Validity of Incident Opioid Use Disorder (OUD) Diagnoses in Administrative Data: a Chart Verification Study.

BACKGROUND: An important strategy to address the opioid overdose epidemic involves identifying people at elevated risk of overdose, particularly those with opioid use disorder (OUD). However, it is unclear to what degree OUD diagnoses in administrative data are inaccurate. OBJECTIVE: To estimate the prevalence of inaccurate diagnoses of OUD among patients with incident OUD diagnoses. SUBJECTS: A random sample of 90 patients with incident OUD diagnoses associated with an index in-person encounter between October 1, 2016, and June 1, 2018, in three Veterans Health Administration medical centers. DESIGN: Direct chart review of all encounter notes, referrals, prescriptions, and laboratory values within a 120-day window before and after the index encounter. Using all available chart data, we determined whether the diagnosis of OUD was likely accurate, likely inaccurate, or of indeterminate accuracy. We then performed a bivariate analysis to assess demographic or clinical characteristics associated with likely inaccurate diagnoses. KEY RESULTS: We identified 1337 veterans with incident OUD diagnoses. In the chart verification subsample, we assessed 26 (29%) OUD diagnoses as likely inaccurate; 20 due to systems error and 6 due to clinical error; additionally, 8 had insufficient information to determine accuracy. Veterans with likely inaccurate diagnoses were more likely to be younger and prescribed opioids for pain. Clinical settings associated with likely inaccurate diagnoses were non-mental health clinical settings, group visits, and non-patient care settings. CONCLUSIONS: Our study identified significant levels of likely inaccurate OUD diagnoses among veterans with incident OUD diagnoses. The majority of these cases reflected readily addressable systems errors. The smaller proportion due to clinical errors and those with insufficient documentation may be addressed by increased training for clinicians. If these inaccuracies are prevalent throughout the VHA, they could complicate health services research and health systems responses.

Nursing Insights on Delirium in the Intensive Care Unit: A Quality Improvement Study.

Delirium is a common complication of critical illness. As frontline providers, nurses (registered nurses) are uniquely positioned to inform interventions to improve intensive care unit (ICU) patient outcomes. This article reports a study of attitudes and knowledge about ICU delirium assessment at an urban academic medical center. Findings suggest a knowledge deficit regarding the spectrum of delirium. ICU nurses also identified that a lack of effective collaboration within the treatment team was the biggest barrier to effective care for the patient with hypoactive delirium. The study findings indicate that both educational and management initiatives are needed to improve clinical practices for patients with manifestations of hypoactive and hyperactive delirium.

Comparison of COVID-19 Pandemic-Related Stress among Frontline Medical Personnel in Daegu City, Korea.

Background and Objectives: Frontline medical staff usually experience high levels of stress, which could greatly impact their work output. We conducted a survey to investigate the level of stress and its association with job types, work departments, and medical centers among COVID-19 pandemic frontline medical personnel. Materials and Methods: We conducted a cross-sectional survey using a self-administered questionnaire among 307 frontline medical staff who cared for COVID-19 patients in Daegu city. We used a 33-item questionnaire to assess respondents' general characteristics, job stress, personal effects associated with the COVID-19 pandemic, and their stress level. A general health questionnaire-12 (GHQ-12) was included in our questionnaire. Results: Majority (74.3%) of the respondents were in the stress group. The mean GHQ-12 score was 14.31 ± 4.96. More females (67.4%, p < 0.05) and nurses (73.3%, p = 0.001) were in the stress group compared to males and doctors. Medical staff in the general ward considered the severity of the COVID-19 pandemic situation higher. Nurses perceived work changes (p < 0.05), work burden (p < 0.05), and personal impact (p < 0.05) more serious than doctors. Medical staff in Level 3 emergency department (ED) perceived a lack of real-time information (p = 0.012), a lack of resources, and negative personal impacts associated with the pandemic as more serious than staff in Level 1 and Level 2 EDs. Medical staff in the intensive care unit perceived work changes (p < 0.05), work burden (p < 0.05), and lack of personal protective equipment (p = 0.002) as more serious than staff in the ED and general ward. Conclusion: Providing real-time information and resources for reducing work burden and negative personal impact is central to maximizing the work output of the COVID-19 pandemic frontline medical staff. Supporting their mental health through regular programs and intervention is also imperative.

Trauma-informed Drug Screens for Veterans with Co-occurring Disorders: A Case Series.

Objective: This case series describes and illustrates the effective use of a trauma-informed approach, GLAPE, to provide drug screens for individuals in substance use treatment programs. The GLAPE approach recognizes that individuals who have experienced traumatic events and are recovering from substance use difficulties may also face unique challenges when engaging in mental health treatment. The nature of drug screening procedures in practice may feel invasive and triggering for clients with trauma histories. Finding ways to decrease barriers to treatment and increase engagement and retention are important components of effective substance use treatment. Methods: This case series involved three veteran cisgender men with posttraumatic stress disorder (PTSD) and co-occurring substance use conditions in an outpatient addiction recovery program in a Veterans' hospital. The cases illustrate how recovery can be aided by trauma-informed approaches for urine drug screens. The treatment team evaluated various monitoring modalities and collaborated with each client to form a treatment plan that implemented the GLAPE approach to bolster their recovery. The GLAPE approach includes five components: Giving detailed instructions prior to the urine screen procedure, listening to and eliciting questions and concerns of the client, articulating options and exhibiting flexibility in the procedure to accommodate the needs of the individual client, giving permission to the client to voice concerns at any point during the procedure, and evaluating the process in collaboration with the client, including what could be improved for next time. Results: Use of the GLAPE approach effectively helped to engage and retain military veterans with co-occurring PTSD and substance use disorder within a trauma informed outpatient program. Preliminary evidence from three cases provides that this approach may be useful for use in substance use treatment with clients who have trauma histories. Conclusions: Given widespread use of observed urine drug screens in substance use treatment programs, and prominent co-occurrence of substance use disorder and PTSD, it is essential that staff approach this procedure in a trauma-informed way. This case series illustrates an approach that can improve client experience, aid clients in treatment engagement, and assist staff in the provision of effective care.

Protective effects of triple fermented barley extract (FBe) on indomethacin-induced gastric mucosal damage in rats.

BACKGROUND: Hordeum vulgare L (barley) contains numerous phenolic substances with proven anticancer, antioxidant and gastroprotective activities. Saccharification increases the functionality and bioavailability of these compounds thus can aid in the development of a natural product based medicine. This study aimed to investigate the possible gastroprotective effects of saccharification on the indomethacin (IND)-induced gastric ulcers in rats using Weissella cibaria- and Saccharomyces cerevisiae-triple fermented H. vulgare extract (FBe). METHODS: In total, 60 healthy male 6-week old Sprague-Dawley SD (SPF/VAF Outbred CrljOri:CD1) rats were commercially purchased. The FBe extract (100, 200, and 300 mg kg- 1) was orally administered 30 min before an oral treatment of IND (25 mg kg- 1). Six hours after IND treatment, variations in the histopathology, myeloperoxidase (MPO) activity, gross lesion scores, lipid peroxidation, and antioxidant defense system component (superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)) levels were measured. RESULTS: FBe treatment showed significant (p < 0.01 or p < 0.05) and dose-dependent decrease in gastric mucosal damage. In the present study hemorrhagic gross lesions, gastric MPO activity, and histopathological gastric ulcerative lesions were observed in IND-treated rats compared to the IND control rats. In particular, FBe, in a dose-dependent manner, strengthened the antioxidant defense systems, decreased lipid peroxidation and CAT activity by increasing the GSH levels and SOD activity, respectively. The 200 mg kg- 1 dose of FBe was similarly gastroprotective as the 10 mg kg- 1 dose of omeprazole in rats with IND-induced gastric mucosal damage. CONCLUSIONS: The findings of the present study show that an oral administration of FBe had positive gastroprotective effects through strengthening the body antioxidant defense system and anti-inflammatory effects.

Laxative effects of triple fermented barley extracts (FBe) on loperamide (LP)-induced constipation in rats.

BACKGROUND: Constipation, a common health problem, causes discomfort and affects the quality of life. This study intended to evaluate the potential laxative effect of triple fermented barley (Hordeum vulgare L.) extract (FBe), produced by saccharification, Saccharomyces cerevisiae, and Weissella cibaria, on loperamide (LP)-induced constipation in Sprague-Dawley (SD) rats, a well-established animal model of spastic constipation. METHODS: Spastic constipation was induced via oral treatment with LP (3 mg/kg) for 6 days 1 h before the administration of each test compound. Similarly, FBe (100, 200 and 300 mg/kg) was orally administered to rats once a day for 6 days. The changes in number, weight, and water content of fecal, motility ratio, colonic mucosa histology, and fecal mucous contents were recorded. The laxative properties of FBe were compared with those of a cathartic stimulant, sodium picosulfate. A total of 48 (8 rats in 6 groups) healthy male rats were selected and following 10 days of acclimatization. Fecal pellets were collected one day before administration of the first dose and starting from immediately after the fourth administration for a duration of 24 h. Charcoal transfer was conducted after the sixth and final administration of the test compounds. RESULTS: In the present study, oral administration of 100-300 mg/kg of FBe exhibited promising laxative properties including intestinal charcoal transit ratio, thicknesses and mucous producing goblet cells of colonic mucosa with decreases of fecal pellet numbers and mean diameters remained in the lumen of colon, mediated by increases in gastrointestinal motility. CONCLUSION: Therefore, FBe might act as a promising laxative agent and functional food ingredient to cure spastic constipation, with less toxicity observed at a dose of 100 mg/kg.

Anti-osteoporotic effects of mixed compositions of extracellular polymers isolated from Aureobasidium pullulans and Textoria morbifera in ovariectomized mice.

BACKGROUND: Extracellular polymeric substances isolated from Aureobasidium pullulans (EAP), containing specifically 13% ß-1,3/1,6-glucan, have shown various favorable bone-preserving effects. Textoria morbifera Nakai (TM) tree has been used as an ingredient in traditional medicine and tea for various pharmacological purposes. Thus, the present study was aimed to examine the synergistic anti-osteoporotic potential of mixtures containing different proportions of EAP and TM compared with that of the single formulations of each herbal extract using bilateral ovariectomized (OVX) mice, a renowned rodent model for studying human osteoporosis. METHODS: Thirty five days after bilateral-OVX surgery, 9 combinations of EAP:TM (ratios = 1:1, 1:3, 1:5, 1:7, 1:9, 3:1, 5:1, 7:1, 9:1) and single separate formulations of EAP or TM were supplied orally, once a day for 35 days at a final concentration of 200 mg/kg. Variations in body weight gains during the experimental periods, as well as femur weights, bone mineral density (BMD), bone strength (failure load), and mineral content (calcium [Ca] and inorganic phosphorus [IP]) following sacrifice were measured. Furthermore, histomorphometric and histological profile analyses of serum biochemical parameters (osteocalcin content and bone specific alkaline phosphatase [bALP] activity) were conducted following sacrifice. Femurs histomorphometric analyses were also conducted for bone resorption, structure and mass. The results for the mixed formulations of EAP:TM and separate formulations were compared with those of risedronate sodium (RES). RESULTS: The EAP:TM (3:1) formulation synergistically enhanced the anti-osteoporotic potential of individual EAP or TM formulations, possibly due to enhanced variety of the active ingredients. Furthermore, the effects of EAP:TM were comparable to those of RES (2.5 mg/kg) treatment. CONCLUSION: The results of this study suggest that, the EAP:TM (3:1) combination might act as a new pharmaceutical agent and/or health functional food substance for curing osteoporosis in menopausal women.

Low molecular weight fucoidan improves endoplasmic reticulum stress-reduced insulin sensitivity through AMP-activated protein kinase activation in L6 myotubes and restores lipid homeostasis in a mouse model of type 2 diabetes.

Low molecular weight fucoidan (LMWF) is widely used to treat metabolic disorders, but its physiologic effects have not been well determined. In the present study, we investigated the metabolic effects of LMWF in obese diabetic mice (leptin receptor-deficient db/db mice) and the underlying molecular mechanisms involved in endoplasmic reticulum (ER) stress-responsive L6 myotubes. The effect of LMWF-mediated AMP-activated protein kinase (AMPK) activation on insulin resistance via regulation of the ER stress-dependent pathway was examined in vitro and in vivo. In db/db mice, LMWF markedly reduced serum glucose, triglyceride, cholesterol, and low-density lipoprotein levels, and gradually reduced body weights by reducing lipid parameters. Furthermore, it effectively ameliorated glucose homeostasis by elevating glucose tolerance. In addition, the phosphorylation levels of AMPK and Akt were markedly reduced by ER stressor, and subsequently, glucose uptake and fatty acid oxidation were also reduced. However, these adverse effects of ER stress were significantly ameliorated by LMWF. Finally, in L6 myotubes, LMWF markedly reduced the ER stress-induced upregulation of the mammalian target of rapamycin-p70S61 kinase network and subsequently improved the action of insulin via AMPK stimulation. Our findings suggest that AMPK activation by LMWF could prevent metabolic diseases by controlling the ER stress-dependent pathway and that this beneficial effect of LMWF provides a potential therapeutic strategy for ameliorating ER stress-mediated metabolic dysfunctions.

Predicting problematic pornography use among male returning US veterans.

Problematic Pornography Use (PPU) is the most common problem behavior among individuals with compulsive sexual behavior (CSB). Previous research suggests US veterans are at a greater risk of engaging in PPU. The present study sought to investigate further PPU among male military veterans. Data from 172 male veterans who endorsed ever watching pornography and completed the Problematic Pornography Use Scale (PPUS) were included in the study. Participants completed self-report questionnaires, including demographic information, psychiatric co-morbidities, impulsivity, as measured by the UPPS-P, pornography-related behaviors, and pornography craving as measured by Pornography Craving Questionnaire (PCQ). Younger age and lower educational attainment were associated with higher PPUS scores. Depression, anxiety, post-traumatic stress disorder (PTSD), insomnia, and impulsivity were positively associated with higher PPUS scores. There was no statistically significant association between PPU with suicidal ideation or alcohol use disorder. In the multivariable hierarchical regression, depression, frequency of use, and higher PCQ scores were associated with higher PPUS scores, although only the latter two remained significant in the final model. Understanding the risk factors via more frequent screening for PPU will help with the development of treatment protocols for this problematic behavior.

Behavioral addiction and autism spectrum disorder: A systematic review.

BACKGROUND: According to DSM-5 criteria, Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficiencies in social communication and interaction along with the presence of restrictive and repetitive patterns of behavior. Few studies have explored the prevalence of behavioral addiction in individuals with ASD. Since addiction and ASD share common characteristics, individuals with ASD may be more vulnerable to addictive behaviors. Some typical behavioral addictions include internet, gaming, and gambling addiction. While most previous studies on ASD and addiction have looked at chemical addiction, behavioral addiction has not been thoroughly studied to date. AIMS: The objective of this study was to investigate the presence of behavioral addiction among individuals diagnosed with autism spectrum disorder. METHODS AND PROCEDURES: A systematic literature search of five databases was conducted in accordance with the PRISMA guidelines. Search results were reviewed for the predetermined inclusion criteria independently by two authors. OUTCOMES AND RESULTS: The search yielded 539 publications after the removal of duplicates. 61 met the inclusion criteria for title and abstract review. Full texts were reviewed resulting in an additional 31 being removed. The remaining 30 included 4 case reports and 26 original studies. Results included 27 studies that found a positive correlation (15 of significance, 12 of unknown significance) between a behavioral addiction and either ASD or Autistic traits, 1 found a significant negative correlation, 3 did not find a correlation. CONCLUSIONS AND IMPLICATIONS: This review is inconclusive about links between ASD and behavioral addictions. While a vast majority of studies show a positive correlation, many do not provide the statistical analysis to show if the correlations are significant. In addition, a positive correlation between ASD and behavioral addiction is observed in the presence of comorbid mental health conditions in many of the studies. Further research with proper controls and statistical analysis is needed to determine whether the development of behavioral addiction is directly influenced by ASD or if the presence of a comorbid mental health condition is the true cause.

Protective effects of a triple-fermented barley extract (FBe) against HCl/EtOH-induced gastric mucosa damage in mice.

This study was designed to observe the possible protective effects of a triple-fermented barley (Hordeum vulgare L.) extract (FBe) obtained by saccharification and using Saccharomyces cerevisiae and Weissella cibaria in alleviating gastric damage induced by a hydrochloric acid (HCl) and ethanol (EtOH) mixture in mice. After oral administration of FBe (300, 200, and 100 mg/kg) followed by 1 hr before and after the single treatment of HCl/EtOH (H/E) mixture, the hemorrhagic lesion scores, histopathology of the stomach, gastric nitrate/nitrite content, lipid peroxidation, and antioxidant defense systems including catalase and superoxide dismutase activities were observed. Following a single oral treatment of H/E-induced gastric damages as measured by hemorrhagic gross lesions and histopathological gastric, ulcerative lesions were significantly and dose-dependently (p < 0.01 or p < 0.05) inhibited in mice, when all three different doses of FBe were administered as compared to those in H/E control mice. In particular, FBe also increased gastric nitrate/nitrite content and strengthened the antioxidant defense, with a decrease in the level of gastric lipid peroxidation, but increased the activities of CAT and SOD. Moreover, the effects of FBe are comparable to that of ranitidine, a reference drug. The obtained results suggest that this fermented barley extract prevented mice from H/E-induced gastric mucosal damages through the suppression of inflammatory responses and oxidative stress-responsive free radicals. Thus, FBe can be useful to treat patients suffering from gastric mucosal disorders as a potent food supplement, and thereby, it would increase the necessity of application in the food industry.

Ingestion of Exopolymers from Aureobasidium pullulans Reduces the Duration of Cold and Flu Symptoms: A Randomized, Placebo-Controlled Intervention Study.

AIM: The objective of the study was to assess the efficacy of exopolymers from Aureobasidium pullulans (EAP) on the incidence of colds and flu in healthy adults. METHODS: We conducted a randomized, double-blind, placebo-controlled study at the onset of the influenza season. A total of 76 subjects (30-70 years of age) were recruited from the general population. The subjects were instructed to take one capsule per day of either EAP or a placebo for a period of 8 weeks. The duration of cold and flu symptoms, a primary variable in assessing effectiveness, and serum cytokine levels as well as WBC counts as secondary variables were also evaluated. RESULTS: EAP was associated with a statistically significant decrease in the duration of cold and flu symptoms, a primary variable in assessing effectiveness. Although cold and flu symptom levels were not significantly different at a significance level of 5%, the cold and flu symptom levels of the EAP group were less severe compared to the placebo group. No statistically significant changes of serum cytokine levels as well as WBC counts were observed. CONCLUSION: The results showed that EAP is a useful pharmaceutical and functional food material for preventing and treating colds and flu.

Extracellular polysaccharides purified from Aureobasidium pullulans SM­2001 (Polycan) inhibit dexamethasone­induced muscle atrophy in mice.

The present study assessed the beneficial skeletal muscle­preserving effects of extracellular polysaccharides from Aureobasidium pullulans SM­2001 (Polycan) (EAP) on dexamethasone (DEXA)­induced catabolic muscle atrophy in mice. To investigate whether EAP prevented catabolic DEXA­induced muscle atrophy, and to examine its mechanisms of action, EAP (100, 200 and 400 mg/kg) was administered orally, once a day for 24 days. EAP treatment was initiated 2 weeks prior to DEXA treatment (1 mg/kg, once a day for 10 days) in mice. Body weight alterations, serum biochemistry, calf thickness, calf muscle strength, gastrocnemius muscle thickness and weight, gastrocnemius muscle antioxidant defense parameters, gastrocnemius muscle mRNA expression, histology and histomorphometry were subsequently assessed. After 24 days, DEXA control mice exhibited muscle atrophy according to all criteria indices. However, these muscle atrophy symptoms were significantly inhibited by oral treatment with all three doses of EAP. Regarding possible mechanisms of action, EAP exhibited favorable ameliorating effects on DEXA­induced catabolic muscle atrophy via antioxidant and anti­inflammatory effects; these effects were mediated by modulation of the expression of genes involved in muscle protein synthesis (AKT serine/threonine kinase 1, phosphatidylinositol 3­kinase, adenosine A1 receptor and transient receptor potential cation channel subfamily V member 4) and degradation (atrogin­1, muscle RING­finger protein­1, myostatin and sirtuin 1). Therefore, these results indicated that EAP may be helpful in improving muscle atrophies of various etiologies. EAP at 400 mg/kg exhibited favorable muscle protective effects against DEXA­induced catabolic muscle atrophy, comparable with the effects of oxymetholone (50 mg/kg), which has been used to treat various muscle disorders.

Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells.

NADPH is an important cofactor in many biosynthesis pathways and the regeneration of reduced glutathione, critically important in cellular defense against oxidative damage. It is mainly produced by glucose 6-phosphate dehydrogenase (G6PD), malic enzyme, and the cytosolic form of NADP(+)-dependent isocitrate dehydrogenase (IDPc). Little information is available about the role of IDPc in antioxidant defense. In this study we investigated the role of IDPc against cytotoxicity induced by oxidative stress by comparing the relative degree of cellular responses in three different NIH3T3 cells with stable transfection with the cDNA for mouse IDPc in sense and antisense orientations, where IDPc activities were 3-4-fold higher and 35% lower, respectively, than that in the parental cells carrying the vector alone. Although the activities of other antioxidant enzymes, such as superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and G6PD, were comparable in all transformed cells, the ratio of GSSG to total glutathione was significantly higher in the cells expressing the lower level of IDPc. This finding indicates that IDPc is essential for the efficient glutathione recycling. Upon transient exposure to increasing concentrations of H(2)O(2) or menadione, an intracellular source of free radicals and reactive oxygen species, the cells with low levels of IDPc became more sensitive to oxidative damage by H(2)O(2) or menadione. Lipid peroxidation, oxidative DNA damage, and intracellular peroxide generation were higher in the cell-line expressing the lower level of IDPc. However, the cells with the highly over-expressed IDPc exhibited enhanced resistance against oxidative stress, compared to the control cells. This study provides direct evidence correlating the activities of IDPc and the maintenance of the cellular redox state, suggesting that IDPc plays an important role in cellular defense against oxidative stress.

Glyceollin improves endoplasmic reticulum stress-induced insulin resistance through CaMKK-AMPK pathway in L6 myotubes.

Glyceollin has been shown to have antidiabetic properties, although its molecular mechanism is not known. Here, we have investigated the metabolic effects of glyceollin in animal models of insulin resistance and in endoplasmic reticulum (ER) stress-responsive muscle cells. db/db mice were treated with glyceollin for 4weeks and triglycerides, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels were measured. Glyceollin reduced serum insulin and triglycerides and increased HDL levels in db/db mice. Furthermore, glyceollin caused a significant improvement in glucose homeostasis without altering body weight and food intake in db/db mice. In muscle cells, glyceollin increased the activity of AMP-activated protein kinase (AMPK) as well as cellular glucose uptake. Fatty acid oxidation was also increased. In parallel, phosphorylation of acetyl-CoA carboxylase (ACC) at Ser-79 was increased, consistent with decreased ACC activity. An insulin-resistant state was induced by exposing cells to 5µg/ml of tunicamycin as indicated by decreased insulin-mediated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and glucose uptake. Inhibition of insulin-mediated tyrosine phosphorylation of IRS-1 and glucose uptake under ER stress was prevented by glyceollin. Strikingly, glyceollin reduced ER stress-induced, c-Jun NH2-terminal kinase activation and subsequently increased insulin signaling via stimulation of AMPK activity in L6 myotubes. Pharmacologic inhibition or knockdown of Ca(2+)/calmodulin-dependent protein kinase kinase blocked glyceollin-increased AMPK phosphorylation and insulin sensitivity under ER stress conditions. Taken together, these results indicate that glyceollin-mediated enhancement of insulin sensitivity under ER stress conditions is predominantly accomplished by activating AMPK, thereby having beneficial effects on hyperglycemia and insulin resistance.

Antitumor Effects and Immunomodulating Activities of Phellinus linteus Extract in a CT-26 Cell-Injected Colon Cancer Mouse Model.

The antitumor effects of Phellinus linteus extract (Keumsa Linteusan) were investigated in a CT-26 cell-injected colon cancer mouse model. When administered orally (250~1,000 mg/kg body weight), Keumsa Linteusan significantly inhibited the growth of solid colon cancer. The highest dose was highly effective, reducing tumor formation by 26% compared with the control group. The anticomplementary activity of Keumsa Linteusan increased in a dose-dependent manner. Lysosomal enzyme activity of macrophages was increased by 2-fold (100 µg/ml) compared with the control group. Keumsa Linteusan can be regarded as a potent enhancer of the innate immune response, and can be considered as a very promising candidate for antitumor action.

Oral Single Dose Toxicity Study of Low Molecular Fucoidan in Mice.

This study was conducted to obtain information of the oral dose toxicity of low molecular fucoidan (LMF) in male and female mice. In order to calculate 50% lethal dose (LD50) and approximate lethal dose (LD), test material was once orally administered to male and female ICR mice at dose levels of 2000, 1000, 500, 250, 125 and 0 (vehicle control) mg/kg (body wt.). The mortality and the changes on body weight, clinical signs, gross observation and organ weight and histopathology of principle organs were monitored 14 days after LMF treatment. We could not find any mortalities, clinical signs, body weight changes and gross findings. In addition, significant changes in the organ weight and histopathology of principal organs were not observed except for some sporadic findings. The results obtained in this study suggest that LMF may not be toxic in mice and may be therefore safe for clinical use. The LD50 and approximate LD in mice after single oral dose of LMF were considered over 2000 mg/kg in both female and male mice.

Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism.

NADPH is an essential cofactor for many enzymatic reactions including glutathione metabolism and fat and cholesterol biosynthesis. We have reported recently an important role for mitochondrial NADP(+)-dependent isocitrate dehydrogenase in cellular defense against oxidative damage by providing NADPH needed for the regeneration of reduced glutathione. However, the role of cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDPc) is still unclear. We report here for the first time that IDPc plays a critical role in fat and cholesterol biosynthesis. During differentiation of 3T3-L1 adipocytes, both IDPc enzyme activity and its protein content were increased in parallel in a time-dependent manner. Increased expression of IDPc by stable transfection of IDPc cDNA positively correlated with adipogenesis of 3T3-L1 cells, whereas decreased IDPc expression by an antisense IDPc vector retarded adipogenesis. Furthermore, transgenic mice with overexpressed IDPc exhibited fatty liver, hyperlipidemia, and obesity. In the epididymal fat pads of the transgenic mice, the expressions of adipocyte-specific genes including peroxisome proliferator-activated receptor gamma were markedly elevated. The hepatic and epididymal fat pad contents of acetyl-CoA and malonyl-CoA in the transgenic mice were significantly lower, whereas the total triglyceride and cholesterol contents were markedly higher in the liver and serum of transgenic mice compared with those measured in wild type mice, suggesting that the consumption rate of those lipogenic precursors needed for fat biosynthesis must be increased by elevated IDPc activity. Taken together, our findings strongly indicate that IDPc would be a major NADPH producer required for fat and cholesterol synthesis.