Skin- and airway-deliverable TRPA1 inhibitor.

This study explored the potential of perfumery compounds as sources of transient receptor potential ankyrin 1 (TRPA1) inhibitors that could be formulated for effective delivery to the skin and airways. A highly potent, small, and selective TRPA1 inhibitor, 2-methyl-4-phenyl-1-pentanol (1), was discovered in perfumery compounds. Compound 1 demonstrated promising inhibitory activity against a broad range of TRPA1 agonists. A single stereoisomer of 1 was identified as the most effective TRPA1 inhibitor, indicating the potential for stereoselective synthesis to enhance its potency. Additionally, the structure-activity relationship of 1 was evaluated to elucidate the structural features of TRPA1 inhibitors within the fragrance-like compounds. Notably, the topical application of 1 alleviated sensory irritation in individuals with sensitive skin, while the inhalation of 1 resulted in a significant reduction in ammonia irritation, underscoring its efficacy in both skin and airway applications.

Destruxin E backbone modification effects on osteoclast Morphology: Synthesis and SAR study of N-Desmethyl and N-Methyl analogs.

The design and synthesis of N-desmethyl and N-methyl destruxin E analogs have been demonstrated. The X-ray single crystal structure of destruxin E (1a) revealed a stable three-dimensional (3D) structure, including a s-cis amide bond at the MeVal-MeAla moiety and two intramolecular hydrogen bonds between NH(ß-Ala) and OC(Ile) and between NH(Ile) and OC(ß-Ala). N-Desmethyl analogs 2a (MeAla â†’ Ala) and 2b (MeVal â†’ Val) were synthesized through macrolactonization similar to our previously reported synthesis of 1a. Conversely, for the synthesis of N-methyl analogs 2c (Ile â†’ MeIle) and 2d (ß-Ala â†’ Meß-Ala), macrolactonization did not proceed; therefore, cyclization precursors 10c and 10d were designed to maintain the intramolecular hydrogen bonds described above during their cyclization. The macrolactamization proceeded despite the presence of a less reactive N-methylamino group at the N-terminus in both cases. Analog 2a, which exhibits multiple conformers in solutions, was inactive at 50 µM, whereas analog 2b, which exhibits a conformation similar to that of 1a in solutions, exhibited morphological changes against osteoclast-like multinuclear cells at 1.6 µM. The activity of the MeIle analog 2c, which cannot take the intramolecular hydrogen bond (Ile)NH•••OC(ß-Ala) in 1a, was markedly diminished compared with that of 1a, and that of the Meß-Ala analog 2d, which cannot take the intramolecular hydrogen bond (ß-Ala)NH•••OC(Ile) in 1a, was further reduced to one-fourth of that of 2c. The overall results indicate that both the s-cis amide bond at the MeVal-MeAla moiety and two intramolecular hydrogen bonds (ß-Ala)NH•••OC(Ile) and (Ile)NH•••OC(ß-Ala) are important for constraining the conformation of the macrocyclic peptide backbone in destruxin E, thereby exhibiting its potent biological activity.

Anterior Cruciate Ligament-Injured Knees With Meniscal Ramp Lesions Manifest Greater Anteroposterior and Rotatory Instability Compared With Isolated Anterior Cruciate Ligament-Injured Knees.

PURPOSE: To investigate the effects of ramp lesion (RL) and its repair on knee instability in patients with anterior cruciate ligament (ACL) injury by quantitatively assessing anteroposterior and rotational knee instability before and after ACL reconstruction. METHODS: All primary double-bundle ACL reconstructions using hamstring autografts between 2016 and 2021 were evaluated retrospectively. Patients with RLs without other meniscal injuries were included in group R, whereas those with isolated ACL injuries constituted group C. RL was repaired using all-inside devices in all patients in group R. Knee instability, including the amount of anterior tibial translation (ATT), and the acceleration and external rotational angular velocity of the knee joint (ERAV) during the pivot-shift test were assessed at the time of surgery. The pivot-shift test grade was recorded. RESULTS: A total of 73 patients were included in this study. Preoperatively, group R (n = 23) had significantly greater pivot-shift grades (P = .039), ATT (6.0 mm, group R; 4.5 mm, group C, P < .001), acceleration (6.8, 2.8; P = .037), and ERAV (3.9, 2.8; P = .001) than group C (n = 50). Intraoperatively, ATT (-1.0 mm, -1.0 mm; P < .001), acceleration (1.2, 1.1; P < .001), and ERAV (1.4, 1.2; P < .001) were significantly decreased compared with the preoperative values in both groups. No significant differences in these values were observed between groups R and C. CONCLUSIONS: ACL-injured knees accompanied by RLs exhibited significantly greater anteroposterior and rotatory instability than knees with isolated ACL injuries; increased knee instability can be effectively addressed by performing RL repair in conjunction with ACL reconstruction. The quantitative assessments employed-specifically measuring ATT, acceleration, and ERAV during the pivot-shift test-have allowed us to delineate these aspects of knee instability with greater precision. LEVEL OF EVIDENCE: Level Ⅲ, retrospective comparative study.

Comparison of visibility in needle arthroscopy of the ankle according to surgical experience: A cadaveric study.

BACKGROUND: Literature regarding the feasibility of inexperienced surgeons using needle arthroscopy is limited. The present study aimed to clarify the feasibility of performing ankle needle arthroscopy for inexperienced surgeons. METHODS: Diagnostic needle arthroscopy was performed for 10 cadaveric ankles by two surgeons with different levels of experience in ankle arthroscopy (inexperienced and expert surgeons). The visibility of arthroscopy was assessed based on a 15-point checklist and compared between surgeons. In addition, iatrogenic articular cartilage injury created by the inexperienced surgeon was investigated. RESULTS: The number of visible points was significantly larger for the expert surgeon than for the inexperienced surgeon (14.1 ± 1.0 vs. 13.7 ± 1.0, P = 0.035). The location of cartilage injury was greatest on the medial talar dome when viewing from the anteromedial portal at a rate of 30%. CONCLUSION: Ankle needle arthroscopy may be an option for surgeons in the future, however, differences in surgeon experience may impact effective visualization.

Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6.

Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-protein-coupled receptors to provoke various cellular reactions. Because LPA signalling has been implicated in cancer and fibrosis, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1-LPA3) and the phylogenetically distant non-EDG family (LPA4-LPA6). The structure of LPA1 has enhanced our understanding of the EDG family of LPA receptors. By contrast, the functional and pharmacological characteristics of the non-EDG family of LPA receptors have remained unknown, owing to the lack of structural information. Although the non-EDG LPA receptors share sequence similarity with the P2Y family of nucleotide receptors, the LPA recognition mechanism cannot be deduced from the P2Y1 and P2Y12 structures because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 Å crystal structure of LPA6, the gene deletion of which is responsible for congenital hair loss, to clarify the ligand recognition mechanism of the non-EDG family of LPA receptors. Notably, the ligand-binding pocket of LPA6 is laterally open towards the membrane, and the acyl chain of the lipid used for the crystallization is bound within this pocket, indicating the binding mode of the LPA acyl chain. Docking and mutagenesis analyses also indicated that the conserved positively charged residues within the central cavity recognize the phosphate head group of LPA by inducing an inward shift of transmembrane helices 6 and 7, suggesting that the receptor activation is triggered by this conformational rearrangement.

Increased superior translation following multiple simulated anterior dislocations of the shoulder.

PURPOSE: Recurrent shoulder dislocations can result in kinematic changes of the glenohumeral joint. The number of prior shoulder dislocations may contribute to increased severity of capsulolabral lesions. The kinematics of the glenohumeral joint following multiple dislocations remain poorly understood. The purpose of this study was to assess the kinematics of the glenohumeral joint during anterior dislocations of the shoulder, and more specifically, altered translational motion following multiple dislocations. The kinematics of the glenohumeral joint were hypothesized to change and correlate with the number of dislocations. METHODS: Eight fresh-frozen cadaveric shoulders were dissected free of all soft tissues except the glenohumeral capsule. Each joint was mounted in a robotic testing system. At 60 degrees of glenohumeral abduction, an internal and external rotational torque (1.1 Nm) were applied to the humerus, and the resulting joint kinematics were recorded. Anterior forces were applied to the humerus to anteriorly dislocate the shoulder and the resulting kinematics were recorded during each dislocation. Following each dislocation, the same rotational torque was applied to the humerus, and the resulting joint kinematics were also recorded. A repeated-measures analysis of variance (ANOVA) was used to compare the kinematics following each dislocation. RESULTS: During the 7th, 8th, 9th, and 10th dislocations, the humerus significantly translated superiorly compared with the shoulder during the 1st dislocation (p < 0.05). Following the 3rd, 4th, 5th, and 10th dislocations, the humeral head significantly translated superiorly compared with the shoulder following the 1st dislocation in the position of 60 degrees of abduction in response to external rotation torque (p < 0.05). CONCLUSION: Multiple anterior shoulder dislocations lead to abnormal translational kinematics and result in increased superior translation of the humerus. This may contribute to pathologic superior extension of capsulolabral injuries. Superior translation of the humerus with overhead motion in the setting of recurrent instability may also place the shoulder at risk for extension of the capsulolabral injuries.

Structure Revision of Trichomide D by Total Synthesis.

A structure revision of trichomide D has been achieved by its total synthesis. The sterically hindered peptide sequence was successfully prepared using not only a conventional amidation with EDCI but also coupling with an Fmoc-protected amino acid chloride derivative. The cyclization precursor was synthesized by coupling of a tetrapeptide with an acylproline derivative and subsequent removal of silyl groups at the N- and C-termini. Macrolactonization using MNBA/DMAPO followed by preparation of a chlorohydrin moiety furnished the proposed structure of trichomide D, whose spectra were not identical to those of the natural product. Finally, we succeeded in the elucidation of the true structure of trichomide D by its total synthesis, and the absolute configuration of the chlorohydrin moiety was revised to be S. The cytotoxicities of the natural product and its synthetic derivatives against MCF-7 and HeLa S3 cells were evaluated by the MTT method, revealing that the configuration of the chlorohydrin moiety is a pivotal factor for exhibiting potent cytotoxicity against cancer cells.

Diagnosis of medial meniscal ramp lesion is difficult by pre-operative magnetic resonance imaging evaluation and needs a methodical arthroscopic exploration.

BACKGROUND: Meniscal ramp lesion (RL) is the peripheral lesion of the posterior horn of the medial meniscus (PHMM) associated with anterior cruciate ligament (ACL) tear. The purpose of this study was to evaluate the accuracy of pre-operative magnetic resonance imaging (MRI) evaluation in diagnosing RL and to identify whether the difficulty in diagnosis differs depending on the location of RL. METHODS: ACL-injured patients undergoing ACL reconstruction from January 2017 to January 2019 were enrolled. A methodical arthroscopic exploration to identify RL was conducted intra-operatively using three steps, namely, the anterior visualization step, the inter-condylar visualization step, and the posteromedial step. The location of the RLs was evaluated and classified into two types as follows: Red-red zone (RR) - a meniscal tear of the red-red zone of the PHMM. Menisco-capsular junction (MCJ) - a lesion at the menisco-capsular junction of the PHMM, which is more peripheral than RR. Furthermore, the accuracy of 1.5-T MRI evaluation to diagnose RL by two testers using sagittal proton-density fat-saturated images was calculated. RESULTS: Of the 81 patients enrolled, 11 had RL: 5 cases each were at the MCJ and RR, and 1 case was at both locations. The sensitivity of MRI for detecting RL was 27.3-45.5%, whereas the specificity was 84.3-95.7% in total. The sensitivity of MRI in detecting RL at the RR and MCJ was 40.0-80.0%, 0-20.0%, respectively. The intra-observer reliability of the MRI evaluation was moderate (κ coefficient: 0.40-0.46), while the inter-observer reliability was fair to moderate (κ coefficient: 0.27-0.41). CONCLUSIONS: A low sensitivity of the MRI in detecting RL at the MCJ was observed, and the reliability of the MRI evaluation for diagnosis of RL was not high. Therefore, methodical arthroscopic exploration is essential to diagnose RL even when it is not suspected on pre-operative MRI.

Bilateral suprascapular notches are asymmetrically shaped in a third of the Asian population.

PURPOSE: The side-to-side differences within an individual's suprascapular notch (SSN) and the clinical characteristics of an ossified superior transverse scapular ligament are unclear. Therefore, the morphological asymmetry of the SSN was investigated, and the factors associated with the ossification of the superior transverse scapular ligament were analyzed. METHODS: Two hundred and seventy-six computed tomography images were retrospectively analyzed, which included those of both scapulae of Asian patients (mean age, 62.1 ± 19.1 years; males, 197) with high-energy injuries or respiratory diseases. Variations in the SSN were classified into six types based on Rengachary's classification using reconstructed three-dimensional computed tomography. The group with a type VI SSN (completely ossified superior transverse scapular ligament) in at least one scapula was compared with the other group for age, sex, and chronic comorbidities. RESULTS: Among 276 patients, 95 (34.4%) had asymmetric SSNs and 15 (5.4%) had type VI SSNs. There were no significant differences in age, sex, or comorbidities between both the groups. However, on comparing age groups, the prevalence of type VI SSN was higher in patients aged > 70 years than in those aged < 70 years. Fifteen patients had type VI SSNs, which were unilateral in 10 patients. CONCLUSION: Asymmetric SSNs were observed in a third of the Asian patients. There were variations in SSNs between individuals and also within an individual. In the cases with suprascapular nerve paralysis, the difference in SSN morphology compared to a healthy side should be considered. LEVEL OF EVIDENCE: III.

A BRET-based assay reveals collagen-Hsp47 interaction dynamics in the endoplasmic reticulum and small-molecule inhibition of this interaction.

Molecular chaperones perform pivotal roles in proteostasis by engaging in protein-protein interactions (PPIs). The collagen-specific molecular chaperone Hsp47 (heat shock protein 47) interacts with procollagen in the endoplasmic reticulum (ER) and plays crucial roles in collagen synthesis. PPIs between Hsp47 and collagen could offer a therapeutic target for fibrosis, which is characterized by abnormal collagen accumulation in the extracellular matrix of fibrotic organs. Herein, we established a bioluminescence resonance energy transfer (BRET) system for assessing Hsp47-collagen interaction dynamics within the ER. After optimization and validation of the method, we could demonstrate inhibition of the interaction between Hsp47 and collagen by a small molecule (Col003) in the ER. Using the BRET system, we also found that Hsp47 interacts not only with the Gly-Pro-Arg motif but also weakly with Gly-Pro-Hyp motifs of triple-helical collagen in cells. Moreover, we found that the serpin loop of Hsp47 (SerpinH1) contributes to its binding to collagen. We propose that the method developed here can provide valuable information on PPIs between Hsp47 and collagen and on the effects of PPI inhibitors important for the management of fibrotic disorders.

Structure-Activity Relationship Study on Col-003, a Protein-Protein Interaction Inhibitor between Collagen and Hsp47.

This study demonstrates the structure-activity relationship of Col-003, a potent collagen-heat-shock protein 47 (Hsp47) interaction inhibitor. Col-003 analogues were successfully synthesized by Pd(0)-catalyzed cross-coupling reactions of 5-bromosalicylaldehyde derivatives with alkyl-metal species, and the inhibitory activities of the synthetic analogues were evaluated using surface plasmon resonance analysis (BIAcore). We succeeded in discovering two potent inhibitors that showed 85 and 81% inhibition at a concentration of 1.9 µM against the collagen-Hsp47 interaction. This indicates that elongation of an alkyl linker between two aromatic rings could considerably improve inhibitory activity due to the adjustment of a pendant phenyl moiety to an appropriate position, in addition to the hydrophobic interaction with an alkyl linker moiety.

Localized Rotator Cuff Tendon Degeneration for Cadaveric Shoulders with and Without Tears Isolated to the Supraspinatus Tendon.

Localized differences in tissue degeneration throughout intact and torn rotator cuff tendons have not been well quantified. The objective of this study was to investigate histological differences in localized degeneration in tendons with and without rotator cuff tears isolated to the supraspinatus tendon. Four intact shoulders and four shoulders with rotator cuff tears isolated to the supraspinatus tendon were dissected down to the infraspinatus and supraspinatus tendons. Biopsies were taken throughout the tendon insertion, mid-substance, myotendinous junction, and around the tear if present. Samples were stained with hematoxylin and eosin and tendon degeneration was graded based on collagen fiber organization, nuclei shape, cellularity, and lipoid degeneration. Comparisons in degeneration parameters were made based on the tendon type (supraspinatus vs. infraspinatus), location within the tendon, and presence of a tear. Supraspinatus tendons exhibited more degeneration than the infraspinatus tendon (P < 0.05). Significant increases in lipoid degeneration were found near the myotendinous junction compared to the rest of the tendon (P < 0.001). Tendons with rotator cuff tears showed greater amounts of lipoid degeneration compared to intact tendons (P = 0.03). A strong negative correlation was found between lipoid degeneration and collagen fiber organization (r = -0.922, P = 0.001). No differences in degeneration were found between medial, anterior, and posterior edges of the tear. The study highlights specific factors of tendon degeneration contributing to the local differences in tendon degeneration. By understanding local differences in tendon degeneration, surgical protocols for repair can be improved. Clin. Anat., 33:1007-1013, 2020. © 2019 Wiley Periodicals, Inc.

The Correlation of Quantitative Ultrasound Measures and Supraspinatus Tendon Quality: A Pilot Study.

BACKGROUND: The objective of this study was to determine the feasibility of assessing tendon quality as quantified by histology through changes in quantitative ultrasound measures. METHODS: Eight cadaveric shoulders (four with a small supraspinatus tendon tear) were examined using conventional B-mode ultrasound in the transverse plane by internally rotating and hyperextending the humerus. Quantitative ultrasound measures (skewness, kurtosis, variance, and echogenicity) were calculated based on the grayscale distribution of the ultrasound image taken of the supraspinatus tendon near the insertion site. The specimens were then dissected to the supraspinatus tendon where tendon biopsies were taken near the insertion site, mid-substance, and myotendinous junction. Through histology, tendon quality was evaluated based on collagen fiber organization, fatty infiltration, nuclei shape, and cellularity. Correlations between quantitative ultrasound measures and histological grades of tendon quality were determined through Pearson or Spearman's rho correlations. RESULTS: A total of three significant correlations between quantitative ultrasound measures and histological parameters of tendon quality were found. Significant correlations between kurtosis and cellularity at the insertion site (r = 0.724) (P < 0.05) as well as variance and fatty infiltration at the myotendinous junction (ρ = -0.843) (P < 0.05) and for the whole tendon (ρ = -0.826) (P < 0.05) were found. CONCLUSION: The results show the potential for quantitative ultrasound measures to assess factors of tendon quality that can only be determined through histology. With further development of the methodology that utilizes quantitative ultrasound measures, clinicians might be able to evaluate the tendon quality noninvasively in future.

Total Synthesis and Structural Revision of Cyclotetrapeptide Asperterrestide A.

The structural revision of cyclotetrapeptide asperterrestide A has been achieved based on total synthesis and molecular modeling. For these studies, (2 R,3 S)-MePhe(3-OH) and (2 S,3 S)-MePhe(3-OH) suitably protected for peptide synthesis were prepared via a stereoselective reduction of a ketone precursor derived from L- or d-serine, using L-selectride or DIBAL-H. The synthesis of the proposed structure of asperterrestide A (1a) was accomplished by solution-phase synthesis of a linear precursor followed by macrolactamization. The NMR spectra of our synthetic 1a were not identical to those reported for the natural compound. Molecular modeling studies suggested that the correct structure 1b was the one in which the stereochemistry at the α-positions of the Ala and MePhe(3-OH) residues is the opposite to that of the proposed structure. This was confirmed by the total synthesis of 1b and its subsequent structural characterization.

Combinatorial Synthesis and Biological Evaluation of Destruxins.

The combinatorial synthesis and biological evaluation of destruxins are described herein. First, the total synthesis of destruxin E was achieved, and its absolute configuration was successfully determined to be (S). In addition, the preparation of a combinatorial library based on the structure of destruxins was carried out by the split-and-pool method. Biological evaluation of the resulting analogs against osteoclast-like multinuclear cells (OCLs) revealed that the N-methyl-alanine residue was crucial to inducing morphological changes in OCLs. In particular, functionalization at the ß-position of the proline (Pro) residue was found to be tolerant of the desired biological activity of destruxin E, suggesting that the ß-position of the Pro residue should be a promising site for the introduction of a chemical tag toward the preparation of a molecular probe.

Preoperative sonographic measurement can accurately predict quadrupled hamstring tendon graft diameter for ACL reconstruction.

PURPOSE: Previous studies reported sonography was inferior to MRI to predict hamstring tendon graft diameter for ACL reconstruction. This study aimed to investigate the correlation between intraoperative hamstring tendon graft diameter and its preoperative measurement using different sonographic scanning protocol from previous studies. METHODS: Two cadaveric knees were utilized for validation. Sonographically guided gracilis tendon (G) and semitendinosus tendon (ST) injections were performed at myotendinous junction of sartorius using colored latex and then dissection was performed. In the clinical studies, 28 patients underwent primary ACL reconstruction were enrolled. Cross-sectional area (CSA) of G and ST were measured at myotendinous junction of Sartorius. The diameter of doubled G (2G), doubled ST (2ST) and quadrupled ST + G (4STG) were intraoperatively measured using graft sizing devices with 0.5-mm increments. RESULTS: Cadaveric dissection showed the presence of latex on the surface of G and ST at myotendinous junction of Sartorius in all specimens. In the clinical studies, CSA of G, ST, and ST + G significantly correlated with diameter of 2G (r = 0.464, p = 0.039), 2ST (r = 0.712, p < 0.001), and 4STG (r = 0.792, p < 0.001), respectively. As a result of the simple linear regression analysis, 4STG diameter could be predicted by the following formula: 4.345 + 0.210 × CSA. The differences between calculated diameter by this formula and intraoperative 4STG diameter were within ± 0.5 mm in 89.3% (25/28) of subjects. CONCLUSIONS: The diameter of 2ST and 4STG can be reliably predicted based on sonographic CSA measurement preoperatively. Sonography is a cost-effective alternate to repeat MRI to predict hamstring graft diameter preoperatively. LEVEL OF EVIDENCE: Diagnostic study; Level II.

Superior clavicle drilling points and fluoroscopic inclination for anatomic coracoclavicular ligament reconstruction: a cadaveric study.

PURPOSE: This study aims to investigate the superior clavicle cortex drilling points and fluoroscopic inclination angles for anatomic tunnel drilling in coracoclavicular ligament reconstruction. METHODS: Twelve cadaveric shoulders with a mean age of 55.9 ± 6.2 years were investigated. Two 2.0 mm Kirschner wires were inserted penetrating the footprint centers of conoid and trapezoid both on the clavicle and coracoid. The location of the Kirschner wires on the superior clavicle cortex was measured. Fluoroscopy was used to obtain three views of shoulder: an anteroposterior, lateral, and cortical ring sign view. Reproducible angles were then recorded. RESULTS: The Kirschner wire penetrating the conoid was located 40.0 ± 3.9 mm from the distal end and 18.1 ± 3.0 mm from the anterior edge of the clavicle. For the trapezoid, the Kirschner wire was located 19.1 ± 3.6 mm from the distal end and 9.9 ± 3.9 mm from the anterior edge. On the anteroposterior view, the conoid was 11.1° ± 10.1° medially and trapezoid was 26.8° ± 11.8° laterally tilted to the glenohumeral joint line. On the lateral view, the conoid was 42.8° ± 15.1° and trapezoid was 15.5° ± 12.0° superiorly tilted to the scapular spine. On the cortical ring sign view, the conoid was 50.8° ± 12.9° and trapezoid was 14.2 °± 11.0° superiorly tilted to the scapular spine. CONCLUSIONS: The superior clavicle cortex drilling points and fluoroscopic inclination angles for anatomic tunnel drilling in coracoclavicular ligament reconstruction were demonstrated. Arthroscopy-assisted anatomic coracoclavicular ligament reconstruction has increased in popularity, and these findings may facilitate a more anatomic approach to coracoclavicular ligament reconstruction.

The differences of humeral torsion angle and the glenohumeral rotation angles between young right-handed and left-handed pitchers.

BACKGROUND: The differences between young right-handed and left-handed baseball players are not well known. This study compared the range of the shoulder motion and humeral torsion angle (HTA) between right-handed and left-handed young baseball pitchers. METHODS: A total of 65 young baseball pitchers (age, 9-12 years; 46 right-handed throwers, R group; and 19 left-handed throwers, L group) were analyzed. The glenohumeral internal rotation (IR) angle and external rotation (ER) angle were measured at 90° shoulder abduction, and HTA was assessed using indirect ultrasonographic techniques. The side-to-side difference in HTA (d-HTA), glenohumeral ER difference (GERD), and glenohumeral IR deficit (GIRD) were calculated. The adjusted GIRD and adjusted GERD were defined as the angles obtained by subtracting d-HTA from GIRD and GERD, respectively, to exclude the influence of humeral retrotorsion difference. RESULTS: HTA and ER of the throwing limb were significantly greater than those of the nonthrowing limb in the R group (HTA: 84° vs. 77°; P < .001, ER: 116° vs. 111°; P < .001), but no significant differences were observed in the L group (HTA: 79° vs. 77°, P = .103; ER: 113° vs. 114°, P = .380). Compared with the R group, the L group showed a significantly smaller d-HTA (2° vs. 8°, P < .001) and GERD (5° vs. -2°, P = .004), but no significant difference was observed in adjusted GERD between the groups (-3° vs. -4°, P = .690). CONCLUSION: Compared with the right-handed pitchers, the side-to-side differences of glenohumeral external rotation angle and humeral torsion angle were significantly smaller in the left-handed pitchers at a young age.

Relationship between bilateral humeral retroversion angle and starting baseball age in skeletally mature baseball players-existence of watershed age.

BACKGROUND: Repetitive pitching in childhood was thought to restrict the physiological derotation process of the humeral head. Some studies reported that the side-to-side differences of humeral retroversion in baseball players occurred between the age of 9 and 11 years. The present study investigated the relationship between bilateral humeral retroversion angle and starting baseball age in skeletally mature baseball players. METHODS: One hundred and seventeen male baseball players, who belonged to a college or amateur team, were investigated. Bilateral humeral retroversion was assessed using an ultrasound-assisted technique as described by previous studies. All players were divided into four groups: players who had started playing baseball before the age of 6 years, between 7 and 8 years, between 9 and 10 years and after 11 years. Bilateral humeral retroversion angle was compared among the four starting age groups. RESULTS: All players started playing baseball between 5 and 12 years. Comparing the throwing arm, humeral retroversion in starting age group 11-12 (72°) was significantly smaller than the other 3 groups (81°, 82°, and 80° for groups 5-6, 7-8, and 9-10, respectively). Comparing the non-throwing arm revealed no significant differences among the 4 starting age groups (71°, 72°, 70°, and 66° for groups 5-6, 7-8, 9-10, and 11-12, respectively). CONCLUSIONS: Skeletally mature baseball players who started playing baseball after 11 years had significantly smaller humeral retroversion in the throwing arm than those who started baseball before 11 years.

A small-molecule compound inhibits a collagen-specific molecular chaperone and could represent a potential remedy for fibrosis.

Fibrosis can disrupt tissue structure and integrity and impair organ function. Fibrosis is characterized by abnormal collagen accumulation in the extracellular matrix. Pharmacological inhibition of collagen secretion therefore represents a promising strategy for the management of fibrotic disorders, such as liver and lung fibrosis. Hsp47 is an endoplasmic reticulum (ER)-resident collagen-specific molecular chaperone essential for correct folding of procollagen in the ER. Genetic deletion of Hsp47 or inhibition of its interaction with procollagen interferes with procollagen triple helix production, which vastly reduces procollagen secretion from fibroblasts. Thus, Hsp47 could be a potential and promising target for the management of fibrosis. In this study, we screened small-molecule compounds that inhibit the interaction of Hsp47 with collagen from chemical libraries using surface plasmon resonance (BIAcore), and we found a molecule AK778 and its cleavage product Col003 competitively inhibited the interaction and caused the inhibition of collagen secretion by destabilizing the collagen triple helix. Structural information obtained with NMR analysis revealed that Col003 competitively binds to the collagen-binding site on Hsp47. We propose that these structural insights could provide a basis for designing more effective therapeutic drugs for managing fibrosis.