulation on behavior disorders in elderly patients with dementia: a double-blind study.

The efficacy of transcranial electrostimulation for sleep-wake and behavior disorders in elderly patients with dementia was tested in a double-blind study. The subjects were 27 inpatients with multi-infarct dementia (12 males and 15 females, aged 58-86). They were randomly divided into two groups: active treatment (n = 14) and placebo treatment (n = 13). For electrostimulation, a device (HESS-100) was used which delivered repetitive rectangular electric pulses of 6-8 V at increasing frequencies from 6 to 80 Hz, each pulse lasting 0.2 ms and with a root mean square value of 256-530 microA. Electrostimulation was performed for 20 minutes from 10:00 h every morning. The active or placebo treatment was performed for 2 weeks in each group. The electrostimulation was significantly effective in behavior disorders such as wandering or nocturnal delirium, and decreased motivation during the daytime. It was also effective in improving night sleep. Electroencephalograms confirmed increased vigilance levels in the daytime both during and after the treatment.

K-complex evoked in NREM sleep is accompanied by a slow negative potential related to cognitive process.

Evoked cortical responses to two kinds of auditory stimuli (rare and frequent) were analyzed to determine whether or not a K-complex evoked in stage 2 of NREM sleep is accompanied by some endogenous cognitive components of the event-related potential. All the 7 subjects examined in this sleep state failed to provide the correct behavioral response to auditory stimuli, but a K-complex was evoked more frequently by rare stimuli than by frequent stimuli. EEG segments in stage 2 were averaged separately according to the presence or absence of K-complexes emerging just after the stimulation. In cases where K-complexes did not emerge, a long-lasting negative potential of relatively low voltage appeared in the difference wave, which was obtained by subtracting the averaged EEG for frequent stimuli from that for rare stimuli. In cases where K-complexes emerged, a similar long-lasting negative potential of large amplitude appeared in the difference wave. These data may indicate that a K-complex evoked by an external stimulus is accompanied by a potential related to a cognitive process, which appears with greater amplitude in cases where a K-complex is evoked.

Morning bright light therapy for sleep and behavior disorders in elderly patients with dementia.

Fourteen inpatients with dementia showing sleep and behavior disorders (average age = 75 years), and 10 control elderly people (average age = 75 years) were carefully observed for 2 months. Four weeks of morning light therapy markedly improved sleep and behavior disorders in the dementia group. The measurement of sleep time and the serum melatonin values suggests that sleep and behavior disorders in the dementia group are related to decreases in the amplitude of the sleep-wake rhythm and decreases in the levels of melatonin secretions. Morning light therapy significantly increased total and nocturnal sleep time and significantly decreased daytime sleep time. These results indicate that morning bright light is a powerful synchronizer that can normalize disturbed sleep and substantially reduce the frequency of behavior disorders in elderly people with dementia.

Four congenitally blind children with circadian sleep-wake rhythm disorder.

Four congenitally blind children aged 4-12 years, with severe or moderate mental retardation, were chronobiologically studied. Three of them showed a free-running rhythm of sleep-wake, and the fourth showed an irregular sleep-wake rhythm. To entrain their sleep-wake rhythm to a 24-h rhythm, several trials based on chronotherapy were performed. The free-running rhythms in the three children were considered their own endogenous rhythms, revealed through some disorder in the mechanism synchronizing the endogenous rhythm to the normal 24-h environmental rhythm. The irregular sleep-wake rhythm in the fourth child may have been the result of immaturity or failure of the pacemaker of the circadian rhythm. Because of their severe mental retardation, all the children were lacking in social time cues, which are the most potent "Zeitgebers" for human biological clocks.