Influence of clozapine on neurodevelopmental protein expression and behavioral patterns in animal model of psychiatric disorder induced by low-level of lead.

Exposure to lead during pregnancy is a risk factor for the development of psychiatric disorders in the offspring. In this study, we investigated whether exposure to low levels of lead acetate (0.2%) in drinking water during pregnancy and lactation causes behavioral impairment and affects the expression of proteins associated with neurodevelopment. Lead exposure altered several parameters in rat offspring compared with those unexposed in open-field, social interaction, and pre-pulse inhibition tests. These parameters were restored to normal levels after clozapine treatment. Western blot and immunohistochemical analyses of the hippocampus revealed that several neurodevelopmental proteins were downregulated in lead-exposed rats. The expression was normalized after clozapine treatment (5 mg/kg/day, postnatal day 35-56). These findings demonstrate that downregulation of several proteins in lead-exposed rats affected subsequent behavioral changes. Our results suggest that lead exposure in early life may induce psychiatric disorders and treatment with antipsychotics such as clozapine may reduce their incidence.

Effects of tianeptine on symptoms of fibromyalgia via BDNF signaling in a fibromyalgia animal model.

Previous reports have suggested that physical and psychological stresses may trigger fibromyalgia (FM). Stress is an important risk factor in the development of depression and memory impairments. Antidepressants have been used to prevent stress-induced abnormal pain sensation. Among various antidepressants, tianeptine has been reported to be able to prevent neurodegeneration due to chronic stress and reverse decreases in hippocampal volume. To assess the possible effect of tianeptine on FM symptoms, we constructed a FM animal model induced by restraint stress with intermittent cold stress. All mice underwent nociceptive assays using electronic von Frey anesthesiometer and Hargreaves equipment. To assess the relationship between tianeptine and expression levels of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and phosphorylated cAMP response element-binding protein (p-CREB), western blotting and immunohistochemistry analyses were performed. In behavioral analysis, nociception tests showed that pain threshold was significantly decreased in the FM group compared to that in the control group. Western blot and immunohistochemical analyses of medial prefrontal cortex (mPFC) and hippocampus showed downregulation of BDNF and p-CREB proteins in the FM group compared to the control group. However, tianeptine recovered these changes in behavioral tests and protein level. Therefore, this FM animal model might be useful for investigating mechanisms linking BDNF-CREB pathway and pain. Our results suggest that tianeptine might potentially have therapeutic efficacy for FM.

Frequency-tunable metamaterial absorber using a varactor-loaded fishnet-like resonator.

A frequency-tunable metamaterial absorber is designed with the unit cell consisting of a varactor-loaded fishnet-like resonator. This geometry allows all cathode and anode pads of the unit cells to be connected to their counterparts. Hence, only the ends of the periodic structure need to be biased, reducing the complexity of the bias network. The absorber was modeled using a full-wave simulation tool and verified experimentally with a 20×20 unit-cell prototype. Using free-space measurements, the absorber shows >90% absorption ratio from 3.96 to 5.29 GHz with a frequency tuning ratio of 28.7%, when the reverse voltage varied from 0 to 19 V.

A Fluidically Tunable Metasurface Absorber for Flexible Large-Scale Wireless Ethanol Sensor Applications.

In this paper, a novel flexible tunable metasurface absorber is proposed for large-scale remote ethanol sensor applications. The proposed metasurface absorber consists of periodic split-ring-cross resonators (SRCRs) and microfluidic channels. The SRCR patterns are inkjet-printed on paper using silver nanoparticle inks. The microfluidic channels are laser-etched on polydimethylsiloxane (PDMS) material. The proposed absorber can detect changes in the effective permittivity for different liquids. Therefore, the absorber can be used for a remote chemical sensor by detecting changes in the resonant frequencies. The performance of the proposed absorber is demonstrated with full-wave simulation and measurement results. The experimental results show the resonant frequency increases from 8.9 GHz to 10.04 GHz when the concentration of ethanol is changed from 0% to 100%. In addition, the proposed absorber shows linear frequency shift from 20% to 80% of the different concentrations of ethanol.

Toxicokinetics of paraquat in Korean patients with acute poisoning.

To conduct a kinetic study of paraquat (PQ), we investigated 9 patients with acute PQ intoxication. All of them ingested more than 20 ml of undiluted PQ herbicide to commit suicide and arrived at our hospital early, not later than 7 h after PQ ingestion. The urine dithionite test for PQ in all of the nine patients was strongly positive at emergency room. Blood samples were obtained every 30 min for the first 2~3 h and then every 1 or 2 h, as long as the clinical progression was stable among the patients for 30 h after PQ ingestion. The area under the plasma concentration-time curve (AUCinf), which was extrapolated to infinity, was calculated using the trapezoidal rule. Toxicokinetic parameters, such as the terminal elimination half-life, apparent oral clearance, and apparent volume of distribution (Vd/F) were calculated. The maximum PQ concentration (Cmax) and the time to reach maximum PQ concentration (Tmax) were also obtained. Plasma PQ concentrations in nine patients were well described by a bi-exponential curve with a mean terminal elimination half-life of 13.1±6.8 h. Cmax and AUCinf were 20.8±25.7 mg/l and 172.5±160.3 h·mg/l, respectively. Apparent volume of distribution and apparent oral clearance were 50.9±61.3 l/kg and 173.4±111.2 l/h, respectively. There were a significant correlation (r =0.84; p<0.05) between the PQ amount ingested and Cmax. AUCinf also showed a significant correlation (r =0.83; p<0.05) with the PQ amount ingested. These correlations provide evidence that PQ has dose-linear toxicokinetic characteristics.

Flexible inkjet-printed metamaterial absorber for coating a cylindrical object.

In this paper, a novel flexible inkjet-printed metamaterial absorber is proposed. The unit cell of the metamaterial is designed with a modified Jerusalem-cross ring resonator and is inkjet printed with silver nanoparticle ink on a flexible polymer film. All fabrication processes are performed using a commercial printer (EPSON WF-7011). The absorber's flexibility and absorption performance are demonstrated by measuring the absorption ratio after coating the proposed absorber on a cylindrical object with a radius of 4.56 cm. An absorption rate exceeding 99% is achieved at 9.21 GHz for both flat and cylindrical surfaces. In addition, the cylindrical model attains an absorption rate higher than 96% for all polarization angles, and a high absorption rate of 95% is preserved until the incident angle is less than 30þ.

Frequency-Switchable Metamaterial Absorber Injecting Eutectic Gallium-Indium (EGaIn) Liquid Metal Alloy.

In this study, we demonstrated a new class of frequency-switchable metamaterial absorber in the X-band. Eutectic gallium-indium (EGaIn), a liquid metal alloy, was injected in a microfluidic channel engraved on polymethyl methacrylate (PMMA) to achieve frequency switching. Numerical simulation and experimental results are presented for two cases: when the microfluidic channels are empty, and when they are filled with liquid metal. To evaluate the performance of the fabricated absorber prototype, it is tested with a rectangular waveguide. The resonant frequency was successfully switched from 10.96 GHz to 10.61 GHz after injecting liquid metal while maintaining absorptivity higher than 98%.

Cystatin C is a good predictor of hepatorenal syndrome and survival in patients with cirrhosis who have normal serum creatinine levels.

BACKGROUND/AIMS: We evaluated the usefulness of cystatin C as a prognostic marker in patients with liver cirrhosis and normal serum creatinine. METHODOLOGY: We retrospectively analyzed prospectively enrolled patients with liver cirrhosis and normal serum creatinine from February 2007 to March 2008. We checked liver function and kidney variables including serum creatinine, cystatin C and glomerular filtration rate from 51Cr-EDTA on the same day for all patients. The endpoints of the study were either development of hepatorenal syndrome or mortality. RESULTS: In total, 112 patients with liver cirrhosis were enrolled in the study (87 men and 25 women, age 52 ± 12 years). Twelve (11%), 59 (53%) and 41 (36%) patients were in Child-Pugh class A, B and C, respectively. Cystatin C was better correlated with glomerular filtration rate from 51Cr-EDTA than creatinine. The 1-year cumulative incidence of hepatorenal syndrome and the 1-year survival rate of patients were 20.5% and 79.5%, respectively. Cystatin C, Model for End-Stage Liver Disease and serum sodium were the independent predictive factors for hepatorenal syndrome. Cystatin C, serum sodium and prothrombin time were the independent factors for predicting survival. CONCLUSIONS: In patients with liver cirrhosis and normal creatinine levels, cystatin C is a useful marker for predicting hepatorenal syndrome and survival.

Melatonin and melatonergic drugs in sleep disorders.

Melatonin is an endogenous chronobiological regulator secreted mainly from the pineal gland, which has been used as a dietary supplement in the treatment of sleep problems, including insomnia, parasomnia, and circadian rhythm sleep disorders. However, the short half-life and rapid metabolism of melatonin limit its suitability as a drug. There are many melatonergic drugs used in the treatment of sleep disorders and several drugs are under investigation for approval. Ramelteon was the first melatonergic agonist approved as hypnotic agent by U.S. Food and Drug Administration for the treatment of insomnia. It exhibits higher selective affinity for melatonin 1a (MT1) receptor than melatonin 1b (MT2) receptor. This selectivity suggests that it targets sleep onset with no significant adverse effect or dependency. Agomelatin, naphtahalenic compound, act as a potent MT1/MT2 melatonergic receptor agonist and serotonergic receptor antagonist was approved for treatment of depression in 2009. This dual action drug is the first melatonergic agent used in depression. Another melatonergic agonist, tasimelteon has high affinity for the MT1/MT2 receptors in humans. It was approved for the treatment of non-24 hours sleep-wake rhythm disorder. The newly developed melatonin and melatonergic drugs have the potential to be used extensively in various clinical situations and substitute the old benzodiazepine and its derivatives in the treatment of insomnia. However, the efficacy and safety of newly developed melatonergic drugs should be elucidated through long-term clinical trials.

Outcome of palliative self-expanding metal stent placement in malignant colorectal obstruction according to stent type and manufacturer.

BACKGROUND: Self-expandable metallic stents (SEMS) of varying designs and materials have been developed to reduce complications, but few comparative data are available with regard to the type of stent and the stent manufacturer. We analyzed the success rates and complication rates, according to stent type (uncovered vs. covered stent) and individual stent manufacturer, in malignant colorectal obstruction. METHODS: From November 2001 to August 2008, 103 patients were retrospectively included in this study: four types of uncovered stents in 73 patients and two types of covered stents in 30 patients. The SEMS was inserted into the obstructive site by using the through-the-scope method. RESULTS: Technical and clinical success rates were not different between stent type or among stent manufacturers: 100 and 100% (p = ns) and 100 and 96.6% (p > 0.05), respectively, in uncovered and covered stents. Stent occlusion and migration rates were 12.3 and 3.3% (p = 0.274) and 13.7 and 16.7% (p = 0.761), respectively, in uncovered and covered stents, and 11.1, 5, and 9% (p = 0.761) and 25.9, 15, and 0% (p = 0.037) in Wallstent, Niti-S, and Bonastent uncovered stents, respectively. CONCLUSIONS: The placement of SEMS is an effective and safe treatment for patients with malignant colorectal obstruction. Although minor differences in outcome were detected according to the type and the manufacturer of the stents, no statistically significant difference was observed, except in stent migration among the stent manufacturer.

[A case of locally invasive obstructive jejunal cancer with curative resection after stenting and chemotherapy].

Small bowel adenocarcinoma is a relatively rare malignancy. In Korea, 13.1% of small bowel adenocarcinoma occurs in the jejunum. The absence of effective screening methods and relatively obscure symptoms contribute to the higher percentage of advanced cases at the time of diagnosis. Although curative resection is the mainstay of treatment, it is often impossible. Chemotherapy and radiotherapy have shown a disappointing treatment result for advanced staged small bowel adenocarcinoma. We report a 54-year-old woman with locally invasive jejunal cancer who underwent curative resection after stent insertion with enteroscopy and chemotherapy.

Antiwrinkle effect of adipose-derived stem cell: activation of dermal fibroblast by secretory factors.

BACKGROUND: Adipose-derived stem cells (ADSC) have wound-healing and antioxidant effects on human skin via secretion of growth factors and activation of dermal fibroblasts. OBJECTIVE: Paracrine mechanism reducing ultraviolet-B (UVB)-induced wrinkles by ADSC is investigated in this study. METHODS AND RESULTS: Wrinkles were induced by an eight-week UVB irradiation, and were significantly improved by the subcutaneous injection of ADSC in hairless mice. In a replica analysis, parameters involving wrinkles were improved with mid-level and high doses of ADSC (1x10(4) and 1x10(5) cells). Dermal thickness and collagen contents in the dermis also were increased in the ADSC-injected groups. To characterize the paracrine mechanism involving the antiwrinkle effect of ADSC, a conditioned medium of ADSC (ADSC-CM) was directly incubated in human dermal fibroblasts (HDF). UVB irradiation reduced the proliferation of HDF, but this was reversed by the pretreatment of ADSC-CM in a dose-dependent manner. In a cell cycle analysis, ADSC-CM decreased the UVB-induced apoptotic cell death, which was demonstrated by the reduced sub-G1 phase of HDF. In addition, the ADSC-CM increased the protein expression of collagen type I and decreased the protein level of matrix metalloproteinase 1 in HDF, which may account for the increased collagen contents in the dermis. CONCLUSIONS: Collectively, these results indicate that the ADSC and its secretory factors are effective for UVB-induced wrinkles, and the antiwrinkle effect is mainly mediated by reducing UVB-induced apoptosis and stimulating collagen synthesis of HDF.

Evidence supporting antioxidant action of adipose-derived stem cells: protection of human dermal fibroblasts from oxidative stress.

BACKGROUND: Mesenchymal stem cells within the stromal-vascular fraction of subcutaneous adipose tissue, adipose-derived stem cells (ADSCs), produced soluble factors and they exhibit diverse pharmacological effects in skin biology. OBJECTIVE: The present study examines the protective effect of ADSCs for human dermal fibroblasts (HDFs) through anti-oxidation in a tert-butyl hydroperoxide (tbOOH) induced oxidative injury model. METHODS AND RESULTS: The conditioned medium of ADSCs (ADSC-CM) was harvested and tested for antioxidant action. ADSC-CM had an antioxidant effect as potent as 100 microM ascorbic acid and various antioxidant proteins were detected in ADSC-CM by proteomic analysis. Morphological change and cell survival assay revealed that incubation with ADSC-CM aided HDFs to resist free radicals induced by tbOOH. In addition, activities of superoxide dismutase and glutathione peroxidase were enhanced in the ADSC-CM treated HDFs which confirmed the study hypothesis that ADSCs protect HDFs through antioxidant action. In a cell cycle analysis, ADSC-CM treatment reversed the apoptotic cell death induced by tbOOH and caused a decrease of sub-G1 cells with respect to untreated cells. The anti-apoptotic effect of ADSC-CM was also reproduced by caspase-3 activity assay. CONCLUSION: These results suggest that ADSCs have potent antioxidant activity and protect HDFs from oxidative injury by decreasing apoptotic cells. Therefore, ADSCs and ADSC-CM are good candidates for control and prevention of skin damage from free radicals in various skin conditions.

A Novel Secretory Vesicle from Deer Antlerogenic Mesenchymal Stem Cell-Conditioned Media (DaMSC-CM) Promotes Tissue Regeneration.

Multipotent stem cells have the capacity to generate terminally differentiated cell types of each lineage; thus, they have great therapeutic potential for a wide variety of diseases. The most widely available stem cells are derived from human tissues, and their use for therapeutic application is limited by their high cost and low productivity. Herein, we report that conditioned media of mesenchymal stem cells (MSCs) isolated from deer antlers enhanced tissue regeneration through paracrine action via a combination of secreted growth factors and cytokines. Notably, DaMSC-conditioned media (DaMSC-CM) enhanced hair regeneration by activating the Wnt signaling pathway. In addition, DaMSC-CM had regenerative potential in damaged skin tissue through induction of skin regeneration-related genes. Remarkably, we identified round vesicles derived from DaMSC-CM, with an average diameter of ~120 nm that were associated with hair follicle formation, suggesting that secretory vesicles may act as paracrine mediators for modulation of local cellular responses. In addition, these secretory vesicles could regulate the expression of Wnt-3a, Wnt-10b, and lymphoid enhancer-binding factor-1 (LEF-1), which are related to tissue renewal. Thus, our findings demonstrate that the use of DaMSC-CM as a unique natural model for rapid and complete tissue regeneration has possible application for therapeutic development.

Effects of Panax ginseng C.A. Meyer extract on the offspring of adult mice with maternal immune activation.

To understand maternal immune activation (MIA) during prenatal development, the synthetic double­stranded RNA polyriboinosinic­polyribocytidylic acid [poly(I:C)] has been widely used in animal models to induce behavioral deficits similar to those in schizophrenia and other psychotic disorders. Panax ginseng C.A. Meyer (PG) extract is widely used to treat various kinds of nervous system disorders in Asia particularly China and Korea. The present study aimed to examine the effects of PG extract on MIA offspring using behavioral activity tests and protein expression analyses. Pregnant mice were exposed to poly(I:C) (5 mg/kg) or vehicle treatment on gestation day 9, and the resulting MIA offspring were subjected to vehicle or PG (300 mg/kg) treatment. In the acoustic startle response test, MIA­induced sensorimotor gating deficit was ameliorated by PG. The majority of behavioral parameters measured in the social interaction (non­aggressive or/and aggressive pattern), open field (number/duration of behavior) and forced swimming test (immobility behavior) were significantly altered in the MIA offspring. Western blot and immunohistochemical analyses of the medial prefrontal cortex indicated that the expression levels of certain neurodevelopmental proteins, including dihydropyrimidinase­related 2, LIM and SH3 domain 1, neurofilament medium, and discs large homolog 4, were decreased in the untreated MIA offspring, whereas PG treatment improved behavioral impairments and increased neurodevelopmental protein expression in MIA offspring. These results suggested that PG may be useful in neurodevelopmental disorder therapy, including psychiatric disorders such as schizophrenia, owing to its antipsychotic effects.

Antinociceptive effect of Valeriana fauriei regulates BDNF signaling in an animal model of fibromyalgia.

The genus Valeriana has been widely used in popular medicine for centuries, to treat sleep disorders, anxiety, epilepsy and insomnia. Recent studies have focused on the novel pharmacological effects of Valeriana fauriei Briq. (VF) species. Previous studies have attempted to determine the pharmacological functions of Valeriana in various human diseases, particularly with regards to its neuroprotective effects, and its ability to reduce pain and stress. The present study constructed an animal model of fibromyalgia (FM), which was induced by intermittent cold stress with slight modification. Subsequently, the study aimed to determine whether VF exerts antinociceptive effects on the FM­like model following oral administration of VF extracts. The effects of VF extracts on the FM model were investigated by analyzing behavioral activity, including pain, and detecting protein expression. In the behavioral analysis, the results of a nociception assay indicated that the pain threshold was significantly decreased in the FM group. Subsequently, western blotting and immunohistochemical analyses of the hippocampus demonstrated that the protein expression levels of brain­derived neurotrophic factor (BDNF) and phosphorylated­cAMP response element­binding protein were downregulated in the FM group. Conversely, VF restored these levels. These results suggested that the effects of VF extract on a model of FM may be associated with its modulatory effects on the BDNF signaling pathway in the hippocampus and medial prefrontal cortex. In conclusion, the mechanism underlying the protective effects of VF as a therapeutic agent against FM may involve the BDNF signaling pathway.

Effects of Tianeptine on Adult Rats Following Prenatal Stress.

OBJECTIVE: Exposing a pregnant female to stress during the critical period of embryonic fetal brain development increases the risk of psychiatric disorders in the offspring. The objective of this study was to investigate the effect of antidepressant tianeptine on prenatally stressed (PNS) rats. METHODS: In this study, a repeated variable stress paradigm was applied to pregnant rats during the last week of gestation. To investigate the effects of antidepressant tianeptine on PNS rats, behavioral and protein expression analyses were performed. Forced swim test, open field test, and social interaction test were performed to determine changes in PNS rats compared to non-stressed offspring. Haloperidol was used as a positive control as an antipsychotic drug based on previous studies. RESULTS: Behavioral changes were restored after treatment with tianeptine or haloperidol. Western blot and immunohistochemical analyses of the prefrontal cortex revealed downregulation of several neurodevelopmental proteins in PNS rats. After treatment with tianeptine or haloperidol, their expression levels were increased. CONCLUSION: Downregulation of several proteins in PNS rats might have caused subsequent behavioral changes in PNS rats. After tianeptine or haloperidol treatment, behavioral changes in PNS rats were restored. Therefore, tianeptine might decrease incidence of prenatal stress related-psychiatric disorders such as depression and schizophrenia.

BBOX1 is down-regulated in maternal immune-activated mice and implicated in genetic susceptibility to human schizophrenia.

Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorders such as bipolar disorder, autism, and schizophrenia in later life. Gamma-butyrobetaine hydroxylase (BBOX 1) is an enzyme responsible for the biosynthesis of l-carnitine, a key molecule in fatty acid metabolism. This cytosolic dimeric protein belongs to the dioxygenase family. In this study, we investigated whether BBOX 1 expression was related to psychiatric disorder in an animal model. We also conducted a case-control study using 284 schizophrenia patients and 409 controls with single-nucleotide polymorphisms (SNPs) in the 5'-near region of BBOX 1. BBOX 1 expression was increased in the medial frontal cortex of a mouse model of schizophrenia induced by maternal immune activation. Furthermore, the genotype and allele frequencies of two SNPs (rs7939644 and rs10767592) were significantly associated with schizophrenia susceptibility. Our results suggest that BBOX 1 might be associated with maternal immune activation and schizophrenia susceptibility. Therefore, it might be involved in the pathophysiology of schizophrenia.

Association between endothelin­1 and fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is characterized by widespread chronic musculoskeletal pain, stiffness and pressure hyperalgesia at soft tissue tender points. Patients with FMS may exhibit a tendency towards cold extremities and cold­induced vasospasm. Endothelin­1 (EDN1) is a potent vasoconstrictor that is mainly produced by endothelial cells. The present study aimed to determine whether plasma expression levels avvnd single­nucleotide polymorphism (SNP; rs1800541) of the EDN1 gene were associated with FMS and/or any of its clinical variables. Plasma EDN1 levels were assessed by ELISA, and SNP genotypes were determined using polymerase chain reaction­high­resolution melting curve analysis. Patients with the TG genotype and the G allele may have an elevated risk of FMS. In addition, patients with FMS with the TG genotype and/or T allele exhibited higher plasma EDN1 levels compared with healthy controls. EDN1 levels increased significantly in patients with FMS compared with normal controls. In addition, EDN1 SNP was found to be associated with susceptibility to FMS.

PER2 is downregulated by the LPS-induced inflammatory response in synoviocytes in rheumatoid arthritis and is implicated in disease susceptibility.

The clinical symptoms of rheumatoid arthritis (RA) present with circadian variation, with joint stiffness and pain more prominent in the early morning. The mammalian clock genes, which include circadian locomotor output cycles kaput, brain and muscle Arnt-like protein 1, period and cryptochrome, regulate circadian rhythms. In order to identify the association between genetic polymorphisms in the circadian clock gene period 2 (PER2) and RA, the present study genotyped three PER2 single nucleotide polymorphisms (SNPs), rs934945, rs6754875, and rs2304674, using genetic information from 256 RA patients and 499 control subjects. Primary cultured rheumatoid synovial cells were stimulated with 10 µM lipopolysaccharide (LPS). Total protein was then extracted from the synovial cells following 12 and 24 h, and PER2 protein expression was assayed by immunoblotting. The rs2304674 SNP demonstrated a significant association with susceptibility to RA following Bonferroni correction. However, statistical analysis indicated that the SNPs were not associated with any clinical features of patients with RA. Immunoblotting analysis demonstrated that PER2 protein expression was decreased by LPS­induced inflammation in RA synovial cells; however, this was not observed in normal synovial cells. The results suggest that the PER2 gene may be a risk factor for RA, and expression of the PER2 protein may be affected by inflammation. Therefore, PER2 may contribute to the pathogenesis of RA.