Efficacy of Combination Treatment with Tadalafil and Mirabegron in Patients with Benign Prostatic Hyperplasia Who Presented with Persistent Storage Symptoms After Tadalafil Monotreatment: A Prospective, Multicenter, Open-Labeled Study

Background: The aim of this study is to evaluate the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, plus mirabegron, a β3-adrenoreceptor agonist, in patients with benign prostatic hyperplasia who presented with persistent storage symptoms after tadalafil monotreatment. Methods: The registration of this study started in August 2016 and ended in July 2019. The inclusion criteria included patients aged ? 50 years who were diagnosed with benign prostatic hyperplasia and who presented with overactive bladder symptoms. Patients were treated with oral tadalafil 5 mg once daily for 4 weeks. Then, its efficacy was evaluated. Patients who responded to the treatment received oral tadalafil 5 mg once daily for 4 more weeks (monotreatment group). Meanwhile, those who did not respond received oral tadalafil 5 mg and mirabegron 50 mg, which is an add-on treatment, once daily for 4 more weeks (combination therapy group). Results: After 8 weeks, the monotreatment group (n = 19) and the combination group (n = 56) had significantly better total Overactive Bladder Symptom Score and International Prostate Symptom Score and International Prostate Symptom Score voiding and storage subscale scores. Moreover, the two groups experienced significant improvements in the total Overactive Bladder Questionnaire and Nocturia Quality of Life Questionnaire scores, and Nocturia Quality of Life Questionnaire Bother/Concern subscale score after 8 weeks. However, there were no cases of urinary retention or serious adverse events. Conclusion: Combination treatment with tadalafil and mirabegron is effective and safe for patients with benign prostatic hyperplasia who presented with persistent storage symptoms after tadalafil monotreatment. Hence, tadalafil plus mirabegron is a promising therapeutic option, and it can improve overactive bladder related-quality of life

Relationship Between Age and Frequency of Side Effects Associated with Postoperative Analgesia

Study Objective: Although patient-controlled analgesia (PCA) is a valid analgesic method, it is necessary to pay attention to associated side effects, especially in elderly patients. It is unclear whether the incidence of side effects increases with age. In this study, we examined the incidence of side effects by age to confirm whether the frequency of side effects varies depending on age group. Patients: Patients who underwent gastroenterological surgery at Hiroshima University Hospital between 2009 and 2013 and received postoperative analgesia using PCA [either epidural PCA (PCEA) or intravenous PCA (IVPCA) were included]. Measurements: The degree of pain using the visual analog scale, number of PCA requests, and frequency of side effects, including nausea, vomiting, pruritus, urinary disturbance, drowsiness, low blood pressure, delirium, and respiratory depression, was determined from PCA records. Main Results: A total of 2,881 patients were enrolled and categorized into PCEA (n = 1,965) or IVPCA (n = 916) group based on postoperative analgesia. The incidence of delirium significantly increased with age in both groups (P < 0.001). In the PCEA group, the incidence of nausea, vomiting, and itching decreased, whereas that of hypotension significantly increased with age. Visual analog scale scores both at rest and during activity on postoperative day 2 were not correlated with age in either group. There was a significant negative correlation with age in both groups for the number of PCA requests on postoperative day 2. Conclusions: The incidence of postoperative delirium increases with age regardless of pain relief method. Side effects related to postoperative analgesia are not necessarily more likely to occur with age

Ordered kinetochore assembly in the human-pathogenic basidiomycetous yeast Cryptococcus neoformans

Kinetochores facilitate interaction between chromosomes and the spindle apparatus. The formation of a metazoan trilayered kinetochore is an ordered event in which inner, middle, and outer layers assemble during disassembly of the nuclear envelope during mitosis. The existence of a similar strong correlation between kinetochore assembly and nuclear envelope breakdown in unicellular eukaryotes is unclear. Studies in the hemiascomycetous budding yeasts Saccharomyces cerevisiae and Candida albicans suggest that an ordered kinetochore assembly may not be evolutionarily conserved. Here, we utilized high-resolution time-lapse microscopy to analyze the localization patterns of a series of putative kinetochore proteins in the basidiomycetous budding yeast Cryptococcus neoformans, a human pathogen. Strikingly, similar to most metazoa but atypical of yeasts, the centromeres are not clustered but positioned adjacent to the nuclear envelope in premitotic C. neoformans cells. The centromeres gradually coalesce to a single cluster as cells progress toward mitosis. The mitotic clustering of centromeres seems to be dependent on the integrity of the mitotic spindle. To study the dynamics of the nuclear envelope, we followed the localization of two marker proteins, Ndc1 and Nup107. Fluorescence microscopy of the nuclear envelope and components of the kinetochore, along with ultrastructure analysis by transmission electron microscopy, reveal that in C. neoformans, the kinetochore assembles in an ordered manner prior to mitosis in concert with a partial opening of the nuclear envelope. Taken together, the results of this study demonstrate that kinetochore dynamics in C. neoformans is reminiscent of that of metazoans and shed new light on the evolution of mitosis in eukaryotes

Suppression of inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 22(R)-hydroxycholesterol requires de novo protein synthesis in activated macrophages

Liver X receptors (LXRs) play an important role in lipid metabolism. Recently, a role for these proteins was identified in suppressing the inflammatory response. However, it is not known whether the natural ligands of LXRs, e.g. 22(R)-hydroxycholesterol (22R-HC), can suppress the inflammatory response after the onset of inflammation. We demonstrate here that treatment of Lipopolysaccharide (LPS)-activated RAW264.7 macrophages with 22R-HC markedly suppressed nitric oxide (NO) production and inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression. Additionally, 22R-HC did not affect the DNA binding activity of NF-κB, AP-1 and C/EBP(s), important transcriptional factors for iNOS and COX-2 genes expression. Furthermore iNOS and COX-2 mRNA suppression by 22R-HC was diminished by cellular treatment with cycloheximide. These results suggest that 22R-HC suppresses the expression of iNOS and COX-2 genes through de novo protein synthesis of an unidentified protein in LPS-activated macrophages. © 2005 Elsevier Ltd. All rights reserved

Capsaicin Treatment Inhibits Osteopenia and Heat Hyperalgesia Induced by Chronic Constriction Injury to the Sciatic Nerve in Rats

Chronic constriction injury (CCI) to the rat sciatic nerve results in osteopenia in the affected hind limb. One possible mechanism for this osteopenia is neurogenic inflammation, in which neuropeptides, represented by substance P (SP), are involved. We attempted to determine whether capsaicin treatment, which can deplete SP from nerve terminals, is effective in inhibiting osteopenia induced by CCI. Capsaicin (total dose, 125 mg/kg) or the vehicle alone was given intraperitoneally to adult rats 2 days before (Experiment 1) and 7 days after (Experiment 2) CCI surgery. Paw withdrawal latency (PWL) was measured prior to and every week for 5 weeks after surgery. Bone mineral density (BMD) and the number of osteoclasts in tibial bones were determined 5 weeks after surgery. In rats treated with the vehicle, BMD on the CCI side was decreased significantly, while the number of osteoclasts was significantly increased in both experiments. Capsaicin treatment either before or 1 week after surgery inhibited the decreases in BMD as well as the increase in the number of osteoclasts on the CCI side. PWL for the CCI side in the vehicle group was significantly shorter than for the sham side in both experiments. However, capsaicin treatment before surgery resolved heat hyperalgesia in Experiment 1, while in Experiment 2, even though heat hyperalgesia developed on the CCI side, it was resolved by capsaicin treatment. The results of the present study show that capsaicin inhibits the development of osteopenia as well as heat hyperalgesia induced by CCI. They also support our hypothesis that neurogenic SP release is involved in the pathogenesis of bony changes induced by CCI

Lymphocyte Responses to Chymotrypsin- or Trypsin V-Digested β-Lactoglobulin in Patients with Cow's Milk Allergy

<p/> <p>Chymotrypsin- or trypsin V- (a mixture of trypsin and chymotrypsin) digested β-lactoglobulin (BLG) peptides were prepared and were confirmed to have much less immunoglobulin (lg)G and lgE reactivity compared with intact BLG by IgG inhibition enzymelinked immunosorbent assay and IgE dot blotting. The lymphocyte responses to intact BLG and these peptides were examined using peripheral blood mononuclear cells (PBMCs) from 10 patients with cow's milk allergy. The PBMCs from most patients had lower lymphocyte responses to chymotrypsin- and trypsin V-digested BLG peptides than those to intact BLG. However, PBMCs from one and two patients retained significant proliferative responses to both peptides and to only the former peptide, respectively. Interferon-c production stimulated by chymotrypsin-digested peptides was still detectable in all five patients tested. Chymotrypsindigested BLG reduced lgE reactivity but still induced some lymphocyte responses.</p

Estimation of Arterial Viscosity Based on an Oscillometric Method and Its Application in Evaluating the Vascular Endothelial Function

This paper proposes an algorithm for estimating the arterial viscosity using cuff pressures and pulse waves measured by an automatic oscillometric sphygmomanometer. A change in the arterial viscosity during the enclosed-zone flow-mediated dilation test is calculated as an index for evaluating the vascular endothelial function %η. In all, 43 individuals participated in this study. After the index %η was calculated, the accuracy of the index %η in distinguishing healthy subjects and subjects at a high risk of arteriosclerosis was tested via a receiving operating characteristic (ROC) analysis. The calculated %η for the healthy participants and those at a high risk of arteriosclerosis was 13.4 ± 55.1% and −32.7 ± 34.0% (mean ± S.D.), respectively. The area under the ROC curve was 0.77. Thus, it was concluded that the proposed method can be used to evaluate the vascular endothelial function.This research was partly supported by the Transportation Technology Development Promotion Competitive Funding Program from Ministry of Land, Infrastructure, Transport and Tourism, and the Center of Innovation Program from Japan Science and Technology Agency

Effect of high-fat diet on phosphorus absorption

Objective: Dietary carbohydrate/fat ratio may affect phosphorus metabolism because both calcium and phosphorus are regulated by similar metabolic mechanisms, and a high-fat diet (HF) induces deleterious effects on the absorption of dietary calcium. We hypothesized that the HF induces an increase in phosphorus absorption; therefore, this study aimed to evaluate the effects of differences in the quantity and quality of dietary fat on phosphorus metabolism over the short and long term. Research Methods & Procedures: Eighteen 8-week-old Sprague-Dawley male rats were fed an isocaloric diet containing varied carbohydrate/fat energy ratio and sources of fat (control diet [Control], HF, and high saturated-fat diet [HF-SFA]). At 3 days and 7 weeks after the allocation and initiation of the test diets, feces and urine were collected and used for phosphorus and calcium measurement. Results: The fecal phosphorous concentration (F-Pi) was lower in the HF-SFA group than in the other two groups; however, the urine phosphorus concentration (U-Pi) was significantly higher in the HF-SFA group than the other two groups when the rats were fed over the short (p<0.01) and long term (p<0.01 vs Control group, p<0.05 vs HF group). There were no significant differences in type-IIa sodium-phosphate cotransporter (NaPi-2a) and type-IIc sodium-phosphate cotransporter (NaPi-2c) mRNA expression, which are renal phosphate transport-related genes; however, the expression of type-IIb sodium-phosphate cotransporter (NaPi-2b) and type-III sodium-phosphate cotransporter (Pit-1) mRNA in the duodenum was higher in the HF and HF-SFA groups than in the Control group (p<0.05), although there were no significant differences in these in the jejunum. Conclusions: Our results indicated that HF, particularly HF-SFA, increases intestinal phosphate absorption compared with Control