Scalp EEG-recorded high-frequency oscillations can predict seizure activity in Panayiotopoulos syndrome.

OBJECTIVE: We studied the relationship between the clinical course of Panayiotopoulos syndrome (PS) and high-frequency oscillations (HFOs) captured during interictal scalp electroencephalography (EEG) to determine the feasibility of using HFOs to detect seizure activity in PS. METHODS: We analyzed the interictal scalp EEGs of 18 children with PS. Age parameters, seizure frequencies, and antiepileptic drugs were compared between the HFO-positive (HFOPG) and HFO-negative (HFONG) groups. RESULTS: Thirteen patients (72.2%) had HFOs while five patients (27.8%) had no HFOs in 194 interictal EEG records. We found no statistically significant differences in the mean age of epilepsy onset and last seizure, seizure frequency, or frequency of status epilepticus. However, the seizure activity period of the HFOPG was significantly longer than that of the HFONG. Patients with an HFO duration longer than 2 years were intractable to treatment. In most cases, seizures did not occur in the absence of HFOs, even when the spikes remained. CONCLUSIONS: HFOs are related to the seizure activity period in patients with PS. SIGNIFICANCE: We propose that HFOs are a biomarker of epileptogenicity and an indicator for drug reduction because seizures did not occur if HFOs disappeared even if the spikes remained.

Nutritional counseling needs of patients with mental disorders in psychiatric care: A cross-sectional survey.

BACKGROUND: The exploration of diet and nutrition as they relate to mental health and psychiatric disorders is a developing field. Anxiety, depression, and pharmacological treatments used to treat these disorders are likely to have side effects that induce decreases in activity and irregular eating habits, resulting in persistent nutritional imbalance. Unhealthy dietary patterns are associated with an increased risk of developing physical and mental health conditions. Despite this, nutritional support to patients in psychiatric care is not adequate. AIMS: This study aimed to determine the factors underlying the need for nutritional counseling among patients with a mental disorder in psychiatry. The factors explored are eating-related symptoms, eating behavior, interest in food, seeking nutritional counseling, and impact on quality of life (QOL). METHODS: We utilized a cross-sectional study design. Eligible patients were asked to complete a questionnaire regarding physical measurements and nutritional counseling. In addition, patients' diagnoses and blood test data were referenced from their medical records. The analysis focused on two groups: those who desired to consult a nutritionist and those who did not. RESULTS: Ninety-three patients completed the study. The nutritional status and need for nutritional counseling in psychiatry patients indicates that patients with dietary problems requested nutritional counseling (p < .001). Patients who were more likely to need nutritional counseling had lower QOL in daily life (p = .011), pain/discomfort (p = .024), and anxiety/depression (p = .010) on the EuroQol 5-Dimension 5-level (EQ-5D-5L). CONCLUSIONS: Patients with mental disorders who need nutritional counseling tend to have food-related problems and low QOL. It is necessary to establish an interdisciplinary system for nutritional counseling.

Qualitative analysis of actual Standard for Exchange of Nonclinical Data (SEND) datasets for Data Domains: Proposition from Japan Pharmaceutical Manufacturers Association SEND Taskforce Team on standardization of nonclinical data.

The Standard for Exchange of Nonclinical Data (SEND) has been adopted by the US FDA, which has required pharmaceutical companies who are developing new drugs for the US market to implement SEND. The Japan Pharmaceutical Manufacturers Association (JPMA) SEND Taskforce Team responded to this situation by starting a project to better understand the contents of SEND datasets. The project focused on domains generally included in the SEND domains for single- and repeat-dose general toxicology studies, and surveyed what kind of information are populated in which domains and in what way. The qualitative analysis of the results indicated that variations exist based on whether or not an individual variable was populated and on how the variable was populated. The Taskforce Team recommends reducing variations not only in the SEND datasets but also in the descriptions in the study protocol and/or final study report. Reduction of such variations should lead to higher quality datasets with powerful and increased searchability so that accumulated SEND datasets should become more valuable. These efforts would provide regulatory agencies with easier review of SEND datasets, which contributes to efficient development of new drug candidates.

"Violence and love and drugs it all goes hand in hand": A mixed methods analysis of the substance abuse, violence, and HIV/AIDS syndemic among women who use methamphetamine.

Background: The synergistic epidemics of substance use, violence, and HIV/AIDS, also known as the SAVA syndemic, disproportionately affects vulnerable women in the United States. Methamphetamine use is closely linked with physical and sexual violence, including intimate partner violence (IPV), which heightens women's vulnerability to HIV. This mixed methods study examined the prevalence and correlates of violence among women who use methamphetamine, (n = 209) enrolled in an HIV intervention study in San Diego, California. Methods: At baseline, 209 women completed an interviewer-administered computer-assisted survey. A sub set of women who reported lifetime IPV (n = 18) also participated in qualitative interviews to contextualize our understanding of patterns of violence over time. Results: In the overall cohort, reports of lifetime (66.0%) and past 2-month (19.6%) IPV were prevalent. Moreover, women reported lifetime physical only (27.3%), sexual only (6.2%), or both forms of violence (50.7%) by multiple perpetrators. Factors independently associated with lifetime IPV were having unprotected sex with a steady partner (odds ratio [OR]: 2.50, 95% confidence interval [CI]: 1.04, 6.00) and being high on methamphetamine during unprotected sex with a steady partner (OR: 2.56, 95% CI: 1.30, 5.09) within the past 2 months. Our qualitative narratives illuminated how IPV in women's steady relationships often reflects a culmination of violent victimization throughout their lifetime which is further exacerbated by methamphetamine use and sexual risk through gendered power dynamics. Conclusions: HIV prevention interventions should address the SAVA syndemic in a holistic manner, including the role of methamphetamine use in the context of women's abusive steady relationships.

Coffin-Siris syndrome with bilateral macular dysplasia caused by a novel exonic deletion in ARID1B.

Coffin-Siris syndrome (CSS) is a congenital anomaly syndrome characterized by developmental delay, coarse facial features, and hypoplasia of the fifth digit's nail or phalanges. Herein, we report a case of the 8-year-old female patient who showed developmental delay associated with dysplasia in the macular and large toe area. Comprehensive genomic analysis showed no possible candidate variants, but the subsequent genomic copy number analysis revealed a novel exonic deletion in the coding region of AT-rich interactive domain-containing protein 1B (ARID1B), a gene responsible for CSS. Genomic copy number analysis can aid in diagnosing CSS by confirming undiagnosed exonic deletions in ARID1B. Furthermore, this is the first report of CSS associated with bilateral macular dysplasia.

Recent Partner Violence, Sexual Relationship Power, and STIs among Women Who Use Methamphetamine: Does Type of Sexual Partner Matter?

Methamphetamine use, sexual relationship power (SRP), and partner violence (PV) are associated with increased risk of sexually transmitted infections (STIs) among women. The objective of our study was to examine the association of recent PV and SRP on STIs by partner type among HIV-negative, heterosexual women who use methamphetamine in San Diego, CA. Using baseline survey data from 209 women enrolled in FASTLANE II, an HIV behavioral intervention trial, we conducted logistic regression analyses to examine associations between PV, SRP, and self-reported lifetime STIs (e.g., chlamydia, gonorrhea). Models focused on PV perpetrated within the past 2 months by: (1) spouse, live-in, or steady sexual partners and (2) casual or anonymous sexual partners. Seventy-eight percent of women reported lifetime physical PV and 57% reported lifetime sexual PV. In the past 2 months, 19.6% reported physical and/or sexual violence by a spouse, live-in, or steady sexual partner, and 7.2% reported physical and/or sexual PV by a casual or anonymous partner. Median SRP score was 2.36 (interquartile range: 2.02-2.68). Twenty-six percent of women reported ever being diagnosed with ≥ 1 STI. While recent physical violence and sexual violence were not associated with STI history among women in steady relationships, women who reported recent sexual violence by casual/anonymous partners were approximately 8 times more likely to ever have an STI compared with those with no history of recent PV by casual/anonymous partners (AOR: 7.70; 95% CI: 1.32, 44.84). SRP was not associated with lifetime STIs among women who reported either partner type. Our findings support a relationship between recent sexual violence perpetrated by casual/anonymous partners and women's STI history. Women who use methamphetamine need help in navigating partner violence experiences. Risk reduction interventions to support this marginalized population are needed.

Long-lasting immunosuppressive effects of tacrolimus-loaded micelle NK61060 in preclinical arthritis and colitis models.

AIM: Tacrolimus (TAC) is an important drug for inflammatory diseases. However, TAC has several limitations, such as variable trough concentrations among individuals and a high medication frequency. In this study, we created NK61060, a novel micellar TAC formulation, to circumvent these disadvantages. MATERIALS & METHODS: Immunosuppressive activity of NK61060 was determined in the collagen-induced arthritis rat model, mannan-induced arthritis mouse model and dextran sodium sulfate-induced colitis mouse model. The pharmacokinetics and toxicology of NK61060 were evaluated in those models. RESULTS: In arthritis and colitis models, NK61060 exhibited superior immunosuppressive activity compared with that of TAC. Pharmacokinetic and toxicological analyses indicated that NK61060 had a wider safety margin and could be administered at a reduced medication frequency. CONCLUSION: NK61060 mitigates the trough concentration variability and the medication frequency and it may be a safer and more effective option for use in clinical settings. Further studies are needed to determine its clinical usefulness.

An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation.

In our previous rodent studies, the paclitaxel (PTX)-incorporating polymeric micellar nanoparticle formulation NK105 had showed significantly stronger antitumor effects and reduced peripheral neurotoxicity than PTX dissolved in Cremophor® EL and ethanol (PTX/CRE). Thus, to elucidate the mechanisms underlying reduced peripheral neurotoxicity due to NK105, we performed pharmacokinetic analyses of NK105 and PTX/CRE in rats. Among neural tissues, the highest PTX concentrations were found in the dorsal root ganglion (DRG). Moreover, exposure of DRG to PTX (Cmax_PTX and AUC0-inf._PTX) in the NK105 group was almost half that in the PTX/CRE group, whereas exposure of sciatic and sural nerves was greater in the NK105 group than in the PTX/CRE group. In histopathological analyses, damage to DRG and both peripheral nerves was less in the NK105 group than in the PTX/CRE group. The consistency of these pharmacokinetic and histopathological data suggests that high levels of PTX in the DRG play an important role in the induction of peripheral neurotoxicity, and reduced distribution of PTX to the DRG of NK105-treated rats limits the ensuing peripheral neurotoxicity. In further analyses of PTX distribution to the DRG, Evans blue (Eb) was injected with BODIPY®-labeled NK105 into rats, and Eb fluorescence was observed only in the DRG. Following injection, most Eb dye bound to albumin particles of ~8 nm and had penetrated the DRG. In contrast, BODIPY®-NK105 particles of ~90 nm were not found in the DRG, suggesting differential penetration based on particle size. Because PTX also circulates as PTX-albumin particles of ~8 nm following injection of PTX/CRE, reduced peripheral neurotoxicity of NK105 may reflect exclusion from the DRG due to particle size, leading to reduced PTX levels in rat DRG (275).

Risk Factors for Recent Intimate Partner Violence among Methamphetamine-Using Men and Women.

The Substance Abuse, Violence, and HIV/AIDS (SAVA) syndemic model describes how the confluence of the three epidemics of substance abuse, violence, and HIV risk work synergistically to create excess burden among populations. We sought to identify risk factors associated with recent intimate partner violence (IPV) victimization among heterosexual methamphetamine (meth)-using men (n = 108) and women (n = 122) enrolled in FASTLANE-II, an HIV behavioral intervention in San Diego, CA. Women and men reported high rates of physical-only (women: 20%; men: 18%) and sexual (women: 25%; men: 23%) IPV. Multinomial regression analysis revealed that individuals who reported lower social support and individuals who reported a greater likelihood of engaging in risky sexual behaviors while high on meth were more likely to report IPV versus no IPV. Women who reported a greater likelihood of engaging in risky sexual behaviors while high on meth were 1.58 times more likely to report physical-only IPV versus no IPV, while men who reported similar behaviors were 1.15 times more likely to report physical-only IPV versus no IPV. Our findings highlight the influence of interpersonal factors on IPV. This research supports further study on gender-specific risk/protective factors and the development of gender-specific interventions targeting the SAVA syndemic among meth users.

Intimate Partner Violence and its Health Impact on Ethnic Minority Women [corrected].

In the United States, intimate partner violence (IPV) against women disproportionately affects ethnic minorities. Further, disparities related to socioeconomic and foreign-born status impact the adverse physical and mental health outcomes as a result of IPV, further exacerbating these health consequences. This article reviews 36 U.S. studies on the physical (e.g., multiple injuries, disordered eating patterns), mental (e.g., depression, post-traumatic stress disorder), and sexual and reproductive health conditions (e.g., HIV/STIs, unintended pregnancy) resulting from IPV victimization among ethnic minority (i.e., Black/African American, Hispanic/Latina, Native American/Alaska Native, Asian American) women, some of whom are immigrants. Most studies either did not have a sufficient sample size of ethnic minority women or did not use adequate statistical techniques to examine differences among different racial/ethnic groups. Few studies focused on Native American/Alaska Native and immigrant ethnic minority women and many of the intra-ethnic group studies have confounded race/ethnicity with income and other social determinants of health. Nonetheless, of the available data, there is evidence of health inequities associated with both minority ethnicity and IPV. To appropriately respond to the health needs of these groups of women, it is necessary to consider social, cultural, structural, and political barriers (e.g., medical mistrust, historical racism and trauma, perceived discrimination, immigration status) to patient-provider communication and help-seeking behaviors related to IPV, which can influence health outcomes. This comprehensive approach will mitigate the racial/ethnic and socioeconomic disparities related to IPV and associated health outcomes and behaviors.

GABA-mediated modulation of ATP-induced intracellular calcium responses in nodose ganglion neurons of the rat.

We examined ATP-induced intracellular Ca(2+) ([Ca(2+)]i) responses in the neurons and satellite cells from one of the viscerosensory ganglia, the nodose ganglion (NG), as well as the GABA-mediated modulation of ATP-induced neuronal [Ca(2+)]i responses using intracellular calcium imaging. In neurons with satellite cells, ATP induced [Ca(2+)]i increases in both the neurons and satellite cells. The P2X receptor agonist, α,ß-meATP, induced [Ca(2+)]i increases in neurons and this response was inhibited by the P2X receptor antagonist, PPADS. On the other hand, the P2Y receptor agonist, ADP, induced [Ca(2+)]i increases in satellite cells, and this response was inhibited by the P2Y receptor antagonist, MRS2179. RT-PCR detected the expression of P2X2, P2X3, P2Y1, and P2Y2 receptor mRNAs in NG extracts. Immunohistochemistry revealed that NG neurons and satellite cells were immunoreactive to P2X2 and P2X3, and P2Y1 and P2Y2 receptors, respectively. In isolated neurons, the ATP-evoked [Ca(2+)]i increase was inhibited by GABA. However, in neurons with satellite cells, the GABAA receptor antagonist, bicuculline, enhanced the ATP-induced [Ca(2+)]i increase in neurons. These results suggest that viscerosensory neuronal excitability may be modulated by GABA from satellite cells in NG.

Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model.

Recent studies have shown that epigenetic alterations correlate with carcinogenesis in various tissues. Identification of these alterations might help characterize the early stages of carcinogenesis. We comprehensively analyzed DNA methylation and gene expression in livers obtained from rats exposed to nitrosodiethylamine (DEN) followed by a promoter of hepatic carcinogenesis, phenobarbital (PB). The combination of DEN and PB induced marked increases in number and area of glutathione S-transferase-placental form (GST-P)-positive foci in the liver. In the liver of rats that received 30 mg/kg of DEN, pathway analysis revealed alterations of common genes in terms of gene expression and DNA methylation, and that these alterations were related to immune responses. Hierarchical clustering analysis of the expression of common genes from public data obtained through the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) showed that carcinogenic compounds clustered together. MBD-seq and GeneChip analysis indicated that major histocompatibility complex class Ib gene RT1-CE5, which has an important role in antigen presentation, was hypomethylated around the promoter region and specifically induced in the livers of DEN-treated rats. Further, immunohistochemical analysis indicated that the co-localization of GST-P and protein homologous to RT1-CE5 was present at the foci of some regions. These results suggest that common genes were altered in terms of both DNA methylation and expression in livers, with preneoplastic foci indicating carcinogenic potential, and that immune responses are involved in early carcinogenesis. In conclusion, the present study identified a specific profile of DNA methylation and gene expression in livers with preneoplastic foci. Early epigenetic perturbations of immune responses might correlate with the early stages of hepatocarcinogenesis.

Detection of initiating potential of non-genotoxic carcinogens in a two-stage hepatocarcinogenesis study in rats.

We previously reported a toxicogenomics-based prediction model for hepatocarcinogens in which the expression patterns of signature genes following repeated doses of either genotoxic or non genotoxic compounds were similar. Based on the results of our prediction model, we hypothesized that repeated doses of non-genotoxic carcinogens might have initiating potential. Here, we conducted a two stage hepatocarcinogenesis study in rats exposed to the initiating agent nitrosodiethylamine (DEN), and hepatotoxic compounds thioacetamide (TAA), methapyrilene (MP) and acetaminophen (APAP) for 1-2 weeks followed by the liver tumor promoter phenobarbital (PB). The duration of initial treatment was determined based on positive results from our prediction model. Combined treatment of 3 or 30 mg/kg of genotoxic DEN and PB induced marked increases in altered hepatocellular foci and a DEN dose-dependent increase in the number and area of glutathione S-transferase-placental form (GST-P)-positive foci. A low number of altered hepatocellular foci were also observed in rats treated with TAA at a dose of 45 mg/kg.MP at a dose of 100 mg/kg induced a very low number of foci, but APAP did not. Hierarchical clustering analysis using gene expression data revealed that 2-week treatment with TAA at a dose of 30 mg/kg and MP at 45 mg/kg induced specific expression of DNA damage-related genes, similar to 1-week treatment with DEN at a dose of 30 mg/kg. These results suggest that TAA and MP induce DNA damage, which partially supports our hypothesis. Although this study does not indicate whether tumor growth in response to these compounds can be assessed in this model, our results suggest that cumulative treatment with non genotoxic TAA might have initiating potential in the liver.

Modifying effects of liver tumor promotion in rats subjected to co-administration of indole-3-carbinol and phenobarbital.

Indole-3-carbinol (I3C) and phenobarbital (PB) are cytochrome P450 (CYP) 1A and CYP2B inducers, respectively, and have liver tumor-promoting effects in rats. In this study, we investigated the modifying effects on tumor promotion by I3C and PB co-administration. Six-week-old male F344 rats received a single intraperitoneal injection of N-diethylnitrosamine for initiation treatment. Two weeks after the initiation, rats were given no tumor-promoting agents (DEN alone), I3C (2,500 or 5,000 ppm in diet), PB (60 or 120 ppm in drinking water), or 2,500 ppm I3C + 60 ppm PB for 6 weeks. One week after the I3C/PB treatments, all animals underwent a two-thirds partial hepatectomy. The number and area of liver cell foci positive for glutathione S-transferase placental form (GST-P(+) foci) were not significantly fluctuated in the PB+I3C group in the isoadditive statistical model. On the contrary, the mRNA levels of Cyp2b1/2 and Nqo1 were suppressed and enhanced, respectively, in the PB+I3C group in the isoadditive model, but there was no enhancement in the microsomal reactive oxygen species (ROS) production, thiobarbituric acid-reactive substance levels, and Ki-67(+) cell ratio in this group. The results suggest that the co-administration of I3C and PB causes no modifying effects in liver tumor promotion in rats.

Inhibition by hydrogen sulfide of rabbit platelet aggregation and calcium mobilization.

Hydrogen sulfide (H2S), a gasotransmitter, plays a variety of roles in the mammalian body including the cardiovascular system. Given evidence that H2S donors including NaHS inhibit human platelet aggregation, we examined and characterized the effects of NaHS on rabbit platelet aggregation and cytosolic Ca(2+) mobilization. Rabbit platelet aggregation was determined in platelet-rich plasma (PRP) and washed platelets. Intracellular Ca(2+) levels were monitored in Fura2-loaded washed platelets. NaHS prevented rabbit platelet aggregation induced by collagen or ADP, and the effective concentration range of NaHS was 0.1-0.3 mM in PRP and 1-3 mM in washed platelets. In washed platelets, NaHS attenuated cytosolic Ca(2+) mobilization induced by collagen or ADP and also reduced platelet aggregation induced by ionomycin, a Ca(2+) ionophore. The anti-platelet effect of NaHS was blocked by an adenylyl cyclase inhibitor and enhanced by a phosphodiesterase inhibitor. H2S thus suppresses rabbit platelet aggregation by interfering with both upstream and downstream signals of cytosolic Ca(2+) mobilization in a cAMP-dependent manner.

Aberrant activation of M phase proteins by cell proliferation-evoking carcinogens after 28-day administration in rats.

We have previously reported that hepatocarcinogens increase liver cells expressing p21(Cip1), a G1 checkpoint protein and M phase proteins after 28-day treatment in rats. This study aimed to identify early prediction markers of carcinogens available in many target organs after 28-day treatment in rats. Immunohistochemical analysis was performed on Ki-67, p21(Cip1) and M phase proteins [nuclear Cdc2, phospho-Histone H3 (p-Histone H3), Aurora B and heterochromatin protein 1α (HP1α)] with carcinogens targeting different organs. Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls. All carcinogens increased Ki-67(+), nuclear Cdc2(+), p-Histone H3(+) or Aurora B(+) carcinogenic target cells, except for both colon carcinogens, which did not increase cell proliferation. On the other hand, p21(Cip1+) cells increased with SDM and CC. HP1α responded only to BHA. Results revealed carcinogens evoking cell proliferation concurrently induced cell cycle arrest at M phase or showing chromosomal instability reflecting aberration in cell cycle regulation, irrespective of target organs, after 28-day treatment. Therefore, M phase proteins may be early prediction markers of carcinogens evoking cell proliferation in many target organs.

Aberrant activation of ubiquitin D at G2 phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats.

We have previously reported that renal carcinogens examined in rats increase tubular cell proliferation and topoisomerase (Topo) IIα(+) cells. The present study was aimed at identifying early prediction markers of carcinogens after 28-day treatment in rats. Following gene expression screening by microarrays in renal tubules with renal carcinogens, immunohistochemical analysis and TUNEL-assay were performed with carcinogens targeting different organs. All renal carcinogens tested (ferric nitrilotriacetic acid, ochratoxin A (OTA), monuron, tris(2-chloroethyl) phosphate, and potassium bromate) increased tubular cells immunoreactive for minichromosome maintenance 3 (Mcm3) or ubiquitin D (Ubd) or those showing apoptosis, compared with untreated controls or non-carcinogenic renal toxicants. Carcinogens targeting the liver (thioacetamide (TAA), fenbendazole, piperonyl butoxide (PBO) and methyleugenol), thyroid (sulfadimethoxine), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole), glandular stomach (catechol), and colon (chenodeoxycholic acid and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) were examined for induction of Mcm3, Ubd, Topo IIα, Ki-67 and apoptosis using non-carcinogenic toxicants as negative controls. All carcinogens increased Mcm3(+), Ubd(+), Topo IIα(+), Ki-67(+) or TUNEL(+) cells, except for hepatocarcinogen PBO and both colon carcinogens, which did not increase cell proliferation. Ubd(+) cells co-expressing Topo IIα was increased without changing phospho-Histone H3-co-expressing cell population as examined with OTA and TAA. Results revealed cooperative responses of Topo IIα, Ubd and apoptosis by carcinogens inducing high proliferation activity, irrespective of target organs, examined here after a 28-day administration. Aberrant expression of Ubd at G(2) phase and increased apoptosis reflecting aberrant cell cycle regulation may be the common feature of these carcinogens.

Induction of ovarian toxicity in a subchronic oral toxicity study of citrinin in female BALB/c mice.

The present study was performed to elucidate toxicity profile of citrinin (CTN) after repeated oral doses for 90 days, especially on the kidneys and female reproductive organs using female BALB/c mice. We first performed a 70-day repeated oral dose toxicity study of CTN by setting the doses at 1.25 and 7.5 ppm in the drinking water (Experiment 1). As a result, CTN did not produce any toxicity in the kidneys, liver, and female genital organs/tracts, except for a slight increase of relative ovary weight. We, next, performed 90-day repeated oral dose toxicity study of CTN by increasing the dose levels at 15 and 30 ppm in the drinking water. The results suggested that CTN did not produce any toxicity in the kidneys, liver, and female genital organs/tracts, except for increase of both absolute and relative ovary weights accompanying increase of large follicles at ≥ 15 ppm. On the basis of these findings, the lowest-observable-adverse-effect level of CTN was 15 ppm (2.25 mg/kg body weight/day) in the drinking water for female BALB/c mice after 90-day oral treatment.

Enhanced liver tumor promotion but not liver initiation activity in rats subjected to combined administration of omeprazole and ß-naphthoflavone.

Omeprazole (OPZ) and ß-naphthoflavone (BNF) are cytochrome P450 (CYP)1A inducers and have liver tumor promoting effects. In this study, we investigated the co-promoting and co-initiating effects of OPZ and BNF in rats. In Experiment 1, male rats were subjected to partial hepatectomy (PH), and given oral doses of 138 or 276 mg/kg OPZ, 0.125% or 0.25% BNF or 138 mg/kg OPZ+0.125% BNF (n = 9~12) for 6 weeks after N-diethylnitrosamine (DEN) initiation. In Experiment 2, male rats were treated with oral doses of 138 or 276 mg/kg OPZ, 0.03% or 0.06% BNF or 138 mg/kg OPZ+0.03% BNF (n = 11~12) for 9 days starting 1 week before initiating treatment. As an initiating treatment, 2-Amino-3,4-dimethylimidazo[4,5-f]quinolone (MeIQx) was orally administered 12 hr after PH. The rats were fed a basal diet for 15 days, followed by a diet containing 0.015% 2-acetylaminofluorene for the next 10 days with a single oral dose of carbon tetrachloride. In Experiment 1, the number and area of glutathione S-transferase placental form-positive foci in the OPZ+BNF group were significantly higher than the average values of the High OPZ or the High BNF group. The expression of cyclooxygenase-2 (Cox-2) and COX-2 protein in the liver significantly increased in the OPZ+BNF group. In Experiment 2, liver initiation activity was not enhanced by the co-administration of OPZ+BNF. The results of our studies suggest that the co-administration of OPZ and BNF results in synergistic effects in the liver tumor promotion probably owing to increased COX-2 expression, but no modifying effect in the liver initiation activity of MeIQx in rats.

Nutritional status in relation to adipokines and oxidative stress is associated with disease activity in patients with rheumatoid arthritis.

OBJECTIVE: We assessed whether disease activity was associated with dietary habits, nutritional status, adipokines, and oxidative stress in patients with rheumatoid arthritis. METHODS: The subjects were 37 patients with RA. The assessment of the nutritional status included anthropometric and biochemical parameters. A food-frequency questionnaire and a 3-d diet record to assess dietary intake were used. The serum levels of adipokines and oxidative stress markers in sera and saliva were measured. The disease activity was determined using the 28 Disease Activity Score (DAS28). We divided the subjects into high (DAS28 ≥3.2) and low (DAS28 <3.2) disease activity groups. RESULTS: The serum leptin and albumin levels were significantly lower, whereas the inflammatory markers were increased, in the high disease activity group. The dietary intake assessment showed a lower intake of fish oil and a lower ratio of monounsaturated fatty acid intake in the high disease activity group. There was a negative correlation between the DAS28 and the dietary intake of the ratio of monounsaturated fatty acid to total fatty acid intake. The serum oxidative stress marker (reactive oxygen metabolites) showed a positive correlation to the DAS28. The salivary reactive oxygen metabolites also correlated with C-reactive protein and serum reactive oxygen metabolites. CONCLUSION: Altered serum adipokine levels with decreased albumin may reflect the deterioration that is associated with rheumatoid arthritis. An increased oxidative stress was observed in sera and saliva. Intakes of ω-3 polyunsaturated fatty acids, fish oil, and monounsaturated fatty acid seem to affect disease activity and may have beneficial effects by decreasing inflammation.