Evaluation of a novel severe combined immunodeficiency mouse model for antiviral drug evaluation against Chandipura virus infection.

Chandipura virus (CHPV) is a negative-sense single-stranded RNA virus known to cause fatal encephalitis outbreaks in the Indian subcontinent. The virus displays tropism towards the pediatric population and holds significant public health concerns. Currently, there is no specific, effective therapy for CHPV encephalitis. In this study, we evaluated a novel C.B-17 severe combined immunodeficiency (SCID) mouse model which can be used for pre-clinical antiviral evaluation. Inoculation of CHPV developed a lethal infection in our model. Plaque assay and immunohistochemistry detected increased viral loads and antigens in various organs, including the brain, spinal cord, adrenal glands, and whole blood. We further conducted a proof-of-concept evaluation of favipiravir in the SCID mouse model. Favipiravir treatment improved survival with pre-symptomatic (days 5-14) and post-symptomatic (days 9-18) treatment. Reduced viral loads were observed in whole blood, kidney/adrenal gland, and brain tissue with favipiravir treatment. The findings in this study demonstrate the utility of SCID mouse for in vivo drug efficacy evaluation and the potential efficacy of favipiravir against CHPV infection.

Quality of life and the prevalence of urinary incontinence after surgical treatment for gynecologic cancer: a questionnaire survey.

BACKGROUND: Although there have been a number of reports on urinary voiding symptoms associated with surgical interventions for gynecologic cancer and post-voiding symptoms, there have been few reports on urinary storage symptoms such as urinary incontinence (UI) and overactive bladder (OAB). The purpose of this study was to examine the rates and impact on quality of life (QOL) of urinary storage symptoms after gynecologic cancer surgery. METHODS: A questionnaire survey, including Japanese-language versions of the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), Overactive Bladder Symptom Score (OABSS), and Incontinence Impact Questionnaire-7 (IIQ-7), was distributed to gynecologic cancer patients who underwent hysterectomy between 2008 and 2013. RESULTS: Of the 145 patients analyzed, 49 (33.8%) had UI pre-surgery, and 76 (52.4%) had UI post-surgery, including 34 (35.4%) first-time UI patients, with a significant difference between pre- and post-surgery. Of the 49 subjects with UI pre-surgery, 43 (87.7%) had stress incontinence, while of the 76 patients with UI post-surgery, 44 (57.1%) had stress incontinence, and 24 (31.2%) had mixed incontinence. Seven (4.8%) subjects had OAB pre-surgery, whereas 19 (13.1%) had OAB symptoms post-surgery (including 15 first-time OAB patients), with a significant difference between pre- and post-surgery. IIQ-7 scores were markedly higher for patients with mixed incontinence post-surgery than for those with stress incontinence, indicating a lower QOL. Logistic regression analysis identified the number of Cesarean sections and days of urinary bladder catheterization as risk factors for postoperative UI. CONCLUSIONS: UI and OAB rates were higher after gynecologic cancer surgery than in the general female population. The mixed incontinence rate was markedly higher post-surgery; QOL was low for such patients due to the combination of urge and stress incontinence. Multiple Cesarean sections and urinary bladder catheterization post-surgery were risk factors for post-surgical UI.

A novel homozygous missense SLC25A20 mutation in three CACT-deficient patients: clinical and autopsy data.

Carnitine-acylcarnitine translocase (CACT) deficiency is a fatty acid ß-oxidation disorder of the carnitine shuttle in mitochondria, with a high mortality rate in childhood. We evaluated three patients, including two siblings, with neonatal-onset CACT deficiency and revealed identical homozygous missense mutations of p.Arg275Gln within the SLC25A20 gene. One patient died from hypoglycemia and arrhythmia at 26 months; his pathological autopsy revealed increased and enlarged mitochondria in the heart but not in the liver.

An Evaluation of Family-Based Treatment for OCD in Japan: A Pilot Randomized Controlled Trial.

Objective: Although family involvement in the treatment of obsessive-compulsive disorder (OCD) produces a reduction in OCD symptoms and has significant effects on global functioning, few studies have focused on family intervention as part of OCD treatment in Japan. This study aims to examine the feasibility and efficacy of the family-based exposure and response prevention (FERP) program for adult patients with OCD and their family members. Design: Randomized controlled pilot study. Methods: A total of 18 outpatients aged 18-65 years with a primary diagnosis of OCD and one family member of each patient were randomized to an intervention group or a control group (1:1). The intervention group received the FERP program, which consisted of 16 weekly face-to-face cognitive behavioral therapy (CBT) sessions, including eight joint sessions with family members, in addition to treatment-as-usual (TAU). The control group received TAU alone. The primary outcome was the alleviation of OCD symptoms, as measured by changes in the total Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score from baseline to posttreatment. Analyses were provided on an intention-to-treat basis, and linear mixed models were used to test for significant group differences. Results: After 16 weeks, patients allocated to the FERP program showed improvement in OCD symptom severity, as measured by the total change score of the Y-BOCS (Hedges' g = -1.58), as compared to the control group. Two patients (22.2%) in the FERP group reached remission, and five patients (55.6%) in the FERP group achieved treatment response. Clinical global improvement measured by the FAS-SR scores, K6 scores, and CGI-S scores was also observed (Hedges' g = -1.35, -1.25, and -1.26, respectively) in the FERP group as compared to the control group. The dropout rate from the study was low (n = 2, 11.8%), and no adverse events were reported in the FERP group. Conclusion: Our results suggest that FERP may be an effective program for reducing patients' OCD symptoms. Clinical Trial Registration: www.umin.ac.jp/ctr/, identifier UMIN000021763.

Successful Control of Pain from Malignant Psoas Syndrome by Spinal Opioid with Local Anesthetic Agents.

BACKGROUND: Malignant psoas syndrome (MPS) is a rare but distressing pain syndrome observed in advanced cancer patients. Pain due to MPS is often refractory to multimodal analgesic treatment, including opioid analgesics. As only 1 case demonstrating the efficacy of neuraxial analgesia in managing pain due to MPS has been reported, its role in MPS remains uncertain. CASES: We present 3 cases demonstrating the successful management of pain due to MPS using spinal opioids with local anesthetic agents. All patients were under the care of the palliative care consultation service in an acute care hospital and refractory to multimodal analgesic treatment, including opioid, non-opioid, and adjuvant analgesics. Switching opioid administration to the epidural or intrathecal route with a local anesthetic agent provided good pain control in all 3 patients. Moreover, all patients showed improvements in both Palliative Performance Scale and Functional Independence Measure scores after starting a spinal opioid with a local anesthetic agent. CONCLUSIONS: The findings in the present cases indicate neuraxial analgesia may be of benefit, in terms of managing pain and improving functional status, in MPS patients with insufficient pain control by multimodal analgesic treatment. Physicians should consider the use of neuraxial analgesia in cases of MPS where pain is uncontrolled with multimodal analgesic treatment to provide the best possible quality of life for patients with MPS.

Smoking counteracts the favorable effect of exercise training on endothelial function in patients with type 2 diabetes.

BACKGROUND: Exercise training can improve endothelial function in patients with diabetes. We hypothesized that the favorable effect of exercise training on endothelial function in patients with diabetes is counteracted by cigarette smoking. PURPOSE: To assess whether there is a difference in the effect of exercise on endothelial function in smokers and non-smokers with type 2 diabetes. METHODS: We performed a 3-month controlled trial in 27 never-smoking and 17 smoking individuals with type 2 diabetes who participated in a home-based walking program. The percentage decrease in post-exercise ankle-brachial pressure index (ABI), which is an index of endothelial function, was assessed at baseline and after 3 months. RESULTS: Compared to the smoking group, the never-smoking group showed a more significant improvement in post exercise ABI during the 3 months of home-based training (interaction, P < 0.01). CONCLUSIONS: These results indicate that smoking may counteract the favorable effects of exercise training on endothelial function. Endothelial function plays an important role in the prevention of cardiovascular disease among patients with diabetes. Therefore, a Certified Diabetes Educator should strongly advise diabetic patients not to smoke.

Post-exercise ankle-brachial pressure index demonstrates altered endothelial function in the elderly.

BACKGROUND: The ankle-brachial pressure index (ABI), the ratio of the systolic blood pressure of the ankle to the systolic brachial pressure, is commonly measured at rest, but ABI values post-exercise enhance the sensitivity of the test and can be used to identify atherosclerotic vascular damage. However, it has not been established whether or not enhanced post-exercise ABI is also associated with endothelial dysfunction. We hypothesized that a decrease in post-exercise ABI is related to impaired endothelial function. PURPOSE: To investigate alterations in post-exercise ABI values and endothelial dysfunction in the elderly. METHODS: The study population comprised 35 men and women aged 51-77 years (mean age: 66 years). Patients with peripheral arterial disease or a history of heart failure were excluded. The ABI was estimated at rest and immediately after exercise. The exercise protocol comprised 2.5 min of active pedal flexion exercises at a speed of 60 times/min. Endothelial function was assessed by measuring flow-mediated vasodilation (FMD) in the brachial artery using ultrasound imaging. RESULTS: No correlation was found between FMD and the ABI at rest. However, a weak correlation was found between FMD and post-exercise ABI (r = 0.46, P = 0.06). A strong correlation was observed between FMD and a decrease in post-exercise ABI compared to baseline readings (r = -0.52, P = 0.01). Multiple linear regression analysis was used to generate a prediction equation for FMD using the percentage decrease in post-exercise ABI. Significant correlations were observed between the ultrasound imaging-measured FMD and the predicted FMD (R(2) = 0.27, P = 0.001). CONCLUSIONS: Post-exercise ABI appears to be a simple surrogate marker for endothelial function in the elderly, although larger studies are required for validation.

Multiple POU-binding motifs, recognized by tissue-specific nuclear factors, are important for Dll1 gene expression in neural stem cells.

We cloned the 5'-flanking region of the mouse homolog of the Delta gene (Dll1) and demonstrated that the sequence between nucleotide position -514 and -484 in the 5'-flanking region of Dll1 played a critical role in the regulation of its tissue-specific expression in neural stem cells (NSCs). Further, we showed that multiple POU-binding motifs, located within this short sequence of 30bp, were essential for transcriptional activation of Dll1 and also that multiple tissue-specific nuclear factors recognized these POU-binding motifs in various combinations through differentiation of NSCs. Thus, POU-binding factors may play an important role in Dll1 expression in developing NSCs.

Geochemical and microbiological evidence for a hydrogen-based, hyperthermophilic subsurface lithoautotrophic microbial ecosystem (HyperSLiME) beneath an active deep-sea hydrothermal field.

Subsurface microbial communities supported by geologically and abiologically derived hydrogen and carbon dioxide from the Earth's interior are of great interest, not only with regard to the nature of primitive life on Earth, but as potential analogs for extraterrestrial life. Here, for the first time, we present geochemical and microbiological evidence pointing to the existence of hyperthermophilic subsurface lithoautotrophic microbial ecosystem (HyperSLiME) dominated by hyperthermophilic methanogens beneath an active deep-sea hydrothermal field in the Central Indian Ridge. Geochemical and isotopic analyses of gaseous components in the hydrothermal fluids revealed heterogeneity of both concentration and carbon isotopic compositions of methane between the main hydrothermal vent (0.08 mM and -13.8 per thousand PDB, respectively) and the adjacent divergent vent site (0.2 mM and -18.5 per thousand PDB, respectively), representing potential subsurface microbial methanogenesis, at least in the divergent vent emitting more 13C-depleted methane. Extremely high abundance of magmatic energy sources such as hydrogen (2.5 mM) in the fluids also encourages a hydrogen-based, lithoautotrophic microbial activity. Both cultivation and cultivation-independent molecular analyses suggested the predominance of Methanococcales members in the superheated hydrothermal emissions and chimney interiors along with the other major microbial components of Thermococcales members. These results imply that a HyperSLiME, consisting of methanogens and fermenters, occurs in this tectonically active subsurface zone, strongly supporting the existence of hydrogen-driven subsurface microbial communities.

Nuclear factor of activated T cells (NFAT) is involved in the depolarization-induced activation of growth hormone-releasing hormone gene transcription in vitro.

GHRH plays a pivotal role in the regulation of both synthesis and secretion of GH in the anterior pituitary. In this study, we examined the molecular mechanism of depolarization-induced GHRH gene transcription using the hypothalamus cell line, Gsh+/+, revealing the involvement of the transcription factor called nuclear factor of activated T cells (NFAT). GHRH, NFAT1, NFAT4, and related genes were endogenously expressed in Gsh+/+ cells and the rat arcuate nucleus, where NFAT1 and GHRH were colocalized. Cellular excitation with high potassium potently stimulated endogenous GHRH gene 5'-promoter activity as well as the NFAT-mediated gene transcription, the former being further enhanced by coexpression of NFAT. On the other hand, cyclosporin A (a calcineurin-NFAT inhibitor) or EGTA (a calcium chelator) significantly blocked the depolarization-induced GHRH gene transcription. EMSA and site-directed mutagenesis experiments showed the direct binding of NFAT at five sites of the GHRH promoter, among which the relative importance of three distal sites (-417/-403, -402/-387, -317/-301) was suggested. Finally, elimination of all five sites completely abolished the NFAT-induced GHRH gene up-regulation. Altogether, our results suggest that the transcription factor NFAT is involved in the depolarization-induced transcriptional activation of GHRH gene in the neuronal cells.