Adverse Events Associated with Melatonin for the Treatment of Primary or Secondary Sleep Disorders: A Systematic Review.

BACKGROUND: Melatonin is widely available either on prescription for the treatment of sleep disorders or as an over-the-counter dietary supplement. Melatonin has also recently been licensed in the UK for the short-term treatment of jetlag. Little is known about the potential for adverse events (AEs), in particular AEs resulting from long-term use. Concern has been raised over the possible risks of exposure in certain populations including pre-adolescent children and patients with epilepsy or asthma. OBJECTIVES: The aim of this systematic review was to assess the evidence for AEs associated with short-term and longer-term melatonin treatment for sleep disorders. METHODS: A literature search of the PubMed/Medline database and Google Scholar was conducted to identify randomised, placebo-controlled trials (RCTs) of exogenous melatonin administered for primary or secondary sleep disorders. Studies were included if they reported on both the types and frequencies of AEs. Studies of pre-term infants, studies of < 1 week in duration or involving single doses of melatonin and studies in languages other than English were excluded. Findings from open-label studies that raised concerns relating to AE reports in patients were also examined. Studies were assessed for quality of reporting against the Consolidated Standards of Reporting Trials (CONSORT) checklist and for risk of bias against the Cochrane Collaboration risk-of-bias criteria. RESULTS: 37 RCTs met criteria for inclusion. Daily melatonin doses ranged from 0.15 mg to 12 mg. Subjects were monitored for up to 29 weeks, but most studies were of much shorter duration (4 weeks or less). The most frequently reported AEs were daytime sleepiness (1.66%), headache (0.74%), other sleep-related AEs (0.74%), dizziness (0.74%) and hypothermia (0.62%). Very few AEs considered to be serious or of clinical significance were reported. These included agitation, fatigue, mood swings, nightmares, skin irritation and palpitations. Most AEs either resolved spontaneously within a few days with no adjustment in melatonin, or immediately upon withdrawal of treatment. Melatonin was generally regarded as safe and well tolerated. Many studies predated publication of the CONSORT checklist and consequently did not conform closely to the guidelines. Similarly, only eight studies were judged 'good' overall with respect to the Cochrane risk-of-bias criteria. Of the remaining papers, 16 were considered 'fair' and 13 'poor' but publication of almost half of the papers preceded that of the earliest version of the guidelines. CONCLUSION: Few, generally mild to moderate, AEs were associated with exogenous melatonin. No AEs that were life threatening or of major clinical significance were identified. The scarcity of evidence from long-term RCTs, however, limits the conclusions regarding the safety of continuous melatonin therapy over extended periods. There are insufficient robust data to allow a meaningful appraisal of concerns that melatonin may result in more clinically significant adverse effects in potentially at-risk populations. Future studies should be designed to comply with appropriate quality standards for RCTs, which most past studies have not.

Association of blood n-3 fatty acid with bone mass and bone marrow TRAP-5b in the elderly with and without hip fracture.

The plasma n-3 fatty acid level was 26.2% lower in patients with osteoporotic hip fracture than in those with osteoarthritis. In all patients, n-3 fatty acid was positively associated with bone mineral density and inversely associated with tartrate-resistant acid phosphatase-5b level in bone marrow aspirates, reflecting the bone microenvironment. INTRODUCTION: Despite the potential beneficial role of n-3 fatty acid (FA) on bone metabolism, the specific mechanisms underlying these effects in humans remain unclear. Here, we assessed whether the plasma n-3 level, as an objective indicator of its status, is associated with osteoporosis-related phenotypes and bone-related markers in human bone marrow (BM) samples. METHODS: This was a case-control and cross-sectional study conducted in a clinical unit. n-3 FA in the blood and bone biochemical markers in the BM aspirates were measured by gas chromatography/mass spectrometry and immunoassay, respectively. BM fluids were collected from 72 patients who underwent hip surgery because of either osteoporotic hip fracture (HF; n = 28) or osteoarthritis (n = 44). RESULTS: After adjusting for confounders, patients with HF had 26.2% lower plasma n-3 levels than those with osteoarthritis (P = 0.006), and each standard deviation increment in plasma n-3 was associated with a multivariate-adjusted odds ratio of 0.40 for osteoporotic HF (P = 0.010). In multivariate analyses including all patients, a higher plasma n-3 level was associated with higher bone mass at the lumbar spine (ß = 0.615, P = 0.002) and total femur (ß = 0.244, P = 0.045). Interestingly, the plasma n-3 level was inversely associated with the tartrate-resistant acid phosphatase-5b level (ß = - 0.633, P = 0.023), but not with the bone-specific alkaline phosphatase level, in BM aspirates. CONCLUSIONS: These findings provide clinical evidence that n-3 FA is a potential inhibitor of osteoclastogenesis that favors human bone health.

Oleanolic acid (OA) regulates inflammation and cellular dedifferentiation of chondrocytes via MAPK signaling pathways.

Oleanolic acid (OA) is a bioactive triterpenoid in medicinal plants. It possesses various pharmacological properties, including analgesic, anti-inflammatory, and antitumor effects. The effects of OA in chondrocytes, however, are not well characterized. Here, we used rabbit articular chondrocytes as a cellular model to investigate the effects and regulatory mechanisms of OA on dedifferentiation and pro-inflammation. OA promoted dedifferentiation of chondrocytes by inhibiting type II collagen and pro-inflammatory activity by increasing cyclooxygenase-2 (COX-2) expression. Furthermore increased phosphorylation of p38 kinases and down-regulated phosphorylation of ERK was observed. Inhibition of p38 with SB203580 in OA-treated cells rescued the expression of type II collagen and suppressed the expression of COX-2. However, ERK inhibition with PD98059 accelerated the OA-induced inflammatory responses. These results suggest that OA induces loss of type II collagen expression via the p38 pathway and induces inflammation through the p38 and ERK pathways in rabbit articular chondrocytes.

Preparation of Pluronic Grafted Dendritic alpha,epsilon-poly(L-lysine)s and Characterization as a Delivery Adjuvant of Antisense Oligonucleotide.

A series of pluronic grafted dendritic alpha,epsilon-poly(L-lysine)s (DPL-PF127) were synthesized by a conjugation reaction and evaluated the potential use of DPL-PF127 as a delivery agent of antisense oligonucleotide into A375 B3 cells. The structural features of the DPL-PF127 were identified by NMR and FT-IR. The number of pluronic F127 on DPL surface, determined by fluorescamine assay, increased proportionally to the mole ratio between DPL and activated PF127 in reaction. DPL- PF127 showed the physical properties of decrease in zetapotential and increase in size as the mole ratio of PF127 to DPL increased. The complex formation of DPL-PF127 with oligonucleotide was confirmed by running capillary zone electrophoresis (CZE) and agarose gel electrophoresis. DPL-PF127, prepared at the mole ratio of 1:10 in reaction, was the most suitable as a delivery adjuvant of oligonucleotide. In addition, DPL-PF127/oligonucleotide complexes were taken into A375B3 cell without cellular toxicity and delivered antisense oligonucleotide into cell.

Cellular mechanisms for trazodone-induced cardiotoxicity.

The second-generation selective 5-HT2 receptor antagonists and reuptake inhibitors (SARIs) class antidepressants are known to have fewer cardiovascular side effects than the older ones. However, several case reports showed that trazodone, one of the second-generation SARIs, induces QT prolongation, cardiac arrhythmia, and ventricular tachycardia. Although these clinical cases suggested trazodone-induced cardiotoxicity, the toxicological actions of trazodone on cardiac action potentials (APs) beyond the human ether-a-go-go related gene (hERG) remain unclear. To elucidate the cellular mechanism for the adverse cardiac effects of trazodone, we investigated its effects on cardiac APs and ion channels using whole-cell patch clamp techniques in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and transiently transfected human embryonic kidney cells (HEK293) with cardiac ion channel complementary DNA. Trazodone dose-dependently decreased the maximum upstroke velocity (Vmax) and prolonged the AP duration, inducing early after depolarizations at 3 and 10 µM that triggered ventricular arrhythmias in hiPSC-CMs. Trazodone also inhibited all of the major ion channels (IKr, IKs, INa, and ICa), with an especially high inhibitory potency on hERG. These data indicate that the prolonged AP duration and decreased Vmax due to trazodone are mainly the result of hERG and sodium ion inhibition, and its inhibitory effects on cardiac ion channels can be exhibited in hiPSC-CMs.

Rubi Fructus (Rubus coreanus) activates the expression of thermogenic genes in vivo and in vitro.

OBJECTIVE: To investigate the anti-obesity effect of Rubi Fructus (RF) extract using brown adipose tissue (BAT) and primary brown preadipocytes in vivo and in vitro. METHODS: Male C57BL/6 J mice (n=5 per group) were fed a high-fat diet (HFD) for 10 weeks with or without RF. Brown preadipocytes from the interscapular BAT of mice (age, post-natal days 1-3) were cultured with differentiation media (DM) including isobutylmethylxanthine, dexamethasone, T3, indomethacin and insulin with or without RF. RESULTS: In HFD-induced obese C57BL/6 J mice, long-term RF treatment significantly reduced weight gain as well as the weights of the white adipose tissue, liver and spleen. Serum levels of total cholesterol and low-density lipoprotein cholesterol were also reduced in the HFD group which received RF treatment. Furthermore, RF induced thermogenic-, adipogenic- and mitochondria-related gene expressions in BAT. In primary brown adipocytes, RF effectively stimulated the expressions of thermogenic- and mitochondria-related genes. In addition, to examine whether LIPIN1, a regulator of adipocyte differentiation, is regulated by RF, Lipin1 small interfering RNA (siRNA) and RF were pretreated in primary brown adipocytes. Pretreatment with Lipin1 siRNA and RF downregulated the DM-induced expression levels of thermogenic- and mitochondria-related genes. Moreover, RF markedly upregulated AMP-activated protein kinase. Our study shows that RF is capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes. CONCLUSIONS: This study demonstrates that RF prevents the development of obesity in mice fed with a HFD and that it is also capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes, which suggests that RF has potential as a therapeutic application for the treatment or prevention of obesity.

Lactoferrin causes IgA and IgG2b isotype switching through betaglycan binding and activation of canonical TGF-ß signaling.

Lactoferrin (LF), a pleiotropic iron-binding glycoprotein, is known to modulate the humoral immune response. However, its exact role in Ig synthesis has yet to be elucidated. In this study, we investigated the effect of LF on Ig production by mouse B cells and its underlying mechanisms. LF, like transforming growth factor (TGF)-ß1, stimulated B cells to produce IgA and IgG2b, while downregulating other isotypes. Using limiting dilution analysis, LF was shown to increase the frequency of IgA-secreting B-cell clones. This was paralleled by an increase in Ig germ-line α (GLα) transcripts, indicating that LF plays a role as an IgA switch factor. Interestingly, LF directly interacted with betaglycan (TGF-ß receptor III, TßRIII) and in turn induced phosphorylation of TßRI and Smad3 through formation of the TßRIII/TßRII/TßRI complex, leading to IgA isotype switching. Peroral administration of LF increased intestinal/serum IgA production as well as number of IgA plasma cells in lamina propria. Finally, we found that LF has an adjuvant activity when nontoxigenic Salmonella typhimurium was inoculated perorally, conferring protection against intragastrical infection of toxigenic S. typhimurium. These results suggest that LF has an important effect on the mucosal/systemic IgA response and can contribute to protection against intestinal pathogens.

Anti-oxidant activity with inhibition of osteoclastogenesis by Atractylodes Rhizoma extract.

BACKGROUND AND OBJECTIVES: Astractylodes Rhizoma is commonly used in Korean folk medicine for digestion, diuresis, sedation, antibacterial agent. The present study was performed to explore the antioxidant capacities of methanolic extract of Astractylodes Rhizoma. In addition, its effect on the expression of inducible nitric oxide synthase (iNOS) in response to lipopolysaccharides (LPS) and osteoclastogenesis in macrophage cells was also tested. MATERIALS AND METHODS: The anti-oxidative activities were tested by measuring free radical scavenging activity (DPPH, NO) and reducing power. The potential mechanism of anti-oxidative action of Astractylodes Rhizoma extract was determined by performing Western blot analysis for iNOS expression in LPS-stimulated RAW 264.7 cells. The RAW cells were induced to osteoclastic cells by RANKL and LPS and the Astractylodes Rhizoma extract was tested to determine whether it inhibits osteoclastogenesis of the cells. RESULTS: The extract exerted significant NO and DPPH radical scavenging activity and it had dramatic reducing power. Induction of iNOS and NO by LPS was significantly inhibited by the extract, suggesting that the Astractylodes Rhizoma extract inhibits nitric oxide (NO) production by suppressing iNOS expression. Strikingly, the Astractylodes Rhizoma extract significantly inhibited the osteclastic differentiation of RAW cells. The Astractylodes Rhizoma extract contains significant amount of anti-oxidant components including phenolics, flavonoids and anthocyanins. CONCLUSIONS: These results suggest that methanolic extract of Astractylodes Rhizoma exerts remarkable anti-oxidant activity potentially via inhibiting free radicals and iNOS induction, those could lead to the inhibition of osteoclastogenesis.

MRI findings in cervical spinal cord type II neurological decompression sickness: a case report.

Decompression illness affecting the cervical spinal cord is uncommon. We report a case that presented with mixed signs and symptoms of cervical myelopathy and Type II neurological decompression sickness. This presented a diagnostic dilemma that required the use of magnetic resonance imaging (MRI) scan to elucidate the underlying cause. Cervical spine MRI revealed the presence of tiny hypointensities and edema within the spinal cord that corresponded to the clinical findings. The patient recovered with residual neurological deficits after hy-perbaric oxygen (HBO2) therapy. To our knowledge, these MRI findings have yet to been described in literature and we recommend the use of MRI to assist diving physicians in the management of complex cases as long as it does not delay recompression.

Construction of novel immune-related signature for prediction of pathological complete response to neoadjuvant chemotherapy in human breast cancer.

BACKGROUND: The aim of this study was to construct a novel prediction model for the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) using immune-related gene expression data. PATIENTS AND METHODS: DNA microarray data were used to perform a gene expression analysis of tumor samples obtained before NAC from 117 primary breast cancer patients. The samples were randomly divided into the training (n = 58) and the internal validation (n = 59) sets that were used to construct the prediction model for pCR. The model was further validated using an external validation set consisting of 901 patients treated with NAC from six public datasets. RESULTS: The training set was used to construct an immune-related 23-gene signature for NAC (IRSN-23) that is capable of classifying the patients as either genomically predicted responders (Gp-R) or non-responders (Gp-NR). IRSN-23 was first validated using an internal validation set, and the results showed that the pCR rate for Gp-R was significantly higher than that obtained for Gp-NR (38 versus 0%, P = 1.04E-04). The model was then tested using an external validation set, and this analysis showed that the pCR rate for Gp-R was also significantly higher (40 versus 11%, P = 4.98E-23). IRSN-23 predicted pCR regardless of the intrinsic subtypes (PAM50) and chemotherapeutic regimens, and a multivariate analysis showed that IRSN-23 was the most important predictor of pCR (odds ratio = 4.6; 95% confidence interval = 2.7-7.7; P = 8.25E-09). CONCLUSION: The novel prediction model (IRSN-23) constructed with immune-related genes can predict pCR independently of the intrinsic subtypes and chemotherapeutic regimens.

Nonsteroidal anti-inflammatory drugs (NSAID) sparing effects of glucosamine hydrochloride through N-glycosylation inhibition; strategy to rescue stomach from NSAID damage.

Gastrointestinal or cardiovascular complications limit nonsteroidal anti-inflammatory drugs (NSAID) prescription. Glucosamine hydrochloride (GS-HCl) alternatively chosen, but debates still exist in its clinical efficiency. COX-2 instability through inhibiting COX-2 N-glycosylation of GS-HCl raised the possibility of NSAID sparing effect. Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect. IEC-6 cells were stimulated with TNF-α and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS-HCl by Western blotting and RT-PCR. C57BL/6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS-HCl after 3 weeks. TNF-α increased the expression of COX-2, iNOS and inflammatory cytokines, but GS-HCl significantly attenuated TNF-α-induced COX-2 expression. Decreased COX-2 after GS-HCl was caused by N-glycosylation inhibition as much as tunicamycin. Combination of reduced dose of indomethacin and GS-HCl significantly reduced the expressions of ICAM-1, VCAM-1, IL-8, IL-1ß, MMP-2, MMP-7, MMP-9, and MMP-11 mRNA as well as NF-κB activation better than high dose indomethacin alone. These NSAID sparing effect of GS-HCl was further proven in collagen-induced arthritis model. Combination of GS-HCl and 2.5 mg/kg indomethacin showed significant protection from gastric damages as well as efficacious anti-arthritic effect. Taken together, COX-2 N-glycosylation inhibition by GS-HCl led to indomethacin sparing effects, based on which combination of GS-HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID-induced gastric damage as well as excellent anti-arthritic effects.

Anti-inflammatory effects and the underlying mechanisms of action of daidzein in murine macrophages stimulated with Prevotella intermedia lipopolysaccharide.

BACKGROUND AND OBJECTIVE: Host modulatory agents directed at inhibiting specific proinflammatory mediators could be beneficial in terms of attenuating periodontal disease progression and potentially enhancing therapeutic responses. The aim of this study was to investigate whether daidzein could modulate the production inflammatory mediators in macrophages stimulated with lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen implicated in periodontal disease, and to delineate underlying mechanisms of action. MATERIAL AND METHODS: LPS was extracted from P. intermedia ATCC 25611 cells by the standard hot phenol-water method. The amounts of nitric oxide (NO) and interleukin-6 (IL-6) secreted into the culture medium were assayed. A real-time PCR was performed to quantify inducible nitric oxide synthase (iNOS) and IL-6 mRNA expression. We used immunoblot analysis to characterize iNOS protein expression, phosphrylation of c-Jun N-terminal kinase (JNK) and p38, degradation of inhibitory κB-α (IκB-α), nuclear translocation of nuclear factor-κB (NF-κB) subunits and phosphorylation of signal transducer and activator of transcription 1 (STAT1). The DNA-binding activity of NF-κB was assessed by using ELISA-based kits. RESULTS: Daidzein significantly inhibited the production of NO and IL-6, as well as their mRNA expression, in P. intermedia LPS-treated RAW264.7 cells. The JNK and p38 pathways were not involved in the regulation of LPS-induced NO and IL-6 release by daidzein. Daidzein inhibited the degradation of IκB-α induced by P. intermedia LPS. In addition, daidzein suppressed NF-κB transcriptional activity via regulation of the nuclear translocation and DNA-binding activity of NF-κB p50 subunit and blocked STAT1 phosphorylation. CONCLUSION: Although additional studies are required to dissect the molecular mechanism of action, our results suggest that daidzein could be a promising agent for treating inflammatory periodontal disease. Further research in animal models of periodontitis is necessary to better evaluate the potential of daidzein as a novel therapeutic agent to treat periodontal disease.

Effects of Asparagus officinalis extracts on liver cell toxicity and ethanol metabolism.

Asparagus officinalis is a vegetable that is widely consumed worldwide and has also long been used as a herbal medicine for the treatment of several diseases. Although A. officinalis is generally regarded as a supplement for the alleviation of alcohol hangover, little is known about its effects on cell metabolism. Therefore, this study was conducted to analyze the constituents of the young shoots and the leaves of asparagus and to compare their biochemical properties. The amino acid and inorganic mineral contents were found to be much higher in the leaves than the shoots. In addition, treatment of HepG2 human hepatoma cells with the leaf extract suppressed more than 70% of the intensity of hydrogen peroxide (1 mM)-stimulated DCF fluorescence, a marker of reactive oxygen species (ROS). Cellular toxicities induced by treatment with hydrogen peroxide, ethanol, or tetrachloride carbon (CCl(4)) were also significantly alleviated in response to treatment with the extracts of A. officinalis leaves and shoots. Additionally, the activities of 2 key enzymes that metabolize ethanol, alcohol dehydrogenase and aldehyde dehydrogenase, were upregulated by more than 2-fold in response to treatment with the leaf- and shoot extracts. Taken together, these results provide biochemical evidence of the method by which A. officinalis exerts its biological functions, including the alleviation of alcohol hangover and the protection of liver cells against toxic insults. Moreover, the results of this study indicate that portions of asparagus that are typically discarded, such as the leaves, have therapeutic use.

Efficacy and pharmacokinetics of intravitreal non-steroidal anti-inflammatory drugs for intraocular inflammation.

OBJECTIVE: To determine the efficacy and pharmacokinetics of intraocularly delivered non-steroidal anti-inflammatory drugs in an animal model of ocular inflammation. METHODS: Lipopolysaccharide was injected into the vitreous of rabbit eyes to induce inflammation. Treated eyes were injected with 3 mg of ketorolac or 0.3 mg of diclofenac. Twenty-four hours later, total leucocyte concentrations and prostaglandin E2 concentrations were determined. For intraocular pharmacokinetics, 0.1 ml of ketorolac (3 mg) and 0.1 ml of diclofenac (0.3 mg) were injected into rabbit eyes. Reverse-phase high-performance liquid chromatography was used to analyse drug levels within the retina/choroid at 0.25 (15 min), 1, 2, 4, 24, and 48 h after injection. RESULTS: Eyes treated with ketorolac and diclofenac demonstrated reduced aqueous leucocyte concentrations of 62% and 64% respectively, compared with untreated controls (p<0.05). Ketorolac and diclofenac reduced aqueous prostaglandin E2 levels by 85% (p<0.005) and 59% (p<0.005), respectively. Ketorolac and diclofenac achieved a peak vitreous concentration of 234 and 73 microg/ml, respectively. After 48 h, ketorolac was barely detectable (0.06 microg/ml) in the vitreous, and diclofenac was undetectable. The peak concentration of each drug in the retina/choroid was 201 microg/g for ketorolac and 4.1 microg/g for diclofenac. Both drugs were undetectable in the retina/choroid after 48 h. CONCLUSIONS: Both ketorolac and diclofenac have potent anti-inflammatory effects after intraocular injection. Pharmacokinetic analysis demonstrated good penetration into the retina/choroid but rapid clearance by 48 h.

Neuroprotective effect of transpupillary thermotherapy in the optic nerve crush model of the rat.

PURPOSE: Transpupillary thermotherapy (TTT) has been shown to induce heat shock protein (Hsp) 72 in optic nerve head tissue. The neuroprotective effect of TTT was investigated in an optic nerve crush rat model. METHODS: TTT was performed onto the optic nerve head in the right eye of subject rats. After 24 h, an optic nerve crush injury using an aneurysm clip was performed at 2 mm from the optic nerve head for 60 s. At 7 and 14 days later, retrograde labelling of retinal ganglion cells (RGCs) with DTMR crystal was carried out and the density of the surviving RGCs was evaluated. Immunohistochemical staining was performed to confirm the expression of Hsp72. RESULTS: At 7 days after optic nerve crush injury, the mean density of surviving RGCs was higher in TTT group (372.7+/-149.8 per mm(2)) than in optic nerve crush group (252.9+/-96.7 per mm(2)) with borderline significance. In the retinal areas at 1 mm from the optic nerve head, a significant increase in surviving RGCs from TTT treated eyes was observed at both 7 and 14 days after optic nerve crush injury. However, no significant differences in surviving RGCs were demonstrated 2 and 3 mm from the optic nerve head. CONCLUSIONS: These results demonstrate that TTT aimed onto the optic nerve head showed a neuroprotective effect.

Gray matter deficits in young adults with narcolepsy.

OBJECTIVES: The aim of this study was to investigate gray matter volume changes in narcolepsy. MATERIALS AND METHODS: An optimized voxel-based morphometry was conducted for 17 young adults with a sole diagnosis of human leukocyte antigen DQB(1) 0602 positive narcolepsy with cataplexy (26.6 +/- 5.2 years old) and 17 comparison subjects (24.6 +/- 4.9 years old) using 3 Tesla scanner. Gray matter volumes in the bilateral hypothalamic voxel of interests (VOI) were also calculated. RESULTS: Compared with the comparison subjects, narcoleptic patients had gray matter volume decrease in the right hypothalamus and other regions including subcortical, prefrontal, limbic and occipital areas. Narcoleptic patients also had lower gray matter volume on predefined VOI at the bilateral hypothalamus, which correlated with the Ullanlinna Narcolepsy Scale score. CONCLUSIONS: Current findings suggest that narcoleptic patients have structural abnormalities in hypothalamus, which might be related to the clinical manifestation of narcolepsy with cataplexy.

Decreased cerebral blood flow of thalamus in PTSD patients as a strategy to reduce re-experience symptoms.

OBJECTIVE: To investigate alterations of regional cerebral blood flow (rCBF) in subjects with post-traumatic stress disorder (PTSD). METHOD: Using [99Tcm]-hexamethyl propylenamino oxime single photon emission computed tomography, the rCBF under resting condition was compared between 19 survivors of the Taegu subway fire with PTSD and 19 comparison subjects. RESULTS: PTSD patients showed a decreased rCBF in the right thalamus and an increased rCBF in the right superior parietal lobe relative to comparison subjects (corrected P < 0.05). The rCBF in the right thalamus positively correlated with the severity of current re-experience symptoms in PTSD subjects. CONCLUSION: Our finding of the thalamic rCBF decrease in PTSD patients may be a strategy to reduce re-experience symptom, by evading the process of external and internal information which can evoke traumatic memory. In addition, the parietal rCBF increase in our PTSD patients might be related to altered information processing in PTSD.

Acute oral toxicity study of Asiasari radix extract in mice.

Acute oral toxicity of methanol extract of Asiasari radix was evaluated in ICR mice of both sexes. In this study, mice were administrated orally with dosages of 1000, 3000, and 5000 mg/kg body weight of Asiasari radix extract. Mortality, signs of toxicity, body weight, food consumption, and gross findings were observed for 14 days post treatment of Asiasari radix extract. No mortality, signs of toxicity, and abnormalities in gross findings were observed. In addition, no significant differences were noticed in the body and organ weights between the control and treated groups of both sexes. These results show that the methanol extract of Asiasari radix is toxicologically safe by oral administration.

Taurine-diabetes interaction: from involvement to protection.

Taurine is a sulfur amino acid (2-amino ethane sulfonic acid) and has been claimed for a number of beneficial actions ranging from anti-epilepsy to anti-hypertension. Taurine in diabetes has an age old story; taurine is involved in the development and protection of insulin apparatus. Taurine and insulin both have mutual stimulating actions with hypoglycemic properties. On the clinical front, taurine supplementation has an acceptable beneficial effect in platelet aggregation and, to name few more, in neuropathy, cardiomyopathy, and nephropathy to retinopathy. Recent studies have provided a role for taurine in fetal development and in blocking the transfer of diabetes from diabetic mother to offspring. A number of mechanisms for the actions of taurine have been advocated, from osmoregulation to anti-oxidation. Though sulfonylurea and recently introduced thiazolidinediones are effective, however they are not free from complications, thus there is a need to design new therapeutics. As taurine is also a sulfonyl derivative, it will be of great interest to develop taurine analogues as an alternative therapy. Considering the great involvement of taurine in diabetes, this review may provide a holistic view of taurine in diabetes and in its prevention in this century.

Stimulating effect of Japanese herbal (kampo) medicine, hochuekkito on upper respiratory mucosal immune system.

Japanese herbal (Kampo) medicine, Hochuekkito (Bu-Zhong-Yi-Qi-Tang in Chinese, TJ-41) and Juzentaihoto (Shi-Quan-Da-Bu-Tang in Chinese, TJ-48) are well-known Kampo formulas used as tonic. Although these medicines have separately been applied to the patients clinically depending on their symptoms, the differences of the pharmacological activities for these medicines have not been fully understood. TJ-48 and TJ-41 were compared for their effects on antibody response in upper respiratory mucosal immune system in vivo. Oral administration of TJ-41 (100 mg kg(-1) per day) to early aged BALB/c mice, which were nasally sensitized with influenza hemagglutinin vaccine, significantly enhanced influenza virus-specific IgA and IgG antibody titers in nasal cavity and sera, respectively. However, oral administration of TJ-48 (100 mg kg(-1) per day) failed to show the enhancing activity. TJ-41 increased not only influenza virus-specific IgA antibody titer but also total IgA antibody titer in nasal cavity. The stimulating activity of TJ-41 disappeared after treatment with methotrexate. The present study strongly suggests that TJ-41 can stimulate the mucosal immune system of upper respiratory tract, and results in enhancement of antigen-specific antibody response in upper respiratory mucosal and systemic immune systems.