Cutaneous histopathology of the tick‐bite region in severe fever with thrombocytopenia syndrome

A case of severe fever with thrombocytopenia syndrome (SFTS) in which a skin biopsy from the tick‐bite region was analyzed is reported. The patient was a 72‐year‐old woman who developed fever and thrombocytopenia after a tick bite. SFTS was diagnosed from polymerase chain reaction (PCR) analysis of a blood sample. Histopathological analysis of a skin biopsy specimen from the tick‐bite region showed CD20‐positive perivascular and interstitial immunoblastic cells, which were positive to anti‐SFTS virus (SFTSV) nucleoprotein antibody. In addition, SFTSV RNA was detected by real‐time PCR from this biopsy specimen. Moreover, hemophagocytosis was also found in the tick‐bite region. To the best of our knowledge, this is the first report to analyze the details of the tick‐bite region of skin in SFTS, and the first to detect virus‐infected cells in the skin. The present findings may help elucidate the mechanisms of entry of SFTSV.     

Eicosapentaenoic Acid Improves Cisplatin-Induced Muscle Atrophy Without Accompanying Body Weight Gain

Introduction: Cisplatin (CDDP) induces loss of muscle mass by activating the nuclear factor (NF)-κB signaling pathway. In this study, we investigated the effects of eicosapentaenoic acid (EPA), which inhibits NF-κB activation, on CDDP-induced loss of muscle mass in mice.

Methods: Male C57BL/6J mice received a single dose of CDDP and olive oil, linseed oil, or EPA daily for 4?days. Body weight and food intake were recorded daily for 5?days. Forelimb grip strength was determined using a strain gauge on the fourth day. The mice were killed 24?h after the final dose of fatty acid and the wet weight of their gastrocnemius, soleus, and tibialis anterior muscles measured.

Results: Olive oil, linseed oil, and EPA all failed to prevent decrease in food intake and loss of body weight. However, only EPA prevented loss of muscle mass and strength.

Conclusion: EPA prevents CDDP-related loss of muscle mass and muscle but not CDDP-related loss of body weight.     

A quantitative and qualitative analysis of the virtual unipolar electrograms from non-contact mapping of right or left-sided outflow tract premature ventricular contractions/ventricular tachycardia origins

Objective

This study was conducted to examine the virtual unipolar electrogram configuration of right/left outflow tract (OT) premature ventricular contraction (PVC)/ventricular tachycardia (VT) origins obtained from a non-contact mapping system (NCMS).

Methods

The subjects consisted of 30 patients with OT-PVCs/VT who underwent NCMS-guided ablation. We evaluated the virtual unipolar electrograms of the origin on 3D right ventricular (RV)-OT isochronal maps.

Results

Successful ablation was achieved from the RV in 20 patients (RVOT group), and it failed in 10 (non-RVOT group: including left-sided/pulmonary artery/deep RVOT foci). On the virtual unipolar electrograms, the earliest activation (EA) preceded the QRS onset by 11.2?±?2.6 ms in the RVOT group and by 7.4?±?10.5 ms in the non-RVOT group (P?=?0.138). The negative slope of the electrogram at the EA site (EA slope₅), quantified by the virtual unipolar voltage amplitude 5 ms after the EA onset, was significantly steeper in the RVOT group than in the non-RVOT group (0.66?±?0.52 mV vs. 0.14?±?0.17 mV, P?=?0.005). Cutoff values for the EA-to-QRS onset time and EA slope₅ of ??8 ms and >0.3 mV, respectively, completely differentiated the RVOT group from the non-RVOT group. A lesser EA slope₅ was associated with a greater radiofrequency energy delivery required to terminate RVOT-PVCs/VT.

Conclusions

These demonstrate the importance of the virtual unipolar electrograms from OT-PVC/VT origins obtained with the NCMS. The virtual EA predicts both successful and potentially difficult ablation sites from the RV side.     

Artificial Intelligence Trained by Deep Learning Can Improve Computed Tomography Diagnosis of Nontraumatic Subarachnoid Hemorrhage by Nonspecialists

Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease with a high mortality rate and is known as a disease that is hard to diagnose because it may be overlooked by noncontrast computed tomography (NCCT) examinations that are most frequently used for diagnosis. To create a system preventing this oversight of SAH, we trained artificial intelligence (AI) with NCCT images obtained from 419 patients with nontraumatic SAH and 338 healthy subjects and created an AI system capable of diagnosing the presence and location of SAH. Then, we conducted experiments in which five neurosurgery specialists, five nonspecialists, and the AI system interpreted NCCT images obtained from 135 patients with SAH and 196 normal subjects. The AI system was capable of performing a diagnosis of SAH with equal accuracy to that of five neurosurgery specialists, and the accuracy was higher than that of nonspecialists. Furthermore, the diagnostic accuracy of four out of five nonspecialists improved by interpreting NCCT images using the diagnostic results of the AI system as a reference, and the number of oversight cases was significantly reduced by the support of the AI system. This is the first report demonstrating that an AI system improved the diagnostic accuracy of SAH by nonspecialists.     

Feasibility of fluorodeoxyglucose dual-head gamma camera coincidence imaging in the evaluation of lung cancer: comparison with FDG PET.

The purpose of this study was to elucidate the feasibility of fluorodeoxyglucose gamma camera coincidence imaging (FDG GCI) in the evaluation of lung cancer in comparison with FDG PET. METHODS: Twenty-three patients with recently diagnosed lung cancer were examined with both FDG PET and FDG GCI on the same day. Pulmonary lesions were analyzed visually and semiquantitatively using the ratio of lesion-to-background counts (L/B ratio). The L/B ratio of FDG PET without attenuation correction (AC) was also calculated and compared. Nodal stations were only visually analyzed. RESULTS: FDG GCI and FDG PET could detect 22 and 23, respectively, of 23 pulmonary lesions by visual analysis (95.7% versus 100%). The L/B ratio of FDG GCI was 4.26 +/- 2.55, and significantly lower than that of FDG PET (9.29 +/- 4.95; P < 0.01). The L/B ratio of FDG PET was significantly higher with AC than that without AC (9.29 +/- 4.95 vs. 6.66 +/- 4.65; P < 0.01). When the L/B ratio threshold was set at 5.0 for FDG PET and 2.7 for FDG GCI, their sensitivity was 87.0% and 73.9%, respectively. Of the 3 and 6 patients with false-negative results on semiquantitative analysis, the lesions in 3 patients on FDG PET and 4 patients on FDG GCI were less than or equal to 2.0 cm in greatest diameter, respectively. In the assessment of mediastinal involvement, FDG PET was 77.8% sensitive, 78.6% specific and 78.3% accurate, whereas FDG GCI was 77.8% sensitive, 92.9% specific and 87.0% accurate. In the hilar regions, FDG PET was 100% sensitive, 84.2% specific and 87.0% accurate, whereas FDG GCI was 75.0% sensitive, 89.5% specific and 87.0% accurate. CONCLUSION: In this study, FDG GCI yielded results comparable to FDG PET on visual analysis to detect pulmonary lesions and lymph node metastases. However, the lesion-to-background contrasts of pulmonary lesions and nodal involvement were lower in FDG GCI than in FDG PET. Comparison between the L/B ratio of FDG PET with and without AC indicated that, with AC, FDG GCI would be closer to FDG PET in the evaluation of lung cancer.     

Asymmetric total synthesis of four bioactive lignans using donor–acceptor cyclopropanes and bioassay of (−)- and (+)-niranthin against hepatitis B and influenza viruses

The asymmetric total synthesis of four lignans, dimethylmatairesinol, matairesinol, (−)-niranthin, and (+)-niranthin has been achieved using reductive ring-opening of cyclopropanes. Moreover, we performed bioassays of the synthesized (+)- and (−)-niranthins using hepatitis B and influenza viruses, which revealed the relationship between the enantiomeric structure and the anti-viral activity of niranthin.

The total synthesis of four lignans including (−)- and (+)-niranthin has been achieved utilizing cyclopropanes. Based on bioassays of the (+)- and (−)-niranthins using HBV and IFV, we speculated the bioactive site of niranthin against HBV and IFV.

Lignans are attracting considerable attention due to their widespread distribution in plants and their varied bioactivity.^1–5 For example, matairesinol,² dimethylmatairesinol,³ yatein,⁴ and niranthin⁵ are found in nature and exhibit e.g., cytotoxicity,^2b,d,3b,4b anti-bacterial,^2c anti-allergic,^3c anti-viral,^4d,5b,e anti-leishmanial,^5d and strong insect-feeding-deterrent activity.^4c Among these compounds, anti-viral compounds have received significant attention owing to the worldwide pandemic of coronavirus disease 2019 (COVID-19). Although niranthin exhibits anti-viral activity toward the hepatitis B virus (HBV),^5b,e the enantiomeric SAR (structure–activity relationship) for the anti-viral activity of niranthin has not been revealed so far. To examine the SAR for a pair of enantiomers, an independent asymmetric synthesis of both enantiomers is necessary. However, the alternative synthesis of (−)- or (+)-niranthin has not been reported.⁶ During our recent studies on the transformation of cyclopropanes,⁷ we have reported a reductive ring-opening of enantioenriched donor–acceptor (D–A) cyclopropanes and its application to an asymmetric total synthesis of yatein.⁷ⁱ As a further extension of this synthetic method, we disclose here the asymmetric total synthesis of (−)-dimethylmatairesinol, (−)-matairesinol, (+)-niranthin, and (−)-niranthin. Moreover, the results of bioassays using (+)-niranthin and (−)-niranthin against HVB and influenza virus (IFV) are described (Scheme 1).Open in a separate windowScheme 1Some examples of bioactive dibenzyl lignans. Scheme 2 outlines the enantioselective synthesis of optically active lactones 5a and 5b. Following our previous report,⁷ⁱ we attempted to synthesize the enantio-enriched bicyclic lactones 4a and 4b.Open in a separate windowScheme 2Enantioselective synthesis of key intermediates 5a and 5b.Initially, the cyclopropanation of enal 1 with dimethyl α-bromomalonate 2 using the Hayashi–Jørgensen catalyst afforded the desired optically active cyclopropylaldehydes 3a and 3b in good to high yield with high ee.^{7c,e,h–j,8,9} The reduction of the aldehydes to alcohols and subsequent lactonization with p-TsOH afforded lactones 4a and 4b in high yield with high ee. The optical purity of lactones 4a and 4b were determined using HPLC analyses on a chiral column, and the ee values of the enantioselective cyclopropanations were estimated based on these HPLC analyses. Next, treatment of bicyclic lactones 4a and 4b with hydrogen in the presence of a catalytic amount of Pd–C in AcOEt at 0 °C resulted in a regioselective reductive ring-opening to furnish benzyloxylactones 5a and 5b in good to high yield with high dr and high ee. In the hydrolysis step, debenzylation of the benzyloxyaryl group did not occur under these mild conditions, i.e., in AcOEt at 0 °C.⁷ⁱFor the α-benzylation of 5a and 5b to afford 6a–c, the corresponding substituted benzylhalides were necessary. 3-Methoxy-4-benzyloxybenzylbromide and 3,4-dimethoxybenzylbromide were easily prepared by known methods (for details, see the ESI^†); however, the preparation of 3,4-methylenedioxy-5-methoxybenzylbromide (16) required a modified procedure that involves the regioselective protection of the hydroxy group at the 3-position of 3,4,5-trihydroxybenzene (Scheme 3). The methylenedioxylation of gallic acid (10) during the first step resulted in a low yield of 11.¹⁰ Consequently, we successfully synthesized 12 using a cyclic boron-ester system.¹¹ Arylmethylbromide 16 was derived from ester 12 in two steps in good to high yield.Open in a separate windowScheme 3Preparation of substituted benzylbromide 16.Next, enolates were generated from lactones 5a and 5b using K₂CO₃ in DMF, and successfully attacked the benzylhalides on the less-hindered side to afford α-benzyl lactones 6a–c with excellent dr values (Scheme 4).^7i,12 The trans-α,β-disubstituted lactones 7a–c were obtained via the hydrolysis of the α-methoxycarbonyllactones 6a–c followed by decarboxylation. The transformation from the enol form to the keto form gave the thermodynamically favored trans products (7a–c) with excellent dr values.^7i,12 Finally, the debenzylation of 7a using a catalytic amount of Pd–C in methanol under a hydrogen atmosphere afforded matairesinol (7d) in 96% yield. Thus, the total syntheses of dimethylmatairesinol (7b) and matairesinol (7d) were achieved, and spectral data of these natural products were consistent with reported data.^2e,3d The absolute configuration of these compounds were determined using the known data of optical rotation values. The reduction of lactone 7c using LAH afforded diol 8 in 91% yield (Scheme 4). Subsequent dimethylation of the resulting diol 8 using NaH and MeI furnished (−)-niranthin in 89% yield with 95% ee.¹³ Spectral data of (−)-niranthin was also consistent with reported data.^5b,e,6 Following the total synthesis of (−)-niranthin, we also achieved the total synthesis of (+)-niranthin via an alternative enantioselective cyclopropanation using a different enantiomeric Hayashi–Jørgensen catalyst derived from d-proline instead of l-proline (Scheme 5).¹⁴Open in a separate windowScheme 4Alternative asymmetric total synthesis of dimethylmatairesinol, matairesinol, and (−)-niranthin.Open in a separate windowScheme 5Alternative asymmetric total synthesis of (+)-niranthin.(−)-Niranthin has been reported to exhibit anti-HBV activity.^5b,e Aiming to shed light on the relationship between its enantiomeric structure and activity, we performed a bioassay on the synthesized (−)- and (+)-niranthin against not only HBV, but also the influenza virus (IFV). The anti-HBV activity results are summarized in Fig. 1 and ​and2,2, while the anti-IFV activity is summarized in Fig. 3 (for details, see the ESI^†).Open in a separate windowFig. 1HBV-infection assay using (−)- and (+)-niranthin.Open in a separate windowFig. 2HBV-replication assay using (−)- and (+)-niranthin.Open in a separate windowFig. 3Growth-inhibition assay of IFV using (−)- and (+)-niranthin.Based on the assays using HBV-infected HepG2-hNTCP-C4 cells and HBV-replicating Hep38.7-tet cells, the amount of HBs antigen decreased in a concentration-dependent manner without apparent cytotoxicity. The 50% inhibition concentration (IC₅₀) in the HBV-infected cells was calculated to be 14.3 ± 0.994 μM for (−)-niranthin and 9.11 ± 0.998 μM for (+)-niranthin (Fig. 1), while the IC₅₀ in the HBV-replicating cells was calculated to be 16.2 ± 0.992 μM for (−)-niranthin and 24.2 ± 0.993 μM for (+)-niranthin (Fig. 2). These results show that (−)-niranthin and (+)-niranthin exhibit anti-HBV activity, and that there is no remarkable difference between the anti-HBV activity of both enantiomers. In contrast, based on the bioassay of (−)- and (+)-niranthins against IFV using MDCK cells, cytotoxicity of (−)-niranthin appears at >400 μM judging that cell viability without IFV is less than 80%, and (−)-niranthin inhibited IFV-infection to cells in a concentration-dependent manner on the concentration range of non-cytotoxicity, and exhibits anti-IFV activity at 200–400 μM judging that cell viability with IFV is over 50% (Fig. 3). However, (+)-niranthin does not exhibit anti-IFV activity, and similarly to (−)-niranthin, cytotoxicity appears at >400 μM. Thus, the anti-IFV activity between (−)- and (+)-niranthins is clearly different. Our findings suggest that the enantiomeric site in niranthin endows (−)-niranthin with more potent anti-IFV activity than (+)-niranthin. We speculated that the anti-HBV active site of niranthin might be a part of the molecular structure such as aromatic groups which are far from chiral centers. In contrast, anti-IFV active site of niranthin might be closer to the chiral centers (Scheme 6).Open in a separate windowScheme 6A speculation for the bioactive site of niranthin against HBV and IFV.     

Traumatic facial nerve injury: A case of facial nerve avulsion at the cerebellopontine angle

Post-traumatic facial nerve paralysis is a common disease, but intracranial facial nerve injury after blunt injury has rarely been reported. We report a case of facial nerve avulsion at the cerebellopontine angle. A 23-year-old female with incomplete right-sided facial nerve palsy and facial spasms presented to our hospital. She had a history of traumatic injury, having fallen off a table and hit her head at the age of 2 years. After the accident, she developed complete right-sided facial nerve palsy and underwent conservative treatment with steroids. A magnetic resonance imaging examination performed 21 years later showed avulsion of the facial nerve at the cerebellopontine angle. Magnetic resonance imaging targeting the facial nerves might provide additional information to computed tomography in cases with poor recovery with conservative treatment.