Knockout-Rescue Embryonic Stem Cell-Derived Mouse Reveals Circadian-Period Control by Quality and Quantity of CRY1.

To conduct comprehensive characterization of molecular properties in organisms, we established an efficient method to produce knockout (KO)-rescue mice within a single generation. We applied this method to produce 20 strains of almost completely embryonic stem cell (ESC)-derived mice ("ES mice") rescued with wild-type and mutant Cry1 gene under a Cry1-/-:Cry2-/- background. A series of both phosphorylation-mimetic and non-phosphorylation-mimetic CRY1 mutants revealed that multisite phosphorylation of CRY1 can serve as a cumulative timer in the mammalian circadian clock. KO-rescue ES mice also revealed that CRY1-PER2 interaction confers a robust circadian rhythmicity in mice. Surprisingly, in contrast to theoretical predictions from canonical transcription/translation feedback loops, the residues surrounding the flexible P loop and C-lid domains of CRY1 determine circadian period without changing the degradation rate of CRY1. These results suggest that CRY1 determines circadian period through both its degradation-dependent and -independent pathways.

Incidence of Bowel Wall Swelling Induced by Iodine-Contrast Media and Its Association With Gastrointestinal Manifestation.

PURPOSE: The aim of this study was to investigate the incidence of bowel wall swelling after iodine-contrast media injection and its relationship with gastrointestinal symptoms. METHODS: The incidence of bowel wall swelling was examined in 75 patients who showed adverse reactions to iodine-contrast media (AR[+] group) and 75 controls without adverse reactions (AR[-] group). Bowel wall swelling was identified if there was increased wall thickness on postcontrast computed tomography when compared with precontrast computed tomography. Swelling less than 2-fold of the original wall thickness was defined as grade 1 bowel angioedema, and swelling more than 2-fold was defined as grade 2. RESULTS: The incidence of bowel wall swelling was significantly higher in the AR(+) group (26.6%) than in the AR(-) group (10.6%) ( P = 0.01). Grade 1 bowel wall swelling was observed in 12.0% and 10.7% of AR(+) and AR(-) groups, respectively, whereas grade 2 was observed in 14.7% and 0%, respectively. Bowel wall swelling was observed in the duodenum and jejunum but not in the stomach, ileum, or colon in any patient in either group. In the AR(+) group, nausea and/or vomiting was observed in 15 patients, among whom bowel wall swelling was observed in 9 patients (60%). The frequency of nausea and/or vomiting was significantly higher in the patients with bowel wall swelling (45.0%, 9/20) compared with those without (10.9%, 6/55). CONCLUSION: Bowel wall swelling was more frequent and severe in patients with adverse reactions to iodine-contrast media than those without and was associated with nausea and/or vomiting.

The Relationship Between Conventionally Obtained Serum-Based Liver Function Indices and Intravoxel Incoherent Motion Diffusion-Weighted Imaging and Magnetic Resonance Elastography in Patients With Hepatocellular Carcinoma.

OBJECTIVES: To investigate the relationship between conventionally obtained serum-based biochemical indices and intravoxel incoherent motion imaging (IVIM) parameters compared with magnetic resonance elastography (MRE). METHODS: Patients with hepatocellular carcinoma who underwent ≥2 liver magnetic resonance imaging (MRI) scan, including IVIM and MRE, between 2017 and 2020 and biochemical testing within 1 week before or after MRI were included in this study. Biochemical tests were performed to determine the albumin-bilirubin (ALBI) score and modified ALBI (mALBI) grade, aspartate aminotransferase to platelet ratio index (APRI), and fibrosis-4 index (FIB-4). The diffusion coefficient ( D ), pseudo-diffusion coefficient ( D *), fractional volume occupied by flowing spins ( f ), and apparent diffusion coefficient were calculated for IVIM. The correlations between (1) the imaging parameters and biochemical indices and (2) the changes in mALBI grades and imaging parameters were evaluated. RESULTS: This study included 98 scans of 40 patients (31 men; mean age, 67.7 years). The correlation analysis between the biochemical and IVIM parameters showed that ALBI score and D* had the best correlation ( r = -0.3731, P < 0.001), and the correlation was higher than that with MRE ( r = 0.3289, P < 0.001). However, among FIB-4, APRI, and MRI parameters, MRE outperformed IVIM parameters (MRE and FIB-4, r = 0.3775, P < 0.001; MRE and APRI, r = 0.4687, P < 0.001). There were significant differences in the changes in MRE among the 3 groups (improved, deteriorated, and unchanged mALBI groups) in the analysis of covariance ( P = 0.0434). There were no significant changes in IVIM. CONCLUSIONS: Intravoxel incoherent motion imaging has the potential to develop into a more readily obtainable method of liver function assessment.

Respiratory Displacement of the Right Adrenal Vein: Comparison of Inspiratory and Expiratory Computed Tomography With Catheter Venography.

OBJECTIVE: The aim of the study is to reveal the respiratory displacement of the right adrenal vein (RAV) to predict the exact location of the RAV during adrenal venous sampling (AVS). METHODS: Computed tomography (CT) scans obtained 45 seconds (breath-hold at inhalation) and 70 seconds (breath-hold at exhalation) after contrast material injection were compared to venograms of the RAV of patients with primary aldosteronism who underwent AVS between January 2016 and December 2020. The craniocaudal distance between the center of the Th11/12 disc and the RAV orifice was measured; the craniocaudal location of the RAV orifice was also specified relative to vertebral bodies and intervertebral discs on inspiratory phase CT (In-CT), expiratory phase CT (Ex-CT), and catheter venography. The transverse and vertical angles of the RAV and the position of the RAV orifice on the inferior vena cava (IVC) circumference were measured on In-CT and Ex-CT. RESULTS: In total, 51 patients (30 males, 21 females; mean age, 54.9 ± 11.1 years) were included. Craniocaudal distances between the center of the Th11/12 disc and RAV orifice were significantly different among the following 3 acquisitions: catheter venography versus In-CT (15.2 ± 8.4 mm); venography versus Ex-CT (5.6 ± 4.1 mm); and In-CT versus Ex-CT (19.6 ± 8.0 mm) (all, P < 0.001). The craniocaudal location of the RAV orifice on venography was significantly closer to that on Ex-CT than on In-CT (P < 0.001); measurements using venograms compared with In-CT and Ex-CT scans were within 1 level difference in 18 (35.3%) and 47 (92.2%) patients, respectively (P < 0.001). The vertical angle of the RAV was significantly more likely to be smaller on In-CT than on Ex-CT (P < 0.001). CONCLUSIONS: RAV locations and angles change with respiratory motion. It is crucial to consider the respiratory phase of CT because it can enable a more accurate prediction of the location of the RAV during AVS.

A novel and simple method for measuring nano/microplastic concentrations in soil using UV-Vis spectroscopy with optimal wavelength selection.

A simple method for measuring the concentration of nano/microplastics (N/MPs) in soil, which is difficult owing to the size of the filter mesh and the resolution of the measuring instrument, was investigated. A spectrophotometer was used for the measurements and polystyrene particles were used as the N/MP samples. When measuring N/MP concentrations in soil suspensions, absorbance was measured at two wavelengths, and the best combination of wavelengths for measurement was extracted because soil particles and leached components interfere with N/MP absorbance. A wavelength combination of 220-260 nm and 280-340 nm was found to be suitable for a variety of soils. As N/MPs are adsorbed on the surface of soil particles and precipitate with soil particles in suspension, a calibration curve was created between the concentration of N/MPs in the soil suspension and the N/MP content in the soil. The calibration curve showed a linear relationship, allowing for the estimation of the concentration of N/MPs in the soil. Although other N/MP materials, such as polyethylene and polyethylene terephthalate, must also still be considered and tested, this simple method has the potential to measure N/MPs in various types of soil.

Prediction of Anemia From Cerebral Venous Sinus Attenuation on Deep-Learning Reconstructed Brain Computed Tomography Images.

OBJECTIVE: The aim of the study is to evaluate whether the prediction of anemia is possible using quantitative analyses of unenhanced cranial computed tomography (CT) with deep learning reconstruction (DLR) compared with conventional methods. METHODS: This cross-sectional retrospective study included 116 participants (76 males; mean age, 66.7) who had hemoglobin (Hb) levels obtained within 24 hours of unenhanced cranial CT, which included 2 reconstruction methods: DLR and hybrid iterative reconstruction. Regions of interest were the confluence of sinuses (CoS) and the right and left transverse sinuses. In addition, edge rise distance of cerebrospinal fluid and venous was measured. RESULTS: Spearman rank correlation coefficient demonstrated a positive association between Hb levels and sinus attenuation values. Among these, the CoS in DLR had the best correlation ( r = 0.703, P < 0.001). For the prediction of anemia (Hb < 11 g/dL), the area under the curve of CoS in DLR (area under the curve = 0.874; 95% confidence interval, 0.798-0.949; P < 0.001) was the highest; however, there were no significant differences among reconstruction method and sinus. The attenuation values of DLR were significantly higher than those of hybrid iterative reconstruction ( P < 0.001, paired t test), and the differences between the 2 methods were 4.1 (standard deviation [SD], 1.6) for CoS, 5.2 (SD, 2.2) for right transverse sinuses, and 5.8 (SD, 2.4) for left transverse sinuses. The signal-to-noise ratio ( P < 0.001, paired t test) and edge rise distance ( P < 0.001, Wilcoxon signed rank test) of DLR was significantly higher. CONCLUSIONS: Higher CT attenuation values should be considered for predicting anemia based on brain DLR images.

Immediate effects of head-mounted display adaptation in cases of unilateral spatial neglect: study of straight-ahead pointing.

[Purpose] This study aimed to clarify the effect of an adaptation of a deviation of the visual field in three axes on spatial cognition in patients with unilateral spatial neglect and distorted spatial perception in three dimensions. [Participants and Methods] Fifteen patients with cerebrovascular disease and symptoms of unilateral spatial neglect were included. Forty-eight pointing movements with a camera attached to a head-mounted display changed in three axes were compared with the control condition in which the camera was deflected only in the horizontal plane as with the prism adaptation. The main outcome measures were subjective straight-ahead pointing, line bisection, line cancellation, and star cancellation. [Results] The head-mounted display adaptive therapy was performed under conditions that varied in all three axes. The results indicated that it was possible to deflect the subjective straight-ahead pointing position to the lower left direction. [Conclusion] In contrast to the prism adaptation, which deflects the visual field in a single axis in the horizontal plane, the tri-axial adaptation corrected the median cognition in the left-right direction as well as the cognition of the body center, including the vertical direction.

GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson's disease.

Parkinson's disease (PD) is characterized by dopaminergic (DA) cell loss and the accumulation of pathological alpha synuclein (asyn), but its precise pathomechanism remains unclear, and no appropriate animal model has yet been established. Recent studies have shown that a heterozygous mutation of glucocerebrosidase (gba) is one of the most important genetic risk factors in PD. To create mouse model for PD, we crossed asyn Bacterial Artificial Chromosome transgenic mice with gba heterozygous knockout mice. These double-mutant (dm) mice express human asyn in a physiological manner through its native promoter and showed an increase in phosphorylated asyn in the regions vulnerable to PD, such as the olfactory bulb and dorsal motor nucleus of the vagus nerve. Only dm mice showed a significant reduction in DA cells in the substantia nigra pars compacta, suggesting these animals were suitable for a prodromal model of PD. Next, we investigated the in vivo mechanism by which GBA insufficiency accelerates PD pathology, focusing on lipid metabolism. Dm mice showed an increased level of glucosylsphingosine without any noticeable accumulation of glucosylceramide, a direct substrate of GBA. In addition, the overexpression of asyn resulted in decreased GBA activity in mice, while dm mice tended to show an even further decreased level of GBA activity. In conclusion, we created a novel prodromal mouse model to study the disease pathogenesis and develop novel therapeutics for PD and also revealed the mechanism by which heterozygous gba deficiency contributes to PD through abnormal lipid metabolism under conditions of an altered asyn expression in vivo.

α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson's disease model.

Parkinson's disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson's disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson's disease and a genome-wide association study in Parkinson's disease has identified SNCA as a risk gene for Parkinson's disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson's disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson's disease and a Rep1 polymorphism, all of which are causal of familial Parkinson's disease or increase the risk of sporadic Parkinson's disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson's disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson's disease that showed RBD-like behaviour and hyposmia without motor symptoms.

Evaluation of Computed Tomography Attenuation Value of Proximal Femoral Marrow to Diagnose and Differentiate Hematologic Malignancies, Myelofibrosis, and Aplastic Anemia.

OBJECTIVE: The aim of this study was to diagnose hematologic diseases using computed tomography (CT) number of proximal femoral marrow. METHODS: The average CT number of marrow in hematologic diseases was measured on the caudal side of the greater trochanter. RESULTS: The CT numbers were -60.3 ± 16.8 in 12 patients with aplastic anemia, -53.2 ± 19.4 in 11 patients with monoclonal gammopathy of undetermined significance, -44.2 ± 21.1 in 10 normal controls, -30.9 ± 42.3 in 9 patients with chronic lymphatic leukemia, -29.8 ± 29.9 in 17 patients with benign anemia, -13.7 ± 40.9 in 33 patients with multiple myeloma, 0.32 ± 44.6 in 17 patients with myelodysplastic syndrome (MDS), 18.7 ± 40.0 in 44 patients with acute myeloid leukemia, 50.3 ± 27.4 in 13 patients with acute lymphatic leukemia, 51.5 ± 16.8 in 8 patients with myelofibrosis, and 56.4 ± 15.6 in 9 patients with chronic myeloid leukemia. Significant differences were observed between acute myeloid leukemia and MDS, between MDS and aplastic anemia, and between multiple myeloma and monoclonal gammopathy of undetermined significance (P < 0.01). CONCLUSION: The marrow CT numbers may be indicators of hematologic diseases and can be used as a diagnostic tool.

Relationship between iliopsoas muscle thickness and hip angle during squats in different pelvic positions.

[Purpose] This study aimed to investigate the relationships among the changes in iliopsoas muscle thickness, hip angle, and lower limb joint moment during squatting in different pelvic positions to help in performing hip-dominant squatting exercises. [Participants and Methods] The participants were seven healthy adult males. The measurement task consisted of squatting with 60 degrees of knee flexion in three positions: the anterior, neutral, and posterior pelvic tilt positions. The iliopsoas muscle thickness was measured in the center of the inguinal region using ultrasonography. A three-dimensional motion analysis system was used to measure the joint angles and joint moments. [Results] There were no significant differences in pelvic angles between the pelvic positions. The hip angle differences were significantly higher in the anterior and neutral pelvic tilt positions compared to those in the posterior tilt position. Only the anterior pelvic tilt position had a significantly positive correlation with iliopsoas muscle thickness and hip angle differences. [Conclusion] Squatting in the neutral or posterior pelvic tilt position was not associated with hip angle and iliopsoas muscle thickness changes, whereas squatting in an anterior pelvic tilt position was associated with changes in the iliopsoas muscle thickness and hip flexion angle. Our findings suggest that activation of the iliopsoas muscle might be necessary to promote hip-dominant squatting.

Clarification of generation mechanism of volatilization flux based on detailed analysis of transport phenomena near the ground surface and quantitative evaluation of influencing factors.

Assessing human health risks associated with inhalation exposure of volatile chemical substances (VCSs) volatilized from contaminated soil requires quantitative evaluation of volatilization fluxes (VFs) and an understanding of how environmental factors impact VF generation. We developed a numerical model that considers advection-dispersion and VCSs volatilization in unsaturated soil, enabling VF prediction through parameter optimization using soil column tests. We conducted parametric analyses to assess how key parameters, such as soil particle size, contamination depth, temperature, and surface soil thickness affect VF generation. By analyzing VCS transport near the ground surface, we uncovered the mechanisms underlying VF generation. We also identified characteristic differences in VF generation behavior linked to soil particle size and gas saturation at the ground surface. Under specific soil particle size conditions, significant VF generation occurred even when contamination was deep underground. This was primarily observed when capillary effect was pronounced, and VCSs continued to be supplied to the ground surface through upward advection. Considering the significant impact of VF generation on human health, our parametric study provides valuable insights into relationships between different parameters and VF behavior, especially under varying ground surface temperatures and surface soil thicknesses. This study contributes to developing effective remediation and risk-reduction strategies. ENVIRONMENTAL IMPLICATION: This research examines the environmental implications of volatile chemical substances (VCSs), including hazardous materials like benzene and trichloroethylene, in contaminated soil. VCSs pose health risks when they volatilize from soil. The study quantifies volatilization fluxes (VF) and elucidates the environmental factors affecting VF generation. These findings are vital for effective environmental management. By comprehending the mechanisms governing VF generation, particularly regarding soil properties like particle size, this research enhances the effectiveness of soil contamination remediation and risk reduction. It emphasizes the essential need for a comprehensive VCS assessment in contaminated soils to protect both human health and the environment.

Investigation of factors affecting CT attenuation and glucose metabolism of bone marrow as seen on PET/CT scans.

The aim of this study is to determine the factors affecting the CT attenuation of bone marrow, and its correlation with 18F-FDG uptake. The mean standardized uptake value (SUV) of vertebral bone marrow (Vertebral-SUV) and femoral bone marrow (Femoral-SUV) as well as CT number of bone marrow (BM-CT number) were measured in 243 patients who had undergone 18F-FDG PET/CT. The correlations among BM-CT number, Femoral-SUV, and Vertebral-SUV were investigated. The relationships of Femoral-SUV, Vertebral-SUV, and BM-CT number with blood parameters, age, blood sugar, and body weight were analyzed by correlation and multi-regression analyses. The Mann-Whitney U test and chi-square test and Binomial logistic analysis were used to examine the relationships between high BM-CT number (≥ 0 HU) and the above parameters. Significant correlations were observed between: BM-CT number and Femoral-SUV (r = 0.73, P < 0.01); Vertebral-SUV and Femoral-SUV (r = 0.78, P < 0.01); and BM-CT number and Vertebral-SUV (r = 0.52, P < 0.01). BM-CT number was correlated with patients' age in both univariable (r = -0.27) and multivariable analyses (ß = -0.20). Positive BM-CT number correlated with WBC in both univariable (P = 0.04) and multivariable (P < 0.01) analyses. Bone marrow glucose metabolism had a tendency to decrease with age, was increased in patients with elevated CRP. In conclusion, CT attenuation of bone marrow correlated well with bone marrow metabolism and also tended to decrease with age. High bone marrow attenuation (≥ 0 HU) could predict elevated serum WBC.

Impact of iodine contrast media on gamma camera-based GFR and factors affecting the difference between serum creatinine-based estimated GFR and Gate's GFR.

OBJECTIVE: We aimed to elucidate the factors underlying the difference between estimated glomerular filtration rate (eGFR) calculated from serum creatinine and Gate's GFR (gGFR) measured using technetium-99m diethylene triamine pentaacetic acid ( 99m Tc-DTPA) scintigraphy. METHODS: This study was based on consecutive patients who underwent 99m Tc-DTPA scintigraphy at our hospital between January 2021 and December 2022 and whose blood serum creatinine data were obtained on the same day as the 99m Tc-DTPA scintigraphy. Relationships between the ratio of gGFR and eGFR (gGFR/eGFR) and age, sex, BMI, visceral fat, psoas muscle index (PMI), serum blood urea nitrogen, and creatinine level were investigated based on 75 patients. Additionally, for 44 patients who had two or more follow-up DTPA studies, we compared gGFR values for studies that used iodine contrast media (ICM) for computed tomography before same-day 99m Tc-DTPA studies and those that did not in the same patients. RESULTS: Weak correlations were observed between gGFR/eGFR and PMI ( r  = 0.30), BMI ( r  = 0.24), and the visceral fat area ( r  = 0.33). Multi-regression analyses showed that gGFR/eGFR was correlated with PMI ( ß â€…= 0.34, P  < 0.01) and approached significance with the visceral fat area ( ß â€…= 0.24, P  = 0.05). A significant difference was observed in gGFR between patients who received ICM before the 99m Tc-DTPA renogram and those who did not ( P  < 0.001, eGFR 80.5 ±â€…19.0 vs. 91.7 ±â€…27.8 ml/min). CONCLUSION: ICM administration temporarily decreased gGFR, and increased muscle mass increased the difference between eGFR and gGFR values.

Capillary electrophoresis-mass spectrometry-based metabolome analysis of serum and saliva from neurodegenerative dementia patients.

Despite increasing global prevalence, the precise pathogenesis and terms for objective diagnosis of neurodegenerative dementias remain controversial, and comprehensive understanding of the disease remains lacking. Here, we conducted metabolomic analysis of serum and saliva obtained from patients with neurodegenerative dementias (n = 10), including Alzheimer's disease, frontotemporal lobe dementia, and Lewy body disease, as well as from age-matched healthy controls (n = 9). Using CE-TOF-MS, six metabolites in serum (ß-alanine, creatinine, hydroxyproline, glutamine, iso-citrate, and cytidine) and two in saliva (arginine and tyrosine) were significantly different between dementias and controls. Using multivariate analysis, serum was confirmed as a more efficient biological fluid for diagnosis compared to saliva; additionally, 45 metabolites in total were identified as candidate markers that could discriminate at least one pair of diagnostic groups from the healthy control group. These metabolites possibly provide an objective method for diagnosing dementia-type by multiphase screening. Moreover, diagnostic-type-dependent differences were observed in several tricarboxylic acid cycle compounds detected in serum, indicating that some pathways in glucose metabolism may be altered in dementia patients. This pilot study revealed novel alterations in metabolomic profiles between various neurodegenerative dementias, which would contribute to etiological investigations.

Relating memory to functional performance in normal aging to dementia using hierarchical Bayesian cognitive processing models.

Determining how cognition affects functional abilities is important in Alzheimer disease and related disorders. A total of 280 patients (normal or Alzheimer disease and related disorders) received a total of 1514 assessments using the functional assessment staging test (FAST) procedure and the MCI Screen. A hierarchical Bayesian cognitive processing model was created by embedding a signal detection theory model of the MCI Screen-delayed recognition memory task into a hierarchical Bayesian framework. The signal detection theory model used latent parameters of discriminability (memory process) and response bias (executive function) to predict, simultaneously, recognition memory performance for each patient and each FAST severity group. The observed recognition memory data did not distinguish the 6 FAST severity stages, but the latent parameters completely separated them. The latent parameters were also used successfully to transform the ordinal FAST measure into a continuous measure reflecting the underlying continuum of functional severity. Hierarchical Bayesian cognitive processing models applied to recognition memory data from clinical practice settings accurately translated a latent measure of cognition into a continuous measure of functional severity for both individuals and FAST groups. Such a translation links 2 levels of brain information processing and may enable more accurate correlations with other levels, such as those characterized by biomarkers.

Galectin-9 prolongs the survival of septic mice by expanding Tim-3-expressing natural killer T cells and PDCA-1+ CD11c+ macrophages.

INTRODUCTION: Galectin-9 ameliorates various inflammatory conditions including autoimmune diseases by regulating T cell and macrophage/dendritic cell (DC) functions. However, the effect of galectin-9 on polymicrobial sepsis has not been assessed. METHODS: We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in mice. The survival rate was compared between galectin-9- and PBS-treated CLP mice. An ELISA was used to compare the levels of various cytokines in the plasma and culture supernatants. Fluorescence-activated cell sorting analysis was further performed to compare the frequencies of subpopulations of spleen cells. RESULTS: Galectin-9 exhibited a protective effect in polymicrobial sepsis as demonstrated in galetin-9 transgenic mice and therapeutic galectin-9 administration. In contrast, such effect was not observed in nude mice, indicating the involvement of T cells in galectin-9-mediated survival prolongation. Galectin-9 decreased TNFα, IL-6, IL-10 and, high mobility group box 1 (HMGB1) and increased IL-15 and IL-17 plasma and spleen levels. Galectin-9 increased the frequencies of natural killer T (NKT) cells and PDCA-1+ CD11c+ macrophages (pDC-like macrophages) but did not change the frequency of CD4 or CD8 T cells, γδT cells or conventional DC. As expected, galectin-9 decreased the frequency of Tim-3+ CD4 T cells, most likely Th1 and Th17 cells. Intriguingly, many spleen NK1.1+ NKT cells and pDC-like macrophages expressed Tim-3. Galectin-9 increased the frequency of Tim-3-expressing NK1.1+ NKT cells and pDC-like macrophages. Galectin-9 further increased IL-17+ NK1.1+ NKT cells. CONCLUSION: These data suggest that galectin-9 exerts therapeutic effects on polymicrobial sepsis, possibly by expanding NKT cells and pDC-like macrophages and by modulating the production of early and late proinflammatory cytokines.

Hierarchical Bayesian cognitive processing models to analyze clinical trial data.

Identifying disease-modifying treatment effects in earlier stages of Alzheimer's disease (AD)-when changes are subtle-will require improved trial design and more sensitive analytical methods. We applied hierarchical Bayesian analysis with cognitive processing (HBCP) models to the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and MCI (mild cognitive impairment) Screen word list memory task data from 14 Alzheimer's disease AD patients of the Myriad Pharmaceuticals' phase III clinical trial of Flurizan (a γ-secretase modulator) versus placebo. The original analysis of 1649 patients found no treatment group differences. HBCP analysis and the original ADAS-Cog analysis were performed on the small sample. HBCP analysis detected impaired memory storage during delayed recall, whereas the original ADAS-Cog analytical method did not. The HBCP model identified a harmful treatment effect in a small sample, which has been independently confirmed from the results of other γ-secretase inhibitor. The original analytical method applied to the ADAS-Cog data did not detect this harmful treatment effect on either the full or the small sample. These findings suggest that HBCP models can detect treatment effects more sensitively than currently used analytical methods required by the Food and Drug Administration, and they do so using small patient samples.

Different prognostic outcomes in two cases of FDG-PET/CT-Positive and -negative cardiac angiosarcoma.

Cardiac angiosarcoma is a rare malignant tumor with a poor prognosis, characterized by the high uptake of 18F-fluorodeoxyglucose (FDG). This case report presents two cases of cardiac angiosarcoma with a marked difference in FDG uptake and prognosis.Case Summary:Case 1: A 40-year-old male presented with syncope. Ultrasound echocardiography demonstrated a cardiac tumor with a high uptake of 18F-FDG (maximum standardized uptake value=9.2). The patient underwent heart catheterization and tumor biopsy. The pathological result was high-grade angiosarcoma, and the MIB-1(Ki-67) proliferation index was approximately 20%. Systemic chemotherapy was administered; however, the patient died 2 years and 5 months after disease onset.Case 2: A 65-year-old female had a right atrial tumor incidentally diagnosed during routine ultrasound echocardiography. The tumor exhibited a low uptake of 18F-FDG (maximum standardized uptake value=1.8). Open heart surgery was performed, and the tumor was completely resected. Histological analysis revealed low-grade angiosarcoma, and the MIB-1(Ki-67) proliferation index was less than 5%. The patient was followed-up and had not relapsed 2 years after surgery.Conclusion: 18F-FDG uptake may reflect pathological tumor grade and prognosis in cardiac angiosarcoma.

A Remotely Coached Multimodal Lifestyle Intervention for Alzheimer's Disease Ameliorates Functional and Cognitive Outcomes.

BACKGROUND: Comprehensive treatment of Alzheimer's disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. Personalized, multimodal therapies are needed to best prevent and treat Alzheimer's disease (AD). OBJECTIVE: The Coaching for Cognition in Alzheimer's (COCOA) trial was a prospective randomized controlled trial to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage AD. METHODS: Participants with early-stage AD were randomized into two arms. Arm 1 (N = 24) received standard of care. Arm 2 (N = 31) additionally received telephonic personalized coaching for multiple lifestyle interventions. The primary outcome was a test of the hypothesis that the Memory Performance Index (MPI) change over time would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test was assessed for a secondary outcome. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints (dynamic dense data) across two years for each participant. RESULTS: The intervention arm ameliorated 2.1 [1.0] MPI points (mean [SD], p = 0.016) compared to the control over the two-year intervention. No important adverse events or side effects were observed. CONCLUSION: Multimodal lifestyle interventions are effective for ameliorating cognitive decline and have a larger effect size than pharmacological interventions. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.