GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome.

Fragile X syndrome is a genetic condition resulting from FMR1 gene mutation that leads to intellectual disability, autism-like symptoms, and sensory hypersensitivity. Arbaclofen, a GABA-B agonist, has shown efficacy in some individuals with FXS but has become unavailable after unsuccessful clinical trials, prompting interest in publicly available, racemic baclofen. The present study investigated whether racemic baclofen can remediate abnormalities of neural circuit function, sensory processing, and behavior in Fmr1 knockout mice, a rodent model of fragile X syndrome. Fmr1 knockout mice showed increased baseline and auditory-evoked high-frequency gamma (30-80 Hz) power relative to C57BL/6 controls, as measured by electroencephalography. These deficits were accompanied by decreased T maze spontaneous alternation, decreased social interactions, and increased open field center time, suggestive of diminished working memory, sociability, and anxiety-like behavior, respectively. Abnormal auditory-evoked gamma oscillations, working memory, and anxiety-related behavior were normalized by treatment with baclofen, but impaired sociability was not. Improvements in working memory were evident predominantly in mice whose auditory-evoked gamma oscillations were dampened by baclofen. These findings suggest that racemic baclofen may be useful for targeting sensory and cognitive disturbances in fragile X syndrome.

Positional relationship between recurrent intracerebral hemorrhage/lacunar infarction and previously detected microbleeds.

BACKGROUND AND PURPOSE: Although MBs, ICH, and LI are secondary to cerebral microangiopathy, it remains unclear whether the location of subsequent ICH/LI corresponds to the previous location of MBs. We performed this study to clarify the positional relationship between recurrent ICH/LI and previously detected MBs. MATERIALS AND METHODS: We evaluated patients with recurrent ICH/LI who had MBs, as shown on prior T2*-weighted MR imaging. We assessed retrospectively whether the location of recurrent ICH/LI corresponded to that of the prior MB. Patients with ICH were divided into the deep ICH group and the lobar ICH group, and the positional relationship between hematoma and previously detected MBs was evaluated. RESULTS: A total of 55 patients, including 34 with recurrent ICH and 21 with recurrent LI were evaluated. Although the location of the LI corresponded to prior MBs in only 1 patient (4.8%), the location of ICH corresponded to prior locations of MBs in 21 patients (61.8%) (OR, 32.3; 95% CI, 3.86-270.3; P < .001). Among the patients with ICH, the correspondence ratio was higher in the deep ICH group (19 of 24 patients, 79.2%) than in the lobar ICH group (2 of 10 patients, 20%) (OR, 15.2; 95% CI, 2.42-95.3; P < .002). CONCLUSIONS: The close positional association between recurrent ICH and prior MBs suggests that MBs represent hemorrhage-prone microangiopathy. In addition, different correspondence ratios between the deep ICH group and the lobar ICH group may be attributable to their different pathogenesis.

Low-level laser therapy improves bone repair in rats treated with anti-inflammatory drugs.

Nowadays, selective cyclooxygenase-2 non-steroidal anti-inflammatory drugs have been largely used in surgical practice for reducing oedema and pain. However, the association between these drugs and laser therapy is not known up to now. Herein, the aim of this study was to evaluate the action of anti-COX-2 selective drug (celecoxib) on bone repair associated with laser therapy. A total of 64 rats underwent surgical bone defects in their tibias, being randomly distributed into four groups: Group 1) negative control; Group 2) animals treated with celecoxib; Group 3) animals treated with low-level power laser and Group 4) animals treated with celecoxib and low-level power laser. The animals were killed after 48 h, 7, 14 and 21 days. The tibias were removed for morphological, morphometric and immunohistochemistry analysis for COX-2. Statistical significant differences (P < 0.05) were observed in the quality of bone repair and quantity of formed bone between groups at 14 days after surgery for Groups 3 and 4. COX-2 immunoreactivity was more intense in bone cells for intermediate periods evaluated in the laser-exposed groups. Taken together, such results suggest that low-level laser therapy is able to improve bone repair in the tibia of rats as a result of an up-regulation for cyclooxygenase-2 expression in bone cells.

Dose effect for South Serbians due to 238U in natural drinking water.

The use of depleted uranium ammunition in South Serbia during the 1999 Kosovo conflict raised a great deal of public concern in the Balkans. Radioactivity levels of 238U in 20 wells and lake water samples were checked from the viewpoint of internal radiation exposure for South Serbian subjects. We have measured 238U concentration using inductively coupled plasma mass spectrometry, whereas thermal ionisation mass spectrometry has been used for the measurement of isotope ratios, e.g. 234U/238U and 235U/238U. The concentration of uranium in water samples varies in the range 1.37-63.18 mBq/L. 234U belongs to the 238U natural radioactive decay series, and at secular equilibrium, the abundance ratio, 234U/238U, corresponds to the ratio of their half-lives. The 234U/238U activity ratio varies in the range 0.88-2.2 and 235U/238U isotope ratio varies from 0.00698 to 0.00745. These findings indicate that uranium in water was a mixture of natural and anthropogenic origin. The annual effective dose due to 238U was estimated to be in the range 9.2 x 10(-5)-2.1 x 10(-3) mSv.

Reducing sediment and phosphorus in tributary waters with alum and polyacrylamide.

The Salton Sea is the largest inland water body in California, covering an area of 980 km(2). Inflow to the Salton Sea (1.6 km(3) yr(-1)) is predominately nutrient-rich agricultural wastewater, which has led to eutrophication. Because internal phosphorus release from the bottom sediments is comparatively low and external phosphorus loading to the Salton Sea is high, reduction of tributary phosphorus is expected to reduce algal blooms, increase dissolved oxygen, and reduce odors. Removing both dissolved phosphorus and phosphorus-laden sediment from agricultural drainage water (ADW) should decrease eutrophication. Both alum and polyacrylamide (PAM) are commonly used in wastewater treatment to remove phosphorus and sediment and were tested for use in tributary waters. Laboratory jar tests determined PAM effectiveness (2 mg L(-1)) for turbidity reduction as cationic > anionic = nonionic. Although cationic PAM was the most effective at reducing turbidity at higher speeds, there was no observed difference between the neutral and anionic PAMs at velocity gradients of 18 to 45 s(-1). Alum (4 mg L(-1) Al) reduced turbidity in low energy systems (velocity gradients < 10 s(-1)) by 95% and was necessary to reduce soluble phosphorus, which comprises 47 to 100% of the total P concentration in the tributaries. When PAM was added with alum, the anionic PAM became ineffective in aiding flocculation. The nonionic PAM (2 mg L(-1)) + alum (4 mg L(-1) Al) is recommended to reduce suspended solids in higher energy systems and reduce soluble P by 93%.

Evaluation of developmental toxicity of 1-butanol given to rats in drinking water throughout pregnancy.

The objective of this study was to evaluate the developmental toxicity of 1-butanol in rats. Pregnant rats were given drinking water containing 1-butanol at 0.2%, 1.0% or 5.0% (316, 1454 or 5654 mg/kg/day) on days 0-20 of pregnancy. A significant decrease in maternal body weight gain accompanied by reduced food and water consumption was found at 5.0%. No significant increase in the incidence of pre- and postimplantation embryonic loss was observed in any groups treated with 1-butanol. Fetal weight was significantly lowered at 5.0%. Although a significant increase in the incidence of fetuses with skeletal variations and decreased degree of ossification was found at 5.0%, no increase in the incidence of fetuses with external, skeletal and internal abnormalities was detected in any groups treated with 1-butanol. The data demonstrate that 1-butanol is developmental toxic only at maternal toxic doses. No evidence for teratogenicity of 1-butanol was noted in rats. Based on the significant decreases in maternal body weight gain and fetal weight, it is concluded that the no observed adverse effect levels (NOAELs) of 1-butanol for both dams and fetuses are 1.0% (1454 mg/kg/day) in rats.

Exfoliation of Helicobacter pylori from gastric mucin by glycopolypeptides from buttermilk.

In the human stomach, Helicobacter pylori, an ulcer pathogenic bacterium, colonizes the gastric mucosal layer primarily. The ability of glycopolypeptides (GPP) prepared from buttermilk to exfoliate H. pylori bound to gastric mucin was investigated. The GPP were prepared from buttermilk by digestion with trypsin, papain, pancreatin, bromelain, or pepsin. Helicobacter pylori ATCC 43504T and 43579 adhered more strongly to all of the GPP tested than to whole buttermilk, the soluble fraction of buttermilk, gastric mucin prepared from mouse stomach, or commercial pig gastric mucin. The GPP digested with trypsin, papain, or pancreatin were significantly more adherent. When the GPP concentration was 10 mg/mL, bound H. pylori ATCC 43504T, 43579, and 5 clinical isolates were exfoliated markedly from immobilized porcine gastric mucin following treatment with GPP digested with trypsin or pancreatin. This ability of GPP did not correlate with sialic acid content, indicating that sialic acid content is not important in the exfoliation of this microorganism. Such an ability may depend on the structure or number of sugar chains, or the position of sialic acid. We conclude that GPP promote the exfoliation of H. pylori bound to gastric mucin and prevent the de novo adherence of this microorganism. As such, GPP are a promising food material for preventing H. pylori infection.

Antibacterial activity of polyphenol components in oolong tea extract against Streptococcus mutans.

The purpose of the present study was to determine the antibacterial activity of oolong tea extract on oral streptococci, including Streptococcus mutans and Streptococcus sobrinus, and to identify the response to its components. Antibacterial activity was found when the extract was added to S. mutans cells in chemically defined medium but not in complex broth media. Further, pretreatment with bovine serum albumin reduced the antibacterial activity. The extract showed antibacterial activity against all of the oral streptococci examined, with the highest activity against S. mutans MT8148R. This activity was found to originate from a monomeric polyphenol-rich fraction, and it was stronger than that of pure polyphenols. Moreover, some combinations of monomeric polyphenols showed the highest level of antibacterial activity. These results suggest that the antibacterial activity of oolong tea extract is caused by a synergistic effect of monomeric polyphenols, which can easily bind to proteins.

Molecular analysis of the inhibitory effects of oolong tea polyphenols on glucan-binding domain of recombinant glucosyltransferases from Streptococcus mutans MT8148.

An oolong tea polyphenol (OTF6) has been shown to possess a strong anti-glucosyltransferase (GTF) activity and inhibit experimental dental caries in rats infected with mutans streptococci. The effects of OTF6 on the functional domains of GTFs of Streptococcus mutans, an N-terminal catalytic domain (CAT), and a C-terminal glucan-binding domain (GBD), were examined. The maximum velocity of glucan synthesis by recombinant GTFB (rGTFB) and GTFD (rGTFD) became significantly slower in the presence of OTF6, however, Km values remained stable when compared in their absence. These results suggest that OTF6 reduces glucan synthesis by non-competitively inhibiting the GBD of S. mutans GTFB and GTFD. Further, the recombinant proteins of CAT (rCAT) and GBD (rGBD) were expressed using Escherichia coli, and purified by affinity column chromatography. rGBD but not rCAT was found to possess dextran-binding activity, which was shown to be inhibited by OTF6. These results indicate that OTF6, a polymeric polyphenol specific for oolong tea is able to reduce glucan synthesis by inhibiting the GBD of S. mutans GTFB.

Oral administration of persimmon leaf extract ameliorates skin symptoms and transepidermal water loss in atopic dermatitis model mice, NC/Nga.

BACKGROUND: We have previously shown that persimmon leaf extract and its major flavonoid constituent, astragalin, inhibited histamine release by basophils and that oral administration of these substances prior to the onset into an atopic dermatitis (AD) model mouse, NC/Nga, prevented development of dermatitis. OBJECTIVES: This study was designed to assess the clinical therapeutic effect of persimmon leaf extract and astragalin in NC/Nga mice suffering from dermatitis and the dose-response preventive effects of persimmon leaf extract on dermatitis and transepidermal water loss (TEWL). METHODS: The efficacy of persimmon leaf extract or astragalin in NC/Nga mice was judged by measurement of skin severity, scratching behaviour, serum IgE levels or TEWL. RESULTS: Oral administration of persimmon leaf extract (250 mg kg(-1)) or astragalin (1.5 mg kg-1) for 4 weeks into NC/Nga mice with overt dermatitis resulted in a decrease in the severity of the condition. The preventive effect of persimmon leaf extract on the dermatitis was dose-dependent and continuous intake of persimmon leaf extract significantly decreased its onset and development. In addition, TEWL was also suppressed at a persimmon leaf extract dose of 250 mg kg(-1). No significant adverse reaction by these substances could be observed. CONCLUSIONS: These observations suggest that persimmon leaf extract or the flavonoid astragalin may be alternative substances for the management of AD.

Progressive muscle relaxation, breathing exercises, and ABC relaxation theory.

This study compared the psychological effects of Progressive Muscle Relaxation (PMR) and breathing exercises. Forty-two students were divided randomly into two groups and taught PMR or breathing exercises. Both groups practiced for five weeks and were given the Smith Relaxation States Inventory before and after each session. As hypothesized, PMR practitioners displayed greater increments in relaxation states (R-States) Physical Relaxation and Disengagement, while breathing practitioners displayed higher levels of R-State Strength and Awareness. Slight differences emerged at Weeks 1 and 2; major differences emerged at Weeks 4 and 5. A delayed and potentially reinforcing aftereffect emerged for PMR only after five weeks of training--increased levels of Mental Quiet and Joy. Clinical and theoretical implications are discussed.

The development of a pollen information system for the improvement of QOL.

The Kochi Prefecture Japanese Cedar and Cypress Pollen Information System (P-Net Kochi) was established in 1991 on the initiative of the Pharmaceuticals and Sanitation Division to improve the quality of life of people in Kochi Prefecture, particularly patients with pollinosis. Kochi Prefecture has the highest forests percentage (84%) in Japan. In addition, 40% of the population of the prefecture is concentrated in Kochi City. The average pollen count at 10 observation points an one year was about 20,000/cm2 during the observation period, but it exceeded 110,000/cm2 in 1995, when it was also high nationwide. Kochi Prefecture organized a system to promote people's understanding of pollinosis in connection with environmental problems, and to enlighten people on appropriate preventive measures. The system has been improved in the rapid and efficient transmission of information over the years with technological advances. The introduction of an automatic monitoring system not dependent on human labor and the support of the users proved to be indispensable for the maintenance of the system.

Successful hyperbaric oxygen treatment of life-threatening hemorrhagic cystitis after allogeneic bone marrow transplantation.

Hemorrhagic cystitis (HC) is a major cause of morbidity after allogeneic bone marrow transplantation (BMT). Many therapies have been investigated to prevent or treat HC, but effective treatment for HC is still limited. While the efficacy of hyperbaric oxygen therapy has been established for HC due to chemotherapy and/or radiation therapy, its role in HC occurring after allogeneic BMT has yet to be defined. We report two cases of life-threatening late-onset HC after allogeneic BMT in children, which resolved after treatment with hyperbaric oxygen.

Rapid improvement of osteomalacia by treatment in a case with Sjögren's syndrome, rheumatoid arthritis and renal tubular acidosis type 1.

We present here a case of Sjögren's syndrome (SjS) with osteomalacia based on renal tubular acidosis type 1 (RTA-1). A 53-year-old woman, diagnosed as having rheumatoid arthritis (RA) at the age of 33, was admitted to our hospital because of sicca complex, fatigability and worsening general aching. The activity of RA had been low, but it was complicated by SjS, RTA-1 and remarkable osteomalacia. Acidosis was corrected by alkali supplement therapy. By treatment with a regimen consisting of alfacalcidol, calcium L-aspartate, elcatonin and ipriflavone, her bone mineral density (BMD) was remarkably improved within months and the generalized aching gradually diminished.

U box proteins as a new family of ubiquitin-protein ligases.

The U box is a domain of approximately 70 amino acids that is present in proteins from yeast to humans. The prototype U box protein, yeast Ufd2, was identified as a ubiquitin chain assembly factor that cooperates with a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein ligase (E3) to catalyze ubiquitin chain formation on artificial substrates. E3 enzymes are thought to determine the substrate specificity of ubiquitination and have been classified into two families, the HECT and RING finger families. Six mammalian U box proteins have now been shown to mediate polyubiquitination in the presence of E1 and E2 and in the absence of E3. These U box proteins exhibited different specificities for E2 enzymes in this reaction. Deletion of the U box or mutation of conserved amino acids within it abolished ubiquitination activity. Some U box proteins catalyzed polyubiquitination by targeting lysine residues of ubiquitin other than lysine 48, which is utilized by HECT and RING finger E3 enzymes for polyubiquitination that serves as a signal for proteolysis by the 26 S proteasome. These data suggest that U box proteins constitute a third family of E3 enzymes and that E4 activity may reflect a specialized type of E3 activity.

Evidence of Qi-gong energy and its biological effect on the enhancement of the phagocytic activity of human polymorphonuclear leukocytes.

In order to test for an effect of phosphate buffered saline (PBS) treated externally with Qi energy ("Qi-treated" PBS) on the phagocytic activity of human polymorphonuclear leukocytes (PMNs), rigorously controlled experiments employing masking and randomized procedures were carried out under independent monitoring. In all experiments, Qi treatment was externally applied under monitoring to newly purchased unopened 100 ml bottles of PBS, and the PMN phagocytic activity was assayed by one experimenter in masked, randomized and monitored conditions using a highly sensitive chemiluminescence method. Phagocytic activity data were obtained in triplicate for each sample and then statistically analyzed. The PBS samples Qi-treated by the Qi-gong master and by one of the Qi-gong trainees showed clear stimulation of PMN phagocytic activity which was significant statistically, and this phenomenon was highly reproducible. Out of 10 experiments by the Qi-gong master, only twice did Qi-treatment fail to influence the PBS. The activity of Qi-treated PBS decayed over days or weeks. Furthermore, it was found that Qi-treated PBS had decreased phagocytic stimulatory activity after microwave treatment, but not after autoclave treatment. We also demonstrated that microwave irradiation and infrared laser pulse irradiation have similar effects on PBS as Qi-treatment. The results obtained in this experiment provide evidence of the existence of Qi energy, its ability to influence an electrolyte solution and its biological effect. Furthermore, microwave or infrared laser pulse treatment was found to partly mimic the Qi-treatment of PBS.

Effects of Orengedoku-to and Senkanmeimoku-to, traditional herbal medicines, on the experimental elevation of aqueous flare in pigmented rabbits.

We investigated the effects of Orengedoku-to (Huanglian-Jie-Du-Tang in Chinese) and Senkanmeimoku-to (Xygan-Ming-Mu-Tang in Chinese), traditional herbal medicines, on experimantal elevation of aqueous flare in pigmented rabbits. To produce the elevation of aqueous flare in rabbits, prostaglandin E2 (PGE2) was applied to the cornea with use of a glass cylinder, or lipopolysaccharides (LPS) were injected into the ear vein. Animals were pretreated by the oral administration of 150 g/day of food containing 0.7%, 0.2% or 0.07% (w/w) Orengedoku-to, or 2%, 0.6% or 0.2% (w/w) Senkanmeimoku-to for 5 days. Aqueous flare was measured with a laser flare-cell meter. Pretreatment with 0.7% or 0.2% Orengedoku-to and 2% Senkanmeimoku-to did suppress significantly (P < 0.05) elevation of aqueous flare induced by PGE2. Pretreatment with 0.7% or 0.2% Orengedoku-to and 2% or 0.6% Senkanmeimoku-to significantly suppressed (P < 0.001) elevation of aqueous flare induced by LPS. It is possible that Orengedoku-to and Senkanmeimoku-to may migrate some forms of uveitis.

Effects of traditional Sino-Japanese herbal medicines on aqueous flare elevation after small-incision cataract surgery.

We evaluated prospectively the effects of traditional Sino-Japanese herbal medicines on elevation of aqueous flare. Fifty-four patients with age-related cataract undergoing phacoemulsification with intraocular lens implantation were studied. In the control group, 20 patients received no herbal medicine. In the treated groups, 14 patients were given Orengedoku- to (Huanglian-Jie-Du-Tang in Chinese) granules (7.5 g daily), 10 patients were given Kakkon-to (Ge-Gen-Tang in Chinese) granules (7.5 g daily), and 10 patients were given Sairei-to (Cai-Ling-Tang in Chinese) granules (9.0 g daily), for 3 days before surgery, the day of surgery, and for 7 days after surgery. Aqueous flare was measured before and after surgery. The differences in preoperative flare intensities among the four groups were not significant. In the control group, the flare was 29.4 photon counts/msec on day 1, and then gradually decreased. The flare intensities on days 1, 3, and 5 in the Orengedoku-to and Kakkon-to groups were significantly lower than in the control group. The flare intensities in the Sairei-to group were the same as those of the controls. Oral administration of Orengedoku-to and Kakkon-to decreased aqueous flare elevation after small-incision cataract surgery. Sairei-to had no effect on the elevation.

Words of Tohkaku Wada: medical heritage in Japan.

The origins of Japan's medical ideas, which are deeply rooted in its religion, culture and history, are not widely understood in medical societies of other countries. We have taken up the task of summarising this tradition here so that some insight can be gained into the unique issues that characterise the practice of medicine in Japan. We borrow from the sayings of Tohkaku Wada, a medical philosopher of late eighteenth-century Japan, for a look at Japanese medical tradition. Wada's medical thought was very much reflective of the Buddhism, Zen, and swordsmanship that informed eighteenth-century philosophy in Japan. His central concepts were "chu" and "sei", that is, complete and selfless dedication to the patient and the practice of medicine. This paper explores Wada's thought, explaining it mainly from the standpoint of Japanese traditional culture.

Identification of cariostatic substances in the cacao bean husk: their anti-glucosyltransferase and antibacterial activities.

The cacao bean husk has been shown to possess two types of cariostatic substances, one showing anti-glucosyltransferase (GTF) activity and the other antibacterial activity, and to inhibit experimental dental caries in rats infected with mutans streptococci. In the present study, chromatographic purification revealed high-molecular-weight polyphenolic compounds and unsaturated fatty acids as active components. The former, which showed strong anti-GTF activity, were polymeric epicatechins with C-4beta and C-8 intermolecular bonds estimated to be 4636 in molecular weight in an acetylated form. The latter, which showed bactericidal activity against Streptococcus mutans, were determined to be oleic and linoleic acids, and demonstrated a high level of activity at a concentration of 30 microgram/mL. The cariostatic activity of the cacao bean husk is likely caused by these biologically active constituents.