DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity of flavonoids obtained from some medicinal plants.

A reactive oxygen species has been implicated in a range of human pathological diseases such as atherosclerosis and certain cancers. Flavonoids are reported to exhibit various biological activities, including antioxidative and free radical scavenging activities. Several flavonoids obtained from barley leaves, soybean and some medicinal plants, Silybum marianum, Sophorae Flos, Cinnamon, Ephedrae Herba and Scutellariae Radix, were tested for their DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity. The structure-activity relationships suggested that not only the numbers of hydroxy group but also the position of hydroxy group might be important for mediating potent activity.

Interaction of phytoestrogens with estrogen receptors alpha and beta.

The human estrogen receptor (hER) exists as two subtypes, hER alpha and hER beta, that differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activities of soy isoflavones after digestion with enteric bacteria in competition binding assays with hER alpha or hER beta protein, and in a gene expression assay using a yeast system. The estrogenic activities of these isoflavones were also investigated by the growth of MCF-7 breast cancer cells. Isoflavone glycoside binds weakly to both receptors and estrogen receptor-dependent transcriptional expression is poor. The aglycones bind more strongly to hER beta than to hER alpha. The binding affinities of genistein, dihydrogenistein and equol are comparable to the binding affinity of 17 beta-estradiol. Equol induces transcription most strongly with hER alpha and hER beta. The concentration required for maximal gene expression is much higher than expected from the binding affinities of the compounds, and the maximal activity induced by these compounds is about half the activity of 17 beta-estradiol. Although genistin binds more weakly to the receptors and induces transcription less than does genistein, it stimulates the growth of MCF-7 cells more strongly than does genistein.

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.

A new oleanene glucuronide obtained from the aerial parts of Melilotus officinalis.

A new oleanene glucuronide called melilotus-saponin O2 (1) was isolated together with three known ones (soyasaponin I, astragaloside VIII, wistariasaponin D) from the aerial parts of Melilotus officinalis (L.) Pallas (Leguminosae). The structure of 1 was determined to be 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranosyl- (1-->2)-beta-D-glucuronopyranosyl melilotigenin by spectroscopic and chemical methods.

Double-blind test on the efficacy of methylcobalamin on sleep-wake rhythm disorders.

The therapeutic effect of methylcobalamin (Met-12) on sleep-wake rhythm disorders was examined in a double-blind test. In the test group which was given a large dosage, a higher percentage of improvement was found compared to the control group with a small dosage, although the difference was not significant. The test group inconsistently showed significant improvement in both the sleep-wake cycle parameters and in clinical symptoms. The tendency was for the results to show a beneficial effect of Met-12 on rhythm disorders. However, because the percentage of improvement was low and significant improvement was inconsistent, Met-12 might be considered to have a low therapeutic potency and possible use as a booster for other treatment methods of the disorders.

HPLC profile analysis of hepatoprotective oleanene-glucuronides in Puerariae Flos.

In order to confirm the constitution of hepatoprotective oleanene glucuronide (OG), HPLC profile analyses of the total OG fractions of both Puerariae Thomsonii Flos (the flowers of Pueraria thomsonii) and Puerariae Lobatae Flos (the flowers of P. lobata) were performed. No remarkable difference in the HPLC profiles with respect to OGs in the flowers was shown, in contrast to those of the roots. By repeated chromatography of the total OG fraction of Puerariae Thomsonii Flos, soyasaponin I (1), kaikasaponin III (2) and kakkasaponin I (3), which had been already isolated from Puerariae Lobatae Flos, were obtained. The hepatoprotective activity of 2 towards immunologically induced liver injury was significantly more effective than that of 1. This information supported previously obtained structure-hepatoprotective relationship data which was measured on another model. The structure-activity relationship information which suggested that the hydroxymethyl group of the galactosyl unit would enhance the hepatoprotective activity was also substantiated.

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.

Continuous measurement of temperature in non-24 hour sleep-wake syndrome.

The onset of the low temperature (LT) zone which was defined as a period when the rectal temperature was below its daily mean is a convenient circadian phase marker. In this study, we document three cases of non-24 h sleep-wake syndrome in which identification of the LT zone as an evening circadian phase marker contributed to clinical judgments. We found that the LT zone was correlated well with dim light melatonin onset. Moreover, calculating the LT zone was useful in determining phase position in irregular sleep pattern and in determining the timing of bright light therapy.

Trials of bright light exposure and melatonin administration in a patient with non-24 hour sleep-wake syndrome.

We report a patient with non-24 h sleep-wake syndrome (non-24) whose free-running sleep-wake cycle was successfully treated with both scheduled bright light exposure and melatonin treatment. In the present study, morning bright light as well as evening melatonin phase-advanced sleep-wake cycles and melatonin rhythm. Both these procedures achieved appropriate entrainment to a 24 h day. However, the patient did not continue morning bright light therapy after the discharge. Rising at appropriate times in the morning for bright light therapy was difficult for him to continue. Melatonin treatment was better tolerated because of its ease of application.

Periodic fatigue symptoms due to desynchronization in a patient with non-24-h sleep-wake syndrome.

A 43-year-old man complaining of recurrent fatigue symptoms and sleep disorders occurring periodically every 4 weeks was studied. Using a wrist worn actigraphy and an ambulatory rectal temperature monitoring apparatus, his sleep-wake cycle and rectal temperature were measured continuously for 4 months, while diagnostic evaluation and therapeutic interventions were conducted. It was found that after he gave up an attempt to keep to a 24-h-day, a free-running sleep wake pattern appeared but his fatigue symptoms disappeared. An analysis of the relationship between his sleep-wake cycle and the rectal temperature rhythm found that his fatigue symptoms did not appear when both rhythms were synchronized with each other. Artificial bright light therapy entrained him to a 24-h day without relapsing of fatigue symptoms. Desynchronization between a 24-h sleep-wake schedule and his circadian pacemaker may have caused his periodically appearing fatigue symptoms.

Circadian rhythm sleep disorders in adolescents: clinical trials of combined treatments based on chronobiology.

Delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake rhythm are circadian rhythm sleep disorders that are common in adolescents. Most patients have difficulty adjusting to school life, poor class attendance or refuse to go to school. Since a treatment has not been established, the present paper is presented to propose a strategy for treating circadian rhythm sleep disorders in adolescents, based on our clinical studies. Twenty subjects (12 males and eight females, mean age 16.2+/-1.7 years) participated in the study. The onset of sleep disorder occurred between the ages of 11 and 17. The most common factors affecting the onset of disorders were changes in social environment. The subjects kept a sleep-log for the periods before and during treatments. The treatments were based on chronobiology: resetting the daily life schedule, chronotherapy, regulation of the lighting environment, methylcobalamin, and/or melatonin. Bright light exposure was successful in 10 patients, of whom four were treated with methylcobalamin. Melatonin treatment was successful in two patients (one with and one without chronotherapy). Thirteen of the 20 patients were successfully, treated with therapies based on chronobiology. After consideration of these results, a step-by-step procedure of combined treatments for the circadian rhythm sleep disorders is proposed.

[Clinical evaluation of chemoradiotherapy for advanced cervical cancer].

Locally advanced cervical cancer has a poor prognosis, poor survival rate, and high local failure rate. A number of questions regarding the optimal agents and schedule of concurrent chemoradiation remain unanswered. To improve the cure rate for advanced or recurrent cervix cancer, we studied intra-arterial infusion chemotherapy (IAIC) with or without radiotherapy. We analyzed 52 cases of advanced or recurrent cervical cancer treated by IAIC with or without radiotherapy. IAIC regimen was separated into two groups: group I consisted of 5-FU + MMC+/-ADM (30 cases) and group II of CDDP + MMC+/-5-FU (22 cases). The tip of the catheter was placed in the bifurcation of abdominal aorta or the bilateral internal iliac arteries (7 cases). The overall response rate (CR + PR) was 71%, 87% in patients receiving radiotherapy, 50% in those without radiotherapy, and 100% in primary cases. The five-year survival rate was 20% in primary cases, 14% in recurrent cases, 3% in group I and 38% in group II by chemotherapy regimen. Severe (more than grade III) hematological acute side effects were found in 48% of all cases, but recovered by interruption of drugs. In 7 cases in which the tip of the catheter was placed in internal iliac arteries, there were severe skin ulcers in 2 cases and severe pain of leg or gluteal region which need narcotics in 2 cases. These data suggest that IAIC mainly with cisplatin with or without radiotherapy is one of the effective treatments for advanced or recurrent cervical cancer. But we should check blood flow distribution periodically, and control the concentration of drugs. To improve the survival rate for advanced or recurrent cervical cancer, we should discuss neoadjuvant chemotherapy followed by chemoradiotherapy and maintenance systemic chemotherapy.

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.

A multicenter study of sleep-wake rhythm disorders: therapeutic effects of vitamin B12, bright light therapy, chronotherapy and hypnotics.

One hundred and six subjects with primary sleep-wake rhythm disorders [13 non-24 hour sleep-wake syndrome (non-24), 76 delayed sleep phase syndrome (DSPS), 11 irregular sleep-wake pattern (irregular) and six long sleepers] were treated with vitamin B12, bright light, chronotherapy and/or hypnotics. These therapies caused moderate or remarkable improvement in 32% of the non-24, 42% of DSPS, 45% of irregular and 67% of long sleepers. A lack of adequate sleep, unpleasant feelings at waking and daytime drowsiness were also improved in DSPS.

[The role and future of radiotherapy in cancer treatment].

The basic principle of radiotherapy for cancer patients is that it has the possibility of a good result (curability), is tolerable and promises a comfortable life thereafter. Radiotherapy is the important tool for early stage cancer by conserving the organ and function and for an advanced or recurrent stage of cancer by helping improve the quality of life. Radiotherapy must be planned on the basis of considering the therapeutic ratio with a 3-dimensional technique. It should be performed with optimum radiation methods in the multimodal treatment of cancer and will undoubtedly prove effective in the future.

[Multiple colonic ulcers in a patient with Sjögren's syndrome].

A 25-year-old female with Sjögren's syndrome was admitted to our hospital because of fever and abdominal pain. Multiple colonic ulcers were demonstrated by gastrographin enema and colonoscopy. Histological examination revealed the presence of necrotizing vasculitis in the submucosal region. Large dose of prednisolone (60 mg/day) brought a prompt relief of her symptoms and an improvement of positive inflammatory signs. Pseudoaneurysm in the arteria colica media, which had been demonstrated by abdominal selective angiography at the time of diagnosis, became extinct after the steroid treatment. Healing of ulcers were also noted by colonoscopy. A variety of extraglandular symptoms has been reported in Sjögren's syndrome. Multiple colonic ulcers due to vasculitis are rarely complicated but may have a great impact on the prognosis of the disease.

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.

Atypical depressive symptoms possibly predict responsiveness to phototherapy in seasonal affective disorder.

Phototherapy was administered to 24 depressed patients with seasonal affective disorder (SAD), of which 62%, 24%, and 14%, respectively, showed improvements of greater than or equal to 50%, 25-50%, and less than 25% based on the Hamilton rating scale for depression for SAD (HAMSAD). No patients showed aggravation or side effects. Although the improvement rate in HAMSAD correlated significantly with the pretreatment severity of atypical symptoms of depression, it did not correlate with that of typical symptoms. This suggests that phototherapy is a useful treatment in SAD and that responsiveness to phototherapy in SAD can possibly be predicted by the atypical depressive symptoms before treatment.