A case of esophageal carcinosarcoma with a component of small cell carcinoma

We experienced a case of esophageal carcinosarcoma with a component of small cell carcinoma. The patient was a 73-year-old man. We administered chemotherapy of CDDP+VP-16, and performed an operation after 2 courses of this chemotherapy. Subtotal esophagectomy and reconstruction with the small intestine was performed. More than three years after resection, he remains alive and recurrence-free. There are few cases of esophageal carcinosarcoma and small cell carcinoma. We report this rare case herein

Effects of single therapeutic doses of promethazine, fexofenadine and olopatadine on psychomotor function and histamine-induced wheal- and flare-responses: a randomized double-blind, placebo-controlled study in healthy volunteers

Since most first-generation antihistamines have undesirable sedative effects on the central nervous systems (CNS), newer (second-generation) antihistamines have been developed to improve patients’ quality of life. However, there are few reports that directly compare the antihistaminic efficacy and impairment of psychomotor functions. We designed a double-blind, placebo controlled, crossover study to concurrently compare the clinical effectiveness of promethazine, a first-generation antihistamine, and fexofenadine and olopatadine, second-generation antihistamines, by measuring their potency as peripheral inhibitors of histamine-induced wheal and flare. Further, we investigated their sedative effects on the CNS using a battery of psychomotor tests. When single therapeutic doses of fexofenadine (60 mg), olopatadine (5 mg) and promethazine (25 mg) were given in a double-blind manner to 24 healthy volunteers, all antihistamines produced a significant reduction in the wheal and flare responses induced by histamine. In the comparison among antihistamines, olopatadine showed a rapid inhibitory effect compared with fexofenadine and promethazine, and had a potent effect compared with promethazine. In a battery of psychomotor assessments using critical flicker fusion, choice reaction time, compensatory tracking, rapid visual information processing and a line analogue rating scale as a subjective assessment of sedation, promethazine significantly impaired psychomotor function. Fexofenadine and olopatadine had no significant effect in any of the psychomotor tests. Promethazine, fexofenadine and olopatadine did not affect behavioral activity, as measured by wrist actigraphy. These results suggest that olopatadine at a therapeutic dose has greater antihistaminergic activity than promethazine, and olopatadine and fexofenadine did not cause cognitive or psychomotor impairment

Involvement of the Precuneus/Posterior Cingulate Cortex Is Significant for the Development of Alzheimer’s Disease: A PET (THK5351, PiB) and Resting fMRI Study

Background: Imaging studies in Alzheimer’s disease (AD) have yet to answer the underlying questions concerning the relationship among tau retention, neuroinflammation, network disruption and cognitive decline. We compared the spatial retention patterns of 18F-THK5351 and resting state network (RSN) disruption in patients with early AD and healthy controls.Methods: We enrolled 23 11C-Pittsburgh compound B (PiB)-positive patients with early AD and 24 11C-PiB-negative participants as healthy controls. All participants underwent resting state functional MRI and 18F-THK5351 PET scans. We used scaled subprofile modeling/principal component analysis (SSM/PCA) to reduce the complexity of multivariate data and to identify patterns that exhibited the largest statistical effects (variances) in THK5351 concentration in AD and healthy controls.Findings: SSM/PCA identified a significant spatial THK5351 pattern composed by mainly three clusters including precuneus/posterior cingulate cortex (PCC), right and left dorsolateral prefrontal cortex (DLPFC) which accounted for 23.6% of the total subject voxel variance of the data and had 82.6% sensitivity and 79.1% specificity in discriminating AD from healthy controls. There was a significant relationship between the intensity of the 18F-THK5351 covariation pattern and cognitive scores in AD. The spatial patterns of 18F-THK5351 uptake showed significant similarity with intrinsic functional connectivity, especially in the PCC network. Seed-based connectivity analysis from the PCC showed significant decrease in connectivity over widespread brain regions in AD patients. An evaluation of an autopsied AD patient with Braak V showed that 18F-THK5351 retention corresponded to tau deposition, monoamine oxidase-B (MAO-B) and astrogliosis in the precuneus/PCC.Interpretation: We identified an AD-specific spatial pattern of 18F-THK5351 retention in the precuneus/PCC, an important connectivity hub region in the brain. Disruption of the functional connections of this important network hub may play an important role in developing dementia in AD

A Quantum Chemical Study on the Anti-SARS-CoV-2 Activity of TMPRSS2 Inhibitors

Nafamostat and camostat are known to inhibit the spike protein-mediated fusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by forming a covalent bond with the human transmembrane serine protease 2 (TMPRSS2) enzyme. Previous experiments revealed that the TMPRSS2 inhibitory activity of nafamostat surpasses that of camostat, despite their structural similarities; however, the molecular mechanism of TMPRSS2 inhibition remains elusive. Herein, we report the energy profiles of the acylation reactions of nafamostat, camostat, and a nafamostat derivative by quantum chemical calculations using a combined molecular cluster and polarizable continuum model (PCM) approach. We further discuss the physicochemical relevance of their inhibitory activity in terms of thermodynamics and kinetics. Our analysis attributes the strong inhibitory activity of nafamostat to the formation of a stable acyl intermediate and its low activation energy during acylation with TMPRSS2. The proposed approach is also promising for elucidating the molecular mechanisms of other covalent drugs

The Prominent Role of Charge Transfer in the Spectral Tuning of Photosynthetic Light-Harvesting I Complex

Purple bacteria possess two ring-shaped protein complexes, light-harvesting 1 (LH1) and 2 (LH2), which exhibit distinct absorption properties and function as antennas for solar energy utilization for photosynthesis. The amount of bacteriochlorophyll (BChl) a is different in the two antennas; however, their relationship with spectral tuning remains elusive. Herein, we report a high-precision evaluation of the physicochemical factors contributing to the difference in absorption maxima between LH1 and LH2 in the model purple bacterium Rhodospirillum rubrum in terms of BChl a structural distortion, protein electrostatic interaction, excitonic coupling, and charge transfer (CT) effects, derived from detailed spectral calculations using an extended version of the exciton model. Spectral analysis confirmed that the electronic structure of the excited state in LH1 extended to the BChl a 16-mer, and further analysis revealed that the CT effect due to the closer inter-BChl distance in LH1 than in LH2 predominantly contributed to the LH1-specific redshift (~61% in energy). Our analysis explains how LH1 and LH2, which possess chemically identical chromophores of BChl a, use distinct physicochemical effects to enable a progressive redshift from LH2 to LH1 for efficient energy transfer to the reaction center special pair

Extended theoretical modeling of reverse intersystem crossing for thermally activated delayed fluorescence materials

Thermally activated delayed fluorescence (TADF) materials and multi-resonant (MR) variants are promising organic emitters that can achieve an internal electroluminescence quantum efficiency of approximately 100%. The reverse intersystem crossing (RISC) is key for harnessing triplet energies for fluorescence. Theoretical modeling is thus crucial to estimate its rate constant kRISC for material development. Herein, we present a comprehensive assessment of the theory for simulating the RISC of MR-TADF molecules within a perturbative excited-state dynamics framework. Our extended rate formula reveals the importance of the concerted effects of nonadiabatic spin-vibronic coupling and vibrationally induced spin-orbital couplings in reliably determining kRISC of MR-TADF molecules. The excited singlet-triplet energy gap is another factor influencing kRISC. We present a new scheme for gap estimation using experimental Arrhenius plots of kRISC. Erroneous behavior caused by approximations in Marcus theory is elucidated by testing 121 MR-TADF molecules. Our extended modeling offers in-depth descriptions of kRISC

Sex Differences in the Prevalence, Progression, and Improvement of Chronic Kidney Disease

Background/Aims: We examined sex differences in prevalence, progression, and improvement in early-stage chronic kidney disease (CKD). Methods: We analyzed data from 533 participants who took 4 consecutive annual CKD detection tests. Results: Urine albumin-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and hemoglobin (Hb) at baseline in men with and without CKD and in women with and without CKD were 8.3±6.1, 149.2±310.4, 10.2±5.8, and 96.7±246.8 mg/g Cr; 83.4±14.7, 63.8±18.8, 79.9±13.0, and 69.4±20.0 mL/min/1.73 m2; and 14.8±1.2, 14.3±1.4, 13.0±1.0, and 13.0±1.2 mg/dL, respectively. ACR levels decreased significantly over time in men and women with CKD and they increased significantly over time in men and women without CKD. eGFR levels in men and women with CKD did not significantly change over time, but they decreased significantly over time in men and women without CKD. CKD prevalence and progression rate were not significantly different between sexes. Among the CKD participants, significantly more women had a “cured” status at 3 years (39.1% vs. 19.4%, P60 mL/min/1.73 m2 at 3 years had values just below those at baseline. Regression analysis showed that change in eGFR correlated significantly with ACR in men with CKD (change in eGFR = -1.707+0.022×ACR, Pr2=0.201) and with Hb and ACR in women with CKD (change in eGFR = 48.870-3.803×Hb + 0.018×ACR, Pr2=0.134). Conclusions: These results suggest that the slight decrease of Hb within a normal range and mild anemia can be managed in women with early-stage CKD. The key baseline for eGFR is 60 mL/min/1.73 m2