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Neuropathic pain, a heterogeneous condition, affects 7%–10% of the general population. To date, efficacious and safe therapeutic approaches remain limited. Antisense oligonucleotide (ASO) therapy has opened the door to treat spinal muscular atrophy, with many ongoing clinical studies determining its therapeutic utility. ASO therapy for neuropathic pain and peripheral nerve disease requires efficient gene delivery and knockdown in both the dorsal root ganglion (DRG) and sciatic nerve, key tissues for pain signaling. We previously developed a new DNA/RNA heteroduplex oligonucleotide (HDO) technology that achieves highly efficient gene knockdown in the liver. Here, we demonstrated that intravenous injection of HDO, comprising an ASO and its complementary RNA conjugated to α-tocopherol, silences endogenous gene expression more than 2-fold in the DRG, and sciatic nerve with higher potency, efficacy, and broader distribution than ASO alone. Of note, we observed drastic target suppression in all sizes of neuronal DRG populations by in situ hybridization. Our findings establish HDO delivery as an investigative and potentially therapeutic platform for neuropathic pain and peripheral nerve disease.

Inflammatory myofibroblastic tumor (IMT) of the urinary bladder is a rare soft tissue tumor characterized by spindle cell proliferation with inflammatory cell infiltration. We present a case of bladder IMT occurring in a 6-year-old boy. Pretreatment CT images depicted a polypoid and broad-based mass measuring 18 mm in the superior to the front wall of the bladder, and the mass showed isodensity on precontrast image and ring enhancement of the mass after the intravenous administration of contrast material. Pelvic MRI demonstrated the 18 × 17 × 16 mm broad-based mass, suggesting submucosal tumor in the dome of the bladder. The mass showed low-to-moderate signal intensity on T1-weighted images and slight high signal intensity on T2-weighted images and restricted diffusion with low signal intensity on ADC map and abnormal high signal intensity on DWI. Transurethral resection of the bladder tumor and partial cystectomy were undertaken, and the pathology revealed IMT of the bladder. We suggest its inclusion in the differential diagnosis of cases of a polypoid and broad-based mass on the superior wall or the front wall of the bladder with ring enhancement on contrast-enhanced CT and MRI.

Treatment of bipolar disorder is prone to prolongation despite various treatments, including medication. The efficacy of exercise treatment (i.e., interventions involving physical exercise and sports intervention) for major depressive disorders has been reported for depressive symptoms, cognitive function, and sleep disturbances. However, its efficacy for bipolar disorder has yet to be established. We designed a randomized, controlled, double-blind clinical trial that includes 100 patients with bipolar disorder aged 20–65 years. This will be a cluster-randomized, two-group trial that will be conducted in ten psychiatric hospitals. The hospitals will be randomly assigned to an exercise intervention + treatment as usual (exercise) group or a placebo exercise intervention (stretching) + treatment as usual (control) group. Patients will be assessed using an extensive battery of clinical tests, physical parameters, sleep status, biological parameters (cytokines, neurotrophic factors), and genetic parameters (DNA and RNA) at baseline after a 6-week intervention period, at 10-week follow-up, and at 6-month follow-up. This innovative study may provide important evidence for the effectiveness of exercise in the treatment of bipolar depression based on clinical, biological, genetic, and physiological markers.

Super-resolution in two-photon excitation (2PE) microscopy offers new approaches for visualizing the deep inside the brain functions at the nanoscale. In this study, we developed a novel 2PE stimulated-emission-depletion (STED) microscope with all-synchronized picosecond pulse light sources and time-gated fluorescence detection, namely, all-pulsed 2PE-gSTED microscopy. The implementation of time-gating is critical to excluding undesirable signals derived from brain tissues. Even in a case using subnanosecond pulses for STED, the impact of time-gating was not negligible; the spatial resolution in the image of the brain tissue was improved by approximately 1.4 times compared with non time-gated image. This finding demonstrates that time-gating is more useful than previously thought for improving spatial resolution in brain tissue imaging. This microscopy will facilitate deeper super-resolution observation of the fine structure of neuronal dendritic spines and the intracellular dynamics in brain tissue.

Primary angiosarcomas of the kidney are very rare but highly aggressive tumors showing poor prognosis. We present a case of primary renal angiosarcoma occurring in a 60-year-old man with left flank pain. CT images depicted a huge exophytic mass (14 cm in diameter) in the left kidney, exhibiting central extensive hemorrhage or necrosis without contrast enhancement. The mass showed centripetal peripheral nodular enhancement on dynamic contrast-enhanced CT images. We suggest its inclusion in the differential diagnosis of cases of hemorrhagic renal tumors with prominent vasculature.

Abstract Aims Clinical guidelines for improving the patients' quality of care vary in clinical practice, particularly in super‐aging societies, like in Japan. We aimed to develop a set of appropriate‐use criteria (AUC) for contemporary heart failure (HF) management to assist physicians in decision making. Methods and results With the use of the RAND methodology, a multidisciplinary writing group developed patient‐based clinical scenarios in 10 selected key topics, stratified mainly by HF stage, age, and renal function. Nine nationally recognized expert panellists independently rated the clinical scenario appropriateness twice on a scale of 1–9, as ‘appropriate’ (7–9), ‘may be appropriate’ (4–6), or ‘rarely appropriate’ (1–3). Decisions were based on clinical evidence and professional opinions in the context of available resource use and costs. An interactive round‐table discussion was held between the first and second ratings; the median score of the nine experts was then assigned to an appropriate‐use category. Most clinical scenarios without strong evidence were evaluated as ‘may be appropriate’. Frailty assessments in elderly patients (age ≥ 75 years), regardless of the HF stage, and advanced care planning in patients with stage C/D HF, regardless of age, were considered ‘appropriate’. For HF with reduced ejection fraction, beta‐blocker administration in elderly patients (age ≥ 75 years) with heart rate

IEEE 802.11ad is the practical networking technology widely used as a 60 GHz millimeter-wave communication method ahead of Beyond 5G and 6G networks. However, compared with the existing Wi-Fi systems that use 2.4/5 GHz, it is difficult to manage the communication quality due to the high carrier frequency, e.g., the signal strength suddenly and significantly degrades due to various factors such as distance and obstacles. For IEEE 802.11ad to be widely adopted, a simple and inexpensive measurement method is needed for non-specialists, including end users, to build and manage a stable IEEE 802.11ad network. In addition, easy-to-understand performance indicators are required. This paper then proposes a multilayer measurement methodology with open-source tools, i.e., iperf3, ping, and iw, for IEEE 802.11ad communication. Our methodology selects indicators necessary to evaluate IEEE 802.11ad communication performance. The tools iperf3 and ping mainly evaluate the IP layer indicators such as throughput, jitter, packet retries, packet loss, and RTT. On the other hand, the RSSI and Tx bitrates of the iw results are used to investigate the wireless link quality. Through empirical results with our measurement methodology in real environments, we show that in addition to traditional indicators such as through-put, the Tx bitrate output by iw can be a new indicator for understanding the IEEE 802.11ad communication quality.

We report a 49-year-old male with castration-resistant prostate cancer (CRPC) with oligometastasis diagnosed by 11C-choline positron emission tomography-computed tomography (PET/CT) and treated with target radiotherapy. In the diagnosis of CRPC (serum prostate-specific antigen [PSA] level of 6.53 ng/mL after maximum androgen blockade (MAB) therapy, high-dose brachytherapy, and external beam radiotherapy), 11C-choline PET/CT detected one tiny obturator lymph node metastasis which fluorodeoxyglucose PET/CT could not detect. He underwent intensity-modulated radiation therapy and MAB was restarted. The PSA value decreased and reached nadir (0.091 ng/mL) after 6 months. The time to PSA progression was 10 months. The choline PET/CT finding and the corresponding local treatment could play an important role in the management sequence of oligoprogressive CRPC.

Schwann cell proliferation in peripheral nerve injury (PNI) enhances axonal regeneration compared to central nerve injury. However, even in PNI, long-term nerve damage without repair induces degeneration of neuromuscular junctions (NMJs), and muscle atrophy results in irreversible dysfunction. The peripheral regeneration of motor axons depends on the duration of skeletal muscle denervation. To overcome this difficulty in nerve regeneration, detailed mechanisms should be determined for not only Schwann cells but also NMJ degeneration after PNI and regeneration after nerve repair. Here, we examined motor axon denervation in the tibialis anterior muscle after peroneal nerve transection in thy1-YFP mice and regeneration with nerve reconstruction using allografts. The number of NMJs in the tibialis anterior muscle was maintained up to 4 weeks and then decreased at 6 weeks after injury. In contrast, the number of Schwann cells showed a stepwise decline and then reached a plateau at 6 weeks after injury. For regeneration, we reconstructed the degenerated nerve with an allograft at 4 and 6 weeks after injury, and evaluated functional and histological outcomes for 10 to 12 weeks after grafting. A higher number of pretzel-shaped NMJs in the tibialis anterior muscle and better functional recovery were observed in mice with a 4-week delay in surgery than in those with a 6-week delay. Nerve repair within 4 weeks after PNI is necessary for successful recovery in mice. Prevention of synaptic acetylcholine receptor degeneration may play a key role in peripheral nerve regeneration. All animal experiments were approved by the Institutional Animal Care and Use Committee of Tokyo Medical and Dental University on 5 July 2017, 30 March 2018, and 15 May 2019 (A2017-311C, A2018-297A, and A2019-248A), respectively.

We report a patient with a 6q22.1 deletion, who presented with a rare syndrome of generalized epilepsy, myoclonic tremor, and intellectual disability. There was no clinical progression after follow-up for more than 10 years. Our report presents the genetic basis for a phenotype involving a non-progressive generalized epilepsy with tremor. The efficacy of valproic acid for seizure control and the partial efficacy of deep brain stimulation with propranolol for myoclonic tremor is detailed.

Vehicular Ad-hoc NETworks (VANETs), a special kind of Mobile Ad-hoc NETworks (MANETs), play an important role in Intelligent Transportation Systems (ITS). Via wireless technology, vehicles exchange information related to road conditions and their status, and, thereby, VANETs enhance transportation safety and efficiency. A critical aspect of VANETs is providing privacy for the vehicles. The employment of pseudonym certificates is a well-known solution to the privacy problems in VANETs. However, certificate management faces challenges in renewing certificates and revoking vehicles. The centralized certificate management, especially resulting in the delay of the revocation process, harms the nodes of VANETs. This paper proposes a blockchain structure-based certificate management for VANETs and voting-based revocation to halt misbehaving vehicles’ actions. Moreover, this paper presents extended privacy for the participants of the voting process using ring signatures.

This survey reviews the two most prominent group-oriented anonymous signature schemes and analyzes the existing approaches for their problem: balancing anonymity against traceability. Group signatures and ring signatures are the two leading competitive signature schemes with a rich body of research. Both group and ring signatures enable user anonymity with group settings. Any group user can produce a signature while hiding his identity in a group. Although group signatures have predefined group settings, ring signatures allow users to form ad-hoc groups. Preserving user identities provided an advantage for group and ring signatures. Thus, presently many applications utilize them. However, standard group signatures enable an authority to freely revoke signers’ anonymity. Thus, the authority might weaken the anonymity of innocent users. On the other hand, traditional ring signatures maintain permanent user anonymity, allowing space for malicious user activities; thus achieving the requirements of privacy-preserved traceability in group signatures and controlled anonymity in ring signatures has become desirable. This paper reviews group and ring signatures and explores the existing approaches that address the identification of malicious user activities. We selected many papers that discuss balancing user tracing and anonymity in group and ring signatures. Since this paper scrutinizes both signatures from their basic idea to obstacles including tracing users, it provides readers a broad synthesis of information about two signature schemes with the knowledge of current approaches to balance excessive traceability in group signatures and extreme anonymity in ring signatures. This paper will also shape the future research directions of two critical signature schemes that require more awareness.

Abstract Background The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC). Methods Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety. Results The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0–14.8) and 30.6 months (95% CI, 27.6–33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17.8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy. Conclusions CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC. Trial registration This trial is registered with the University Hospital Medical Information Network in 15 March 2010 ( UMIN000006478 ).

Objectives Early recognition of acute myocardial infarction (AMI) and early activation of emergency medical services (EMS) are essential to reduce delays in patient care. We investigated public awareness of the need to call EMS at onset of AMI and evaluated associated factors. Methods In January 2008, a nationwide population-based survey using quota sampling was conducted in Japan. The primary outcome measure was responsiveness to promptly calling EMS at AMI onset, subdivided by on-time (daytime) and off-time (nights and holidays) hours. Results In total, 1200 participants were surveyed. Their mean age was 46.3 years (standard deviation, 17.4), and 50.3% (n=604) were women. A total of 11.6% (n=139) answered that they would call EMS during on-time hours, and 27.5% (n=330) stated that they would call during off-time hours. Multivariable analysis showed that the participants’ age, female sex, education level, and self-confidence regarding their understanding of AMI were significant associated factors. The associated factors were almost identical during the off-time hours; only sex was no longer significant. Conclusions Public awareness of the need to call EMS at AMI onset in Japan was low. Previous intervention studies that were not effective may not have targeted groups with significant risk factors.