Cost-effectiveness analysis comparing repetitive transcranial magnetic stimulation therapy with antidepressant treatment in patients with treatment-resistant depression in Japan.

Repetitive transcranial magnetic stimulation (rTMS) for patients with treatment-resistant depression (TRD) became covered by the National Health Insurance (NHI) in Japan since 2019. Although the evidence of rTMS for TRD is well established, the cost-effectiveness of rTMS versus antidepressants has not been thoroughly analyzed in Japan. Thus, we aimed to evaluate the cost-effectiveness of rTMS for TRD under the NHI system using a microsimulation model to compare the direct costs and quality-adjusted life years (QALYs). Model inputs of clinical parameters and the utility were derived from published literature. Cost parameters were estimated from the Japanese Claim Database. The robustness of the analyses was evaluated with sensitivity analysis and scenario analysis. The analysis estimated that rTMS increased effectiveness by 0.101QALYs and total cost by ¥94,370 ($689) compared with antidepressant medications. As a result, the incremental cost-effectiveness ratio (ICER) of rTMS was estimated to be ¥935,984 ($6,832)/QALY. In the sensitivity and scenario analyses, ICER did not exceed ¥5 million ($36,496)/QALY as the reference value of the Japanese public cost-effectiveness evaluation system. rTMS therapy for TRD can be a cost-effective treatment strategy compared to antidepressant medication under the NHI system in Japan.

Simultaneous monitoring of activity and heart rate variability in depressed patients: A pilot study using a wearable monitor for 3 consecutive days.

INTRODUCTION: Reduced activity and sleep-wake rhythm disturbances are essential features of depressive episodes. In addition, alterations in heart rate variability (HRV) have been implicated in depression. By using a wearable sensor that monitors 3-dimensional acceleration and HRV simultaneously, we examined the activity and HRV indices in depressive episode of mood disorders. METHODS: Participants were 19 patients (13 major depressive disorder [MDD] and 6 bipolar depression; 11 females) and 18 controls (9 females) matched for age and ethnicity (all Japanese) who completed 3 consecutive days of all-day monitoring by a small and light device attached to the chest. RESULTS: Activity magnitude was significantly reduced while lying/resting time was increased in depressed patients, compared with controls. When males and females were examined separately, male, but not female, patients showed significant reduction in activity. HRV indices such as R-R interval and high-frequency power (a parameter for the parasympathetic system) were significantly decreased in patients than in controls. Significant differences in activity and HRV indices were seen only in males. Sympathetic load during sleep significantly correlated with damped rest-activity rhythm in depressed patients. LIMITATIONS: The number of participants was small, and the majority of the participants were taking psychotropic medications. CONCLUSIONS: We obtained evidence for reduced activity, increased lying/resting time, and reduced HRV indices in male depressed patients. The simultaneous monitoring for activity and HRV suggested greater sympathetic load during sleep is associated with damped rest-activity rhythm (increased activity during sleep and decreased daytime activity), which might be a characteristic pathology of depression.

Emotion estimation using a wearable heart rate monitoring device in Asian elephants (Elephas maximus) during veterinary clinical procedures.

Fatal accidents in captive elephants occasionally occur because humans are unable to gauge elephants' emotions solely by their behavior. The intellectual capacity of elephants makes them capable of understanding circumstantial changes and associated emotions, allowing them to react accordingly. Physiological markers, such as heart rate variability, may be effective in determining an elephant's emotional state. In this study, a wearable heart rate monitor was used to determine the emotional state of a female Indian captive elephant (Elephas maximus indicus). The average heart rate was higher when the elephant underwent painful treatment than when it underwent non-painful treatment. In addition, the heart rate increased both before and after the treatment, which included radiography and blood collection.

Estrogen receptor ligands ameliorate fatty liver through a nonclassical estrogen receptor/Liver X receptor pathway in mice.

UNLABELLED: Liver X receptor (LXR) activation stimulates triglyceride (TG) accumulation in the liver. Several lines of evidence indicate that estradiol-17ß (E2) reduces TG levels in the liver; however, the molecular mechanism underlying the E2 effect remains unclear. Here, we show that administration of E2 attenuated sterol regulatory element-binding protein (SREBP)-1 expression and TG accumulation induced by LXR activation in mouse liver. In estrogen receptor alpha (ERα) knockout (KO) and liver-specific ERα KO mice, E2 did not affect SREBP-1 expression or TG levels. Molecular analysis revealed that ERα is recruited to the SREBP-1c promoter through direct binding to LXR and inhibits coactivator recruitment to LXR in an E2-dependent manner. Our findings demonstrate the existence of a novel liver-dependent mechanism controlling TG accumulation through the nonclassical ER/LXR pathway. To confirm that a nonclassical ER/LXR pathway regulates ERα-dependent inhibition of LXR activation, we screened ERα ligands that were able to repress LXR activation without enhancing ERα transcriptional activity, and, as a result, we identified the phytoestrogen, phloretin. In mice, phloretin showed no estrogenic activity; however, it did reduce SREBP-1 expression and TG levels in liver of mice fed a high-fat diet to an extent similar to that of E2. CONCLUSION: We propose that ER ligands reduce TG levels in the liver by inhibiting LXR activation through a nonclassical pathway. Our results also indicate that the effects of ER on TG accumulation can be distinguished from its estrogenic effects by a specific ER ligand.

Global analysis of DNA methylation in early-stage liver fibrosis.

BACKGROUND: Liver fibrosis is caused by chemicals or viral infection. The progression of liver fibrosis results in hepatocellular carcinogenesis in later stages. Recent studies have revealed the importance of DNA hypermethylation in the progression of liver fibrosis to hepatocellular carcinoma (HCC). However, the importance of DNA methylation in the early-stage liver fibrosis remains unclear. METHODS: To address this issue, we used a pathological mouse model of early-stage liver fibrosis that was induced by treatment with carbon tetrachloride (CCl4) for 2 weeks and performed a genome-wide analysis of DNA methylation status. This global analysis of DNA methylation was performed using a combination of methyl-binding protein (MBP)-based high throughput sequencing (MBP-seq) and bioinformatic tools, IPA and Oncomine. To confirm functional aspect of MBP-seq data, we complementary used biochemical methods, such as bisulfite modification and in-vitro-methylation assays. RESULTS: The genome-wide analysis revealed that DNA methylation status was reduced throughout the genome because of CCl4 treatment in the early-stage liver fibrosis. Bioinformatic and biochemical analyses revealed that a gene associated with fibrosis, secreted phosphoprotein 1 (Spp1), which induces inflammation, was hypomethylated and its expression was up-regulated. These results suggest that DNA hypomethylation of the genes responsible for fibrosis may precede the onset of liver fibrosis. Moreover, Spp1 is also known to enhance tumor development. Using the web-based database, we revealed that Spp1 expression is increased in HCC. CONCLUSIONS: Our study suggests that hypomethylation is crucial for the onset of and in the progression of liver fibrosis to HCC. The elucidation of this change in methylation status from the onset of fibrosis and subsequent progression to HCC may lead to a new clinical diagnosis.

Estrogen inhibits transforming growth factor beta signaling by promoting Smad2/3 degradation.

Estrogen is a growth factor that stimulates cell proliferation. The effects of estrogen are mediated through the estrogen receptors, ERalpha and ERbeta, which function as ligand-induced transcription factors and belong to the nuclear receptor superfamily. On the other hand, TGF-beta acts as a cell growth inhibitor, and its signaling is transduced by Smads. Although a number of studies have been made on the cross-talk between estrogen/ERalpha and TGF-beta/Smad signaling, whose molecular mechanisms remain to be determined. Here, we show that ERalpha inhibits TGF-beta signaling by decreasing Smad protein levels. ERalpha-mediated reductions in Smad levels did not require the DNA binding ability of ERalpha, implying that ERalpha opposes the effects of TGF-beta via a novel non-genomic mechanism. Our analysis revealed that ERalpha formed a protein complex with Smad and the ubiquitin ligase Smurf, and enhanced Smad ubiquitination and subsequent degradation in an estrogen-dependent manner. Our observations provide new insight into the molecular mechanisms governing the non-genomic functions of ERalpha.

PPARgamma ligands suppress the feedback loop between E2F2 and cyclin-E1.

PPARgamma is a nuclear hormone receptor that plays a key role in the induction of peroxisome proliferation. A number of studies showed that PPARgamma ligands suppress cell cycle progression; however, the mechanism remains to be determined. Here, we showed that PPARgamma ligand troglitazone inhibited G1/S transition in colon cancer cells, LS174T. Troglitazone did not affect on either expression of CDK inhibitor (p18) or Wnt signaling pathway, indicating that these pathways were not involved in the troglitazone-dependent cell cycle arrest. GeneChip and RT-PCR analyses revealed that troglitazone decreased mRNA levels of cell cycle regulatory factors E2F2 and cyclin-E1 whose expression is activated by E2F2. Down-regulation of E2F2 by troglitazone results in decrease of cyclin-E1 transcription, which could inhibit phosphorylation of Rb protein, and consequently evoke the suppression of E2F2 transcriptional activity. Thus, we propose that troglitazone suppresses the feedback loop containing E2F2, cyclin-E1, and Rb protein.

[Identification and classification of beta-lactamases in clinical isolates of bacteria].

Emergence of bacterial resistance has rendered ineffective a number of previously valuable antibiotic treatments and now threatens the effectiveness of others. beta-Lactam resistance is no longer predominantly a hospital-treated problem; it has now become an important issue in community medicine. More than 100-beta-lactamases have been identified and classified according to their structure, substrate specificity, and whether they are chromosomal or plasmid-mediated. beta-Lactamase production is rare among Gram-positive pathogens, important exceptions being Staphylococcus aureus and Enterococcus faecalis. By contrast, many Gram-negative pathogens are beta-lactamase-positive; inducible and/or hyper-productive strains are particularly challenging in the clinical setting. Surveillance programs have shown that, in general, beta-lactam resistance is on the increase, and that the plasmid-mediated beta-lactamase have developed rapidly over past decade such as ESBLs and carbapenemases.