A case of refractory adult-onset Still's disease with high serum interleukin-18 levels treated with monitoring of serum levels of cyclosporine

We report the case of a 31-year-old woman who developed adult-onset Still's disease (AOSD) with a high level of serum interleukin (IL)-18. Although treated with high dose steroids, she suffered repeated remissions and her condition deteriorated. After we administered oral cyclosporine A (CsA), 200 mg/d, monitoring C2 and trough levels, her symptoms improved significantly. We decreased the dose of methylprednisolone slowly without noting a relapse. The use of CsA accompanied by C2 and trough level monitoring should be considered for refractory AOSD patients with high levels of serum IL-18.     

Huntingtin-associated protein 1 (HAP1) interacts with androgen receptor (AR) and suppresses SBMA-mutant-AR-induced apoptosis

Huntingtin-associated protein 1 (HAP1), an interactor of huntingtin, has been known as an essential component of the stigmoid body (STB) and recently reported to play a protective role against neurodegeneration in Huntington's disease (HD). In the present study, subcellular association between HAP1 and androgen receptor (AR) with a long polyglutamine tract (polyQ) derived from spinal-and-bulbar-muscular-atrophy (SBMA) was examined using HEp-2 cells cotransfected with HAP1 and/or normal ARQ25, SBMA-mutant ARQ65 or deletion-mutant AR cDNAs. The results provided the first clear evidence that HAP1 interacts with AR through its ligand-binding domain in a polyQ-length-dependent manner and forms prominent inclusions sequestering polyQ-AR, and that addition of dihydrotestosterone reduces the association strength of HAP1 with ARQ25 more dramatically than that with ARQ65. Furthermore, SBMA-mutant-ARQ65-induced apoptosis was suppressed by cotransfection with HAP1. Our findings strongly suggest that HAP1/STB is relevant to polyQ-length-dependent modification on subcellular AR functions and critically involved in pathogenesis of not only HD but also SBMA as an important intrinsic neuroprotectant determining the threshold for cellular vulnerability to apoptosis. Taking together with previous reports that HAP1/STB is selectively expressed in the brain regions spared from degenerative targets in HD and SBMA, the current study might explain the region-specific occurrence of neurodegeneration in both diseases, shedding light on common aspects of their molecular pathological mechanism and yet-to-be-uncovered diagnostic or therapeutic applications for HD and SBMA patients.     

Pups of dams fed low-fat diet during pregnancy and lactation showed strong preference for high-fat diet to achieve optimal growth

To investigate the causes why pups of dams fed a low-fat high-carbohydrate diet (LFD) showed a strong preference for fat, three groups of dams were fed one of three diets during pregnancy and lactation: the LFD, a control diet (CTD) or a high-fat low-carbohydrate diet (HFD). After weaning, pups of each of the three groups were divided into two equal subgroups (Pair 1 and Pair 2), for a total of six pup subgroups. Each subgroup was placed on a two-choice diet program of the LFD and the HFD (Pair 1), or the LFD and a HFDLE (with cellulose added to maintain the same energy concentration as the LFD) (Pair 2), for 3 wk. Although the energy intake of dams fed the LFD during the nursing period was lower than that of the HFD group, no significant difference in body weight was observed among the three groups. At weaning, the body weight of pups nursed by dams fed the LFD was lower than that of the other groups. In Pair 1, the HFD intake ratio of the LFD and the HFD groups during the self-selection period was higher than that of the CTD group. In Pair 2, the HFDLE intake ratio of the LFD and the CTD groups was lower than that of the HFD group. At the end of the self-selection period, no significant difference in body weight was observed among the three groups of Pair 1. However, in Pair 2, the body weight of the LFD group was lower than that of the other groups. Therefore, it was supposed that pups of dams fed the LFD showed strong preference for the HFD containing high energy in order to achieve optimal growth.     

The impact of musculoskeletal diseases on the presence of locomotive syndrome

Objectives: We assessed the impact of musculoskeletal diseases, depressive mental state, and hypertension on locomotive syndrome, a condition of reduced mobility requiring nursing care. Since locomotive syndrome is a major public health issue that needs attention, its relationship with functional inconvenience in performing daily activities was also investigated.

Methods: We conducted a cross-sectional study using an Internet panel survey, comprising 747 persons aged 30–90 years. Demographics, personal medical history, and daily activity data were assessed. The 25-question Geriatric Locomotive Function Scale was used to diagnose locomotive syndrome. Stepwise linear regression analysis and logistic regression analysis were conducted to evaluate the association between locomotive syndrome, musculoskeletal diseases, and functional inconvenience.

Results: Aging, osteoporosis, and low back pain significantly increased the risk of locomotive syndrome, followed by knee osteoarthritis and lumbar spinal stenosis. Locomotive syndrome was significantly related to depressive mental state and hypertension, and led to functional inconvenience in Seiza sitting, cleaning, shopping, and strolling.

Conclusion: Locomotive syndrome was associated with functional inconvenience in performing common daily activities involving the lower extremities and spine. Osteoporosis and aging were significantly associated with locomotive syndrome. The risk of locomotive syndrome may be decreased by treating comorbid osteoporosis and instituting exercise and diet-related modifications.     

Gonadal and adrenal effects on the glucocorticoid receptor in the rat hippocampus,with special reference to regulation by estrogen from an immunohistochemical view-point

Focusing on the hippocampal CA1 region, effects of peripheral gonadal and adrenal steroids on the glucocorticoid receptor (GR) were immunohistochemically evaluated in male and female adult rat brains after adrenalectomy (ADX), gonadectomy (GDX), and administration of estradiol (E2) and/or corticosterone (CS). In ADXed male rats, the hippocampal nuclear GR decreased and turned back to the cytoplasm, whereas in females, nuclear localization persisted even after ADX. In GDX+ADXed female rats, the GR was dispersedly translocated from the nucleus to the cytoplasm as well as in GDX+ADXed males. The dispersed cytoplasmic GR was again translocated into the nucleus by administration of CS. In addition, administration of a small dose of E2 for 4-13 days was found to sufficiently recover the nuclear location of GR in GDX+ADXed rat brains, whereas medium-to-large doses could not do this. Also, a longer administration more strongly enhances the nuclear GR location and expression. The present study provided strong immunohistochemical evidence that the sexually dimorphic effects of ADX on hippocampal GR are attributable to gonadal hormones, and that E2 is implicated in the effects in inversely-dose- and directly-duration-dependent manner. Taken together, intriguing gonadal and adrenal crosstalk is considered to play some important role in regulating hippocampal GR morphology and to have a possibly crucial influence on stress-related disorders such as depression.     

Clinical significance of Cobas Amplicor HCV Monitor test v 2.0 for quantifying a wide range of serum HCV-RNA in patients with chronic hepatitis C

Recently, we evaluated the clinical significance of a new assay, the semi-automated Cobas Amplicor HCV Monitor test v 2.0 (Roche, Cobas-HIGH-RANGE assay), for quantifying serum hepatitis C virus RNA throughout a wider range than the traditional assay, Amplicor GT HCV Monitor test v 2.0 (GT-ORIGINAL assay). We compared the results of the Cobas-HIGH-RANGE assay with results of the GT-ORIGINAL assay. This study was conducted on serum from 91 patients with chronic hepatitis C at the Gastroenterological Center, Yokohama City University Medical Center. The percent coefficient of variation (CV) for the within-run and between-run reproducibility of the Cobas-HIGH-RANGE assay ranged from 0.7 to 2.3% and from 1.3 to 2.0%, respectively. The Cobas-HIGH-RANGE assay exhibited a linear range extending from 5 to 5000 KIU/ml. The values for all 17 samples determined as less than 0.5 KIU/ml by the GT-ORIGINAL assay were also determined as less than 5 KIU/ml by the Cobas-HIGH-RANGE assay. For the 48 samples with values of 0.5 to 850 KIU/ml determined by the GT-ORIGINAL assay, the values obtained by these two assay methods were significantly correlated (r2 = 0.9117, y = 1.0667x-0.0801, p < 0.001), but the values of HCV-RNA determined by the Cobas-HIGH-RANGE assay were significantly (p < 0.05) higher than those determined by the GT-ORIGINAL assay. Consequently, these data indicate that the HIGH-RANGE assay is a useful alternative assay method for measurement of HCV-RNA instead of the ORIGINAL assay, and that the HIGH-RANGE assay could be a useful tool for monitoring the efficacy of antiviral treatment.     

A Lipid-Based Depot Formulation with a Novel Non-lamellar Liquid Crystal Forming Lipid

Pharmaceutical Research - Non-lamellar liquid crystal (NLLC)-forming lipids have gained attention as a novel component because of their ability to self-assemble upon contact with body fluids. In...     

Predictive detection areas for identifying additional MRI-detected breast lesions on second-look ultrasonography

Purpose

Identifying an additional MRI-detected breast lesion on second-look ultrasonography (US) is technically challenging because of lesion displacement with the patient’s position change. The aim of this study is to help identify MRI-detected lesions on second-look US by developing a probing area, called “the predictive detection area” (PDA), and by assessing the PDA.

Methods

We measured the nipple-to-lesion distances (NLDs) for 16 breast lesions on prone- and supine-position MRI sets and calculated the difference and angle between the two NLD vectors, representing the lesion displacement. The minimum and maximum differences and angles were chosen to form the PDA. Another 22 breast lesions, detected in the prone MRI, were identified on US by probing the PDA to evaluate the probability of existence.

Results

The width between the minimum and maximum differences in two NLDs and the angle to form the PDA for the upper-inner, upper-outer, and lower-outer quadrants were 23.0 mm and 95.0°, 29.0 mm and 41.0°, and 18.0 mm and 17.0°, respectively. The respective probabilities of existence were 100, 80, and 100%.

Conclusions

The PDA had a high probability of existence and was acceptably accurate; therefore, the PDA in a second-look US has the potential to help operators to quickly identify additional MRI-detected lesions.

     

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm,International Trial

In adults with X-linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25-dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023-CL304 is an ongoing, open-label, single-arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia-related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, –54%, osteoid thickness, –32%, osteoid surface/bone surface, –26%, [median] mineralization lag time, –83%). Mean serum phosphorus concentration averaged across the mid-point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment-emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure-related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.