Early Postoperative Stiffness After Arthroscopic Rotator Cuff Repair Correlates With Improved Tendon Healing.

PURPOSE: To assess whether early postoperative stiffness predicts long-term stiffness and its relationship with repair integrity in patients who undergo arthroscopic rotator cuff repair (ARCR). METHODS: This was a single-center retrospective study; 427 patients undergoing primary ARCR by a board-certified orthopaedic surgeon over 4 years were considered. Patients with at least 1 year of follow-up were categorized into stiff and non-stiff groups based on their range of motion (ROM) at 3 months' postoperatively. Stiffness was defined as passive forward flexion <120°, external rotation <30°, or internal rotation below L3. We evaluated clinical outcomes using demographics, ROM, Constant Shoulder (CS) score, University of California, Los Angeles (UCLA) score, and visual analog scale (VAS) for pain preoperatively and at 3, 6, and 12 months' postoperatively. Stiffness, retear rates, and tendon integrity were assessed via magnetic resonance imaging at 12 months. RESULTS: Of 155 patients meeting the inclusion criteria, 68 (43.9%) were stiff, and 87 (56.1%) were non-stiff. The stiff group had significantly lower preoperative CS and UCLA scores (P = .013/.014) and greater VAS score (P = .034). At 3 months, this group showed lower ROM and functional scores (P < .001), persisting at 6 and 12 months (except internal rotation) (P < .001). Their 12-month VAS score was greater (P = .024). Postoperative stiffness occurred in 10.3% of the stiff group and 2.3% of the non-stiff group (P = .035). The 12-month retear rate was 5.9% in the stiff group and 17.2% in the non-stiff group (P = .032). Minimal clinically important difference analysis indicated ROM changes but limited functional score changes in the 2 groups. CONCLUSIONS: This study showed that early postoperative shoulder stiffness correlates with lower preoperative functional scores and greater pain levels. Shoulder stiffness at 3 months' post-ARCR predicts 12-month shoulder stiffness but indicates better tendon integrity. While early stiffness is linked to lower functional scores and more pain, its long-term clinical impact seems limited. LEVEL OF EVIDENCE: Level III, retrospective comparison study.

Bisphosphonate FYB-931 Prevents High Phosphate-Induced Vascular Calcification in Rat Aortic Rings by Altering the Dynamics of the Transformation of Calciprotein Particles.

Patients with chronic kidney disease develop vascular calcification, owing to impaired calcium and phosphate metabolism. The prevention of vascular calcification is important to improve the prognosis of such patients. In this study, we investigated whether treatment with FYB-931, a novel bisphosphonate compound, prevents vascular calcification in rat aortic rings cultured in high-phosphate medium for 9 days, assessed by measurement of the calcium content and the degree of calcium deposition, visualized using von Kossa staining. The effect on the transformation of calciprotein particles (CPPs) from primary to secondary CPPs was assessed using a fluorescent probe-based flow cytometric assay. FYB-931 dose-dependently prevented high phosphate-induced aortic calcification, but failed to rapidly cause the regression of high phosphate-induced vascular calcification once it had developed. Furthermore, the treatment dose-dependently inhibited the high phosphate-induced transformation from primary to secondary CPPs. In addition, the treatment with FYB-931 prevented the transformation from primary to secondary CPPs in vitamin D3-treated rats as a model of ectopic calcification, consistent with the results from rat aortic rings. In conclusion, treatment with FYB-931 prevents high phosphate-induced rat aortic vascular calcification by altering the dynamics of CPP transformation. This finding suggests that inhibition of the transformation from primary to secondary CPPs is an important target for the prevention of vascular calcification in patients with chronic kidney disease.

Forecasting surgical costs: Towards informed financial consent and financial risk reduction.

BACKGROUND: Health care expenditure is increasing around the world and surgery is a major cause of financial hardship to patients and their families. Using pancreatoduodenectomy (PD), one of the most complex, morbid and costly operation as an example, this study aimed to identify the cost drivers of surgery, estimate relative contribution of these drivers, and derive and validate a cohort-specific cost forecasting tool. METHODS: Data on the costs of 1406 patients undergoing PD in three tertiary hospitals in India, Italy and the United States were analysed. Cost drivers were identified and cost models developed using a 4-stage process. RESULTS: There was a significant difference in overall cost of PD between the 3 cohorts. The cost drivers common to the 3 cohorts included duration of hospital stay and the outcome of death (Clavien-Dindo 5). Significant cohort-specific cost drivers included co-morbidities, operating theatre utilisation times and operative blood loss, development of pancreatectomy-specific complications (POPF, DGE, PPH), and need for interventional radiology to manage complications. Based on this, a cost forecasting tool was developed. CONCLUSIONS: Drivers of costs for a surgical procedure (e.g. PD) are different between hospitals. Developing cost models/nomograms to predict the expected cost of surgery and perioperative care will not be applicable between hospitals. However, the approach could be used to develop context-specific data that will provide patients (at the time of the informed financial consent) and funding agencies with a more realistic cost estimate for a given operation. The developed cost forecasting tool warrants future validation.

Nonanesthetized Alternatively Repetitive Cast and Brace Treatment for Early-onset Scoliosis.

BACKGROUND: Use of cast is a standard treatment (Tx) choice for early-onset scoliosis. Recently, toxicity from repetitive use of general anesthesia has received attention by the Food and Drug Administration (FDA). We introduce a nonanesthetized cast Tx protocol called alternatively-repetitive-cast-and-brace (ARCB) that we have used since 1995 and have conducted an extensive follow-up on these patients to verify the efficacy of this protocol. STUDY DESIGN: This is a retrospective cohort study. METHODS: Of a consecutive series of 155 patients who have undergone cast Tx at a single institution, 98 patients (male: 36, female: 62) have been identified under the following criteria: (1) Initial age before ARCB of ≤6; (2) Follow-up period of ≥2 years; (3) Initial scoliosis ≥35 degrees. Patients consisted of the following: congenital/structural: 45, idiopathic: 23, neuromuscular: 6, syndromic: 24. Precast, postfinal cast, minimum in-cast Cobb, as well as thoracic and T1-S1 heights were measured. Fifty-six of these patients had available pulse oximetry on days before and after initial cast, and these were also evaluated to assess cardiopulmonary effects that the cast have on the patients. RESULTS: Patients were casted 6.6 times, with a mean initial Cobb of 56.5 degrees and a final follow-up Cobb of 57.1 degrees. Follow-up period was 5.0 years. Mean curve progression per follow-up period was 0.5 degrees/y. Minimum in-cast Cobb was 25.6 degrees. Initially patients had a thoracic and T1-S1 height of 12.6 and 22.5 cm, respectively. At final cast, these were 15.3 and 27.2 cm, respectively. Of these patients, 39 had progression >1 degree/y, of which 83.1% had resulted in surgical correction, while this was true for only 37.3% of those that did not show such progression. Idiopathic patients had the greatest correction rate by cast (69%) and had shown an overall progression rate of -2.3 degrees/y. Pulse-oximetry results were not significant amongst patients before and after cast placement. CONCLUSIONS: ARCB is a versatile and practical Tx choice. It is an effective delaying method in sparing time until surgery with no apparent cardiopulmonary compromise. Curve control was most effective in Idiopathic patients while some curve control was achieved in other etiologies which may have spared time until their eventual surgery. SIGNIFICANCE: Cast Tx without the need of general anesthesia is an increasingly important topic since anesthesia toxicity from its repetitive use has become apparent. This study exemplifies safe and efficacious use of such cast with effective suppression on cast progression in different etiologies at various degrees.

[The prevention and treatment of vascular calcification.]

We had called the various bone disorder in chronic kidney disease(CKD)as a "ROD:renal osteodystrophy" until last decade. However the concept of ROD have changed into the chronic kidney disease-mineral and bone disease(CKD-MBD)within this decade. This concept is containing systemic disorder affected mortality. Vascular calcification is an independent risk factor for the development of cardiovascular disease and mortality. The best strategy to prevent and treat vascular calcification would consist of the CKD-MBD management. It is expected that the treatment of preventing directly vascular calcification to appear by finding the detailed mechanism in the future.

Dietary Changes Involving Bifidobacterium longum and Other Nutrients Delays Chronic Kidney Disease Progression.

BACKGROUND: Recent studies suggest that prebiotic and/or probiotic treatments ameliorate kidney function in humans and animals by improving the gut environment. However, the gut microbiota and kidney disease interactions remain to be determined. This study investigated whether synbiotics modulate the gut microbiota and ameliorate kidney function using a rat model of chronic kidney disease (CKD). As uremic toxins are associated with CKD-related mineral and bone disorder, the secondary aim was to evaluate the relationship between synbiotics and secondary hyperparathyroidism (SHPT). METHODS: 5/6 nephrectomy (Nx) rats were developed as the CKD model. Sham-operated (sham) rats were used as the control. To investigate the effectiveness of prebiotics (glutamine, dietary fiber, and oligosaccharide) and probiotics (Bifidobacterium longum strain; GFOB diet), rats were randomly assigned to 4 groups: Nx group fed the GFOB diet (n = 10); Nx group fed the control (CON) diet (n = 10); sham group fed the GFOB diet (n = 5); and sham group fed the control diet (n = 5). Blood, feces, and kidney samples were collected and analyzed. RESULTS: Serum creatinine (Cre) and blood urea nitrogen in the Nx GFOB group were significantly lower than those in the Nx CON group. Serum indoxyl sulfate in the Nx GFOB group was lower than that in the Nx CON group, and significantly correlated with serum Cre. Inorganic phosphorus and intact parathyroid hormone in the Nx GFOB group were significantly lower than those in the Nx CON group. CONCLUSION: Improving the gut environment using synbiotics ameliorated kidney function and might be a pharmacological treatment for SHPT without any serious adverse events.

Clinical Impact of Corrective Cast Treatment for Early Onset Scoliosis: Is It a Worthwhile Treatment Option to Suppress Scoliosis Progression Before Surgical Intervention?

BACKGROUND: Although corrective cast (CC) has been back in use for the treatment of early onset scoliosis (EOS), no studies have reported how clinically meaningful CC was in comparison with brace-only treatment (BT) in EOS. The aim of this study was to investigate the effect of CC treatment in terms of suppression of scoliosis progression before surgery. METHODS: This study was designed to conduct a comparison of patients treated at 2 spine institutions differing in treating methods (one: mainly CC with brace, the other: BT). Applying casts were performed without general anesthesia and repeatedly with the interval of 2 to 6 months combined with corrective brace application called alternatively repetitive cast and brace treatment (ARCBT). In total, 58 patients met the following criteria: (1) age at the first visit ≤6 years, (2) scoliosis ≥40 degrees, (3) conservative treatment≥2 years. Patients with congenital scoliosis were excluded in this study. In total, 58 patients were divided into 2 groups; cast/brace group (C/B-G) and BT group (B-G). RESULTS: There were no significant differences of diagnosis (P=0.2773), sex (P=0.0670), age at the first visit (P=0.1457), scoliosis magnitude (P=0.1980), and duration for conservative treatment (P=0.2578) between 2 groups. Most of the patients who were treated with ARCBT, were switched to BT due to lower compliance for CC after the age of around 7 years. The progression of scoliosis during ARCBT and BT were 4.4 and 5.8 degree/y, respectively. Those during ARCBT in C/B-G was 2.8 degree/y comparing with 8.4 degree/y after switch to BT after 7 years of age. There was a significant difference between scoliosis progression during ARCBT in C/B-G and that of B-G (P=0.0086). CONCLUSIONS: This study showed that ARCBT had a significant impact on suppression of scoliosis progression compared with BT in EOS. However, the termination of cast application and the switch to BT may be still a clinical question considering the time to surgical intervention. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Three-Dimensional Analysis of Hemimetameric Segmental Shift in Congenital Scoliosis.

STUDY DESIGN: This is a retrospective cohort study. BACKGROUND: Hemimetameric segmental shift (HMMS) is defined as a hemivertebral deformation in which 2 or more hemivertebrae exist on both sides of the spine and are separated by at least 1 normal vertebra. Reports of HMMS are rare and based on simple anterior x-ray images. No reports have used 3-dimensional computed tomography (3D-CT) to analyze both the anterior and posterior elements. The objective of this study was to analyze the morphology and clinical features of HMMS 3 dimensionally. METHODS: HMMS was confirmed in 32 (6.6%, 16 males and 16 females) of 483 patients diagnosed with congenital scoliosis at the study institution between 1998 and 2013. The average age at the first visit was 6 years and 3 months. 3D-CT imaging was performed for 30 patients older than 2 years (average age: 9 y and 8 mo) and used to classify cases according to posterior elements. RESULTS: With regard to the number of hemivertebrae present, 21 patients had 2 hemivertebrae, 7 patients had 3 hemivertebrae, and 2 patients had 4 hemivertebrae. Patients with 2 hemivertebrae predominantly had hemivertebrae in the thoracolumbar spine. Patients were classified into 2 categories: malformation existing at an equal level in anterior and posterior sides (unison HMMS) and malformation existing at nonequal levels (discordant HMMS). Nine patients had unison HMMS and all of them had 2 hemivertebrae (average: 4.6 vertebrae). Twenty-one patients had discordant HMMS, with 12 having 2 hemivertebrae, 7 having 3 hemivertebrae, and 2 having 4 hemivertebrae. CONCLUSIONS: Through 3D-CT analysis, HMMS was categorized as unison or discordant. Discordant HMMS was observed in 21 of 30 (70%) patients and in all patients with >3 hemivertebrae. Diagnosing HMMS, whether unison or discordant, is clinically important and should be done with careful analysis of bone models and/or radiologic images to determine the correct spinal levels. LEVEL OF EVIDENCE: Level IV-diagnostic study.

Spinal fusion as a viable treatment option for scoliosis management in Pompe disease: a postoperative 3-year follow-up.

PURPOSE: This study presents 3-year postoperative outcomes of posterior spinal correction and fusion of a patient diagnosed with late-onset Pompe disease (PD) for his progressive scoliosis. METHODS: The patient was diagnosed for PD during his infancy. Enzyme replacement therapy (ERT) was initiated at the age of 13. First office visit for his spinal deformity was at the age of 15, and 40°, 34°, 6° spinal curvatures were seen in T6-L3, T1-6, and L3-S, respectively. Reduced pulmonary function, limited gait function and atrophied limb were documented. Initial brace treatment could not control curve progression; therefore, posterior spinal correction and fusion were performed at the age of 17. RESULTS: Immediate preoperative curves of 55°, 42° and 23° were corrected to 18°, 26° and 7° in T6-L2, T1-T6 and L2-S, respectively. Spinal fusion was performed from T3 to L4. The patient exhibited an excessively low pulmonary function preoperatively with a VC, FVC, and %VC of 1.45 L, 1.36 L, and 35 %, respectively. This has been managed with only moderate reductions despite reduced pulmonary function from PD throughout the operative period and at 3 years. At the final follow-up, VC, FVC and %VC were 1.33 L, 1.12 L and 28.5 %, respectively. CONCLUSION: Posterior spinal correction and fusion adequately controlled spinal curvatures for 3 years after surgery. Additionally, pulmonary function was managed throughout the follow-up period. Despite ERT, skeletal muscle and pulmonary function can still be severely affected by PD. Spinal correction and fusion is a useful method for the management of spinal curvature and pulmonary function in patients with PD.

Medially misplaced pedicle screws in patients without neurological deficits following scoliosis surgery: to observe or to remove?

PURPOSE: This study investigated whether pedicle screws medially misplaced into the spinal canal without neurological complications should be removed or not. METHODS: A total of 86 patients with scoliosis that underwent spinal fusion using 988 pedicle screws were retrospectively reviewed after a minimum follow-up of 2 years. The inclusion criteria were: (1) patients without outstanding problems during the insertion of pedicle screws, (2) patients without neurological deficits either intraoperatively or postoperatively, and (3) patients that had all implants removed after bone union upon the request of the patient. Medial perforations were evaluated using immediate postoperative helical CT images and classified into three grades: grade 1 (0-2 mm), grade 2 (2-4 mm), and grade 3 (over 4 mm). All unexpected events were recorded at the time of removal. RESULTS: CT images obtained 2 years postoperatively exhibited neither loosening of screws nor pseudoarthrosis in all patients. CSF leakage from screw holes were recognized in 3 of 87 medially misplaced screws (3.4 %). There was no CSF leakage in grade 1 (35 screws), one CSF leakage (2.5 %) in grade 2 (40 screws), and two (16.7 %) in grade 3 (12 screws). No neurological abnormalities occurred either intraoperatively or postoperatively. CONCLUSION: This study indicated that screws medially misplaced at a distance greater than 2 mm, especially 4 mm, may be a cause of negative effects on the neural structure and should be removed during the early phase of the postoperative period, even among patients without postoperative neurological abnormalities.

Comparison of two biosimilarity studies of FKB327 with the adalimumab reference product: randomized phase 1 studies of single-blind, single-dose subcutaneous injection in healthy Japanese male participants.

BACKGROUND: FKB327 has been developed as a biosimilar of the adalimumab reference product (RP). We compared the pharmacokinetics (PK), safety, and immunogenicity of FKB327 with those of the adalimumab RP after a single dose by subcutaneous (SC) injection in Japanese male participants. METHODS: Two randomized, single-blind, single-dose studies were conducted in healthy Japanese male participants to compare PK characteristics between FKB327 and the RP. Study 1 included 130 participants who were randomized in a 1:1 ratio to receive a subcutaneous injection of 40 mg of either FKB327 or the RP into the abdomen. In Study 2, another 130 subjects were randomized in a 1:1 ratio to receive either drug as in Study 1, but the drug administration site was changed to the thigh. The primary PK endpoints of both studies were area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) and maximum serum concentration; area under the concentration-time curve from time zero to 360 h was also evaluated as one of the primary endpoints in Study 1. Biosimilarity in terms of pharmacokinetics was determined if the 90% confidence interval of the mean difference in geometric mean ratio of all primary PK parameters was within the prespecified equivalence criteria (0.80-1.25). Immunogenicity and safety were also evaluated as secondary endpoints. RESULTS: The serum concentration-time profiles were comparable between the FKB327 and the RP treatment groups in both studies. Primary PK parameters were within the prespecified bioequivalence range in Study 2, although AUC0-t was slightly outside the upper side of the range in Study 1. No differences in safety profile were observed in these studies. The incidence of anti-drug antibodies (ADAs) and impact of ADAs on PK profile were similar among the treatment groups in both studies. CONCLUSION: Biosimilarity between FKB327 and the RP after a single 40-mg SC injection was confirmed in healthy Japanese male participants by modifying the study design. TRIAL REGISTRATION: jRCT2071200058 (https://jrct.niph.go.jp/en-latest-detail/jRCT2071200058, https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2071200058) and jRCT2071200057 (https://jrct.niph.go.jp/en-latest-detail/jRCT2071200057, https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2071200057). Retrospectively registered 25/11/2020.

Clinical and health-related quality-of-life outcomes after early and late spinal fusion in pediatric patients with congenital scoliosis at 10-year follow-up.

STUDY DESIGN: A retrospective comparative study. OBJECTIVE: This study compares the effect of age at the time of surgery on clinical and health-related quality-of-life (HRQoL) outcomes at 10-year follow-up in pediatric patients with congenital scoliosis (CS). Several studies have evaluated the outcomes of surgical treatments of CS during the growth period; however, age at surgery and its long-term effects have been assessed in only a few case reports. METHODS: We enrolled patients with CS who underwent spinal fusion at the age of 18 years or younger in our study. We evaluated 97 patients (38 males, 59 females; average age 16.5 years) who met our inclusion criteria, including the availability of outcome data for a minimum of 10-year post-surgery. We divided patients into two groups in terms of the age at surgery: early fusion (EF) and late fusion (LF) groups. Clinical outcomes included re-operations, major curve corrections immediately and at 10-year follow-up, Scoliosis Research Society (SRS)-22 questionnaire, and percentage forced vital capacity (%FVC). RESULTS: The EF group (33 patients) and the LF group (64 patients) did not differ significantly in terms of demographics. In all domains, the EF group had better HRQoL than the LF group. More patients (52%) in the EF group required re-operation than in the LF group (23%). In addition, patients with short fusion (< 7 segments, p = 0.0011) and greater T1-T12 height (≥ 22 cm, p = 0.0088) had better %FVC than their counterparts. CONCLUSIONS: Age at surgery might have some non-negligible impacts on patients' HRQoL and clinical outcomes. Our study highlighted the important factors in surgical considerations of choosing the appropriate timing for spinal fusion, performing shorter fusions, and achieving an acceptable curve correction without allowing further curve progression that required re-operations. LEVEL OF EVIDENCE: Level III.

A novel CC-chemokine receptor 3 antagonist, Ki19003, inhibits airway eosinophilia and subepithelial/peribronchial fibrosis induced by repeated antigen challenge in mice.

CC-chemokine receptor 3 (CCR3) is a chemokine receptor for which major ligands, CC-chemokine ligand (CCL) 11, CCL24, and CCL26, are known to be involved in chemotaxis for eosinophils. In the present study, we evaluated the effect of a low molecular weight CCR3-receptor antagonist, Ki19003 (4-[[5-(2,4-dichlorobenzylureido)pentyl][1-(4-chlorophenyl)ethyl]amino]butanoic acid), on airway remodeling in a mouse model of allergic asthma. BALB/c mice were sensitized twice by intraperitoneal injection of ovalbumin (OA) and exposed daily to 1% OA for 3 weeks. Twenty-four hours after the final antigen challenge, bronchoalveolar lavage and histological examinations were carried out. Ki19003 clearly inhibited antigen-induced increase in the number of eosinophils in bronchoalveolar lavage fluid (BALF), but did not affect the number of other cell types examined in this study. Ki19003 also inhibited the increased production of transforming growth factor-beta1 in BALF and the amount of hydroxyproline in the lungs in a dose-dependent manner. Furthermore, Ki19003 significantly attenuated allergen-induced subepithelial and peribronchial fibrosis. These findings indicate that CCR3 antagonism prevents not only the infiltration of eosinophils into the airways but also the development of allergen-induced subepithelial and peribronchial fibrosis. Therefore, a CCR3 antagonist may be useful in the treatment of airway remodeling, especially subepithelial and peribronchial fibrosis, in allergic asthma.

Immunogenicity of an adalimumab biosimilar, FKB327, and its reference product in patients with rheumatoid arthritis.

AIM: This study, FKB327-003, is a phase 3, open-label extension (OLE) study comparing the long-term immunogenicity of an adalimumab biosimilar, FKB327 (F), with the reference product (RP). METHODS: In the OLE, patients completing 24 weeks of an initial randomized, double-blind (DB) study (Period 1) with clinical response and no safety concerns were rerandomized to F or RP, so that two-thirds of patients remained on the same treatment and one-third switched to the alternate treatment for weeks 24 through 54 (OLE weeks 0-30; Period 2), then all received F through week 100 (OLE week 76; Period 3). Treatment sequences were F-F-F (no switch), RP-F-F and RP-RP-F (single switch), and F-RP-F (double switch). Patients who entered the OLE study were evaluated for immunogenicity across switching sequences. RESULTS: The proportion of patients with positive antidrug antibody (ADA) status at the end of Period 1 was 61.7% and 60.0% for F and RP, respectively. The proportion of patients with positive ADA status did not increase throughout Period 1, and was similar for F and RP at all time points. At the end of Period 3, the proportion of patients with positive ADA status was lower in all treatment sequences, at 51.1%, 54.4%, 48.1%, and 42.5% for F-F-F, F-RP-F, RP-F-F, and RP-RP-F, respectively. CONCLUSION: The RP and F showed comparable immunogenicity characteristics after long-term administration. Development of ADAs with the RP and F was similar, and was not impacted by switching and double switching between F and RP treatment.

Excessive ADAM17 activation occurs in uremic patients and may contribute to their immunocompromised status.

INTRODUCTION: We previously reported that fibroblast growth factor 23 (FGF23)-klotho signaling plays a role in B cell immunity. Despite high serum levels of FGF23, a decline in immunity is frequently observed in patients on hemodialysis (HD); thus, abnormalities in the FGF23-klotho signaling pathway in immune cells may occur in these patients. METHODS: We analyzed the number of klotho-positive cells in peripheral blood mononuclear cells from 10 male and 6 female patients on HD and 5 healthy male subjects using flow cytometry. We analyzed the abundance of cleaved klotho protein in the murine B cell line, A20, and in the serum of HD patients and healthy subjects (HS) using flow cytometry and Western blotting. The serum level of A disintegrin and metalloprotease 17 (ADAM17) was measured in HD patients and HS using enzyme-linked immunosorbent assay. RESULTS: The number of klotho-positive B cells was reduced in HD patients. Serum ADAM17 was responsible for the reduction in klotho, as a specific ADAM17 inhibitor reversed this change. The total serum levels of ADAM17 were similar in HD patients and HS; however, activated ADAM17 was increased in the serum of HD patients. CONCLUSIONS: We concluded that abnormal ADAM17 activation could contribute to the immunocompromised status in patients on HD, in line with the reported role of ADAM17 as an anti-inflammatory and immunosuppressive factor.

Active vitamin D and vitamin D analogs stimulate fibroblast growth factor 23 production in osteocyte-like cells via the vitamin D receptor.

Osteocytes play an important role in the regulation of serum phosphorus by producing fibroblast growth factor 23 (FGF23). FGF23 production is stimulated by 1α,25-dihydroxyvitamin D in osteocytes. However, it is unclear whether vitamin D induces FGF23 production in osteocytes directly. Therefore, we investigated vitamin D-induced FGF23 production in osteocyte-like cells derived from MC3T3-E1 osteocyte progenitor cells. We also investigated differences in the induction of FGF23 by 1α,25-dihydroxyvitamin D and various vitamin D analogs. MC3T3-E1 cells were differentiated into osteocyte-like cells (MCT3-E1-OLCs) by treatment with various agents including ß-glycerophosphate and ascorbic acid. MCT3-E1-OLCs were stimulated with 1α,25-dihydroxyvitamin D3 and subsequent FGF23 gene expression was 2631 ± 605 times higher compared with untreated cells. The expression of FGF23 in MCT3-E1-OLCs transfected with a knockdown sequence against vitamin D receptor (VDR) was significantly decreased compared with that in cells transfected with the control vector. Therefore, the induction of FGF23 in osteocytes by vitamin D may be primarily mediated via VDR. The potential of 25(OH)vitamin D3, paricalcitol, and maxacalcitol to induce FGF23 production was almost the same as that of 1α,25-dihydroxyvitamin D3. However, falecalcitriol and eldecalcitol demonstrated a reduced potential to induce FGF23 compared with 1α,25-dihydroxyvitamin D3. Our results demonstrate that FGF23 induction is different among the analogs of 1α,25-dihydroxyvitamin D3. Therefore, an appropriate vitamin D analog should be chosen for each patient with mineral and bone disorder, considering its effect on FGF23 production.

Population pharmacokinetics of darbepoetin alpha in peritoneal dialysis and non-dialysis patients with chronic kidney disease after single subcutaneous administration.

OBJECTIVE: To characterize the pharmacokinetics of darbepoetin alpha and covariate relationships in chronic kidney disease (CKD) patients after a single subcutaneous administration. METHODS: A total of 989 serum concentration recordings from 64 patients were analyzed using NONMEM with a model including endogenous erythropoietin production. The basic and final models were evaluated for stability using bootstrapping. RESULTS: The selected basic model had one-compartment with a combination of the additive and constant coefficient of variation error models for residual variability. The significant covariate was weight for apparent clearance (CL/f) and apparent volume of central compartment (V(1)/f). The typical values of CL/f, V(1)/f, and absorption rate constant were 0.158 l/h, 13.7 l, and 0.0376/h, respectively. Evaluation by bootstrapping showed that the final model was stable. CONCLUSION: The present analysis indicated that weight is a significant covariate for CL/f and V(1)/f. However, dosage adjustment according to weight is not necessary for subcutaneous administration of darbepoetin alpha in CKD patients.

A phase 1, randomized, open-label, single-dose study to assess the relative bioavailability of a subcutaneous dose of FKB327 when administered using a prefilled syringe, a prefilled auto-injector, or a vial with disposable syringe in healthy subjects.

BACKGROUND/OBJECTIVE: FKB327 is a biosimilar of the adalimumab reference product (RP). The primary objective was to assess the relative bioavailability of FKB327 after a single subcutaneous (SC) dose via prefilled syringe (PFS), auto-injector (AI), or vial with a disposable syringe (vial), in healthy subjects. METHODS: This randomized, open-label, parallel-group, single SC-dose study was conducted in 195 healthy male and female subjects who were randomized 1:1:1 to receive FKB327 40 mg via PFS, AI, or vial. The primary pharmacokinetic (PK) parameters, areas under the serum concentration-time curve to the last detectable value (AUC0-t) and extrapolated to infinity (AUC0-∞), and maximum concentration (Cmax), were compared. Relative bioavailability was established if the ratio of geometric least squares (LS) means of the test product was within the predefined bioequivalence (BE) range of 0.80 to 1.25 of the RP for each comparison. Safety and immunogenicity were assessed. RESULTS: The mean serum FKB327 concentration-time profiles appeared similar across all 3 presentations. AUC0-t, AUC0-∞, and Cmax were within the predefined BE range for PFS compared with vial, suggesting comparable bioavailability. AUC0-∞ and Cmax of AI compared with vial and PFS were fully contained within BE range, although the upper limit of 90% confidence intervals of the geometric LS means ratios for AUC0-t was slightly high. Treatment-emergent adverse events in all 3 groups were mild, with no new safety concern with FKB327 identified. Similar immunogenicity was observed among administrations. CONCLUSION: Among all 3 delivery methods, PK characteristics, safety profiles, and immunogenicity were similar. TRIAL REGISTRATION: EU Clinical Trials Registry EudraCTN2014-004469-26, registered October 14, 2014.

Synthesis and evaluation of [2-(4-quinolyloxy)phenyl]methanone derivatives: novel selective inhibitors of transforming growth factor-beta kinase.

We synthesized and evaluated various [2-(4-quinolyloxy)phenyl]methanone derivatives. These compounds had novel chemical structures that were distinct from those of previously reported inhibitors. Biological data suggested that these compounds inhibited transforming growth factor-beta signaling by interacting with the ATP-binding pocket of the transforming growth factor-beta type I receptor kinase domain. Here, we report on the synthesis and structure-activity relationships of the compounds in this series.

Central role of the proximal tubular αKlotho/FGF receptor complex in FGF23-regulated phosphate and vitamin D metabolism.

Fibroblast growth factor 23 (FGF23) plays critical roles in phosphate handling and vitamin D metabolism in the kidney. However, the effector cells of FGF23 in the kidney remain unclear. αKlotho, a putative enzyme possessing ß-glucuronidase activity and also a permissive co-receptor for FGF23 to bind to FGF receptors (FGFRs), is expressed most abundantly in distal convoluted tubules, whereas it is expressed modestly in proximal tubules. Key molecular players of phosphate homeostasis and vitamin D-metabolizing enzymes are known to localize in proximal tubules. To clarify the direct function of FGF23 on proximal tubules, we ablated αKlotho or Fgfr1-4 genes specifically from these tubules using the Cre-loxP-mediated genetic recombination. Both conditional knockout mouse lines showed similar phenotypes that resembled those of systemic αKlotho or Fgf23 knockout mice. Compared with control mice, they showed significantly elevated levels of plasma phosphate, FGF23 and 1,25-dihydroxyvitamin D, ectopic calcification in the kidney and aging-related phenotypes like growth retardation, osteoporosis and shortened lifespan. These findings suggest that the primary function of FGF23 on mineral metabolism is mediated through αKlotho/FGFR co-receptors expressed in proximal tubular cells, and that the putative enzymatic function of αKlotho in the proximal tubule has a minor role in systemic mineral metabolism.