Evaluation of predictors of third-generation cephalosporin non-susceptibility and factors affecting recurrence or death in bacteremia caused by Citrobacter freundii complex, Enterobacter cloacae complex, and Klebsiella aerogenes.

Factors involved in the susceptibility of third-generation cephalosporins (3GCs) to bacteremia caused by Citrobacter freundii complex, Enterobacter cloacae complex, and Klebsiella aerogenes were investigated based on a case-case-control design. Antimicrobial therapy administered 30 days prior to bacteremia and hospitalization within 90 days were common risk factors for the 3GC susceptible and 3GC non-susceptible groups, while hospitalization from an institution or another hospital was a specific risk factor for the 3GC non-susceptible group. We also attempted to examine the factors affecting the clinical outcome of bacteremia. Hospitalization more than 14 days before the onset of bacteremia was an independent factor indicating poor clinical outcome. In contrast, the implementation of source control was an independent predictor of successful treatment. Although a longer hospital stay before the onset of bacteremia was associated with worse clinical outcomes, implementation of source control may have contributed to improved treatment outcomes for bacteremia.

Structural basis for lysophosphatidylserine recognition by GPR34.

GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron microscopy structures of human GPR34-Gi complex bound with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. The ligand-binding pocket is laterally open toward the membrane, allowing lateral entry of lipidic agonists into the cavity. The amine and carboxylate groups of the serine moiety are recognized by the charged residue cluster. The acyl chain of S3E-LysoPS is bent and fits into the L-shaped hydrophobic pocket in TM4-5 gap, and the aromatic fatty acid surrogate of M1 fits more appropriately. Molecular dynamics simulations further account for the LysoPS-regioselectivity of GPR34. Thus, using a series of structural and physiological experiments, we provide evidence that chemically unstable 2-acyl LysoPS is the physiological ligand for GPR34. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34.

Endogenous reductase activities for the generation of ribitol-phosphate, a CDP-ribitol precursor, in mammals.

The core M3 O-mannosyl glycan on α-dystroglycan serves as the binding epitope for extracellular matrix molecules. Defects in core M3 glycans cause congenital muscular dystrophies that are collectively known as dystroglycanopathies. The core M3 glycan contains a tandem D-ribitol-5-phosphate (Rbo5P) structure, which is synthesized by the Rbo5P-transferases fukutin and fukutin-related protein using CDP-ribitol (CDP-Rbo) as a donor substrate. CDP-Rbo is synthesized from CTP and Rbo5P by CDP-Rbo pyrophosphorylase A. However, the Rbo5P biosynthesis pathway has yet to be elucidated in mammals. Here, we investigated the reductase activities toward four substrates, including ribose, ribulose, ribose-phosphate and ribulose-phosphate, to identify the intracellular Rbo5P production pathway and elucidated the role of the aldo-keto reductases AKR1A1, AKR1B1 and AKR1C1 in those pathways. It was shown that the ribose reduction pathway is the endogenous pathway that contributes most to Rbo5P production in HEK293T cells and that AKR1B1 is the major reductase in this pathway.

Machine learning algorithm-based estimation model for the severity of depression assessed using Montgomery-Asberg depression rating scale.

AIM: Depressive disorder is often evaluated using established rating scales. However, consistent data collection with these scales requires trained professionals. In the present study, the "rater & estimation-system" reliability was assessed between consensus evaluation by trained psychiatrists and the estimation by 2 models of the AI-MADRS (Montgomery-Asberg Depression Rating Scale) estimation system, a machine learning algorithm-based model developed to assess the severity of depression. METHODS: During interviews with trained psychiatrists and the AI-MADRS estimation system, patients responded orally to machine-generated voice prompts from the AI-MADRS structured interview questions. The severity scores estimated from two models of the AI-MADRS estimation system, the max estimation model and the average estimation model, were compared with those by trained psychiatrists. RESULTS: A total of 51 evaluation interviews conducted on 30 patients were analyzed. Pearson's correlation coefficient with the scores evaluated by trained psychiatrists was 0.76 (95% confidence interval 0.62-0.86) for the max estimation model, and 0.86 (0.76-0.92) for the average estimation model. The ANOVA ICC rater & estimation-system reliability with the evaluation scores by trained psychiatrists was 0.51 (-0.09 to 0.79) for the max estimation model, and 0.75 (0.55-0.86) for the average estimation model. CONCLUSION: The average estimation model of AI-MADRS demonstrated substantially acceptable rater & estimation-system reliability with trained psychiatrists. Accumulating a broader training dataset and the refinement of AI-MADRS interviews are expected to improve the performance of AI-MADRS. Our findings suggest that AI technologies can significantly modernize and potentially revolutionize the realm of depression assessments.

Therapeutic efficacy and safety of a free-standing motorized ejaculation aid for patients with intravaginal ejaculatory dysfunction.

Purpose: There are no approved drugs or devices for the treatment of intravaginal ejaculation disorders, and treatment is often difficult. This study aimed to evaluate the efficacy and safety of the A10 Cyclone SA + PLUS® ejaculation aid (Rends Co., Ltd., Chiba, Japan), which allows the user to adjust the intensity of stimulation, for intravaginal ejaculation disorders. Methods: Each participant was instructed to perform practice masturbation with the A10 Cyclone SA + PLUS to simulate vaginal ejaculation. After 8 weeks of training, the participants were asked about their intravaginal ejaculation status. Sexual function was also evaluated before and after the training using several specific questionnaires, including the numerical rating scale for ejaculatory satisfaction. Results: Among the 10 participants (41.5 ± 3.21 years) who completed the training and questionnaire evaluation, four (40%) became capable of intravaginal ejaculation. The questionnaire evaluation showed predominant improvement after training in the ejaculation-capable group according to the numerical rating scale, which expresses satisfaction with ejaculation. The participants experienced no significant adverse events. Conclusion: As no effective treatment currently exists for intravaginal ejaculation disorders, we conclude that the A10 Cyclone SA + PLUS may be one treatment tool for intravaginal ejaculation disorders with good efficacy and no adverse events.

Detection of transient abnormal myelopoiesis blasts in a liver biopsy specimen by double-immunostaining for full-length GATA1 and CD42b.

BACKGROUND: Transient abnormal myelopoiesis (TAM) is characterized by leukocytosis with increased circulating megakaryoblasts that harbor N-terminal truncating mutations in the GATA1 gene. Approximately 10% of affected patients experience early death. OBSERVATIONS: A 2-month-old boy with Down syndrome was diagnosed with TAM and followed without treatment. Although the blasts in the peripheral blood disappeared, liver failure progressed. A pathological examination revealed liver fibrosis, and double-immunostaining for full-length GATA1 and CD42b identified megakaryocytes with a GATA1 mutation. CONCLUSIONS: This simple and cost-effective method can be applied in routine practice to detect TAM blasts during assessment in a TAM crisis.

Case of extragonadal germ cell tumor mimicking left adrenal tumor.

A 30-year-old man presented to his previous physician with left abdominal pain. Computed tomography revealed a left retroperitoneal mass with calcification, measuring 15 × 9 × 6 cm, and the patient was referred to our hospital for further examination. Based on the endocrinologic examination and magnetic resonance imaging results, the patient was diagnosed with a nonfunctional left adrenal tumor, and laparoscopic left adrenalectomy was performed. Histopathology revealed well-defined boundaries between the tumor and the left adrenal gland, and the tumor was diagnosed as a non-seminoma consisting mainly of an immature teratoma with germ cell neoplasm in situ.

Class B1 GPCR activation by an intracellular agonist.

G protein-coupled receptors (GPCRs) generally accommodate specific ligands in the orthosteric-binding pockets. Ligand binding triggers a receptor allosteric conformational change that leads to the activation of intracellular transducers, G proteins and ß-arrestins. Because these signals often induce adverse effects, the selective activation mechanism for each transducer must be elucidated. Thus, many orthosteric-biased agonists have been developed, and intracellular-biased agonists have recently attracted broad interest. These agonists bind within the receptor intracellular cavity and preferentially tune the specific signalling pathway over other signalling pathways, without allosteric rearrangement of the receptor from the extracellular side1-3. However, only antagonist-bound structures are currently available1,4-6, and there is no evidence to support that biased agonist binding occurs within the intracellular cavity. This limits the comprehension of intracellular-biased agonism and potential drug development. Here we report the cryogenic electron microscopy structure of a complex of Gs and the human parathyroid hormone type 1 receptor (PTH1R) bound to a PTH1R agonist, PCO371. PCO371 binds within an intracellular pocket of PTH1R and directly interacts with Gs. The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation. PCO371 stabilizes the significantly outward-bent conformation of transmembrane helix 6, which facilitates binding to G proteins rather than ß-arrestins. Furthermore, PCO371 binds within the highly conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs. Our study identifies a new and conserved intracellular agonist-binding pocket and provides evidence of a biased signalling mechanism that targets the receptor-transducer interface.

Efficacy of testosterone replacement treatment for patients with symptoms of late-onset hypogonadism based on real-world patient satisfaction.

Late-onset hypogonadism is generally treated with testosterone replacement treatment. However, the efficacy rate of treatment for patients with low testosterone is not clear because patients without low testosterone are also treated in real-world clinical settings. This study comprised 110 men with low testosterone concentration of <3.0 ng/mL who underwent testosterone replacement treatment. Physical factors, laboratory and endocrinologic profiles, and scores of several questionnaires were assessed. Testosterone replacement treatment was performed with intramuscular injection of 250 mg of testosterone esters every 2-4 weeks, and efficacy was judged by patient satisfaction. After confirming efficacy, changes in several factors by the treatment were evaluated. Finally, the comparison between evaluation by patient satisfaction and by that with the questionnaires was assessed. Among the 110 patients, 77 (70.0%) were satisfied with the treatment, which was effective in 65.7%, 71.4%, and 73.1% of patients with mental, physical, and sexual dysfunction, respectively. The questionnaire scores including the Aging Males Symptoms rating scale were significantly improved in both the satisfaction and non-satisfaction group. However, no significant differences in the amount of change in questionnaire scores were found for all questionnaire scores improved by testosterone replacement treatment between the groups. Patient satisfaction was not associated with improvement of the Aging Males Symptoms score. Although testosterone replacement treatment was effective for 70.0% of the hypogonadal patients, patient satisfaction did not correlate with improvement of questionnaire scores. We concluded that not only questionnaire results but also patient satisfaction is important when evaluating efficacy in patients undergoing testosterone replacement treatment.

In vitro-based prediction of human plasma concentrations of food-related compounds.

Efforts have been made to replace animal experiments in safety evaluations, including in vitro-based predictions of human internal exposures, such as predicting peak plasma concentration (Cmax) values for xenobiotics and comparing these values with in vitro-based toxicity endpoints. Herein, the authors predicted the Cmax values of food-related compounds in humans based on existing and novel in vitro techniques. In this study, 20 food-related compounds, which have been previously reported in human pharmacokinetic or toxicokinetic studies, were evaluated. Human induced pluripotent stem cell-derived small intestinal epithelial cells (hiPSC-SIEC) and Caco-2 cells, HepaRG cells, equilibrium dialysis of human plasma, and LLC-PK1 cell monolayer were used to assess intestinal absorption and availability, hepatic metabolism, unbound plasma fraction, and secretion and reabsorption in renal tubular cells, respectively. After conversion of these parameters into human kinetic parameters, the plasma concentration profiles of these compounds were predicted using in silico methods, and the obtained Cmax values were found to be between 0.017 and 183 times the reported Cmax values. When the in silico-predicted parameters were modified with in vitro data, the predicted Cmax values came within 0.1-10 times the reported values because the metabolic activities of hiPSC-SIECs, such as uridine 5'-diphospho-glucuronosyl transferase, are more similar to those of human primary enterocytes. Thus, combining in vitro test results with the plasma concentration simulations resulted in more accurate and transparent predictions of Cmax values of food-related compounds than those obtained using in silico-derived predictions alone. This method facilitates accurate safety evaluation without the need for animal experiments.

Construction of extended and functional bile canaliculi using long-term sandwich-cultured cryopreserved human hepatocytes and the application of hepatocytes for predicting the biliary excretion of pharmaceutical and food-related compounds.

The biliary excretion of pharmaceutical and food-related compounds is an important factor for assessing pharmacokinetics and toxicities in humans, and a highly predictive in vitro method for human biliary excretion is required. We have developed a simple in vitro culture method for generating extended and functional bile canaliculi using cryopreserved human hepatocytes. We evaluated the uptake of compounds by hepatocytes and bile canaliculi, and the biliary excretion index (BEI) was calculated. After 21 days of culture, the presence of extended and functional bile canaliculi was confirmed by the uptake of two fluorescent substrates. Positive BEIs were observed for taurocholic acid-d4, rosuvastatin, pitavastatin, pravastatin, valsartan, olmesartan, and topotecan (reported biliary-excreted compounds in humans), but no difference in BEI was observed for salicylic acid (a nonbiliary-excreted compound). Furthermore, 8 of 21 food-related compounds with specific structures and reported biliary transporter involvement exhibited positive BEIs. The developed in vitro system was characterized by functional bile canaliculus-like structures, and it could be applied to the prediction of the biliary excretion of pharmaceutical and food-related compounds.

MRI findings of sporadic/simple lymphoepithelial cyst of the parotid gland.

PURPOSE: This study aimed to determine the MRI features of sporadic/simple lymphoepithelial cyst (SLEC) of the parotid gland. METHODS: Ten patients (seven men, three women; mean age, 60 years; age range, 38-77 years) with histopathologically and clinically proven SLEC of the parotid gland who underwent MRI before surgical resection were enrolled in this study. No enrolled patient had HIV infection or Sjögren syndrome. MRI findings of SLEC were retrospectively assessed. RESULTS: We confirmed 10 SLECs larger than 10 mm with a mean maximum diameter of 26.6 mm (range, 12-42 mm). Nine patients (90%) had a single cyst, and one (10%) had a large cyst accompanied by small cysts (<10 mm) within the ipsilateral parotid gland. Eight SLECs (80%) were unilocular, and two (20%) were bilocular, with complete septa. Among seven SLECs (70%) with internal septa, five unilocular SLECs (50%) had incomplete septa. Six SLECs (60%) had eccentric cyst wall thickening, and five (50%) were surrounded by small solid nodules that were isointense relative to lymph node. On T1-weighted images, all cyst contents were homogeneously hyperintense relative to cerebrospinal fluid. CONCLUSION: SLECs of the parotid gland are usually single unilocular lesions. Internal septa, eccentric cyst wall thickening, and small solid nodules surrounding the lesion were often observed. Cyst contents are always homogeneously hyperintense on T1-weighted images.

Differences in MRI findings of superficial spindle cell lipoma and atypical lipomatous tumor/well-differentiated liposarcoma.

OBJECTIVE: This study aimed to evaluate the efficacy of using MRI findings to differentiate superficial spindle cell lipomas (SCLs) from atypical lipomatous tumor/well-differentiated liposarcomas (ALT/WDLs). METHODS: This study included 12 patients with histopathologically proven superficial SCLs and 11 with ALT/WDLs. MRI findings for both pathologies were retrospectively reviewed and compared between the two pathologies. RESULTS: The neck, upper back, and shoulder regions were more frequent locations of SCLs than of ALT/WDLs (100% vs 55%, p < 0.05), whereas no significant differences were observed in age and sex. The median maximum diameter of the lesion was smaller in SCLs than in ALT/WDLs (44 mm [interquartile range (IQR): 35-63] vs 102 mm [IQR: 86-119], p < 0.05). On T 1 weighted images, non-fatty area was more frequently observed in SCLs than in ALT/WDLs (73% vs 25%, p < 0.05), and the median rate of non-fatty area was larger in SCLs than in ALT/WDLs (7.5% [IQR: 1.0-53] vs 0% [IQR: 0-0.2], p < 0.05). On fat-suppressed T 2 weighted images, a solid hyperintense area was more frequently observed in SCLs than in ALT/WDLs (83% vs 27%, p < 0.05). CONCLUSION: The maximum diameter, non-fatty area on T 1 weighted images, and solid hyperintense area on fat-suppressed T 2 weighted images were useful imaging features for differentiating superficial SCLs from ALT/WDLs. ADVANCES IN KNOWLEDGE: In superficial lipomatous tumors, small tumor size and non-fatty solid area were valuable findings for diagnosing SCLs.

Low serum zinc concentration is associated with low serum testosterone but not erectile function.

OBJECTIVE: To investigate the relation between serum zinc concentration and several factors, including serum testosterone concentration and the score of questionnaires on sexual function in patients with sexual problems. METHODS: This study comprised 720 men (age, 46.3 [21-83] years) with some kind of sexual problem. Age, scores of the Sexual Health Inventory for Men and the Erection Hardness Score, and endocrinologic data including serum concentrations of testosterone, prostate-specific antigen, and zinc were included in this study. After serum zinc concentration of the men was classified into 5 groups (<70, 70≤ <80, 80≤ <90, 90≤ <100, ≤100 µg/dl), the relation of each parameter with serum zinc concentration was assessed for a trend analysis. Finally, the relation between serum concentrations of zinc and testosterone as well sexual function evaluated by the scores of the questionnaires was investigated. RESULTS: Only serum testosterone concentration (ptrend = 0.028) and serum cortisol concentration (ptrend = 0.003) showed a statistically significant relation to serum zinc concentration by trend analysis. Interestingly, trend analysis between serum concentrations of testosterone and zinc still showed a significant association after adjustment for serum cortisol concentration (ptrend = 0.032). However, no significant association was found in the relation between serum zinc concentration and the scores of the questionnaires after adjustment for serum concentrations of testosterone and cortisol. CONCLUSION: We clearly showed that after adjustment for serum cortisol concentration by trend analysis, serum testosterone concentration decreased as serum zinc concentration decreased, although sexual symptoms were not associated with this decrease.

Novel testosterone gel improves serum testosterone concentrations and aging males' symptoms in patients with late-onset hypogonadism: an active control equivalence, randomized, double-blind, crossover study.

Late-onset hypogonadism (LOH) is generally treated with testosterone replacement therapy. Intramuscular injection of testosterone enanthate is used for LOH in Japan but requires regular painful injections administered every 2-3 weeks at a clinic. Testosterone 2% (AndroForte 2® [AF2]) is available for treating LOH but is expensive because it is imported. We developed a new 2% testosterone gel (NTG) and hypothesized that in patients with LOH, NTG would improve serum testosterone concentrations and Aging Males' Symptoms (AMS) scores compared with AF2. We enrolled men with low levels of serum free testosterone (<11.8 pg/mL) and androgen deficiency symptoms (AMS score >27). The primary endpoint was equivalent change in serum testosterone concentrations with NTG compared to AF2. Secondary endpoints were equivalent change in AMS scores for each question with NTG compared to AF2. Each of AF2 or NTG was administered to the study subjects (23 men aged 42-71 years) for 4 weeks separated by a washout period of 2 weeks. The subjects were randomly divided into men who first received NTG and those who first received AF2. No subject experienced any adverse events throughout the study. Compared with the baseline values of serum testosterone, those following NTG and AF2 treatment were significantly higher and were also significantly higher in the subjects taking NTG versus AF2. NTG administration significantly improved the AMS score, whereas AF2 did not. This initial study has shown that this new NTG formulation may be effective in improving serum testosterone concentrations and also LOH-related symptoms.

MRI features of subcutaneous anterior knee mass associated with a focal defect of the patellar retinaculum.

OBJECTIVE: The purpose of this study was to assess the frequency and MRI features of a subcutaneous anterior knee mass herniated from the infrapatellar fat pad (IPFP) through a focal defect of the patellar retinaculum (PR). MATERIALS AND METHODS: This study included 94 patients (44 men; age range, 1-80 years; mean age, 52 years) with clinically palpable subcutaneous anterior knee masses who underwent MRI between January 2007 and July 2022. Two radiologists retrospectively reviewed MRI findings of subcutaneous masses associated with a focal PR defect (location and size of the defect and characteristics of the mass). RESULTS: Among 94 patients, 15 (16%; 5 men; age range, 49-80 years; mean age, 67 years) had subcutaneous masses herniated from the IPFP through a focal PR defect. The defect was single (13/15, 87%) and more frequently observed in the lateral than in the medial (11/15, 73% vs. 4/15, 27%) PR. The defect occurred in the anterior segment (15/15, 100%) and was more frequently observed in the lower (10/15, 67%) than in the middle (5/15, 33%) and upper portions (0/15, 0%). The mean maximum length of the defect in axial and oblique planes was 14 mm and 25 mm, respectively. The defect-associated subcutaneous masses included lipomatous lesion (6/15, 40%), osteochondromatous lesion (5/16, 33%), and synovial fluid or ganglion cyst (4/15, 27%). CONCLUSION: Subcutaneous anterior knee masses were associated with a focal PR defect in 16% cases. The location of a focal PR defect was characterized by the lateral, anterior, and lower segments.

Efficacy and patient satisfaction of low-intensity shockwave treatment for erectile dysfunction in a retrospective real-world study in Japan.

OBJECTIVES: To clarify the efficacy of low-intensity extracorporeal shockwave therapy for patients with erectile dysfunction, compare the efficacy between two types of lithotripters (ED1000 [focused type] and Renova [linear type]), and detect factors indicative of therapeutic gain with the treatment. METHODS: This retrospective study included 76 patients (52.8 ± 11.7 years) treated by ED1000 (12 times over 9 weeks) and 484 patients (52.5 ± 11.6 years) treated by Renova (4 times over 4 weeks). Age, sexual symptoms scores, and blood examinations were assessed. Efficacy was judged by improvement of the scores and patient satisfaction and compared between patients at 1 month after treatment with the lithotripters. Independent factors influencing efficacy by Renova were also assessed. RESULTS: Sexual symptom scores were improved significantly by both lithotripters, although the changes in the scores did not differ significantly between them. Efficacy rate as judged by patient satisfaction was 65.8% with the ED1000 and 71.1% with Renova, also without significant difference. Among several factors including age, sexual symptoms scores, endocrinological factors, metabolic factors, and the rate of phosphodiesterase type 5 inhibitor use, only age was found to be an independent factor influencing the efficacy of Renova. CONCLUSION: We clearly showed the high efficacy of both lithotripters. Although the efficacy rate did not differ between them, we speculated that the fewer treatment sessions needed with the Renova versus the ED1000 would be a great advantage for patients. We also suggest that Renova should be recommended for patients younger than 70 years of age.

The Clinical Evaluation of Third-generation Cephalosporins As Definitive Therapy for Enterobacter spp. and Klebsiella aerogenes Bacteremia.

Objective Third-generation cephalosporins (3GCs) may be susceptible in vitro to Enterobacter spp. and Klebsiella aerogenes. However, treatment with mainly fourth-generation cephalosporins or carbapenems is currently recommended. Diversification of antimicrobial agents in therapy is required to avoid the selection pressure of resistant organisms by broad-spectrum antimicrobial agents. This study investigated the clinical efficacy of 3GC therapy for Enterobacter spp. and Klebsiella aerogenes bacteremia in a multicenter, retrospective, observational study. Methods Patients with Enterobacter spp. or Klebsiella aerogenes detected in blood cultures and treated with a susceptible antimicrobial agent were included in the study. Propensity score matching was performed to align patient background bases, and clinical outcomes between the 3GC and non-3GC groups were compared. Treatment success was defined as having no need for treatment escalation or the addition of other antimicrobial agents, no recurrence, or no death within 30 days. Results The study included 188 cases, of which 57 and 131 were included in the 3GC and non-3GC treatment groups, respectively; 53 patients in each group were matched by propensity score matching. There were no significant differences between groups in rates of switching to a susceptible antimicrobial or adding another agent, relapse within 30 days, or death within 30 days. In the 3GC group, source control was associated with favorable clinical outcomes. Conclusion Definitive 3GC therapy for susceptible Enterobacter spp. and Klebsiella aerogenes bacteremia is as clinically effective and valuable a targeted therapy as non-3GC therapy and can be implemented under conditions in which infection source control measures are in place.

International Prostate Symptom Score and Quality of Life Index for Lower Urinary Tract Symptoms Are Associated with Aging Males Symptoms Rating Scale for Late-Onset Hypogonadism Symptoms.

PURPOSE: Although patients with late-onset hypogonadism (LOH) often experience lower urinary tract symptoms (LUTS), LUTS are not generally included in LOH symptoms. No study has examined the direct relation of the Aging Males Symptoms rating scale (AMS) and the International Prostate Symptom Score (IPSS) with the quality of life (QOL) index. We analyzed the relation between the IPSS and QOL index and various factors including the AMS in patients with LOH syndromes. MATERIALS AND METHODS: This study comprised 1,688 men with LOH symptoms who visited our hospital or affiliated clinic. Factors associated with the IPSS were assessed in terms of age, scores of several questionnaires including the AMS, endocrinological variables, and serum concentration of PSA. Among these same factors, those associated with the QOL index were also evaluated. Finally, the same analyses were repeated in 187 patients with low serum testosterone concentration (<3.0 ng/mL). RESULTS: In a multivariate analysis using the significant items from the univariate analysis, AMS, age, and Erection Hardness Score correlated significantly with the IPSS. A trend analysis using items other than the AMS as adjustment factors also confirmed the relationship between an increase in QOL index and an increase in AMS. Similar results were obtained in the analysis of patients with low serum testosterone concentration. CONCLUSIONS: We revealed that the relation of IPSS with the QOL index for LUTS is closely associated with the AMS for LOH, regardless of testosterone level. When patients complain of LOH symptoms, a careful, detailed inquiry into LUTS is required.

A case of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) with decreased oxidative stress levels after oral prednisone and tocilizumab treatment.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has recently been described as an autoinflammatory disease associated with severe adult-onset inflammatory manifestations. The various clinical manifestations include recurrent high-grade fever, neutrophilic dermatoses, cutaneous vasculitis, chondritis of the ear and nose, pulmonary infiltrates, cytopenia, uveitis, gastrointestinal pain or inflammation, aortitis, hepatosplenomegaly, and hematological disorders. VEXAS syndrome is caused by somatic mutations of the ubiquitin-like modifier activating enzyme 1 (UBA1) gene in myeloid-lineage cells. It is characterized by vacuolated myeloid and erythroid progenitor cells seen by bone marrow biopsy. We report the case of a 64-year-old Japanese man with VEXAS syndrome. At age 63, he was referred to us with a recurrent erythema on the hands associated with a general fever of 38-40°C that had persisted for 4 or 5 days and had recurred about once a month for a year. The skin rash appeared 2 or 3 days after the onset of each fever episode. Computed tomography (CT) of the chest revealed bilateral hilar lymphadenopathy (BHL), and the mediastinal lymph nodes were swollen. Sarcoidosis was suspected but was ruled out by several tests. Laboratory examinations showed elevated inflammatory markers. Bone marrow examination showed the vacuolization of myeloid precursor cells. A skin biopsy revealed dense dermal, predominantly perivascular, infiltrates. These consisted of mature neutrophils admixed with myeloperoxidase-positive CD163-positive myeloid cells, lymphoid cells and eosinophils. Sequencing analysis identified the somatic UBA1 variant c.122T > C, which results in p.Met41Thr. Treatment with oral prednisone (15 mg/day) and monthly intravenous tocilizumab injections (400 mg) completely resolved the symptoms. Neutrophils are a major source of reactive oxygen species, and the present case demonstrated numerous neutrophilic infiltrates. We hypothesize that the patient might have had elevated derivatives of reactive oxygen metabolites (d-ROMs). d-ROM quantification is a simple method for detecting hydroperoxide levels, and clinical trials have proven it useful for evaluating oxidative stress. In this study, we measured serum d-ROM before and after oral prednisone and tocilizumab treatment. The levels decreased significantly during treatment.