Impaired DNA damage repair is a common pathological endophenotype of some types of neurodegenerative diseases, intellectual disabilities, and psychiatric diseases. Dysfunctional DNA repair and DNA ...damage, including DNA double-stranded breaks, are linked to transcriptional dysfunction and abnormal DNA methylation. Impaired DNA repair in neural stem cells leads to microcephaly or cerebellar ataxia. Furthermore, DNA repair defects and DNA damage in mature neurons lead to progressive cognitive impairment, which might be a common feature of Alzheimer's disease, Huntington's disease, and other polyglutamine diseases. Oxidative DNA damage and altered DNA repair gene expression are observed in GABAergic neurons in schizophrenia. These findings indicate that impaired DNA repair is a common pathological endophenotype of neurological diseases, and that DNA damage might lead to diverse disease symptoms dependent on timing and the affected cell type.
Various molecular processes including unfolded protein response, protein transport, synaptic transmission and transcription are implicated in the pathology of polyglutamine diseases caused by the ...expanded polyglutamine-containing proteins. More than 20 transcription-related factors have been reported to interact with disease proteins, and the pathological interaction is known to repress gene expression. The whole shape of nuclear events evoked by disease proteins is now emerging with information on these transcription-related factors and with findings on the similarity between nuclear bodies and pathological inclusion bodies. This article reviews 'transcription theory', a rapidly growing hypothesis in polyglutamine diseases.
Super-Kamiokande (SK) can search for weakly interacting massive particles (WIMPs) by detecting neutrinos produced from WIMP annihilations occurring inside the Sun. In this analysis, we include ...neutrino events with interaction vertices in the detector in addition to upward-going muons produced in the surrounding rock. Compared to the previous result, which used the upward-going muons only, the signal acceptances for light (few-GeV/c^{2}-200-GeV/c^{2}) WIMPs are significantly increased. We fit 3903 days of SK data to search for the contribution of neutrinos from WIMP annihilation in the Sun. We found no significant excess over expected atmospheric-neutrino background and the result is interpreted in terms of upper limits on WIMP-nucleon elastic scattering cross sections under different assumptions about the annihilation channel. We set the current best limits on the spin-dependent WIMP-proton cross section for WIMP masses below 200 GeV/c^{2} (at 10 GeV/c^{2}, 1.49×10^{-39} cm^{2} for χχ→bbover ¯ and 1.31×10^{-40} cm^{2} for χχ→τ^{+}τ^{-} annihilation channels), also ruling out some fraction of WIMP candidates with spin-independent coupling in the few-GeV/c^{2} mass range.
Studies in the 1990s demonstrated that misery perfusion is a predictor of subsequent stroke in medically treated patients with symptomatic major cerebral artery disease. A recent randomized ...controlled trial demonstrated no benefit of bypass surgery for such patients. In this light, outcome in patients with misery perfusion has regained interest. The purpose of this study was to determine whether misery perfusion is still a predictor of subsequent stroke despite recent improvements in medical treatment for secondary prevention of stroke, and if so, whether the predictive value of misery perfusion has changed in recent years. We prospectively studied 165 non-disabled patients with symptomatic atherosclerotic internal carotid artery or middle cerebral artery occlusive diseases who underwent positron emission tomography from 1999 to 2008. Misery perfusion was defined as decreased cerebral blood flow, increased oxygen extraction fraction and decreased ratio of cerebral blood flow to blood volume in the hemisphere supplied by the diseased artery. All patients were followed up for 2 years until stroke recurrence or death. Bypass surgery was performed in 19 of 35 patients with and 16 of 130 patients without misery perfusion. The 2-year incidence of ipsilateral ischaemic stroke was six and four patients with and without misery perfusion, including two and one after surgery, respectively (P < 0.002). Total strokes occurred in nine patients with misery perfusion and 12 patients without (P < 0.01). The relative risk conferred by misery perfusion in whole sample was 6.3 (95% confidence interval 1.7-22.4, P < 0.005) for ipsilateral ischaemic stroke and 3.5 (95% confidence interval 1.4-8.9, P < 0.01) for all strokes, while the respective values in medically treated patients were 12.6 (95% confidence interval 2.7-57.8, P < 0.005) and 4.7 (95% confidence interval 1.3-16.3, P < 0.02). The all-stroke incidence in patients entering the study from 2004 to 2008 (4/72) was significantly lower than in those entering from 1999 to 2003 (17/93; P < 0.02), although the prevalence of misery perfusion or bypass surgery did not differ. Between these periods, patients without misery perfusion demonstrated a decrease in stroke rate (from 16.2% to 0%), but patients with misery perfusion did not (26.3 and 25.0%). In symptomatic major cerebral artery disease, misery perfusion remains a predictor of subsequent stroke, although the recurrence rate was lower than the previous study. In patients without misery perfusion, the risk of stroke was reduced over time. Thus, identification and stricter management of patients with misery perfusion are essential to further improve prognosis.
Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We ...conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.
We report an indication that the elastic scattering rate of solar B8 neutrinos with electrons in the Super-Kamiokande detector is larger when the neutrinos pass through Earth during nighttime. We ...determine the day-night asymmetry, defined as the difference of the average day rate and average night rate divided by the average of those two rates, to be -3.2 ± 1.1(stat) ± 0.5(syst)%, which deviates from zero by 2.7 σ. Since the elastic scattering process is mostly sensitive to electron-flavored solar neutrinos, a nonzero day-night asymmetry implies that the flavor oscillations of solar neutrinos are affected by the presence of matter within the neutrinos' flight path. Super-Kamiokande's day-night asymmetry is consistent with neutrino oscillations for 4 × 10(-5) eV(2) ≤ Δm 2(21) ≤ 7 × 10(-5) eV(2) and large mixing values of θ12, at the 68% C.L.
Super-Kamiokande atmospheric neutrino data were fit with an unbinned maximum likelihood method to search for the appearance of tau leptons resulting from the interactions of oscillation-generated tau ...neutrinos in the detector. Relative to the expectation of unity, the tau normalization is found to be 1.42 ± 0.35(stat)(-0.12)(+0.14)(syst) excluding the no-tau-appearance hypothesis, for which the normalization would be zero, at the 3.8σ level. We estimate that 180.1 ± 44.3(stat)(-15.2)(+17.8) (syst) tau leptons were produced in the 22.5 kton fiducial volume of the detector by tau neutrinos during the 2806 day running period. In future analyses, this large sample of selected tau events will allow the study of charged current tau neutrino interaction physics with oscillation produced tau neutrinos.
To evaluate the capability of integrated 2-18F-fluoro-2-deoxy-d-glucose (FDG)-positron-emission tomography (PET)/magnetic resonance imaging (MRI) to characterise the distinct phenotypes of ...endometrial cancer.
Thirty-one patients with endometrial cancer (23 with type I, including 17 G1 and six G2 endometrioid adenocarcinomas, and eight with type II, including three G3 endometrioid adenocarcinomas, two carcinosarcomas, and three serous carcinomas) underwent pretreatment FDG-PET/MRI with simultaneous reduced field-of-view diffusion-weighted imaging (DWI). The standardised uptake value (SUV), apparent diffusion coefficient (ADC), and SUV-to-ADC ratio were compared between low-risk (type I and stage I and negative for lymph–vascular space invasion LVSI) and high-risk cancers. The diagnostic accuracy for discriminating the cancer phenotypes was evaluated using receiver operating characteristic (ROC) analysis.
The SUV was not significantly different between low-risk and high-risk endometrial cancers. High-risk cancers had a significantly lower ADC (756±232×10−6) and a greater SUV-to-ADC ratio (21.7±7.7×109) than low-risk cancers (937±154×10−6, p<0.05 and 13.1±4.1×109, p<0.005, respectively). On comparison of the area under the ROC curves (AUCs), the SUV-to-ADC ratio demonstrated the greatest diagnostic accuracy (ratio 0.83, ADC 0.72, and SUV 0.66). The AUCs for the ratios were significantly higher than those for the SUV values (p<0.05). The optimal SUV-to-ADC cut-off value of 16.9×109 for predicting high-risk cancer revealed a sensitivity of 73%, specificity of 81%, and accuracy of 77%, which was significantly higher than the accuracy for SUV.
The SUV-to-ADC ratio obtained using integrated FDG-PET/MRI with high-resolution DWI reflects tumour aggressiveness including LVSI, and will be useful for lesion characterisation to decide on an appropriate therapeutic strategy for endometrial cancer.
•Integrated FDG-PET/MRI with simultaneous high-resolution DWI characterized the distinct phenotypes of endometrial cancer.•High-risk endometrial cancers had a significantly lower ADC and a greater SUV-to-ADC ratio than low-risk cancers.•SUV-to-ADC ratio demonstrated the greatest diagnostic accuracy for the distinction of endometrial cancer phenotypes.
Oxidative stress, one of the most probable molecular mechanisms for neuronal impairment, is reported to occur in the affected brain regions of various neurodegenerative diseases. Recently, many ...studies showed evidence of a link between oxidative stress or mitochondrial damage and neuronal degeneration. Basic in vitro experiments and postmortem studies demonstrated that biomarkers for oxidative damage can be observed in the pathogenic regions of the brain and the affected neurons. Model animal studies also showed oxidative damage associated with neuronal degeneration. The molecular imaging method with positron emission tomography (PET) is expected to delineate oxidatively stressed microenvironments to elucidate pathophysiological changes of the in vivo brain; however, only a few studies have successfully demonstrated enhanced stress in patients. Radioisotope copper labeled diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) may be the most promising candidate for this oxidative stress imaging. The tracer is usually known as a hypoxic tissue imaging PET probe, but the accumulation mechanism is based on the electron rich environment induced by mitochondrial impairment and/or microsomal over-reduction, and thus it is considered to represent the oxidative stress state correlated with the degree of disease severity. In this review, Cu-ATSM PET is introduced in detail from the basics to practical methods in clinical studies, as well as recent clinical studies on cerebrovascular diseases and neurodegenerative diseases. Several other PET probes are also introduced from the point of view of neuronal oxidative stress imaging. These molecular imaging methods should be promising tools to reveal oxidative injuries in various brain diseases.
Understanding the expression of tumor specific receptors is important not only for tumor diagnosis but also for planning the strategy for patient treatment. Tumor receptor has been one of the most ...critical targets for treatment in cancer such as breast, prostate and thyroid cancers. Positron emission tomography (PET) is a part of molecular imaging techniques based on detecting the radiopharmaceuticals that can capture functional or phenotypic changes associated with pathology. The advantages of detecting tumor specific receptors by PET are its non-invasiveness, providing comprehensive information about receptor expression, avoiding the sampling errors, selecting strategy for the treatment of patients and monitoring tumor response to therapy. Hormonal therapy plays a major role in cancer treatment. Therefore, we review the PET radiopharmaceuticals for sex steroid hormone receptor imaging in this article.
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