MULTIFUNCTIONAL POTENTIAL THERAPEUTICS TOWARDS OXIDATIVE STRESS MEDIATED NEURODEGENERATIVE DISORDERS AND MODELS THEREOF

The studies described in this dissertation were performed with the goal of understandingthe function of antioxidant compounds delivered in vivo to rodents and the implication of theresults towards oxidative stress (OS)-related neurodegenerative disorders with particularemphasis on Alzheimer\u27s disease (AD). OS has been implicated in AD and is characterized byextensive oxidative damage to protein, lipids and DNA. A major thrust of this dissertation workwas to gain insight into antioxidant properties of compounds used in the following studies andtheir efficacy as potential therapeutics for treatment of OS-related disorders.D609, a glutathione (GSH) mimetic is known to trap OH. Radicals, scavenge H2O2 andreduce the A?? (1-42)-induced OS and cytotoxicity in neurons. The present dissertation studyshowed in vivo protective effect of D609 in synaptosomes and mitochondria isolated fromgerbils against OS mediated by Fe2+/H2O2, AAPH, and A?? (1-42). Upon intraperitonial (i.p.)injection of gerbils, D609 showed protection of subsequently isolated brain moieties against OS.In vivo administration of D609 also modulates brain GSH levels and increases the activity of keyGSH-related enzymes, thereby likely provides a protection against OS.Adriamycin (ADR), a quinone-containing chemotherapeutic, is known to produce ROS inheart. Patients under treatment with ADR often show persistent changes in cognitive function(effect called as chemobrain by patients). Upon i.p. injection, ADR causes OS, increasesexpression of multidrug resistant protein-1 (MRP-1) in brain and alters GSH levels and itsrelated enzyme activities. ??-Glutamyl cysteinyl ethyl ester (GCEE) is known to increase GSHlevels in brain, in vivo. Research reported in this dissertation shows that in vivo GCEE reversesthe ADR-mediated OS in mice brain.N-acetylcysteine (NAC), a GSH precursor provides the limiting substrate cysteine inGSH synthesis. Previously, our laboratory showed increased GSH levels post i.p. injection ofNAC and reduces OS in synaptosomes treated with acrolein. The present study showed thatNAC given in drinking water to APP/PS-1 mice, a model of AD can significantly reduce OS.These results provide a potential therapeutic intervention by antioxidants that can modulateGSH in OS-mediated neurodegenerative disorders

Interposition arthroplasty: an epochal event in a case of bilateral post burn contracture of elbow

A 21 year old female, suffered accidental burns in April 2008 resulting in severe soft tissue contractures and bony ankylosis of both elbows. She was disabled with both nonfunctional upper extremities and reported to our center with deformity and dysfunction of both elbows for past 02 years. On evaluation her elbows were fixed in 40° flexion on right side and 30° flexion on left side. She was completely dependent on her mother for her daily activities like feeding and hygiene care, though she had acceptable wrist and hand function. She was managed with interposition arthroplasty with ipsilateral autogenous tensor fascia lata graft on both elbows. At 5 year follow-up, she has pain free elbows with functional range of motion and no neurovascular deficits. She is able to use both upper extremities for all activities of daily living. Most importantly she is independent and has taken up a job for her livelihood

Radiographic evaluation of tibial component alignment in total knee arthroplasty following extramedullary and intramedullary tibial referencing

Background: Long term survivorship of total knee arthroplasty (TKA) is significantly dependant on prostheses alignment. The debate on optimal referencing for femoral component is largely resolved with Intra-medullary jigs reproducing superior alignment. However there is still a contention about whether intramedullary or extramedullary jigs are better for tibial referencing. This study aims to compare the accuracy of tibial component alignment in TKA using intramedullary and extramedullary tibial referencing jigs.Methods: Between December 2012 and September 2014, 66 primary conventional cemented TKAs were performed using Nexgen-LPS Flex (Zimmer) implants in 55 patients, 50-80 y old (mean 65.54 y) with osteoarthritis/rheumatoid arthritis. Intramedullary and extramedullary tibial referencing was used in alternate patients undergoing TKA after excluding patients with BMI >35 kg/m2, knee deformity >150,excessive tibial bowing, previous fractures/surgeries/retained metalwork around knee. Postoperatively, tibial component alignment (TCA) in coronal plane was assessed using AP radiograph of leg. A 3º cutoff from neutral mechanical axis (i.e., 90o±3o) was considered acceptable.Results: The intramedullary group (n=33) had 4 outliers (TCA >93º or <87º) whereas the extramedullary group (n=33) had 7 outliers (p=0.511). The difference in mean TCA between intramedullary and extramedullary groups was not statistically significant [90.70±2.43 and 90.55±2.17 (p=0.790)]. There were no significant per-operative/post-operative complications in either group.Conclusions: We conclude that both intramedullary and extramedullary tibial referencing guides can be used to achieve desired tibial component alignment (90±3º) in TKA. However the surgeon should appreciate the benefits and deficiencies of either types of tibial referencing and use whichever is suited in a particular case.

Outcomes of patients treated with minimally invasive plate osteosynthesis in the management of distal tibial fractures

Background: Distal tibial fractures are a common injury, often caused by high-energy trauma, and can result in significant morbidity. Traditional surgical management with open reduction internal fixation (ORIF) is associated with complications including infection and soft tissue injury. Minimally invasive plate osteosynthesis (MIPO) has emerged as a potential alternative, with advantages including less soft tissue injury and a faster return to function.  The study aimed to evaluate the outcomes of MIPO for distal tibial fractures. Method: Sample size of 38 patients between 18-80 years of age with distal tibial fractures treated with MIPO was included. Patient demographics, fracture characteristics, surgical details and postop outcomes collected. Results: A total of 38 patients with distal tibia fractures with a mean age of 44.36 years were included in the study. The mean duration of hospital stay was 12.71 days, and the time required for a union was 18.61 weeks. The AOFAS score improved significantly from 3 to 6 months after surgery. However, 15 patients (34.88%) reported complications, with deep infection and skin necrosis being the most common. Out of 43 patients, 11 underwent culture and sensitivity testing, with no growth in 5 cases, and the remaining cases showed various bacterial infections. Seven patients underwent implant removal due to complications. Conclusions: The study provides valuable information about the use of MIPO in treating distal tibia fractures, as well as the risk of complications associated with this approach

Arthroscopic anterior cruciate ligament reconstruction with central quadriceps tendon bone (CQTB) graft: An outcome study in fifty Indian patients

Background: Arthroscopic ACL reconstruction using biologic autografts is the current gold standard in the management of symptomatic ACL tears. The commonly used BPTB (Bone-Patellar Tendon-Bone) and quadrupled hamstring tendon grafts have their own disadvantages. This study was conducted to evaluate the efficacy of CQTB (Central Quadriceps Tendon Bearing) graft as an autograft for ACL reconstruction in relieving instability in ACL deficient knees.Methods: 50 patients (45males; 5 females) with symptomatic ACL laxity, who underwent arthroscopic ACL reconstruction using the CQTB graft were followed up for 1 year. The functional improvement was analyzed by comparing the pre-operative Lysholm scores with those at 03 months, 06 months and 12 months post operatively. The objective improvement was analyzed comparing the Anterior Drawer and Lachman test grades pre-operatively and after 1 year follow up. The mean length of the graft and the post-operative morbidity were also noted.Results: The average Lysholm scores improved from a pre-operative value of 44.34 to 78.98,87.86 and 91.58 at 03months,06 months and 1 year respectively. (p<0.05; ANOVA). The number of patients with Grade I, II and III laxities on Anterior Drawer test improved from 01, 36 and 12 respectively to 43, 06 and 01 respectively 1 year after surgery (p<0.05; paired t test). The number of patients with Grade I, II and III laxities on Lachman test reduced from 1, 34 and 15 y to 39, 10 and 01 respectively. The average thickness of graft harvested was 9.21mm.Conclusions: CQTB autograft is a viable option along with other available autografts in its ability to reconstruct native ACL, without any hazards and additional complications

Role of extracorporeal shockwave therapy and injectable corticosteroids in the treatment of lateral epicondylitis: a comparative study of 100 patients

Background: Even though considered to be self-limiting, lateral epicondylitis (tennis elbow) can cause significant impediment in professional and activities of daily living. A safe and minimally invasive procedure that will enable patients to return to their daily activities as soon as possible should be advocated in the management of this condition. The aim of the present study was to investigate the role of extracorporeal shock wave therapy (ESWT) and injectable corticosteroids in the treatment of lateral epicondylitis with the secondary objective of comparing the difference in pain relief and functional improvement in patients treated with both modalities.Methods: A cross sectional analytical study was conducted over an 18 month period.100 patients were randomized into two groups, A (51 patients) who received three sessions of ESWT on weekly intervals and B (49 patients) who received two intra-lesional injections of 1ml of methylprednisolone and 2% lignocaine on weekly intervals. The patients were followed up at 3 weeks, 6 weeks and 6 months after the interventions. Subjective and objective improvements were measured using visual analogue score (VAS) and Patient Rated Tennis Elbow Evaluation Score (PRTEE).Results: The mean VAS in both groups reduced from 8.47 and 8.53 to 2.51 and 1.67 respectively at the end of the follow up (p <0.001) .The mean PRTEE score in Group A reduced from 80.59 to 26.53 (p<0.001) and Group B from 82.76 to 13.59 (p<0.05). In Group A (ESWT), the average reduction In PRTEE Score at the end of follow up was 54.06 and Group B (steroids) was 69.16. The difference was found to be statistically significant (p<0.001) favouring steroid injections.Conclusions: Both ESWT and steroid injections were found to be effective in producing symptomatic pain relief and improving the functional disability in the management of lateral epicondylitis. The comparison of both modalities showed a statistically significant improvement in pain and functional disability in favour of steroids at a short duration of follow up i.e., 03 weeks, 06 weeks and 06 months.

Experimental investigation and optimization of wall deflection and material removal rate in milling thin-wall parts

The selection of optimal process parameters is essential while machining thin-wall parts since it influences the quality of the product and affects productivity. Dimensional accuracy affects the product quality, whereas the material removal rate alters the process productivity. Therefore, the study investigated the effect of tool diameter, feed per tooth, axial and radial depth of cut on wall deflection, and material removal rate. The selected process parameters were found to significantly influence the in-process deflection and thickness deviation due to the generation of unfavorable cutting forces. Further, an increase in the material removal rate resulted in chatter, thus adversely affecting the surface quality during the final stages of machining. Considering the conflicting nature of the two performance measures, Non-dominated Sorting Genetic Algorithm-II was adopted to solve the multi-objective optimization problem. The developed model could predict the optimal combination of process variables needed to lower the in-process wall deflection and maintain a superior surface finish while maintaining a steady material removal rate

Dynamic Thiol Exchange with β‑Sulfido-α,β-Unsaturated Carbonyl Compounds and Dithianes

A reversible covalent bond exchange of thiols, β-sulfido-α,β-unsaturated carbonyls, and dithianes has been studied in DMSO and D₂O/DMSO mixtures. The equilibrium between thiols and β-sulfido-α,β-unsaturated carbonyls is obtained within a few hours, while the equilibration starting with the β-dithiane carbonyls and thiols requires a few days. This time scale makes the system ideal for utilization in dynamic combinatorial chemistry