Association between DNA methylation levels of thioredoxin-interacting protein (TXNIP) and changes in glycemic traits: a longitudinal population-based study.

Thioredoxin-interacting protein (TXNIP) plays an important role in glucose metabolism, and its expression is regulated by DNA methylation (DNAm). Although the association between TXNIP DNAm and type 2 diabetes mellitus has been demonstrated in studies with a cross-sectional design, prospective studies are needed. We therefore examined the association between TXNIP DNAm levels and longitudinal changes in glycemic traits by conducting a longitudinal study involving 169 subjects who underwent two health checkups in 2015 and 2019. We used a pyrosequencing assay to determine TXNIP DNAm levels in leukocytes (cg19693031). Logistic regression analyses were performed to assess the associations between dichotomized TXNIP DNAm levels and marked increases in glycemic traits. At four years, the TXNIP DNA hypomethylation group had a higher percentage of changes in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) compared to those in the hypermethylation group. The adjusted odds ratios for FPG and HbA1c levels were significantly higher in the TXNIP DNA hypomethylation group than in the hypermethylation group. We found that TXNIP DNA hypomethylation at baseline was associated with a marked increase in glycemic traits. Leukocyte TXNIP DNAm status could potentially be used as an early biomarker for impaired glucose homeostasis.

Long-Term Resveratrol Intake for Cognitive and Cerebral Blood Flow Impairment in Carotid Artery Stenosis/Occlusion.

BACKGROUND AND PURPOSE: Carotid artery stenosis or occlusion (CASO) is a causative disease of vascular cognitive impairment (VCI) attributed to cerebral hypoperfusion, even without the development of symptomatic ischemic stroke. Preclinically, resveratrol has been demonstrated to play an important role in improving cognitive function in rodent CASO models. This study investigated the association between long-term resveratrol intake and improvements in cognitive and cerebral hemodynamic impairments in patients with CASO. METHODS: A retrospective cohort study was conducted on patients with asymptomatic carotid artery stenosis of ≥50% or occlusion who underwent 15O-gas positron emission tomography (15O-gas PET) and neuropsychological tests such as Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog) twice between July 2020 and March 2022 allowing >125-day interval. Patients were administered 30 mg/day resveratrol after the first 15O-gas PET and neuropsychological tests were compared with those who were not. RESULTS: A total of 79 patients were enrolled in this study; 36 received resveratrol and 43 did not. Over a mean follow-up of 221.2 and 244.8 days, long-term resveratrol treatment significantly improved visuospatial/executive function (P=0.020) in MoCA, and memory domain (P=0.007) and total score (P=0.019) in ADAS-Cog. Cerebral blood flow demonstrated improvement in the right frontal lobe (P=0.027), left lenticular nucleus (P=0.009), right thalamus (P=0.035), and left thalamus (P=0.010) on 15O-gas PET. No adverse events were reported. CONCLUSION: Long-term daily intake of oral resveratrol may prevent or treat VCI by improving the cerebral blood flow in asymptomatic patients with CASO.

Low mitochondrial DNA copy number in peripheral blood mononuclear cells is associated with future mortality risk: a long-term follow-up study from Japan.

OBJECTIVES: The mitochondrial DNA (mtDNA) is unique and circular with multiple copies of the genome. The lower mtDNA copy number (mtDNA-CN) in leukocytes is associated with the risk of all-cause mortality. However, its long-term association is unknown. Thus, the study examined the association between mtDNA-CN and the risk of all-cause mortality in a long-term follow-up study in the Japanese population. DESIGN: This longitudinal study included the study cohort from an annual, population-based health checkup in the town of Yakumo, Hokkaido, Japan. SETTING AND PARTICIPANTS: 814 participants (baseline age range: 38-80 years, mean: 56.3 years) were included in this study in 1990. They were followed-up regarding mortality for about 30 years (median: 28.1 years) till 2019. MEASURES: The genomic DNA was extracted from peripheral blood mononuclear cells and the mtDNA-CN was measured using real-time polymerase chain reaction. The level of the mtDNA-CN was divided into tertiles (low, middle, and high). The participants were categorized based on their age into middle-aged (<60 years old) or old-aged (≥60 years old). Survival analysis was performed for tertile of mtDNA-CN and compared using the log-rank test. Univariate and multivariable Cox proportional hazard regression analyses were performed to assess the association between mtDNA-CN and all-cause mortality. The model adjusted with age, sex, body mass index, systolic blood pressure, smoking habit, alcohol consumption, exercise habit, and education level. RESULTS: The low levels of mtDNA-CN resulted in a significant decrease in cumulative survival rate (P < 0.05). The risk of mortality was significantly higher in the middle-aged cohort when mtDNA-CN levels were low (hazard ratios [95% confidence intervals]: 1.98 [1.10-3.56]). CONCLUSION: This study demonstrated that leukocyte mtDNA-CN is associated with future mortality risk. Our study findings may lead to further research on the early prediction of mortality and its underlying mechanisms.

Radiological Findings of the Lumbar Spine in High School and Collegiate Sumo Wrestlers.

Background: Sumo wrestling is a traditional sport in Japan and becoming popular worldwide. Risk factors for lower back injuries in sumo wrestlers are heavier weight and larger body mass index (BMI). The mawashi (loincloth belt) worn by sumo wrestlers has been shown to restrict motion of the lumbar spine. Purpose: To study the effects of sumo wrestling on the lumbar spine of high school and freshmen collegiate wrestlers, investigating the relationship between radiological findings, wearing of the mawashi during training, and lower back symptoms. Study Design: Case series; Level of evidence, 4. Methods: From 2001 to 2017, a total of 197 members of the Japanese Sumo Federation (55 high school and 142 college freshman students) underwent routine radiographic examination of their lumbar spines and answered a questionnaire regarding lumbar symptoms. Wrestlers were classified as symptomatic and asymptomatic based on responses to a custom questionnaire. We used the unpaired t test to evaluate patient demographics and the chi square test to analyze radiographic lumbar spine abnormalities between symptomatic and asymptomatic wrestlers. Results: The wrestlers' mean height, weight, BMI, and duration in the sport were 174.0 ± 6.7 cm, 107.1 ± 22.4 kg, 35.2 ± 6.4, and 8.0 ± 3.2 years, respectively. There were 91 participants in the symptomatic group (46.2%) and 106 (53.8%) in the asymptomatic group. Ten wrestlers (5.1%) had osteophyte formations in the lumbar body; 8 of the 11 osteophytes (72.7%) appeared in the upper lumbar spine. Of the total, 48 wrestlers (24.4%) had deformities (Schmorl nodules) in the lumbar body, and 23 of 50 (46.0%) and 10 of 16 (62.5%) deformities were found in the upper lumbar spine of collegiate and high school wrestlers, respectively. Five wrestlers of the total 197 athletes (2.5%) had disc space narrowing in the lumbar body, with 3 of the 5 cases of disc space narrowing (60.0%) found in the upper lumbar spine. Spondylolysis in the lumbar body was found in 25 wrestlers (12.7%); 19 of the 91 symptomatic wrestlers (20.9%) had spondylolysis, compared with 6 of the 106 (5.7%) asymptomatic wrestlers (P = .0028). Conclusion: Almost one-third of sumo wrestlers had ≥1 abnormal radiological finding in the lumbar spine. There was a significant relationship between symptomatic wrestlers and spondylolysis.

The Ratio of miR-122 to miR-20a (miR-122/miR-20a) Is a Useful Minimally Invasive Biomarker for Non-Alcoholic Fatty Liver Disease Detection.

Background: The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) has become a global health problem. NAFLD has few initial symptoms and may be difficult to detect early, so there is need for a minimally invasive early detection marker. We hypothesized that miR-122 and miR-20a levels combined, as the miR-122/miR-20a ratio might detect NAFLD more sensitively. Methods: This study involved 167 participants with low alcohol intake. Those who had an increase in echogenicity of the liver parenchyma and hepato-renal contrast on ultrasonography were classified as the NAFLD group (n = 44), which was further classified into mild (n = 26) and severe (n = 18) groups based on echogenic intensity and hepatic vessel and diaphragm visualization. Participants without fatty liver were included in the normal group, except for those with an abnormal body mass index, glycated hemoglobin, and systolic blood pressure (n = 123) values. Serum miR-122 and miR-20a expression levels in participants were measured by real-time polymerase chain reaction, and the miR-122/miR-20a was calculated. Results: In the NAFLD group, miR-122 expression was significantly higher and the miR-20a was significantly lower than in the normal group, in agreement with previous studies. miR-122/miR-20a was also significantly higher in the NAFLD group. Receiver operating characteristic curve analysis was performed with miR-122/miR-20a as an NAFLD detection marker, and the area under the curve of miR-122/miR-20a was significantly larger than that of miR-122 or miR-20a alone. Conclusions: The miR-122/miR-20a ratio, combined with miR-122 and miR-20a levels, is a useful biomarker to detect NAFLD with high sensitivity.

Maternal High-Fructose Corn Syrup Intake Impairs Corticosterone Clearance by Reducing Renal 11ß-Hsd2 Activity via miR-27a-Mediated Mechanism in Rat Offspring.

We previously reported that maternal fructose consumption increases blood corticosterone levels in rat offspring. However, the underlying mechanism of action remains unclear. In the present study, we aimed to elucidate the molecular mechanism by which maternal high-fructose corn syrup (HFCS) intake increases circulating GC levels in rat offspring (GC; corticosterone in rodents and cortisol in humans). Female Sprague Dawley rats received HFCS solution during gestation and lactation. The male offspring were fed distilled water from weaning to 60 days of age. We investigated the activities of GC-metabolizing enzymes (11ß-Hsd1 and 11ß-Hsd2) in various tissues (i.e., liver, kidney, adrenal glands, muscle, and white adipose tissue) and epigenetic modification. 11ß-Hsd2 activity decreased in the kidney of the HFCS-fed dams. Moreover, the epigenetic analysis suggested that miR-27a reduced Hsd11b2 mRNA expression in the kidney of offspring. Maternal HFCS-induced elevation of circulating GC levels in offspring may be explained by a decrease in 11ß-Hsd2 activity via renal miR-27a expression. The present study may allow us to determine one of the mechanisms of GC elevation in rat offspring that is often observed in the developmental origins of the health and disease (DOHaD) phenomenon.

Intake of vegetables and fruits rich in provitamin A is positively associated with aryl hydrocarbon receptor repressor DNA methylation in a Japanese population.

DNA methylation can be affected by numerous lifestyle factors, including diet. Tobacco smoking induces aryl hydrocarbon receptor repressor (AHRR) DNA hypomethylation, which increases the risk of lung and other cancers. However, no lifestyle habits that might increase or restore percentage of AHRR DNA methylation have been identified. We hypothesized that dietary intakes of vegetables/fruits and serum carotenoid concentrations are related to AHRR DNA methylation. A total of 813 individuals participated in this cross-sectional study. A food frequency questionnaire was used to assess dietary intake of vegetables and fruits. AHRR DNA methylation in peripheral blood mononuclear cells were measured using pyrosequencing method. In men, dietary fruit intake was significantly and positively associated with AHRR DNA methylation among current smokers (P for trend = .034). A significant positive association of serum provitamin A with AHRR DNA methylation was observed among current smokers (men: standardized ß = 0.141 [0.045 to 0.237], women: standardized ß = 0.570 [0.153 to 0.990]). However, compared with never smokers with low provitamin A concentrations, percentages of AHRR DNA methylation were much lower among current smokers, even those with high provitamin A concentrations (men: ß = -19.1% [-33.8 to -19.8], women: ß = -6.0% [-10.2 to -1.7]). Dietary intake of vegetables and fruits rich in provitamin A may increase percentage of AHRR DNA methylation in current smokers. However, although we found a beneficial effect of provitamin A on AHRR DNA methylation, this beneficial effect could not completely remove the effect of smoking on AHRR DNA demethylation.

Radiological osteoarthritic knee joint changes in high school and collegiate sumo wrestlers: The observational study.

We examined the effects of sumo on their knee joints, and investigated the relationship between radiological changes and knee joints symptoms, and the relationship between knee radiological changes and the physical characteristics of the wrestlers. Fifty-six high-school and 128 college freshman sumo wrestlers who belonged to the Japanese Sumo Federation. To evaluate radiological changes in the knee joints of high-school and college freshmen sumo wrestlers. They underwent routine radiographic examination of their knee joints and were instructed to answer a questionnaire regarding their knee symptoms as a medical check. The mean height, weight, body mass index (BMI), and sumo career/experience of the participants were 174.1 cm, 106.9 kg, 35.1 kg/m2, and 7.9 years, respectively. Twenty-five high-school (44.6%) and 54 collegiate (42.2%) sumo wrestlers had some knee symptoms, which was significantly associated with sumo career as a risk factor. Five high-school (8.9 %) and 18 collegiate (14.1 %) sumo wrestlers had joint space narrowing. Considering the relationship between knee symptoms and radiological changes, significant correlations between osteophyte formation and bony sclerosis and knee symptoms were observed. According to the Kellgren-Laurence (KL) classification, 7 high-school (12.5%) and 26 collegiate (20.3%) sumo wrestlers were grade 2, 3, or 4. The risk factors of degenerative radiographic changes in the knee joints of the participants were heavyweight, large BMI, and older age. The knee osteoarthritic changes had already appeared in 12.5% high-school sumo wrestlers at the admission.

Increased risk of cancer mortality by smoking-induced aryl hydrocarbon receptor repressor DNA hypomethylation in Japanese population: A long-term cohort study.

BACKGROUND: Smoking is well known to be a major risk factor for cancer, and to decrease the levels of aryl hydrocarbon receptor repressor (AHRR) DNA methylation. AHRR is a key regulator for AHR signaling, which is involved in chemical metabolism and cancer development. Therefore, smoking-induced AHRR DNA hypomethylation may be associated with cancer development. However, it has not been reported that association between AHHR DNA methylation and cancer mortality in Asian population. Hence, we examined whether AHRR DNA methylation levels were associated with cancer mortality in a Japanese population. METHODS: This study was conducted with 812 participants (aged 38-80 years) who received a health check-up in 1990, and did not have a clinical histories. We followed up the participants until the end of 2019 (median: 27.8 years), and 100 participants died from cancer. The AHRR DNA methylation levels in peripheral blood mononuclear cells (PBMCs) were measured by the pyrosequencing method. We calculated the hazard ratio (HR) and 95% confidence interval (CI) for cancer mortality according to the baseline levels of AHRR DNA methylation. RESULTS: We found that AHRR DNA hypomethylation was associated with a higher risk of all cancer mortality, especially smoking related cancers and lung cancer. (all cancer: HR, 1.28, 95% CI, 1.09-1.51; smoking-related cancers: HR, 1.35, 95% CI, 1.12-1.62; lung cancer: HR, 1.68, 95% CI, 1.24-2.26). CONCLUSIONS: Smoking-induced AHRR DNA hypomethylation in PBMCs was associated with the risk of cancer mortality in Japanese population; therefore, hypomethylation of AHRR may be a useful biomarker of cancer mortality risk.

Association of drinking behaviors with TXNIP DNA methylation levels in leukocytes among the general Japanese population.

Background: Thioredoxin-interacting protein (TXNIP) controls the cellular redox balance by binding to and inhibiting the expression and function of thioredoxin. DNA methylation of the TXNIP gene is involved in the regulation of TXNIP mRNA expression. Changes in TXNIP DNA methylation levels are associated with the development of various diseases such as type 2 diabetes mellitus (T2DM). However, few studies have focused on the influence of lifestyle factors such as alcohol intake on TXNIP DNA methylation.Objectives: This research examines the association of drinking behaviors with TXNIP DNA methylation levels in the general Japanese population.Methods: We conducted a cross-sectional study of 404 subjects (176 males and 228 females) who were divided into non-, moderate and heavy drinkers based on self-reported drinking behaviors. TXNIP DNA methylation levels in leukocytes were determined using a pyrosequencing assay.Results: The mean TXNIP DNA methylation level in heavy drinkers (74.2%) was significantly lower than that in non- and moderate drinkers (non: 77.7%, p < .001; moderate: 76.6%, p = .011). Multivariable linear regression analysis showed that log-transformed values of daily (b = -1.34; p < .001) and cumulative (b = -1.06; p = .001) alcohol consumption were associated with decreased TXNIP DNA methylation levels.Conclusion: TXNIP DNA methylation levels in heavy drinkers was lower than in non- and- moderate drinkers. Decreased TXNIP DNA methylation level increases the expression of TXNIP and elevates the risk of developing of diseases such as T2DM. Therefore, decreasing alcohol use in heavy drinkers may lessen the likelihood of some alcohol-related illnesses moderated through TXNIP DNA methylation.

Increased brain-derived neurotrophic factor in the serum of persons with nonalcoholic fatty liver disease.

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) is a global health problem. In recent years, the inhibitory effect of brain-derived neurotrophic factor (BDNF) on diabetes mellitus and fatty liver has been clarified. The purpose of this study was to analyze the relationship between serum BDNF and NAFLD which caused by abnormal metabolism of glucose and lipids. This cross-sectional study involved 429 participants (mean age, 63.5 years: men, 38.5%) with low alcohol intake. Of the participants, those who had an increase in echogenicity of the liver parenchyma and hepato-renal contrast on ultrasonography were classified as the NAFLD group (n = 88), and the others were classified as the normal (n = 341) group. The NAFLD group was further classified into a mild group (n = 60) and a severe group (n = 28) based on the intensity of echogenicity and visualization of the hepatic vessels and diaphragm. Median BDNF levels were higher in the NAFLD group than the normal group (35.5 vs. 42.3 ng/mL, p < 0.01). Furthermore, BDNF levels tended to be associated with the severity of NAFLD (p < 0.01). In addition to the univariate analysis, in the sex- and age-adjusted model, there was a significant association between the BDNF levels and NAFLD severity (p < 0.01). The fully adjusted regression analysis also showed a positive association between the serum BDNF level and NAFLD (p < 0.01). These results suggest that NAFLD patients have a compensatory increase in circulating BDNF levels.

Maternal fructose intake predisposes rat offspring to metabolic disorders via abnormal hepatic programming.

Given that fructose consumption has increased by more than 10-fold in recent decades, it is possible that excess maternal fructose consumption causes harmful effects in the next generation. This study attempted to elucidate the mechanism of the harmful effects of excessive maternal fructose intake from the perspective of offspring liver function. Female rats during gestation and lactation were fed water containing fructose, and their offspring were fed normal water. We attempted to elucidate the mechanism of fructose-induced transgenerational toxicity by conducting a longitudinal study focusing on hepatic programming prior to disease onset. Impaired Insulin resistance and decreased high-density lipoprotein-cholesterol levels were observed at 160 days of age. However, metabolic disorders were not observed in 60-day-old offspring. Microarray analysis of 60-day-old offspring livers showed the reduction of hepatic insulin-like growth factor-1 (Igf1) mRNA expression. This reduction continued until the rats were aged 160 days and attenuated Igf1 signaling. Hepatic microRNA-29 (miR-29a) and miR-130a, which target Igf1 mRNA, were also found to be upregulated. Interestingly, these miRNAs were upregulated in the absence of metabolic disorder. In this study, we found that maternal fructose intake resulted in dysregulated expression of Igf1 and its target miRNAs in the offspring liver, and that these offspring were more likely to develop metabolic disorders. Abnormal hepatic programming induced by an imbalanced maternal nutritional environment is maintained throughout life, implying that it may contribute to metabolic disorders.

Maternal fructose consumption downregulates hippocampal catalase expression via DNA methylation in rat offspring.

Some studies have demonstrated that excessive fructose consumption negatively impact brain function. Recently, the Developmental Origins of Health and Disease hypothesis - which suggests that maternal nutritional status during gestation and lactation can alter offspring phenotype - has received much attention. In a previous study, we demonstrated that maternal fructose consumption increases levels of lipid peroxides in hippocampi of offspring. The hypothesis in the present study was that maternal fructose intake would affect hippocampal antioxidant enzyme via epigenetic regulation. Upon confirmation of gestation, female rats were assigned to receive either water (control group) or a 20% fructose solution (fructose-fed group). Water or fructose solution were administered to dams from day 1 of gestation to postnatal day 21. Immediately after weaning, hippocampi of offspring were removed for analysis of antioxidant enzyme (Sod1, Sod2, Gpx1, Gpx4, and Cat) messenger RNA transcript levels. Levels of the Cat transcript were significantly lower in the fructose-fed relative to the control group. The Cat protein level was also significantly lower in the fructose-fed relative to the control group as with the messenger RNA transcript levels. Moreover, Cat promoter DNA methylation levels were higher in the fructose-fed group. The present study indicates that maternal fructose consumption may decrease offspring hippocampal Cat transcript levels via altered DNA methylation, which may result in higher levels of oxidative stress due to a decreased ability to neutralize lipid peroxides.

Discontinuation of oral amphotericin B therapy does not influence the pharmacokinetics of tacrolimus in heart transplant patients.

OBJECTIVE: Amphotericin B (AMPH-B) is used to prevent opportunistic infections associated with immunosuppressive therapy after heart transplantation (HTx), while the blood concentrations of tacrolimus (TAC) are carefully controlled. Although AMPH-B has the potential to inhibit TAC metabolism in in vitro studies, its interaction with clinically used AMPH-B oral suspension has not been investigated. In the present study, we examined whether oral AMPH-B therapy influences the pharmacokinetics of TAC in HTx patients. MATERIALS AND METHODS: A retrospective study was performed at the National Cerebral and Cardiovascular Center in Japan. All patients with HTx enrolled in the study received standard triple-drug immunosuppression therapy including the regular release of TAC, mycophenolate mofetil, and prednisolone as well as prophylactic therapy with AMPH-B oral suspension. Patient characteristics and clinical laboratory data were collected from the electronic medical record system. Blood concentrations of TAC were used for pharmacokinetic analysis. RESULTS: A total of 14 patients were enrolled in the study. There were no statistically significant differences in the variables except for serum creatinine levels and eGFR before and after discontinuation of oral AMPH-B therapy. The dose and trough concentrations of TAC and the area under the time-concentration curve and apparent oral clearance calculated from its concentrations were not influenced by discontinuation of AMPH-B treatment. CONCLUSION: The prophylactic treatment with AMPH-B oral suspension did not influence the pharmacokinetics of TAC and was demonstrated as a safe and easy method to prevent early post-HTx fungal infection.

Maternal high-fructose intake increases circulating corticosterone levels via decreased adrenal corticosterone clearance in adult offspring.

Global fructose consumption is on the rise; however, maternal high-fructose intake may have adverse effects on offspring. We previously demonstrated that excessive fructose intake by rat dams altered steroidogenic gene transcription in the hippocampus of offspring. Herein, we examined how maternal high-fructose intake influences the regulation of adrenal glucocorticoid levels in offspring. Rat dams received 20% fructose solution during gestation and lactation. After weaning, the offspring were provided normal water. Maternal high-fructose intake did not alter mRNA expression levels of adrenal corticosterone-synthesizing and corticosterone-inactivating proteins or the circulating adrenocorticotropic hormone levels of offspring at postnatal day (PD) 21; however, it increased circulating corticosterone levels and decreased mRNA and protein levels of adrenal 5α-reductase type 1 and 11ß-hydroxysteroid dehydrogenase type 2 in offspring at PD160. Furthermore, maternal high-fructose intake enhanced DNA methylation of the adrenal 5α-reductase 1 promoter region in PD160 offspring. Thus, maternal high-fructose intake was found to affect adrenal steroid hormone clearance in adult offspring - at least in part - through epigenetic mechanisms.

Optimization of ionic liquid-incorporated PLGA nanoparticles for treatment of biofilm infections.

Ionic liquids (ILs) containing imidazolium cations have a number of useful properties, such as high permeability to cells, high antimicrobial activity, and good biocompatibility. With the aid of ILs, transdermal delivery, solubilization of poorly soluble drugs were developed and therapeutic effects were improved. In this work, 1­butyl­3­methylimidazolium hexafluorophosphate-incorporated, chitosan-modified, submicron-sized poly(dl­lactide­co­glycolide) (PLGA) nanoparticles (NPs) were prepared using the emulsion solvent diffusion method for the treatment of biofilm infections. Prepared IL-incorporated PLGA NPs using surfactants such as Tween-80 and poloxamer-188 showed a high antibacterial activity to the bacterial cells under the biofilm. Additionally, antibacterial mechanism of IL-incorporated PLGA NPs was revealed by annular dark field scanning transmission electron microscopy combined a simple sample pretreatment method. We established a drug delivery system using IL-incorporated PLGA NPs to enhance the potential of polymeric nanocarriers for treating biofilm infections.

Intravenous lipid emulsion therapy for acute clomipramine intoxication in rats.

AIM: In this study, to assess the utility of lipid emulsion (ILE) therapy as a treatment option for overdoses of lipophilic drugs, we examined the detoxification effect of ILE therapy in rats that were administered overdoses of the tricyclic antidepressant clomipramine hydrochloride (CMI). METHODS: Female Wistar rats were orally administered 50 mg/kg CMI five times in 2-h intervals to examine whether intralipos accelerated the elimination of CMI in the peripheral blood. Rats were divided into the intralipos (i.v. 2 g/kg intralipos) and placebo (i.v. saline) groups. The concentrations of CMI and desmethylclomipramine (DMCMI), a metabolite of CMI, in blood were measured over time by high-performance liquid chromatography. We then gave the animals 100 mg/kg CMI orally to examine whether intralipos could inhibit the distribution of CMI. The CMI and DMCMI concentrations in peripheral blood, liver, and brain were measured 60 min after intralipos administration. RESULTS: The blood concentration of CMI was significantly higher in the intralipos group than in the placebo group at 60 and 120 min. After a single administration of 100 mg/kg CMI, the ratio of the concentration of CMI in liver/serum was significantly lower in the intralipos group than in the placebo group. We also found a significantly faster elimination rate for CMI in peripheral blood in the intralipos group than in the placebo group. CONCLUSION: The distribution of CMI from blood to tissue was suppressed by intralipos. Therefore, ILE therapy is a promising candidate for the treatment of overdoses of lipophilic drugs.

Maternal fructose intake disturbs ovarian estradiol synthesis in rats.

AIMS: Recent increases in fructose consumption have raised concerns regarding the potential adverse intergenerational effects, as maternal fructose intake may induce physiological dysfunction in offspring. However, no reports are available regarding the effect of excess maternal fructose on reproductive tissues such as the ovary. Notably, the maternal intrauterine environment has been demonstrated to affect ovarian development in the subsequent generation. Given the fructose is transferred to the fetus, excess fructose consumption may affect offspring ovarian development. As ovarian development and its function is maintained by 17ß-estradiol, we therefore investigated whether excess maternal fructose intake influences offspring ovarian estradiol synthesis. Rats received a 20% fructose solution during gestation and lactation. After weaning, offspring ovaries were isolated. KEY FINDINGS: Offspring from fructose-fed dams showed reduced StAR and P450(17α) mRNA levels, along with decreased protein expression levels. Conversely, attenuated P450arom protein level was found in the absence of mRNA expression alteration. Consistent with these phenomena, decreased circulating levels of estradiol were observed. Furthermore, estrogen receptor α (ERα) protein levels were also down-regulated. In accordance, the mRNA for progesterone receptor, a transcriptional target of ERα, was decreased. These results suggest that maternal fructose might alter ovarian physiology in the subsequent generation.

Radiological Changes in the Cervical Spine in Freshman Collegiate Sumo Wrestlers.

BACKGROUND: Sumo has long been a traditional sport in Japan and is rapidly attracting enthusiasts abroad. Sumo wrestling entails a risk of impact to the cervical spine during an initial charge. Few reports are available in the English-language literature regarding radiological changes in the cervical spine in sumo wrestlers. PURPOSE: To examine radiological changes in the cervical spine in freshmen collegiate sumo wrestlers. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 53 freshmen sumo wrestlers (age, 18-19 years) who belonged to the Japan Sumo Federation underwent routine radiographic examination of the cervical spine and completed questionnaires on cervical symptoms. RESULTS: Of the 53 wrestlers, 81% showed loss of lordosis, 45% showed osteophyte formation (mainly at C3-C4), 11% showed disc space narrowing (mainly at C5-C6), and 51% showed narrowing of the cervical nerve root foramina (mainly at C3-C4). Fifty-one percent had some cervical symptoms. A correlation was found between deformity of the cervical bodies (such as intervertebral disc ballooning) and cervical symptoms, but no correlation was found between cervical degenerative changes and cervical symptoms. CONCLUSION: Our data suggest that loss of lordosis, osteophyte formation, and narrowing of the cervical nerve root foramina at C3-C4 were frequently present in freshmen wrestlers and may be due to the axial load incurred prior to their collegiate careers.

Effect of lipid emulsion during resuscitation of a patient with cardiac arrest after overdose of chlorpromazine and mirtazapine.

No specific treatment exists for poisoning with most fat-soluble drugs. Intravenous lipid emulsion (ILE) may be effective therapy against such drugs, but effects of ILE treatment are unclear. A 24-year-old woman with depression seen sleeping in the morning was found comatose in the evening, and an emerging lifesaving technologies service was called. After emerging lifesaving technologies departure to hospital, she stopped breathing, became pulseless, and cardiopulmonary life support was started immediately. Electrocardiographic monitoring showed asystole during resuscitation even after arrival at hospital. Empty packaging sheets of 60-tablet chlorpromazine (CPZ) (50 mg/tablet) and 66-tablet mirtazapine (MZP) (15 mg/tablet) found at the scene suggested drug-related cardiopulmonary arrest. Along with conventional administration of adrenaline (total dose, 5 mg), 20% Intralipid 100 mLwas given intravenously 8 minutes after hospital arrival and readministered 27 minutes after hospital arrival because of continued asystole. Return of spontaneous circulation occurred 29 minutes after arrival (70 minutes after cardiac arrest). The patient recovered without any major complications and was transferred to another hospital for psychiatric treatment 70 days after admission. Concentrations of CPZ and MZP were still high when return of spontaneous circulation was achieved with ILE. This case suggested the possible benefit of ILE in treating life threatening cardiotoxicity from CPZ and MZP overdose.