Anti-Interleukin-6 Therapy Decreases Hip Synovitis and Bone Resorption and Increases Bone Formation Following Ischemic Osteonecrosis of the Femoral Head

Legg-Calvé-Perthes disease (LCPD) is a juvenile form of ischemic femoral head osteonecrosis, which produces chronic hip synovitis, permanent femoral head deformity, and premature osteoarthritis. Currently, there is no medical therapy for LCPD. Interleukin-6 (IL-6) is significantly elevated in the synovial fluid of patients with LCPD. We hypothesize that IL-6 elevation promotes chronic hip synovitis and impairs bone healing after ischemic osteonecrosis. We set out to test if anti-IL-6 therapy using tocilizumab can decrease hip synovitis and improve bone healing in the piglet model of LCPD. Fourteen piglets were surgically induced with ischemic osteonecrosis and assigned to two groups: the no treatment group (n = 7) and the tocilizumab group (15 to 20 mg/kg, biweekly intravenous injection, n = 7). All animals were euthanized 8 weeks after the induction of osteonecrosis. Hip synovium and femoral heads were assessed for hip synovitis and bone healing using histology, micro-CT, and histomorphometry. The mean hip synovitis score and the number of synovial macrophages and vessels were significantly lower in the tocilizumab group compared with the no treatment group (p < .0001, p = .01, and p < .01, respectively). Micro-CT analysis of the femoral heads showed a significantly higher bone volume in the tocilizumab group compared with the no treatment group (p = .02). The histologic assessment revealed a significantly lower number of osteoclasts per bone surface (p < .001) in the tocilizumab group compared with the no treatment group. Moreover, fluorochrome labeling showed a significantly higher percent of mineralizing bone surface (p < .01), bone formation rate per bone surface (p < .01), and mineral apposition rate (p = .04) in the tocilizumab group. Taken together, tocilizumab therapy decreased hip synovitis and osteoclastic bone resorption and increased new bone formation after ischemic osteonecrosis. This study provides preclinical evidence that tocilizumab decreases synovitis and improves bone healing in a large animal model of LCPD. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy

The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R² = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.     

Social Support and Strain Across Close Relationships: A Twin Study

Social relationships play a critical role in health and well-being throughout life. We analyzed the genetic and environmental variance co-variance structure for social support and strain across four sets of relationships including with one’s co-twin, spouse/partner, family and friends. The sample included 5288 Norwegian twins aged 40–80. Older people reported less support from their co-twin and friends and less strain from their family and friends. Genetic influences contribute importantly to variation across all the measures, with estimates ranging from 0 to 58%; variance due to shared environmental influences was most important for the twin-relationship, ranging from 0.11 to 0.42%. Social support was negatively correlated with social strain across all sets of relationships. With the exception of the co-twin relationship, these associations were primarily mediated by genetic and non-shared environmental effects.     

Use of gabapentin to reduce chronic neuropathic pain in Fabry disease

The effect of the anticonvulsant gabapentin on neuropathic pain was studied in six male patients with Fabry disease, aged 15–45 years. After 4 weeks of treatment, pain, as measured using the Brief Pain Inventory, was decreased compared with baseline. Treatment was generally well tolerated. This study indicates that gabapentin should be considered as a treatment option for the neuropathic pain of Fabry disease. This revised version was published online in August 2006 with corrections to the Cover Date.     

Prism adaptation for esotropia with a distance-near disparity.

A series of 64 patients who had surgery for esotropia with a distance-near disparity of at least 10 prism diopters was reviewed. Thirty-three patients were prism adapted for their distance deviation (PA distance). Thirty-one patients were prism adapted for near deviation (PA near). Both groups were divided into responders and nonresponders. In the PA distance group, 22 (67%) patients were responders. All responders had surgery for their prism-adapted angle. Postoperatively, 19 (86%) responders had fusion. Thirteen (68%) required bifocals to maintain fusion. In the PA near group, 21 (68%) patients were responders. All responders had surgery for their prism-adapted angle. Ninety-four percent of responders had fusion postoperatively. None needed bifocals for fusion postoperatively and none were overcorrected. The results show that those patients who were prism adapted for their near angle, responded with fusion, and had surgery for their full amount of esotropia at prism response obtained better postoperative fusion, without the need for a bifocal at near and without overcorrection at distance.     

The gradient filter test to assess amblyopia

A new technique, the gradient filter test, was developed for evaluating changes in the visual acuity of preverbal children undergoing treatment for amblyopia. The gradient filter test consists of a series of calibrated photographic fog filter and prism lenses. The combined prism-filter lenses are placed in front of the normal fixing eye. The greatest density (fogging value) filter that causes a switch in fixation from the amblyopic to the normal eye is noted. In both normal eyes of 20 nonamblyopic patients and the fellow (non-amblyopic) eyes of 20 amblyopic patients, visual acuity decreased as the density of the prism-filter lens increased. The gradient filter test accurately detected an improvement in visual acuity when compared with optotype measurements in eight patients undergoing occlusion therapy. The gradient filter test is a useful clinical tool that can assess changes in visual acuity in preverbal children who are being treated for amblyopia.     

Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model

Aim:

Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits.

Methods:

A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg·kg⁻¹·d⁻¹, sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes.

Results:

TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R²=0.74, P<0.01) and global LV function (R²=0.47, P<0.01).

Conclusion:

Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure.     

Surgical outcome after prism adaptation for esotropia with a distance-near disparity.

INTRODUCTION: Prism adaptation for patients with esotropia and a distance-near disparity is controversial. The purpose of this study was to evaluate the surgical outcome for patients who underwent prism adaptation for esotropia with a distance-near disparity and determine whether both preoperative sensory and motor fusion are necessary to determine surgical success. METHODS: The medical records of 65 prism-adapted patients with a distance-near disparity of 9 PD or more were reviewed. Prism responders had a fusion response to near Worth 4-dot test and a deviation with prisms of 8 PD or less of esotropia at near, and 5 PD or less of exotropia at distance, or both. The same criteria were used postoperatively to assess a successful surgical outcome. Patients were operated for the near angle or greater than the near angle. RESULTS: Fifty-eight of 65 patients (89%) demonstrated fusion with prisms. Twenty of 65 patients (31%) had increased deviations that were greater than their original near angle (prism builders). Eleven percent (7 of 65) had no fusion. Postoperatively, 88% (51 of 58) of all fusers, 95% (18 of 19) of prism builders, and 71% (5 of 7) of nonfusers had a good surgical outcome of 8 PD or less of esotropia at near, 5 PD or less of exotropia at distance, or both. CONCLUSIONS: Prism response for distance-near disparity esotropia is a good indicator of postoperative outcome. Responders to prism adaptation had a better surgical outcome compared with nonresponders. In particular, prism adaptation aids in detecting those patients who will benefit from larger amounts of surgical correction.