Investigations of urethral sphincter activity in mice with bladder hyperalgesia before and after drug administration of gabapentin.

PurposeThis study investigated the effect of gabapentin on lower urinary tract dysfunction focusing on urethral activities and cystitis-induced hyperalgesia in a mouse model of painful bladder syndrome/interstitial cystitis (PBS/IC). The electromyography (EMG) of external urethral sphincter (EUS) was difficult to obtain, but contained useful information to examine the drug effect in mice.MethodsFemale C57BL/6J mice were intraperitoneally (ip) administration with either saline or 200 mg/kg of cyclophosphamide (CYP) 48 h before experimental evaluation. Cystitis mice were treated with administration of gabapentin (25 or 50 mg/kg, ip). Cystometry and EUS EMG were obtained and analyzed during continuous bladder infusion. The visceral pain-related visceromotor reflex (VMR) was recorded in response to isotonic bladder distension.ResultsCystitis mice showed shorter inter-contraction intervals and increased occurrence of non-voiding contractions during bladder infusion, with increased VMR during isotonic bladder distension, indicating cystitis-induced bladder hyperalgesia. Gabapentin (50 mg/kg) suppressed effects of CYP on cystometry, but not on EUS EMG activity, during bladder infusion. The effect on urodynamic recordings lasted 4 h. VMR was significantly reduced by gabapentin.ConclusionsThe present study showed that CYP-induced cystitis in mice is a model of visceral hyperalgesia affecting detrusor contractions, not urethral activations. The technique of using EUS EMG to evaluate the drug effects on urethral activities is novel and useful for future investigations. Gabapentin can be as a potential treatment for detrusor overactivity and PBS/IC

Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.

Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation

Cytokine Profile in Plasma Extracellular Vesicles of Parkinson's Disease and the Association with Cognitive Function

Plasma extracellular vesicles (EVs) containing various molecules, including cytokines, can reflect the intracellular condition and participate in cell-to-cell signaling, thus emerging as biomarkers for Parkinson’s disease (PD). Inflammation may be a crucial risk factor for PD development and progression. The present study investigated the role of plasma EV cytokines as the biomarkers of PD. This cross-sectional study recruited 113 patients with PD, with mild to moderate stage disease, and 48 controls. Plasma EVs were isolated, and the levels of cytokines, including pro-interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1, were evaluated. Patients with PD had significantly increased plasma EV pro-IL-1β and TNF-α levels compared with controls after adjustment for age and sex. Despite the lack of a significant association between plasma EV cytokines and motor symptom severity in patients with PD, cognitive dysfunction severity, assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment, was significantly associated with plasma EV pro-IL-1β, IL-6, IL-10, and TNF-α levels. This association was PD specific and not found in controls. Furthermore, patients with PD cognitive deficit (MMSE < 26) exhibited a distinguished EV cytokine profile compared to those without cognitive deficit. The findings support the concept of inflammatory pathogenesis in the development and progression of PD and indicate that plasma EV cytokines may serve as PD biomarkers in future

Incomplete Data Analysis

This chapter discusses missing-value problems from the perspective of machine learning. Missing values frequently occur during data acquisition. When a dataset contains missing values, nonvectorial data are generated. This subsequently causes a serious problem in pattern recognition models because nonvectorial data need further data wrangling before models are built. In view of such, this chapter reviews the methodologies of related works and examines their empirical effectiveness. At present, a great deal of effort has been devoted in this field, and those works can be roughly divided into two types — Multiple imputation and single imputation, where the latter can be further classified into subcategories. They include deletion, fixed-value replacement, K-Nearest Neighbors, regression, tree-based algorithms, and latent component-based approaches. In this chapter, those approaches are introduced and commented. Finally, numerical examples are provided along with recommendations on future development

Retroperitoneal Metastatic Adenocarcinoma Complicated with Necrotizing Fasciitis of the Thigh in a Patient with Advanced Rectal Colon Cancer

Background: Necrotizing fasciitis of the thigh due to colon cancer has not been previously reported, especially during radiotherapy. Case Presentation: A 73-year-old woman admitted to our hospital was diagnosed with sigmoid colon cancer that had spread to the left psoas muscle; radiotherapy was performed. Three months after the initiation of radiotherapy, the patient developed gait disturbance, poor appetite and high fever and was therefore admitted to the emergency department of our hospital. Blood examination revealed generalized inflammation with a high white blood cell count and C-reactive protein level. Computed tomography of the abdomen revealed fluid and gas tracking from the retroperitoneum into the intramuscular plane of the grossly enlarged right thigh. Consequently, emergent debridement was not performed and conservative therapy was done. The patient died. Conclusion: Necrotizing fasciitis of the thigh due to the spread of rectal colon cancer is unusual, but this fatal complication should be considered during radiotherapy in patients with unresectable colorectal cancer

Boosting Image-based Mutual Gaze Detection using Pseudo 3D Gaze

Mutual gaze detection, i.e., predicting whether or not two people are looking at each other, plays an important role in understanding human interactions. In this work, we focus on the task of image-based mutual gaze detection, and propose a simple and effective approach to boost the performance by using an auxiliary 3D gaze estimation task during the training phase. We achieve the performance boost without additional labeling cost by training the 3D gaze estimation branch using pseudo 3D gaze labels deduced from mutual gaze labels. By sharing the head image encoder between the 3D gaze estimation and the mutual gaze detection branches, we achieve better head features than learned by training the mutual gaze detection branch alone. Experimental results on three image datasets show that the proposed approach improves the detection performance significantly without additional annotations. This work also introduces a new image dataset that consists of 33.1K pairs of humans annotated with mutual gaze labels in 29.2K images

Effects of Functional Electrical Stimulation on Peak Torque and Body Composition in Patients with Incomplete Spinal Cord Injury

The aim of this study was to investigate the change in body composition, leg girths, and muscle strength of patients with incomplete spinal cord injury (SCI) after functional electrical stimulation cycling exercises (FESCE). Eighteen subjects with incomplete SCI were recruited. Each patient received FESCE three times per week for 8 weeks. Body composition, thigh and calf girths of bilateral legs, muscle strength of bilateral knee flexors and extensors were measured before and after 4 and 8 weeks of FESCE. A significant increase in bilateral thigh girth after 4 weeks of FESCE and significant increase in muscular peak torque of knee flexion and extension were found after 8 weeks of training. Besides, lean body mass increased significantly after complete treatment. FESCE can increase the thigh girth and muscular peak torque of patients with incomplete spinal cord injury