Comprehensive Evaluation System for Post-Metabolic Activity of Potential Thyroid-Disrupting Chemicals.

Endocrine-disrupting chemicals (EDCs) are compounds that disturb hormonal homeostasis by binding to receptors. EDCs are metabolized through hepatic enzymes, causing altered transcriptional activities of hormone receptors, and thus necessitating the exploration of the potential endocrine-disrupting activities of EDC-derived metabolites. Accordingly, we have developed an integrative workflow for evaluating the post-metabolic activity of potential hazardous compounds. The system facilitates the identification of metabolites that exert hormonal disruption through the integrative application of an MS/MS similarity network and predictive biotransformation based on known hepatic enzymatic reactions. As proof-of-concept, the transcriptional activities of 13 chemicals were evaluated by applying the in vitro metabolic module (S9 fraction). Identified among the tested chemicals were three thyroid hormone receptor (THR) agonistic compounds that showed increased transcriptional activities after phase I+II reactions (T3, 309.1 ± 17.3%; DITPA, 30.7 ± 1.8%; GC-1, 160.6 ± 8.6% to the corresponding parents). The metabolic profiles of these three compounds showed common biotransformation patterns, particularly in the phase II reactions (glucuronide conjugation, sulfation, GSH conjugation, and amino acid conjugation). Data-dependent exploration based on molecular network analysis of T3 profiles revealed that lipids and lipid-like molecules were the most enriched biotransformants. The subsequent subnetwork analysis proposed 14 additional features, including T4 in addition to 9 metabolized compounds that were annotated by prediction system based on possible hepatic enzymatic reaction. The other 10 THR agonistic negative compounds showed unique biotransformation patterns according to structural commonality, which corresponded to previous in vivo studies. Our evaluation system demonstrated highly predictive and accurate performance in determining the potential thyroid-disrupting activity of EDC-derived metabolites and for proposing novel biotransformants.

A systematic approach to metabolic characterization of thyroid-disrupting chemicals and their in vitro biotransformants based on prediction-assisted metabolomic analysis.

Thyroid-disrupting compounds (TDCs) are chemicals that modify thyroid gland function and disrupt hormonal homeostasis. Like other endocrine-disrupting chemicals (EDCs), TDCs often show altered activities following post-metabolic modification via endogenous enzymatic reaction. Hence, we developed evaluation system consisting of (1) in vitro metabolic reaction module, (2) high-resolution mass-spectrometry, and (3) human cell-based reporter gene assay. We developed the reaction module using rat S9 fraction where levothyroxine (T4) as a model compound, was subjected to phase-I or phase-I+II biotransformation. The metabolic profiles of the biotransformants were systematically configured based on in-silico prediction of potential products and experimental validation using liquid-chromatography Orbitrap mass-spectrometry. Thyroid agonistic activities of the biotransformants were evaluated by thyroid receptor-mediated stably transfected transcriptional activation assay using hTRE_HeLa cells. Indeed, we detected the increased activities following metabolic conversion of T4 in a dose-dependent manner. Note that the activity by phase-I+II reaction was much greater than by phase-I reaction (3.8-fold increase). Subsequently, we explored metabolic signatures, which potentially contributed to the hyperactivity by phase-I+II reaction. A total of 77 metabolic features were annotated based on the in-silico prediction, which included biotransformants with deiodination and conjugation. The glucuronide-conjugated form was found at the highest fold-increase (970-fold increase) whereas marginal increases were determined in the deiodinized forms (1.6-fold increase in T3 and 2.0-fold increase in rT3). Further, the systematic approach was evaluated and comparably analyzed by the metabolic profiles of bithionol, which is structurally related to T4. Our current result suggested the potential application of in vitro evaluation system to risk assessment of thyroid-disrupting activity.

Combined effect of change in humeral neck-shaft angle and retroversion on shoulder range of motion in reverse total shoulder arthroplasty - A simulation study.

BACKGROUND: We studied combined effect of change in humeral neck shaft angle and retroversion on shoulder ROM in reverse total shoulder arthroplasty using 3-dimensional simulations. METHODS: Using a 3D model construct based on the CT scans of 3 males and a 3-dimensional analysis program, a humeral component of reverse total shoulder arthroplasty was implanted in 0°, 10°, 20°, 30°,40° retroversion and 135°, 145°, and 155° neck shaft angle. Total horizontal range of motion (sum of horizontal adduction and abduction) at 30° and 60° scaption, adduction in the scapular plane and IR behind the back were measured for various combinations of neck shaft angle and retroversion. FINDINGS: Change in retroversion didn't show any effect on total horizontal range of motion. Total horizontal range of motion at both 30° and 60° scaption, showed maximum values at 135° neck shaft angle and minimum values at 155° neck shaft angle. With any combination of retroversion angles, adduction deficit was maximum at 155° neck shaft angle and no adduction deficit at 135° neck shaft angle. Every 10° decrease in neck shaft angle resulted in an average 10.4° increase in adduction. For every 10° increase in retroversion, there was loss of internal rotation behind the back up to at least one vertebral level. INTERPRETATION: 135° neck shaft angle resulted in maximum total horizontal range of motion both at 30° and 60° scaption regardless of retroversion angles. 135° neck shaft angle also reduced the chances of scapular impingement. Decrease in retroversion angle resulted in more amount of internal rotation behind the back.

Early clinical results of reverse total shoulder arthroplasty in the Korean population.

BACKGROUND: We evaluated the short-term clinical outcomes and compared the component's sizes of reverse total shoulder arthroplasty (RTSA) in Korean Population. MATERIALS AND METHODS: We performed an RTSA on 42 patients between December 2007 to February 2010. The mean age at surgery was 72.5 ± 5.6 (10 men, 32 women) and average follow-up period was 24 months. Twenty-two cuff tears arthropathy, 15 irreparable massive rotator cuff tears with pseudoparalysis, 5 proximal humeral fractures, and 2 infection cases were included. We evaluated clinical outcomes and also the intra- and postoperative complications to determine if any of the complications were unique to the use of a RTSA in a Korean population. In the anatomic study, 92 uninjured shoulders of 92 patients were used for measuring the inferior glenoid size, and we compared the component's sizes of RTSA with those of the normal population. RESULTS: The ASES (American Shoulder and Elbow), UCLA, and KS (Knee Society) scores significantly improved from preoperative 35 (0-63), 12 (5-27), and 39 (3-81) to postoperative 68 (37-95), 24 (16-35), and 68 (34-88), respectively (P < .05). Postoperative complications were seen in 20% and scapular notching 35%. Three patients required further surgery for shoulder dislocation, periprosthetic fracture, and stem loosening. In the anatomic study, mean radius of the inferior glenoid was 17.1 ± 2.1 mm in male and 15.4 ± 1.6 mm in female. CONCLUSION: The short-term clinical results of an RTSA in Korean population are excellent despite high complication rate. However, the size of the glenoid is sometimes smaller than the baseplate (29 mm diameter) in female patients. More adequate size of the glenoid component should be considered.