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IntroductionThis study assessed the performance of a new fully automated immunoassay for fibroblast growth factor (FGF) 23 (Determinar CL FGF23 CL) among healthy individuals and those with chronic hypophosphatemia compared with the previous assay (Kainos FGF23 KI).Materials and methodsA total of 380 serum samples from healthy participants were collected to determine the reference range of FGF23 levels with CL. A total of 200 serum samples from 22 hypophosphatemic patients were collected simultaneously to compare the difference in FGF23 levels between CL and KI. The Mann–Whitney U test and linear regression analysis were adopted to assess the differences and linearity between the two assays.ResultsThe median FGF23 levels among healthy individuals was 31.7 (interquartile: 26.4–37.5) pg/mL. When the reference range was calculated as the mean  ± 2 standard deviation (2SD), it was 16.1–49.3 pg/mL. A total of 363 individuals (96%) among normal cases fell in this range. Among 200 samples from patients with chronic hypophosphatemic disorder, the median FGF23 levels analyzed by CL and KI were 123.0 (90.2–237.7) and 172.5 (115.8–290.7) pg/mL. KI yielded significantly higher FGF23 values than CL (p < 0.001). A linear regression model revealed the correlation between KI (x) and CL (y), which had a slope of 0.76 with a y-intercept of −0.32 and high linearity (R2 = 0.99).ConclusionThe new measurement kit yielded lower FGF23 values when compared with the previous assay. Clinicians should consider this discrepancy when they assay intact FGF23 values with CL.

Purpose of Review The study aims to provide updated information on the genetic factors associated with the diagnoses ‘Diffuse Idiopathic Skeletal Hyperostosis’ (DISH), ‘Ossification of the Posterior Longitudinal Ligament’ (OPLL), and in patients with spinal ligament ossification. Recent Findings Recent studies have advanced our knowledge of genetic factors associated with DISH, OPLL, and other spinal ossification (ossification of the anterior longitudinal ligament [OALL] and the yellow ligament [OYL]). Several case studies of individuals afflicted with monogenic disorders, such as X-linked hypophosphatemia (XLH), demonstrate the strong association of fibroblast growth factor 23-related hypophosphatemia with OPLL, suggesting that pathogenic variants in PHEX , ENPP1 , and DMP1 are associated with FGF23-phosphate wasting phenotype and strong genetic factors placing patients at risk for OPLL. Moreover, emerging evidence demonstrates that heterozygous and compound heterozygous ENPP1 pathogenic variants inducing ‘ Autosomal Recessive Hypophosphatemic Rickets Type 2 ’ (ARHR2) also place patients at risk for DISH and OPLL, possibly due to the loss of inhibitory plasma pyrophosphate (PP i ) which suppresses ectopic calcification and enthesis mineralization. Summary Our findings emphasize the importance of genetic and plasma biomarker screening in the clinical evaluation of DISH and OPLL patients, with plasma PP i constituting an important new biomarker for the identification of DISH and OPLL patients whose disease course may be responsive to ENPP1 enzyme therapy, now in clinical trials for rare calcification disorders.

Little is known about genetic risk factors for idiopathic normal pressure hydrocephalus (iNPH). We examined whether a copy number loss in intron 2 of the SFMBT1 gene could be a genetic risk for shunt-responsive, definite iNPH. Quantitative and digital PCR analyses revealed that 26.0% of shunt-responsive definite iNPH patients (n = 50) had such a genetic change, as compared with 4.2% of the healthy elderly (n = 191) (OR = 7.94, 95%CI: 2.82-23.79, p = 1.8 x 10-5) and 6.3% of patients with Parkinson's disease (n = 32) (OR = 5.18, 95%CI: 1.1-50.8, p = 0.038). The present study demonstrates that a copy number loss within intron 2 of the SFMBT1 gene may be a genetic risk factor for shunt-responsive definite iNPH.

Osteopetrosis is a heterogeneous group of rare hereditary diseases characterized by increased bone mass of poor quality. Autosomal-dominant osteopetrosis type II (ADOII) is most often caused by mutation of the CLCN7 gene leading to impaired bone resorption. Autosomal recessive osteopetrosis (ARO) is a more severe form and is frequently accompanied by additional morbidities. We report an adult male presenting with classical clinical and radiological features of ADOII. Genetic analyses showed no amino-acid-converting mutation in CLCN7 but an apparent haploinsufficiency and suppression of CLCN7 mRNA levels in peripheral blood mononuclear cells. Next generation sequencing revealed low-frequency intronic homozygous variations in CLCN7, suggesting recessive inheritance. In silico analysis of an intronic duplication c.595-120_595-86dup revealed additional binding sites for Serine- and Arginine-rich Splicing Factors (SRSF), which is predicted to impair CLCN7 expression. Quantitative backscattered electron imaging and histomorphometric analyses revealed bone tissue and material abnormalities. Giant osteoclasts were present and additionally to lamellar bone, and abundant woven bone and mineralized cartilage were observed, together with increased frequency and thickness of cement lines. Bone mineralization density distribution (BMDD) analysis revealed markedly increased average mineral content of the dense bone (CaMean T-score + 10.1) and frequency of bone with highest mineral content (CaHigh T-score + 19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except for an unusually circular shape. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture. While the skeletal phenotype and medical history were suggestive of ADOII, genetic analysis revealed that this is a possible mild case of ARO due to deep intronic mutation.

Background. Asfotase alfa is the only approved treatment that can normalize mineralization in patients with hypophosphatasia (HPP). Its interference in alkaline phosphatase (ALP) dependent immunoassays has been reported. Objective. To describe thyroid function tests interfered with by asfotase alfa and elucidate the underlying mechanism. Patients and Methods. Three patients with HPP treated with asfotase alfa were included. Thyroid hormone levels measured using five different immunoassays with or without ALP as a labeling enzyme during asfotase alfa treatment were evaluated. Results. After the initiation of asfotase alfa, three HPP patients showed low free triiodothyronine (FT3) and free thyroxine (FT4) measured with AIA-2000 (Tosoh, Tokyo, Japan), an enzyme immunoassay system that uses ALP as a labeling enzyme, but their thyroid-stimulating hormone (TSH) levels were within the normal range. The other CLEIA system using ALP as a label, AIA-CL2400 (Tosoh, Tokyo, Japan), and ALP-independent immunoassay systems demonstrated normal FT3 and FT4 levels. These data suggested that although the thyroid function of these three patients was normal, asfotase alfa interfered with the thyroid hormone measurements made with AIA-2000. AIA-2000 and AIA-CL2400 adopted one-step and delayed one-step measurements, respectively, and the same antibody was used for both immunoassays. However, asfotase alfa may be absorbed on the magnetic beads used in the AIA reagent with the AIA-2000 system but not absorbed on the microparticles used in AIA-CL2400. Conclusion. Clinicians should be aware of the possible interference in thyroid function measurements by adopting specific types of immunoassays in asfotase alfa-treated HPP patients.

Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue‐nonspecific alkaline phosphatase. Adult‐onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first‐line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64‐year‐old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6‐minute walk test (525 to 606 m). The EQ‐5D‐5L index was also improved (0.757 to 0.895). Within a follow‐up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Abstract Context Tumor-induced osteomalacia (TIO) is one of the most common forms of acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemia and is usually caused by phosphaturic mesenchymal tumors (PMTs). Although the complete resection of PMTs can cure TIO, preoperative localization of tumors by standard imaging modalities is often challenging. In addition to 18F-fluoro-2-deoxy-D-glucose positron emission tomography–computed tomography (FDG-PET) and 111In-pentetreotide scintigraphy (SRS), systemic FGF23 venous sampling (FGF23VS) has been used to help localize PMTs in specialized institutions. Objective This study aimed to evaluate the diagnostic performance of each imaging test and their combinations in localizing PMTs. Methods In an observational retrospective study of patients with adult-onset FGF23-related osteomalacia who underwent all 3 imaging studies (FDG-PET, SRS, and FGF23VS), the rate of successful preoperative localization of the tumors was evaluated only in the patients with pathological diagnoses of PMTs, considering the possibility that pathogenesis of patients without identified tumors might be due to other causes such as late-onset hereditary FGF23-related hypophosphatemia. Results A total of 30 Japanese patients with TIO (median age, 60 years [range, 28-87 years]; 10 women [33.3%]) were included in the study. The success rate of preoperative localization for each test and combinations of 2 or 3 tests among 18 patients with PMTs was as follows: 72% (FDG-PET), 72% (SRS), 94% (FGF23VS), 89% (FDG-PET, SRS), 100% (FDG-PET, FGF23VS), 94% (SRS, FGF23VS), and 100% (FDG-PET, SRS, and FGF23VS). Conclusion We observed the highest localization rate of PMTs in patients with identified PMTs with the combination of FDG-PET and FGF23VS.

Bacterial strain, B-9, isolated from Lake Tsukui, Japan, and characterized as genus Sphingosinicella sp., possesses hydrolytic enzymes capable of degrading various toxic and non-toxic cyanobacterial cyclic peptides, such as microcystins, nodularin, microviridin, microcyclamide and aeruginopeptin. In this study, the degradation activities of the cell extract of B-9 against bacterial cyclic peptides, bacitracin, colistin, polymyxin, mikamycin, thiopeptin and WAP-8294A2, were investigated and the degradation products were analyzed using HPLC and liquid chromatography/ion trap tandem mass spectrometry (LC/ITMS). As a result of extensive experiments, it was confirmed that B-9 could also degrade these bacterial cyclic peptides by hydrolysis of their peptide or ester bonds, except for WAP-8294A2. These results indicated that the functions of the bacterium with its enzymes were further extended and offered the possibility of degrading other types of compounds.

Abstract Context Adults with X-linked hypophosphatemia (XLH) present complications other than osteomalacia. Objective To describe the incidence and severity of comorbidities in adults with XLH. Methods This observational retrospective study included a total of 25 adults with XLH with thorough investigations, including spinal computed tomography scans, x-rays of hip/knee joints and Achilles tendons, abdominal ultrasounds, and audiograms. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of OA/OP/OY index (OS index) were utilized to evaluate the severity of spinal ligament ossification. The Kellgren-Lawrence (KL) classification was adopted to evaluate the severity of the hip/knee osteophytes. Results The participants consisted of 13 male patients and 12 female patients from 21 families, with a median age of 43 (range, 18-72) years. In all, 20 patients (80%) showed spinal ligament ossification. The median OA/OP/OY/OS indices were 2 (0-22), 0 (0-15), 6 (0-13), and 12 (0-41), respectively. Hip/knee osteophytes were reported in 24 (96%) and 17 cases (68%). The median KL grade was 3 in the hip joint and 2 in the knee joint, and 18 cases (72%) developed enthesopathy in the Achilles tendon. Nephrocalcinosis and hearing impairment were observed in 18 (72%) and 8 (32%) cases. Conclusion This study revealed a high prevalence and severity of ectopic ossification and disclosed the incidence of nephrocalcinosis and hearing impairment in adults with XLH. In cases with severe spinal ligament ossification or noticeable osteophytes around the hip/knee joints, undiagnosed XLH should be considered as a possible underlying condition.

LC/MS/MS under ion trap conditions was used to analyze microcystins produced by cyanobacteria. Tandem mass spectrometry using MS 2 was quite effective since ions arising from cleavage at a peptide bond provide useful sequence information. The fragmentation was confirmed by a shifting technique using structurally-related microcystins and the resulting fragmentation pattern was different from those determined by triple stage MS/MS and four sector MS/MS. Analysis of a mixture of microcystins in a bloom sample was successfully performed and two new microcystins were identified by LC/MS/MS under ion trap conditions. Thus, LC/MS/MS under ion trap conditions is effective for the structural characterization of microcystins.