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The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter's nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.

Hashimoto’s encephalopathy with serum anti-NH2-terminal of α-enolase (NAE) antibodies occasionally displays clinical symptoms such as cerebellar ataxia and parkinsonism. We studied the frequency of anti-NAE antibodies in patients with Parkinson-plus syndrome. We examined the positive rates of anti-NAE antibodies in 47 patients with multiple system atrophy (MSA), 29 patients with Parkinson’s disease (PD), eight patients with corticobasal syndrome (CBS), and 18 patients with progressive supranuclear palsy (PSP) using conventional immunoblot analysis. Positive anti-NAE antibody rates of 31.9%, 10.3%, 50.0%, and 11.1% were reported in the MSA, PD, CBS, and PSP patients, respectively. The duration from onset to a wheelchair-bound state in seropositive MSA patients tended to be shorter than that in seronegative MSA patients. Anti-NAE antibodies are detected in some patients clinically diagnosed with MSA and CBS. Although its pathophysiological significance remains uncertain, serum anti-NAE antibodies might represent a prognostic marker in the clinical course of MSA.

APS001F is a strain of Bifidobacterium longum genetically engineered to express cytosine deaminase that converts 5-fluorocytosine (5-FC) to 5-fluorouracil. In the present study, antitumor effects of APS001F plus 5-FC (APS001F/5-FC) in combination with anti-PD-1 monoclonal antibody were investigated using a CT26 syngeneic mouse model. Both of dosing of APS001F/5-FC before and after anti-PD-1 mAb in the combination dosing exhibited antitumor effects as well as prolonged survival over the nontreated control. The survival rate in the combination therapy significantly increased over the monotherapy with APS001F/5-FC and that with anti-PD-1 mAb. Regulatory T cells among CD4+ T cells in tumor decreased in the combination therapy, while the ratio of CD8+ T cells was maintained in all groups. Taken these results together, APS001F/5-FC not only demonstrates a direct antitumor activity, but also immunomodulatory effects once localized in the hypoxic region of the tumor, which allows anti-PD-1 mAb to exert potentiated antitumor effects.

A 66-year-old woman presented with upper abdominal pain and weakness in the limbs. She had bilateral uveitis and gastric ulcers. A neurological examination revealed tetraparesis and sensory disturbance in the right arm. A cerebrospinal fluid (CSF) examination showed polymorphonuclear pleocytosis with elevated pro-inflammatory cytokine levels. Magnetic resonance imaging showed brain lesions and a long spinal cord lesion. She was initially diagnosed with neuro-Behcet's disease and was treated with corticosteroids, resulting in no improvement. A gastric mucosa biopsy indicated T-cell lymphoma colocalizing with neutrophils. The cytokine-mediated neutrophilic inflammation probably caused characteristic CSF and histopathological features. It is noteworthy that T-cell lymphoma may present with CSF neutrophilic inflammation.

Hashimoto's encephalopathy with serum anti-NHWe examined the positive rates of anti-NAE antibodies in 47 patients with multiple system atrophy (MSA), 29 patients with Parkinson's disease (PD), eight patients with corticobasal syndrome (CBS), and 18 patients with progressive supranuclear palsy (PSP) using conventional immunoblot analysis.Positive anti-NAE antibody rates of 31.9%, 10.3%, 50.0%, and 11.1% were reported in the MSA, PD, CBS, and PSP patients, respectively. The duration from onset to a wheelchair-bound state in seropositive MSA patients tended to be shorter than that in seronegative MSA patients.Anti-NAE antibodies are detected in some patients clinically diagnosed with MSA and CBS. Although its pathophysiological significance remains uncertain, serum anti-NAE antibodies might represent a prognostic marker in the clinical course of MSA.

Time series anomaly detection remains a perennially important research topic. If anything, it is a task that has become increasingly important in the burgeoning age of IoT. While there are hundreds of anomaly detection methods in the literature, one definition, time series discords, has emerged as a competitive and popular choice for practitioners. Time series discords are subsequences of a time series that are maximally far away from their nearest neighbors. Perhaps the most attractive feature of discords is their simplicity. Unlike many parameter laden methods, discords require only a single parameter to be set by the user: the subsequence length. In this work we argue that the utility of discords is reduced by sensitivity to this single user choice. The obvious solution to this problem, computing discords of all lengths then selecting the best anomalies (under some measure), seems to be computationally untenable. However, in this work we introduce MERLIN, an algorithm that can efficiently and exactly find discords of all lengths in massive time series archives.

Time series motifs have become a fundamental tool to characterize repeated and conserved structure in systems, such as manufacturing telemetry, economic activities, and both human physiological and cultural behaviors. Recently time series chains were introduced as a generalization of time series motifs to represent evolving patterns in time series, in order to characterize the evolution of systems. Time series chains are a very promising primitive; however, we have observed that the original definition can be brittle in the sense that a small fluctuation in time series may "cut" a chain. Furthermore, the original definition does not provide a measure of the "significance" of a chain, and therefore cannot support top-k search for chains or provide a mechanism to discard spurious chains that might be discovered when searching large datasets. Inspired by observations from dynamical systems theory, this paper introduces two novel quality metrics for time series chains, directionality and graduality, to improve robustness and to enable top-K search. With extensive empirical work we show that our proposed definition is much more robust to the vagaries of real-word datasets and allows us to find unexpected regularities in time series datasets.

It is shown that the ground state of weakly interacting Bose particles in a quasi one-dimensional box trap can be converted into an excited stationary state by an adiabatic cyclic operation that involves a quench of interaction strength: A sharp impurity potential is applied and its strength is varied during the cycle, which induces a nonequilibrium stationary state exhibiting the inversion of population. This process is robust in the sense that the resultant stationary state is almost independent of the details of the cycle, such as the position of the impurity as long as the cycle is far enough from critical regions. The case of the failure of the population inversion due to the strong interparticle interactions is also examined., Comment: 8 pages, 7figures

Myelin oligodendrocyte glycoprotein (MOG)-IgG detected by the cell-based assay is associated with demyelinating diseases of the central nervous system, such as optic neuritis, myelitis, and acute disseminated encephalomyelitis, but rarely with peripheral neuropathy. Here, we describe the case of a 32-year-old MOG-IgG+ woman who developed central and peripheral demyelinating lesions. In contrast to previous similar cases, she uniquely presented with repeated subsequent relapses in the peripheral nerve, mimicking chronic inflammatory demyelinating polyneuropathy. Possible pathogenic implications of MOG-IgG in combined central and peripheral nervous system diseases are considered.

Central nervous system intravascular lymphoma sometimes includes multiple lesions mimicking cerebral infarction. Herein, we report our experience with a case of intravascular large B-cell lymphoma (IVLBCL) with multiple hemorrhages. A 53-year-old woman was admitted to our hospital with clonic convulsions of the left upper limb. Brain MRI revealed a large number of high-intensity areas on FLAIR and low-intensity areas on susceptibility-weighted imaging (SWI). Chest CT showed bilateral multiple high-density lesions in the lungs. Biopsy of pulmonary lesions revealed no abnormal cells. Levetiracetam was administered to prevent the seizures that were assumed to occur due to the cerebral cortex lesions; however, convulsive seizure recurred with a depressed level of consciousness. On a repeat brain MRI examination, severe, multiple new lesions were shown to have developed bilaterally in the cerebral cortex and white matter, exhibiting spotty low intensities on SWI. Biopsy of a new cerebral lesion was carried out and the lesion was pathologically diagnosed as IVLBCL with hemorrhages. IVLBCL should be noted as one of the differential diagnoses not only in case with multiple infarct lesions, but also in case with multiple hemorrhages.

Dysgeusia is rare in Guillain-Barre syndrome, particularly as the initial symptom. We herein report the case of a 59-year-old woman who presented with only dysgeusia as the initial symptom of Guillain-Barre syndrome, followed by gradually worsening muscle weakness and bilateral sensory disturbances in the extremities. Her dysgeusia was so unpleasant that she could not eat anything, so she received nasogastric tube feeding without dysphasia. We speculate that the dysgeusia in our patient was mainly caused by inflammation of the chorda tympani nerves. Guillain-Barre syndrome should be considered a possible cause of acute dysgeusia.

Early neurosyphilis commonly appears in basilar meninges, and its meningeal inflammation can spread to neighboring cranial nerves, resulting in some cranial nerve palsies. Herein, we report a case of a 51-year-old man who presented with right peripheral facial nerve palsy. His symptoms completely disappeared with prednisolone monotherapy without antibiotics use and were not exacerbated during clinical treatment. However, 2 months after remission of seventh cranial neuropathy, fifth and eighth cranial neuropathies appeared on the right side. Serologic tests for syphilis were revealed to be abnormal. Finally, the patient was diagnosed with early neurosyphilis with multiple cranial palsies. His neurological symptoms were markedly improved by combined penicillin-corticosteroid treatment. Systemic corticosteroids could be effective as adjunctive therapy to ameliorate neurological sequelae in early neurosyphilis.

Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an anti-viral agent that selectively and potently inhibits the RNA-dependent RNA polymerase (RdRp) of RNA viruses. Favipiravir was discovered through screening chemical library for anti-viral activity against the influenza virus by Toyama Chemical Co., Ltd. Favipiravir undergoes an intracellular phosphoribosylation to be an active form, favipiravir-RTP (favipiravir ribofuranosyl-5′-triphosphate), which is recognized as a substrate by RdRp, and inhibits the RNA polymerase activity. Since the catalytic domain of RdRp is conserved among various types of RNA viruses, this mechanism of action underpins a broader spectrum of anti-viral activities of favipiravir. Favipiravir is effective against a wide range of types and subtypes of influenza viruses, including strains resistant to existing anti-influenza drugs. Of note is that favipiravir shows anti-viral activities against other RNA viruses such as arenaviruses, bunyaviruses and filoviruses, all of which are known to cause fatal hemorrhagic fever. These unique anti-viral profiles will make favipiravir a potentially promising drug for specifically untreatable RNA viral infections.

This work investigated the solubilities of ethylene in the 10 wt% poly (ethylene-co-vinyl acetate) (EVA) solutions including vinyl acetate (VA) and methanol which are related to production of EVA. The bubble point pressure (BP) for vapor-liquid equilibrium (VLE) and the cloud point pressure (CP) for liquid-liquid equilibrium (LLE) of ethylene + VA + EVA ternary and ethylene + VA + EVA + methanol quaternary systems were measured at temperatures of 313 K, 343 K, 373 K and at pressures up to 20 MPa with a synthetic method. The experimental results revealed that the BP and CP increased with increasing temperature and ethylene weight fraction, especially the influence of ethylene weight fraction on CP was found to be drastic. The Sanchez-Lacombe equation of state (SL EOS) could correlate the BP data of ethylene + VA + EVA ternary and ethylene + VA + EVA + methanol quaternary systems within 3.6% an average relative deviation. The phase equilibria of the EVA + VA + ethylene ternary system could be predicted over wide polymer concentration ranges by the SL EOS with the determined parameters in the correlations. With increasing pressure, phase behavior changed from VLE at low pressure to vapor-liquid-liquid equilibrium (VLLE) and LLE at high pressures.

Anti-cancer therapies targeting EGFR family, including monoclonal antibodies and kinase inhibitors, are the state of art for solid tumors such as colorectal and non-small cell lung cancers. T cell redirecting bispecific antibodies are a promising approach for cancer immune therapy, whereas their application is limited to hematological malignancy due to adverse events caused by the systemic exposure to highly immunologically active molecule. To avoid the immunological adverse events, we have created a recombinant Bifidobacterium (APS002) that specifically colonizes in solid tumor and continuously secretes T cell redirecting antibody. The antibody was designed to form a diabody based on the sequence of dual specific antibody for EGFR/HER3 and CD3. The diabody (termed DBERB1) comprises the equal amount of two polypeptides, anti-h CD3 (VL) - anti-EGFR/hHER3 (VH) and anti-hEGFR/hHER3 (VL) - anti-hCD3 (VH), respectively. DBERB1 bound to human EGFR and HER3, and human CD3. DBERB1 demonstrated potent cytotoxic activities against EGFR- and HER3-expressing human colon cancer HCT116 cells in the presence of human peripheral blood mononuclear cells (hPBMC) with EC50 values of 3 - 9 × 10−12 M. When APS002 was i.v. dosed to HCT116 tumor-bearing SCID mice inoculated with hPBMC, APS002 colonized only in the tumor and DBERB1 was detected in the tumors but not in the plasma. The growth of HCT116 tumors was significantly suppressed by APS002 but not by Bifidobacterium transfected with control vector. In conclusion, our study in the mouse model indicates that APS002 is a novel and an extremely potent anti-cancer agent distributed only in the tumor. We are currently preparing for pre-clinical studies for the future clinical trials. Citation Format: Satoshi Kobayashi, Koichiro Shioya, Yuji Seki, Tomio Matsumura, Yasuyoshi Kanari, Yuko Shimatani, Hikaru Nakazawa, Mitsuo Umetsu, Shiro Kataoka, Takaaki Nakamura. Anti-tumor activity of Bifidobacterium secreting dual specific T cell redirecting antibody against EGFR/HER3-expressing cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 689.

A 28-year-old healthy man was admitted to our hospital because of right-sided headache, vomiting, and lower back pain after the administration of vardenafil. Computed tomography and magnetic resonance imaging of the brain showed a small, right-sided, subdural hematoma. A lumbar magnetic resonance imaging showed a longitudinally extended subdural hematoma. He had no history of trauma. We speculated that vardenafil might have had an association with the bleeding. Several reports have suggested a relationship between phosphodiesterase-5 inhibitors and intracerebral or subarachnoid hemorrhage. Our case suggested that there may also be risks of bleeding into the subdural space. Although headache and nausea are common side effects of vardenafil, hemorrhagic diseases should also be considered when symptoms are severe or prolonged.

Development of paradoxical cerebral embolism requires both unstable venous thrombosis and right-to-left shunt (RLS). Gastrointestinal endoscopy (GE) has the potential to affect intrathoracic and abdominal venous thrombi and to enhance RLS because the procedure alters intrathoracic and abdominal pressure. We describe a patient with Crohn's disease who developed paradoxical cerebral embolism after GE. Both an unstable venous thrombus in the superior vena cava and RLS through patent foramen ovale were thought to be responsible for the stroke. Considering that patients with digestive system diseases undergo GE as a routine examination or therapy, screenings for hypercoagulable state and intrathoracic and abdominal thrombi are important to prevent thromboembolism related to GE.

The stationary states of nonlinear Schr{\"o}dinger equation on a ring with a defect is numerically analyzed. Unconventional connection conditions are imposed on the point defect, and it is shown that the system displays energy level crossings and level shifts and associated quantum holonomies in the space of system parameters, just as in the corresponding linear system. In the space of nonlinearity parameter, on the other hand, the degeneracy occurs on a line, excluding the possibility of any anholonomies. In contrast to the linear case, existence of exotic phenomena such as disappearance of energy level and foam-like structure are confirmed., Comment: LaTeX 13 pages 7 figures

Resistance to azacitidine is a major issue in the treatments of myelodysplastic syndrome and acute myeloid leukemia, and previous studies suggest that changes in drug metabolism are involved in the resistance. Therefore, drugs with mechanisms resistant or alternative to such metabolic changes have been desired for the treatment of resistant disease. We generated azacitidine‐resistant cells derived from SKM‐1 and MOLM‐13 leukemia cell lines in vitro, analyzed the mechanisms, and examined the impact on the efficacy of other antimetabolic drugs. It appeared that the cell growth‐inhibitory effect of azacitidine, expression levels of uridine–cytidine kinase 2, and the concentrations of azacitidine triphosphate were remarkably decreased in the resistant cells compared with those in parent cells. These results were consistent with previous observations that azacitidine resistance is derived from metabolic changes. Cross‐resistance of greater than 10‐fold (shift in IC50 value) was observed in azacitidine‐resistant cells for decitabine and for cytarabine, but not for gemcitabine or the inosine‐5′‐monophosphate dehydrogenase (IMPDH) inhibitors FF‐10501 and mycophenolate mofetil (cross‐resistance to 5‐fluorouracil was cell line dependent). The IMPDH inhibitors maintained their cell growth‐inhibitory activities in the azacitidine‐resistant cell lines, in which the levels of adenine phosphoribosyltransferase (which converts FF‐10501 to its active form, FF‐10501 ribosylmonophosphate [FF‐10501RMP]), FF‐10501RMP, and the target enzyme, IMPDH, were equivalent to those in the parent cell lines. These results suggest that an IMPDH inhibitor such as FF‐10501 could be an alternative therapeutic treatment for leukemia patients with acquired resistance to azacitidine.

ASB2 proteins are E3 ubiquitin (Ub) ligases that ubiquitinate filamins. There are two ASB2 splice variants, ASB2α and ASB2β. ASB2β has a ubiquitin-binding motif (UIM) at the N-terminal region but ASB2α does not. Here, we provide the first evidence that ASB2β but not ASB2α is monoubiquitinated and that this monoubiquitination involves the UIM. Myc-tagged ASB2β and hemagglutinin (HA)-tagged Ub were co-expressed in HEK293 cells using the pCMV expression vector. Immunoprecipitation with an anti-Myc antibody followed by immunoblotting with anti-Myc and anti-HA antibodies showed an additional ASB2β protein band that had both a Myc and a HA tag. The molecular weight of this protein was larger than that of ASB2β, and the difference in molecular weight between these two proteins corresponded to the molecular weight of monoubiquitin, strongly implying that monoubiquitinated ASB2β is produced in cells. ASB2β with mutations in the UIM motif; either Glu·Asp·Glu27-29Ala·Ala·Ala mutations (ASB2β M1) or a Ser38Ala mutation, (ASB2β M2) were not monoubiquitinated, suggesting the importance of the UIM for ASB2β monoubiquitination. Furthermore, an ASB2β mutant that lacked a SOCS box (ASB2β ΔC) and did not show E3 Ub ligase activity was monoubiquitinated to the same extent as the wild-type ASB2β. In contrast, an ASB2β mutant that lacked the UIM-containing domain (ASB2β ΔN) was not monoubiquitinated. These results suggest that ASB2β but not ASB2α might be monoubiquitinated and that the ASB2β UIM motif, but not its E3 Ub ligase activity, plays a pivotal role in this monoubiquitination.