Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ.

Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.

Incidence, management and outcome assessment of post operative infection following single bundle and double bundle acl reconstruction.

INTRODUCTION: Post-operative infection is a dreadful complication of ACL reconstruction with gray zone over management guidelines. We aimed to establish commonest etiology, assess incidence of infection and effect on outcome, individually for single and double bundle ACL reconstruction techniques, so as to formulate appropriate management guidelines. METHODS: Our prospective study involved 1152 patients operated for ACL reconstruction (437- DBACL, 715- SBACL) from 2010-2013. Post-operative infection was diagnosed clinically supported by positive gram stain/ culture and increased cell count in knee aspirate. All patients were started on empirical antibiotics and arthroscopic lavage and debridement was done. Graft was retained if it was stable and intact. Data recorded at follow up was analysed statistically. RESULTS: In SBACL infection rate was 0.84% while in DBACL it was 2.52%. All patients with infection presented with pain, effusion, fever and increased WBC, ESR & CRP. Average time of presentation after the surgery was 2.27 weeks for DBACL and 2.16 weeks for SBACL. In both groups, S.aureus followed by S. epidermidis were commonest isolates. Patients were given IV antibiotics for 2 weeks and oral for further 4 weeks. DISCUSSION: Incidence of infection is higher with the double bundle technique, however, the functional outcome is not affected (p value 0.231). Joint aspirate is the gold standard diagnostic test for infection. CRP and ESR are the next dependable tests with high sensitivity but their specificity is low. A thorough debridement is necessary apart from recommended antibiotic cover of 2 weeks IV followed by 4 weeks oral antibiotics.

Outcome of repair of chronic tear of the pectoralis major using corkscrew suture anchors by box suture sliding technique.

AIM: To assess the functional and clinical results of repair of chronic tears of pectoralis major using corkscrew and sliding suture technique. METHODS: In this retrospective study, we reviewed the results of pectoralis major repair in 11 chronic cases (> 6 wk) done between September 2011 and December 2014 at our institute. In all cases repair was done by same surgeon using corkscrew suture anchors and box suture sliding technique. At 6 mo, after surgery magnetic resonance imaging was done to see the integrity of the repair. Functional evaluation was done using Penn and ASES scores. Pre and postoperative Isokinetic strength was measured. RESULTS: Average follow-up was 48.27 ± 21.0 mo. The Wilcoxon signed rank test was used to evaluate the outcome scores. The average ASES score increased from an average of 54.63 ± 13.0 preoperatively to 95.09 ± 2.60 after surgery at their last follow-up. The average Penn score also increased from 5.72 ± 0.78, 2.81 ± 1.32 and 45.81 ± 1.72 to 9.36 ± 0.80, 8.27 ± 0.90 and 59 ± 1.34 for pain, satisfaction and function respectively. Follow up magnetic resonance imaging (MRI) (at 6 mo) showed continuity and the bulk of pectoralis major muscle in all cases. Average isokinetic strength deficiency in horizontal adduction at 60° was 13.63% ± 6.93% and at 120° was 10.18% ± 4.93% and in flexion at 60° was 10.72% ± 5.08% and at 120° was 6.63% + 3.74%. Results showed that both ASES and Penn score improved significantly (2 tailed P value = 0.0036). CONCLUSION: We could conclude from this series that pectoralis major repair even in chronic cases using 5.5 mm corkscrew anchors give excellent functional and cosmetic results. In chronic cases the repairable length of the tendon is not available and sliding suture technique allows for fixation of worn out tendomuscular junction to bone without letting cutting through the muscle.

Fracture union in closed interlocking nail in humeral shaft fractures.

BACKGROUND: Fracture shaft humerus is a major cause of morbidity in patients with upper extremity injuries. The aim of this study was to evaluate the outcome of interlocking nail in humeral shaft fractures. METHODS: This study was conducted in the Department of Orthopedic Surgery in SMS and R Sharda University from January 2010 to November 2013. Seventy-eight patients were recruited from emergency and out-patient department having a close fracture of humerus shaft. All patients were operated under general anesthesia and closed reamed interlocking nailing was done. All patients were followed for 9 months. RESULTS: Out of 78 patients, 69 patients underwent union in 90-150 days with a mean of 110.68 days. Complications found in four patients who had nonunion, and five patients had delayed union, which was treated with bone grafting. All the patients were assessed clinically and radiologically for fracture healing, joint movements and implant failure. The results were excellent in 88.46% and good in 6.41% patients. Complete subjective, functional, and clinical recovery had occurred in almost 100% of the patients. CONCLUSIONS: The results of the present study indicates that in the presence of proper indications, reamed antegrade intramedullary interlocked nailing appears to be a method of choice for internal fixation of osteoporotic and pathologic fractures.