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The article presents the study related to characterization and identification of gamma-aminobutyric acid (GABA) receptor autoantibodies in Autoimmune Encephalitis. It mentions the association of autoimmune forms of encephalitis with autoantibodies related to synaptic cell surface antigens. It discusses the identification of autoantibodies against the GABA receptor in human sera.

Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders that are caused by the expansion of trinucleotide CAG repeats in the causative genes. Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease that is caused by the expansion of a polyQ tract within the androgen receptor (AR). p62 is a ubiquitin- and light-chain 3-binding protein that is known to regulate the degradation of targeted proteins via autophagy and inclusion formation. In this study, we examined the effects of p62 depletion and overexpression on cultured cells and in a transgenic mouse model that overexpressed the mutant AR. Here, we demonstrate that depletion of p62 significantly exacerbated motor phenotypes and the neuropathological outcome, whereas overexpression of p62 protected against mutant AR toxicity in SBMA mice. Depletion of p62 significantly increased the levels of monomeric mutant AR and mutant AR protein complexes in an SBMA mouse model via the impairment of autophagic degradation. In addition, p62 overexpression improved SBMA mouse phenotypes by inducing cytoprotective inclusion formation. Our results demonstrate that p62 provides two different therapeutic targets in SBMA pathogenesis: (1) autophagy-dependent degradation and (2) benevolent inclusion formation of the mutant AR. [ABSTRACT FROM AUTHOR]

Machine learning approaches are widely used to evaluate ligand activities of chemical compounds toward potential target proteins. Especially, exploration of highly selective ligands is important for the development of new drugs with higher safety. One difficulty in constructing well‐performing model predicting such a ligand activity is the absence of data on true negative ligand‐protein interactions. In other words, in many cases we can access to plenty of information on ligands that bind to specific protein, but less or almost no information showing that compounds don't bind to proteins of interest. In this paper, we suggested an approach to comprehensively explore candidates for ligands specifically targeting toward proteins without using information on the true negative interaction. The approach consists of 4 steps: 1) constructing a model that distinguishes ligands for the target proteins of interest from those targeting proteins that cause off‐target effects, by using graph convolution neural network (GCNN); 2) extracting feature vectors after convolution/pooling processes and mapping their principal components in two dimensions; 3) specifying regions with higher density for two ligand groups through kernel density estimation; and 4) investigating the distribution of compounds for exploration on the density map using the same classifier and decomposer. If compounds for exploration are located in higher‐density regions of ligand compounds, these compounds can be regarded as having relatively high binding affinity to the major target or off‐target proteins compared with other compounds. We applied the approach to the exploration of ligands for β‐site amyloid precursor protein [APP]‐cleaving enzyme 1 (BACE1), a major target for Alzheimer Disease (AD), with less off‐target effect toward cathepsin D. We demonstrated that the density region of BACE1 and cathepsin D ligands are well‐divided, and a group of natural compounds as a target for exploration of new drug candidates also has significantly different distribution on the density map. [ABSTRACT FROM AUTHOR]

We evaluated the clinical course of patients with localized prostate cancer in whom long-term successful androgen deprivation therapy (ADT) was ceased. Study subjects were 24 patients with stage B prostate cancer who were initially treated with ADT for a median duration of 93 months. The median age at the cessation of ADT was 84 years. The median nadir serum prostate specific antigen (PSA) level was 0.022 ng/ml. The median duration of follow-up from the cessation of ADT was 31 months. During follow-up, five patients showed PSA elevation of ≥2 ng/ml from the nadir. Serum testosterone level was tested in 20 patients, and five showed testosterone recovery ≥0.5 ng/ml. Seven patients died from diseases other than prostate cancer, but there were no deaths caused by prostate cancer. This study demonstrated that long-term successful ADT for localized prostate cancer could be ceased with adequate follow-up evaluation.

While amyloid-β lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

Male reproduction encompasses many essential cellular processes and interactions. As a focal point for these events, sperm offer opportunities for advancing our understanding of sexual reproduction at multiple levels during development. Using male sterility genes identified in human, mouse, and fruit fly databases as a starting point, 103 Drosophila melanogaster genes were screened for their association with male sterility by tissue-specific RNAi knockdown and CRISPR/Cas9-mediated mutagenesis. This list included 56 genes associated with male infertility in the human databases, but not found in the Drosophila database, resulting in the discovery of 63 new genes associated with male fertility in Drosophila. The phenotypes identified were categorized into six distinct classes affecting sperm development. Interestingly, the second largest class (Class VI) caused sterility despite apparently normal testis and sperm morphology suggesting that these proteins may have functions in the mature sperm following spermatogenesis. We focused on one such gene, Rack 1, and found that it plays an important role in two developmental periods, in early germline cells or germline stem cells and in spermatogenic cells or sperm. Taken together, many genes are yet to be identified and their role in male reproduction, especially after ejaculation, remains to be elucidated in Drosophila, where a wealth of data from human and other model organisms would be useful., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

A 72-year-old man underwent a bilateral nerve-sparing radical retropubic prostatectomy (RRP) with pelvic lymph node dissection 11 years earlier. His prostate specific antigen (PSA) value at diagnosis was 61.024 ng/ml. Bone scans and computed tomographic (CT) scans showed no metastasis. Pathological findings and stage were adenocarcinoma, Gleason score 4+3, positive surgical margin, pT3b, and no lymph node metastasis. The postoperative PSA nadir was 0.218 ng/ml, and salvage radiotherapy (SRT, total 66 Gy) was performed six months after RRP. However, the PSA value continued to rise after SRT. Therefore, androgen deprivation therapy (ADT) was started 11 months after SRT. Nine years postoperatively, the PSA value showed a continuous rise despite ADT, and prostate cancer was considered to be castration-resistant. Although he was taking enzalutamide, his PSA value rose to 18. 271 ng/ml. Repeated bone scans and CT scans were negative. Eleven years after RRP, the fluoro-2-deoxy-D-glucosepositronemissiontomography (FDG-PET) revealed a nodule lesiondorsal to the left pubic bone. The patient underwent a resection of the lesion. Three months after the resection, his PSA level declined to 0.038 ng/ml, thus ADT was discontinued. Thirteen months after the resection, PSA re-elevation was absent, and follow-up without ADT is ongoing.

A 49-year-old male with untreated diabetes mellitus type 2 experienced eyesight deterioration and general malaise, and was treated for uveitis and orbital cellulitis. Later, he was taken to a local hospital via ambulance for a consciousness disorder and was diagnosed with bilateral infectious endophthalmitis, a right ureteral stone, and emphysematous pyelonephritis. He was then referred to our hospital for further examination and treatment. We immediately initiated intravenous antibiotic therapy with meropenem and glycemic control with continuous subcutaneous insulin infusion, and placed a ureteral and percutaneous drain tube into the right ureter and the emphysema, respectively. We performed a diagnostic and therapeutic vitrectomy on the patient's left eye. Urinary, blood, and vitreous cultures were positive for Klebsiella aerogenes. Abdominal contrast-enhanced computed tomography showed bilaterally comparable renal contrast enhancement. On the 60th hospital day, we performed endoscopic combined intrarenal surgery (ECIRS) and completely removed the urinary stone. Although he lost light sensitivity in his right eye, his left eyesight improved, and his blood glucose level was adequately managed by oral medication. Three months after the surgery, he was discharged from our hospital and he showed no sign of recurrence of the infection at ten months after surgery.

Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC ( p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS ( p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients ( p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma circulating cell-free DNA (cfDNA) and evaluated the AR statuses of patients with CRPC. AR amplification was detectable in VCaP cell line (AR amplified) genomic DNA (gDNA) diluted to 1.0% by digital PCR (dPCR). AR mutation were detectable in LNCaP cell line (AR T878A mutated) gDNA diluted to 0.1% and 1.0% by dPCR and target sequencing, respectively. Next, we analyzed AR status in cfDNA from 102 patients. AR amplification and mutations were detected in 47 and 25 patients, respectively. As a biomarker, AR aberrations in pretreatment cfDNA were associated with poor response to abiraterone, but not enzalutamide. In serial cfDNA analysis from 41 patients, most AR aberrations at baseline diminished with effective treatments, whereas in some patients with disease progression, AR amplification or mutations emerged. The analysis of AR in cfDNA is feasible and informative procedure for treating patients with CRPC. cfDNA may become a useful biomarker for precision medicine in CRPC.

A 66-year-old man had undergone multiple treatments for metastatic renal cell carcinoma, including 11 cycles of nivolumab, which was discontinued because of disease progression. About three weeks after discontinuing nivolumab, he reported suffering from worsening of dyspnea. Pulse oximetry showed no desaturation. His cardiovascular and pulmonary functions were normal. His dyspnea slowly worsened with no underlying diagnosis. Two months after symptoms developed, he was diagnosed with isolated adrenocorticotropic hormone deficiency. His dyspnea disappeared soon after receiving hydrocortisone. Nivolumab-induced isolated adrenocorticotropic hormone deficiency may not present with typical symptoms, and can occur even after discontinuing nivolumab. Cortisol levels should be routinely monitored in patients who receive nivolumab.

We report the successful postoperative pain man- agement of a pediatric patient with end-stage renal failure by ultrasound-guided peripheral nerve block following peritoneal dialysis catheter surgery. A 2-year-old boy with kidney hypoplasia was scheduled for peritoneal dialysis catheter implantation under gen- eral anesthesia. Anesthesia was induced with nitrous oxide and sevoflurane in a slow incremental manner. Airway management was performed with i-gelo to minimize stress and to protect the cervical spine. Maintenance of anesthesia was achieved with sevoflu- rane and remifentanil. For postoperative analgesia, opi- oids were not used in order to avoid respiratory sup- pression or CO2 accumulation. Recovery from anesthe- sia was uneventful and the boy did not experience pain until the next morning.

Anesthestic management with prolonged one-lung ventilation is difficult, especially when the patient continues smoking habit. Here, we report a successful one-lung ventilation and protection with combined use of double-lumen endotracheal tube and bronchial blocker. A 68-year-old man (height 153 cm; weight, 45 kg) was scheduled for simultaneous surgery of right lobectomy and esophagectomy. He kept smoking to the operation day. To protect the ventilated lung, we guided the bronchial lumen of the DLT to the left bronchus under fiberoptic bronchoscope (FOB) guide and inflated the bronchial cuff. Next, we inserted the bronchial blocker from the tracheal lumen of the DLT and inflated the cuff in the left bronchus under FOB guidance. We performed continuous suctioning of the right trachea via the inner lumen of BB. During the operation, non-negligible amount of blood and sputum was aspirated from the inner lumen of the BB. Furthermore, there was no visible blood inflow in the left bronchus. We could protect the ventilated lung with double cuff, i. e. bronchial cuff of DLT in the left bronchus and BB cuff in the right bronchus. Simultaneous operation was uneventfully performed and no oxygenation or ventilation trouble was observed during the operation.

Background: The purpose of this study was to compare the upper gastrointestinal endoscope (UGE) insertion-mediated cuff pressure increase between a tracheal tube with a tapered cuff (Taper) and or conventional high volume low pressure cuff (HVLP) utilizing a porcine larynx model., Methods: The automated cuff pressure was adjusted to 10, 20, and 30 cmH2O. The Taper and HVLP cuff pressure increases by UGE insertion were measured., Results: Significant cuff pressure increase was observed by UGE insertion regardless of initial cuff pressure. The cuff pressure of the Taper was significantly lower than that of the HVLP by UGE insertion., Conclusions: These findings suggest that the Taper may be more effective than the HVLP in preventing tracheal tube cuff increase by UGE insertion.

Unlabelled: BaCKGROUND: The present study aimed to compare nitrous oxide-mediated increases in cuff pressure between the disposable type air-Q (air-Q-DT) and re-use type air-Q (air-Q-RU) in a simulated adult airway model., Methods: Automated cuff pressure was adjusted to 10, 20, and 30 cmH2O. The air-Q-DT and air-Q-RU were exposed to 80% nitrous oxide and cuff pressure was measured 15 and 30 minutes later., Results: Cuff pressure of the air-Q-DT was significantly lower than that of the air-Q-RU after 15 and 30 minutes, regardless of the initial pressure., Conclusions: The polyvinyl chloride-based air-Q-DT may be more effective than the silicon-based air-Q-RU in preventing hyperinflation of the tracheal tube cuff in response to nitrous oxide exposure.

We report use of videolaryngoscope for difficult airway management in an infant with severe tongue swelling after laceration repair. A 3-month-old male infant was transferred to our hospital for respiratory difficulty. He could not open his mouth sufficiently, and the examination revealed massive swelling of the left side of the tongue. Emergent surgical repair of the tongue was scheduled, anticipating a difficult airway. The venous line was kept patent preoperatively, and 8% sevoflurane was administered maintaining spontaneous ventilation. We then inserted the Pentax Airway Scope with an infant-sized Intlock (AWS-I) from the right side of the mouth and obtained a good view at laryngoscopy. A 3.5-mm tracheal tube was passed uneventfully under the view of AWS-I. The AWS-I is useful for difficult airway management in infants, preserving spontaneous ventilation.

Neurovascular bundle (NVB) preservation is a mandatory procedure to maintain erectile function of localized prostate cancer patients after radical prostatectomy (RP). However, in terms of cancer control, indications to select appropriate patients for nerve-sparing RP are still controversial. In this study, we examined the pathological findings of RP specimens to develop a preoperative criterion for NVB preservation during RP. The study included 76 patients who underwent RP at our institution from 2006 to 2008, and we retrospectively analyzed RP specimens pathologically. The distance between NVB and foci of prostate cancer was measured in 135 prostate sides, and preoperative factors which predict the distance of ≤2 mm was evaluated. Univariate analysis showed that side-specific positive biopsy core rate ≥33.3%, side-specific maximum tumor length in biopsy core ≥5 mm and side-specific tumor involvement rate in biopsy core ≥50% was associated with the risk of the distance of ≤2 mm. Multivariate analysis revealed that side-specific positive biopsy core rate ≥33.3% was the only significant predictor of the ipsilateral NVB-tumor distance ≤2 mm (p = 0.0055, odds ratio 3.49). Based on this study, a nerve-sparing criterion of ＜33.3% side-specific percent positive biopsy core was developed at our institution. Prospective data on patients who were applied this criterion are needed to evaluate its clinical safety and feasibility.

We report a successful awake tracheal intubation in an emergency patient with acute exacerbation of aortic stenosis using the Pentax-AWS Airwayscope (AWS). An 83-year-old woman was admitted to our emergency department for severe dyspnea due to exacerbation of aortic stenosis. Her Sp(O2) was 92-93% even after administration of 10 l x min(-1) oxygen through a reservoir-attached face mask. As she could not remain in the supine position, emergency tracheal intubation in the sitting position was required. After topical anesthesia with 8% lidocaine and careful administration of midazolam, the AWS was inserted into her mouth in the sitting, face-to-face position. The AWS allowed for visualization of the glottis and safe placement of the tracheal tube. Sufficient spontaneous ventilation was maintained during interventions with minimum vital sign changes. Awake intubation in the sitting position with the AWS may be helpful in resolving cardiovascular crisis in patients unable to maintain the supine position.

Autoimmune forms of encephalitis have been associated with autoantibodies against synaptic cell surface antigens such as NMDA- and AMPA-type glutamate receptors, GABA(B) receptor, and LGI1. However, it remains unclear how many synaptic autoantigens are yet to be defined. Using immunoproteomics, we identified autoantibodies against the GABA(A) receptor in human sera from two patients diagnosed with encephalitis who presented with cognitive impairment and multifocal brain MRI abnormalities. Both patients had antibodies directed against the extracellular epitope of the β3 subunit of the GABA(A) receptor. The β3-subunit-containing GABA(A) receptor was a major target of the patients' serum antibodies in rat hippocampal neurons because the serum reactivity to the neuronal surface was greatly decreased by 80% when the β3 subunit was knocked down. Our developed multiplex ELISA testing showed that both patients had similar levels of GABA(A) receptor antibodies, one patient also had a low level of LGI1 antibodies, and the other also had CASPR2 antibodies. Application of the patients' serum at the time of symptom presentation of encephalitis to rat hippocampal neuron cultures specifically decreased both synaptic and surface GABA(A) receptors. Furthermore, treatment of neurons with the patients' serum selectively reduced miniature IPSC amplitude and frequency without affecting miniature EPSCs. These results strongly suggest that the patients' GABA(A) receptor antibodies play a central role in the patients' symptoms. Therefore, this study establishes anti-GABA(A) receptor encephalitis and expands the pathogenic roles of GABA(A) receptor autoantibodies., (Copyright © 2014 the authors 0270-6474/14/348151-13$15.00/0.)

We report the successful awake tracheal intubation in a patient with hypopharyngeal cancer and gastroesophageal regurgitation with the TaperGuard Evac tracheal tube (TaperGuard) and Pentax-AWS Airwayscope (AWS). A 63-year-old man with hypopharyngeal cancer with invasion to the glottis was scheduled for total laryngectomy under general anesthesia. He had undergone thoracic esophagectomy and could not maintain supine position due to severe gastroesophageal regurgitation. To avoid vomiting after induction of anesthesia, we planned awake intubation in the sitting position with the AWS. After topical anesthesia with 8% lidocaine and infusion of fentanyl and continuous dexmedetomidine, the AWS was inserted into his mouth in the sitting position from the cranial side. The AWS allowed visualizing the glottis avoiding the cancer, leading to safe placement of the tracheal tube.

This study aimed to investigate factors taken into account when considering the indication of partial nephrectomy (PN). In October 2011, a questionnaire prepared with reference to the American Urological Association small renal mass survey and RENAL nephrometry score, and focusing on the factors taken into account when considering the use of PN, such as differences among candidates for open PN or laparoscopic PN was sent to 40 institutions. We received replies from 32 of the 40 institutions (average 611 beds) to which the questionnaire was sent. The total number of surgeries performed for renal tumors at the 32 institutions was 844 in 2009 and 889 in 2010. The number of PNs performed was 174 in 2009 (open : 61, laparoscopic : 113), and 241 in 2010 (open : 103, laparoscopic : 138), which represents a 38.3% increase. All respondents reported that renal function prior to PN was considered to be important, followed by tumor size, tumor number, and hereditariness. There were significantly more indications for open PN than for laparoscopic PN, and they were based on tumor size, degree of protrusion, and distance from the renal sinus. In addition, a clear tendency toward avoiding laparoscopic PN for cystic renal cancer was found. In addition, the institutions with a larger number of PNs tended to indicate more complicated cases including larger tumor size or entirely endophytic cases. This study has a limitation in that it was intended for a relatively large hospital, but these results can be useful information for institutions that are considering the introduction of open or laparoscopic PN.

A cohort of patients with castration-resistant prostate cancer (CRPC) that were treated with docetaxel (DOC) were retrospectively analyzed in order to examine the factors for continuing DOC therapy. In total, 26 patients treated with DOC at our hospital from August 2007 to August 2011 were recruited into the study. The participants were divided into two groups ; the first comprising 13 patients who received short-term DOC therapy (less than 5 cycles) and the second comprising 13 who received long-term DOC therapy (5 or more cycles). There was no significant difference in the indicators including age, prostate specific antigen level (at initial diagnosis), clinical stage and Gleason score between the groups. Patients with pain or poor performance status were more likely to be found in the short-term DOC group. The Hemoglobin-level was significantly higher in the long-term DOC group. In contrast, alkaline phosphatase, lactate dehydrogenase and C-reactive protein levels were significantly higher in the short-term DOC group. The period from the start of primary endocrine therapy to CRPC diagnosis was significantly longer in the long-term DOC group (p=0.0008). This latter finding suggests that DOC therapy can be continued for a longer time, in CRPC cases which have a long-term response to endocrine therapy, and may be associated with a more favorable survival outcome. However, to validate this suggestion, further investigation with a larger cohort of cases is necessary.

A 78-year-old woman was referred to our hospital with chief complaint of colicky right flank pain. Computed tomography (CT) demonstrated right hydronephrosis and a wall thickening in the right ureteropelvic junction. Right nephroureterectomy was performed under a clinical diagnosis of invasive ureteral cancer. Histological examination revealed immunoglobulin light chain (AL) amyloidosis of the ureter. Although amyloid deposition seemed to be localized to the ureter alone, bone marrow biopsy revealed primary macroglobulinemia. After 23 months, no signs or symptoms suggesting the progression of amyloidosis or macroglobulinemia have been pointed out. AL amyloidosis arising secondarily to plasma cell disorder is called immunocytic amyloidosis. In general, immunocytic amyloidosis accompanies deposition of the amyloid protein to various organs of the whole body, and causes multiple clinical symptoms related to amyloid deposition. Even though the clinical manifestation indicates the localized disease like the presented case, close examination of immunocytic amyloidosis is important.

In the present study we examined the effects of menadione, a redox cycling agent, on structural changes of human osteosarcoma line 143B cells. It has been previously reported that menadione can cause necrotic or apoptotic cell death in a concentration- depending manner. In our experimental model, cells were treated with 100 microM menadione for 24 hours. Using electron microscopy technique cells carrying three kinds of morphological changes were detected: necrotic cells, apoptotic cells and those demonstrating a co-existence of apoptotic and necrotic features in one single cell.