Characterization of structural, genotoxic, and immunological effects of methyl methanesulfonate (MMS) induced DNA modifications: Implications for inflammation-driven carcinogenesis.

Genotoxic DNA damaging agents are the choice of chemicals for studying DNA repair pathways and the associated genome instability. One such preferred laboratory chemical is methyl methanesulfonate (MMS). MMS, an SN2-type alkylating agent known for its ability to alkylate adenine and guanine bases, causes strand breakage. Exploring the outcomes of MMS interaction with DNA and the associated cytotoxicity will pave the way to decipher how the cell confronts methylation-associated stress. This study focuses on an in-depth understanding of the structural instability, induced antigenicity on the DNA molecule, cross-reactive anti-DNA antibodies, and cytotoxic potential of MMS in peripheral lymphocytes and cancer cell lines. The findings are decisive in identifying the hazardous nature of MMS to alter the intricacies of DNA and morphology of the cell. Structural alterations were assessed through UV-Vis, fluorescence, liquid chromatography, and mass spectroscopy (LCMS). The thermal instability of DNA was analyzed using duplex melting temperature profiles. Scanning and transmission electron microscopy revealed gross topographical and morphological changes. MMS-modified DNA exhibited increased antigenicity in animal subjects. MMS was quite toxic for the cancer cell lines (HCT116, A549, and HeLa). This research will offer insights into the potential role of MMS in inflammatory carcinogenesis and its progression.

Molecular pathways and therapeutic targets linked to triple-negative breast cancer (TNBC).

Cancer is a group of diseases characterized by uncontrolled cellular growth, abnormal morphology, and altered proliferation. Cancerous cells lose their ability to act as anchors, allowing them to spread throughout the body and infiltrate nearby cells, tissues, and organs. If these cells are not identified and treated promptly, they will likely spread. Around 70% of female breast cancers are caused by a mutation in the BRCA gene, specifically BRCA1. The absence of progesterone, oestrogen and HER2 receptors (human epidermal growth factor) distinguishes the TNBC subtype of breast cancer. There were approximately 6,85,000 deaths worldwide and 2.3 million new breast cancer cases in women in 2020. Breast cancer is the most common cancer globally, affecting 7.8 million people at the end of 2020. Compared to other cancer types, breast cancer causes more women to lose disability-adjusted life years (DALYs). Worldwide, women can develop breast cancer at any age after puberty, but rates increase with age. The maintenance of mammary stem cell stemness is disrupted in TNBC, governed by signalling cascades controlling healthy mammary gland growth and development. Interpreting these essential cascades may facilitate an in-depth understanding of TNBC cancer and the search for an appropriate therapeutic target. Its treatment remains challenging because it lacks specific receptors, which renders hormone therapy and medications ineffective. In addition to radiotherapy, numerous recognized chemotherapeutic medicines are available as inhibitors of signalling pathways, while others are currently undergoing clinical trials. This article summarizes the vital druggable targets, therapeutic approaches, and strategies associated with TNBC.

Removal of Broken Cannulated Drill Bit.

Breaking of surgical drill bits and subsequent dislodging in the bone are quite common in the field of orthopedics. Even though a few methods have been reported to remove dislodged drill bits, we present a novel method to remove a broken drill bit without additional instruments or a secondary incision. A broken cannulated drill bit within the locking screw hole inside the neck of a femur was retrieved using a depth gauge with a curved tip that hooked onto the edge of the drill bit. By employing a clockwise and counter-clockwise twisting, the broken drill bit was retrieved through the proximal reaming tract. The 4mm tract, which was established by proximal reaming, immensely facilitated safe and time-efficient removal of the drill tip without further trauma or prolonging the surgery time. With our technique, the removal was simple and safe without further soft tissue trauma and blood loss. We advocate this approach for implementation in similar cases.

Total knee replacement: A comparison of the subvastus and medial parapatellar approaches.

OBJECTIVE: The goal of this study is to compare the subvastus method to the usual medial parapatellar technique for total knee replacement in patients with osteoarthritis who present to a tertiary care centre, based on quadriceps function recovery in days after surgery. MATERIALS AND METHODS: We retrospectively reviewed case notes of 76 patients with osteoarthritis who had total knee replacements in a tertiary care hospital over the course of a year from August 2019 to August 2020. We divided them into two groups: group A received TKR via the subvastus approach, and group B received TKR via the medial parapatellar approach. Preoperative quadriceps strength, BMI, and baseline demographics were all recorded from their initial pre-operative workup case notes. Starting on the first postoperative day, patients recorded first unassisted straight leg raise (SLR) was kept as the main determinant for muscle function. The data were evaluated to determine the quadriceps muscle function post TKR. RESULTS: When compared to the medial parapatellar approach, the quadriceps muscle function returns sooner with the subvastus technique. Patients in their sixties showed the highest improvement. Preoperative quadriceps strength has a major impact on muscle recovery after surgery. CONCLUSION: The subvastus method to total knee replacement is linked to a faster recovery of quadriceps muscle strength, resulting in a shorter hospital stay and postoperative therapy.

Financial development, globalization, and CO2 emission in the presence of EKC: evidence from BRICS countries.

This study examines the impact of energy consumption, financial development, globalization, economic growth, and urbanization on carbon dioxide emissions in the presence of Environmental Kuznets Curve (EKC) model for BRICS economies, by using a family of econometric techniques robust to heterogeneity and cross-sectional dependence. Results from LM test, CIPS and CADF unit root test, Westerlund Cointegration test, the Dynamic seemingly unrelated regression (DSUR), and Dumitrescu-Hurlin Granger causality test show that (i) the data is cross sectionally dependent and heterogeneous; (ii) carbon dioxide emissions, energy consumption, financial development, globalization, economic growth, square of GDP and urbanization have integration of order one; (iii) the examined variables are co-integrated; (iv) energy consumption and financial development contribute to the carbon dioxide emissions whereas globalization and urbanization have negative but insignificant relationship with carbon dioxide emissions; (v) supports the EKC hypothesis in BRICS economies; (vi) bidirectional causality exists among energy consumption, financial development, economic growth and square of GDP with carbon dioxide emissions whereas globalization and urbanization have unidirectional relationship with carbon dioxide emissions. Since these panel techniques account for heterogeneity and cross-sectional dependence in their estimation procedure, the empirical results are robust and reliable for policy recommendations. Furthermore, this study also uses time series tests (ADF, P-P, and FMOLS) to find the empirical results for each of the country and finds mixed results. Empirical findings directed towards some important policy implications.

Effect of formalin fixation on surgical margins in breast cancer surgical specimen.

Margin analysis in breast surgery is an important predictor of local recurrence and can have vital impact on the postoperative treatment planning. Objective. The aim was to assess the mean reduction in the closest tumor-free surgical margin in millimeters of breast cancer specimens following formalin fixation. Materials and Methods. We conducted a cross-sectional study at the Aga Khan University Hospital from March 30, 2010 to January 20, 2011. One hundred consecutive breast tumour surgical specimens which had macroscopically visible tumour were included. The cancer type included both in situ and invasive cancers. Excluded were the patients who had previous surgery or systemic/radiation therapy. The closest tumor-free margin was recorded and compared with the margin after formalin fixation. P value of <0.05 was considered significant. Results. The mean age of our 100 patients was 53 years with the majority of the patients having undergone mastectomy for predominantly invasive ductal carcinoma. Following formalin fixation, the mean reduction of the closest tumor-free margin was noted as 2.14 mm which was found statistically significant. Conclusion. Considerable shrinkage of tumor-free surgical margins of breast cancer specimen was noted after formalin fixation. This inference can have implications on the postoperative management plan.

Functional and radiological outcome of Intramedullary nailing vs. plate fixation for humeral shaft fractures. Does treatment method bring any difference?

BACKGROUD: Operative Management of Humeral shaft fractures may be accomplished with the help of Plate fixation or IM Nails. Controversy exists as to which modality is superior to the other in terms of fewer complications and better functional and radiological outcome. OBJECTIVE: To compare the differences in radiological and functional outcome of humeral shaft fractures managed by platefixation and antegrade intramedullary nails. METHODS: The retrospective study was conducted at Aga Khan University Hospital, Karachi, and comprised records of Patients managed surgically for uncomplicated humeral shaft fractures between 2007 and 2012. The patients were followed up for one year at clinic, and radiographs and clinical assessment were used to complete the Quick Disabilities of the Arm, Shoulder and HandQuestionnaire. SPSS 19 was used for statistical analysis. RESULTS: Of the total 61 patients, 39(64%) underwent plating and 22(36%) had intramedullary nailing. There was no significant difference in terms of mean age and mean duration of surgery in the two groups (p>0.05 each). Also, no significant difference was noted in the duration of healing with either of the two methods (p>0.05). Mean Questionnaire score for plating was 23.9±17.7, while for intramedullary nailing it was 21.7±19.8 (p>0.05). CONCLUSIONS: There was no significant difference in the radiological and functional outcome of patients in the two groups.

Transfusion practice in orthopedic patients: do we really need it?

OBJECTIVE: To determine the proportion of inappropriate transfusions in patients undergoing orthopaedic surgery at a tertiary care university hospital, and factors associated with inappropriate transfusions. METHODS: The prospective study was conducted at Aga Khan University Hospital, Karachi, from December 2008 to September 2009, and comprised patients admitted to the Orthopaedic Department and received transfusion of at least one packed cell. Patients were divided into four groups: A, those with haemoglobin < 7, B, haemoglobin 7.1-10 without ischemic heart disease, C, haemoglobin 7.1-10 with ischemic heart disease, and D, haemoglobin >10. Variables recorded were, pre-transfusion haemoglobin level, co-morbids, symptoms of hypovolemia, pre-transfusion volume replacement with fluids, transfusion reactions, and haemoglobin after 48 hours. Indications of transfusion were assessed in accordance with available data. RESULTS: Of the 126 patients, 65(52%) were males and 61(48%) were females. There were 18(14%) patients in group A, 88(70%) in group B, 12(10%) in group C, and 8(6%) in group D. Overall, Overall, 44(35%) were transfused appropriately according to the criteria, and 82(65%) were inappropriate. CONCLUSIONS: The number of inappropriate transfusion was quiet high and demands revision of institutional policy of packed cell transfusion in accordance with available guidelines.

Use of distally based random flap in the management of soft tissue defects in upper two thirds of leg.

OBJECTIVE: To assess the results of cases with complex wounds exposing tibia who were managed with distally based random flaps. METHODS: The retrospective study was conducted at Aga Khan University Hospital, Karachi, and Dow University Hospital, Karachi and comprised data between February 2000 and March 2013of patients who had been admitted with a recent or prior history of trauma with a soft tissue defect in upper two-thirds of tibia and who had undergone coverage procedure using distal based flap. RESULTS: The mean age of the total 21 patients in the study was 29±9 years, and 20(95%)were male. Road traffic accident was the most common mechanism of injury in 13(62%). Tibia was exposed in all the 21(100%) cases requiring soft tissue coverage. There was associated fracture of tibia in 18(86%) patients. Mean flap length was 12±1.7 cm and width was 5.3 ±0.86 cm. Maximum size for the flap dissected was 15x7cm. Donor site was covered with split thickness skin graft in 19(90.5%) patients. Flap survival rate was 100%. Only 2(9.5%) patients developed partial flap necrosis. Clinical outcome was graded as good in 19(90.5%) patients and fair in 2(9.5%). Superficial infection was observed in 2(9.5%) patients. CONCLUSIONS: Distal based flap appeared to be an effective solution for the coverage of soft tissue defects in upper two-thirds of leg.

Locking compression plate in musculoskeletal oncology 'a friend in need'.

BACKGROUND: We are presenting our experience in the use of locking compression plate (LCP) after juxta-articular oncological resections in addition to its use in pathologic fracture. METHODS: A retrospective audit of skeletal reconstruction using LCP in 25 cases of long bone tumors was performed from 2008 to 2010. Reconstruction following limb salvage surgery was done in 17 patients and internal fixation of pathological fracture was done in 8 patients. All patients were available for > 12 months of follow-up, and thus assessed for union at the resected ends. RESULTS: There were 8 males and 17 females in the study. The average age at the time of surgery was 30 years (range, 9 to 66 years). The minimum follow-up was 12 months (range, 12 to 32 months). All patients except three went on to heal successfully. Complications occurred in those three patients: wound infection in one, nonunion in another, and periprosthetic fracture in the other patient. In the remaining patients, union was achieved at an average of 6.5 months after reconstruction in curative resection and 4.75 months after fixation of pathological fractures. CONCLUSIONS: Joint sparing limb salvage surgery was made successfully possible after sekeletal reconstruction with LCP. Its use was also quite effective in pathological fractures with poor bone quality. Use of locking plates for musculoskeletal oncological reconstruction resulted in a good and predictable rate of union.

Effect of early release of tourniquet in total knee arthroplasty.

OBJECTIVE: To evaluate whether tourniquet release intraoperatively is better than postoperative release in reducing overall blood loss, duration of surgery, duration of tourniquet, length of hospital stay, wound related complications and transfusion requirement. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Department of Surgery, The Aga Khan University Hospital, Karachi, from January 2004 to June 2007. METHODOLOGY: One hundred and thirty patient files were reviewed retrospectively. Patients were divided into two groups. Group-A consisted of 65 patients with early deflation of tourniquet and group-B comprised of 65 patients with the release of tourniquet after applying compressive dressing. Total blood loss (determined by Gross method) and other study variables were noted as per objective and computed. RESULTS: There were 22 males and 108 females with comparable BMI. All had undergone posterior stabilized cemented total knee replacement. Calculated blood loss was 1.208 L and 1.108 L in group-A and B respectively (p = 0.27). Significant increase in duration of surgery was noted in group-A patients. Four patients in group-B showed complication related to wound with 3 being minor and 1 requiring additional operation room visit. Mean length of hospital stay was 9 days. Transfusion frequency was higher in group-B despite comparable postoperative haemoglobin values. CONCLUSION: Intraoperative tourniquet release does not reduce overall blood loss with no effect in conserving blood after total knee replacement, however, this group had relatively shorter hospital stay.

Complex biological reconstruction after wide excision of osteogenic sarcoma in lower extremities.

Wide margin resection of extremity tumor sometimes leaves a huge soft tissue and bony defects in limb salvage surgery. Adequate management of these defects is an absolute requirement when aiming for functional limb. Multidisciplinary management in such cases is an answer when complex biologic reconstruction is desired. We aim to present cases of osteogenic sarcoma of lower extremity requiring combined surgical approach to achieve effective musculoskeletal reconstruction. Patients and Methods. From 2006 to 2010 ten patients were operated on for osteogenic sarcoma of lower extremity requiring complex musculoskeletal reconstruction. Results. Six patients had pathology around knee joint, whereas one each with mid tibia, mid femur, proximal femur, and heel bone. Locking compression plate was used in 7 patients including six with periarticular disease. Eight out of ten patients underwent biologic reconstruction using autograft; endoprosthetic reconstruction and hindquarter amputation were done in the remaining two patients. Vascularized fibula was done in five patients, sural artery flap which was primarily done in three patients, spare part fillet flap, free iliac crest flap, and Gastrocnemius flap was done in one patient each. Secondary hemorrhage, infection, nonunion, wound dehiscence, and flap failure were notable complications in four patients. The Average Musculoskeletal Tumor Society score was 89%. Conclusion. Combined surgical approach results in cosmetically acceptable and functional limb.

Preoperative cardiac evaluation in proximal femur fractures and its effects on the surgical outcome.

OBJECTIVE: The aim of the current study was to evaluate the impact of cardiac risk stratification and preoperative cardiac evaluation on final outcomes in patients with acute proximal femur fractures. METHODS: This retrospective review included one hundred and three patients who underwent a preoperative cardiac evaluation prior to proximal femur fracture operation between 2004 and 2007 at a tertiary care hospital. Patients were divided into two groups. Group A included 76 patients who were tested with ECG only and Group B included 27 patients with additional clearance. All of these files were reviewed according to a set pro forma. Statistical analysis was done using the SPSS 17 software. The Student's t-test and Mann-Whitney U test were applied to compare two means. RESULTS: Fifty-three patients had intertrochanteric fractures and 50 had femoral neck fractures. Only 7 patients had a metabolic equivalent task of less than 4. Group B patients had significant delay in time from triage to surgery (p<0.0001) and from surgery to ambulation (p<0.005). Group B patients also had an increased length of hospital stay, although no significant effect on perioperative mortality was observed. CONCLUSION: Preoperative cardiac evaluation is associated with delay in surgery and subsequent ambulation. Delay in surgery is not associated with increased perioperative mortality at our institute. However, the set of guidelines proposed by ACC/AHA should be followed, as the selection of patients for additional investigation was not justifiable in most cases.

Complications of total hip replacement.

OBJECTIVE: To determine the factors causing complications in unilateral total hip replacement. STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi, between 2000 and 2010. METHODOLOGY: During the study period, 199 patients underwent elective unilateral total hip replacement at the Aga Khan University Hospital. Patients were divided into two groups on the basis of postoperative complications within 30 days of surgery. Significant factors at 5% significance level on univariate analysis were further analyzed by multivariate logistic regression. RESULTS: Postoperative complications occurred in 39 patients (19.6%); dislocation being most common in 13 patients (6.5%), followed by wound infection in four (2%), all of these patients required intervention. Other minor complications which were managed conservatively included wound infection (2.5%), urinary tract infection (2.5%), dislocation (1%), pleural effusion and pneumonia (2%), deep venous thrombosis (0.5%) and myocardial infarction (0.5%). On univariate analysis, patients with ASA III and IV, peri-operative blood transfusion, pre-operative hip deformity and post-operative bisphosphonate use were significantly associated with complications. On multi-variate analysis, adjusted odd's ratio for perioperative transfusion (3; 95% CI: 1.17-7.7) and hip deformity (3.2, 95% CI: 1.4-3.4) was found statistically significant. CONCLUSION: Pre-operative hip deformity and perioperative blood transfusion significantly influence the rates of complication after unilateral THR.

Short term results of ligament reconstruction and tendon interposition resection arthroplasty for basal joint arthritis.

Carpometacarpal (CMC) joint of the thumb is the second most common site afflicted by osteoarthritis. Non surgical measures forms the first line of treatment with aim of preventing progression of disease, however, surgery becomes an option when symptoms are refractory to nonsurgical methods. Different procedures have been described in literature. Ligament reconstruction with tendon interposition (LRTI) is the most commonly performed procedure in North America for this problem. The Aim of study was to evaluate early results of ligament reconstruction and tendon interposition for CMC joint arthritis. This is a case series of ten patients operated in a tertiary care hospital from December 2006 to December 2008. All cases were operated by a single surgeon. All of the patients were followed up using Quick DASH questionnaire filled preoperatively and 3 and 6 months postoperatively. All of our patients were female. Mean duration of follow up was 34 weeks. Pain and residual laxity recorded at each clinical follow up visit after removal of thumb spica and Kirschner wire. Mean value for Quick DASH score is 31 in a 0-100 scale with 0 being no disability. Ligament reconstruction and tendon interposition resection arthroplasy is an effective method of controlling symptoms with preservation of motion at CMC joint axis.

Minimally invasive plate osteosynthesis for tibial plateau fractures.

PURPOSE: To evaluate radiological and clinical outcome of minimally invasive plate osteosynthesis (MIPO) for tibial plateau fractures. METHODS: 35 men and 6 women aged 19 to 75 (mean, 40; standard deviation [SD], 14) years underwent MIPO for displaced tibial plateau fractures. According to the Schatzker system, the tibial plateau fractures were classified as types I (n=3), II (n=9), III (n=11), IV (n=6), V (n=7), and VI (n=5). Six patients had open fractures; 2 of them underwent debridement before MIPO. 10 patients needed additional bone grafting. Radiological (at immediate postoperation) and clinical (at the 12-month follow-up) assessments based on the Rasmussen anatomic and functional scoring system were recorded using a proforma. Patients with acceptable and unacceptable outcomes were compared in terms of age. RESULTS: The mean Rasmussen anatomic score was 15.1 (SD, 2.2; range, 10-18); the mean Rasmussen functional score was 25.3 (SD, 3.2; range, 14-29); and the mean range of knee motion was 118 (SD, 10; range, 90-140) degrees. Anatomic outcome was excellent in 10, good in 28, and unacceptable in 3 patients (one each had Schatzker type-I, -II, and -III fractures). 27 (71%) of the 38 patients with acceptable anatomic outcome were aged 45 years or younger, whereas 2 (67%) of the 3 patients with unacceptable anatomic outcome were aged 60 years or older (p=0.001). Functional outcome was excellent in 18, good in 19, and unacceptable in 4 patients (2 had Schatzker type-III and another 2 had Schatzker type-I or -II fractures). 37 of the patients had a range of knee motion of 120 degrees or more; 27 (73%) of them were aged 45 years or younger, whereas 3 (75%) of the 4 patients with unacceptable functional outcome were aged 60 years or older (p=0.001). CONCLUSION: MIPO for tibial plateau fractures achieved good outcome with minimal soft-tissue complications. Older age was the predictor of unacceptable outcome.

Predictors of length of hospital stay after total hip replacement.

PURPOSE: To identify variables affecting length of hospital stay after total hip replacement (THR) while controlling for potential confounders. METHODS: Records of 199 consecutive elective unilateral THRs were reviewed. Clinical and demographic data including age, gender, body mass index, comorbidities, surgical factors (surgical approach, type of prosthesis, use of cement, operating time), anaesthetic factors (type of anaesthesia, ASA physical status), and length of hospital stay were recorded. RESULTS: 64% of patients left hospital within 12 days, 28% within 3 weeks, and 8% after 3 weeks. The median length of hospital stay was longer in women than men (11.5 vs. 9 days, p=0.009), in patients aged >65 years than those younger (13 vs. 9 days, p<0.0001), and in those with American Society of Anesthesiologists (ASA) grades 3 and 4 than grades 1 or 2 (14 vs. 9 days, p<0.0001). A greater proportion of women than men (45% vs. 27%, p=0.007), patients aged >65 years than those younger (61% vs. 37% or 24%, p<0.0001), and those with ASA grades 3 and 4 than grades 1 and 2 (68% vs. 25%, p<0.0001) stayed 12 days or longer. In the multiple regression analysis, the predictors for prolonged hospital stay (12 days or more) were patient age >65 years (p<0.003), female gender (p<0.05), and ASA grades 3 and 4 (p<0.0001). Of the 72 patients with prolonged stay, 7% had no, 26% had one, 42% had 2, and 25% had all 3 predictors. CONCLUSION: Prolonged hospital stay after THR is largely predetermined by case mix. Our study helps to identify individuals who need longer rehabilitation and more care.

Arthroscopic repair of meniscal tears with inside-out technique.

OBJECTIVE: To review the clinical results of arthroscopic meniscal repair and to identify factors that may affect the outcome. METHODS: A total of 15 arthroscopic meniscal repairs with inside-out in 14 patients over a 7-year period were evaluated retrospectively. The mean age was 41.2 +/- 11.5 years with a range of 26-64 years. Eleven patients underwent repair for medial meniscal tear, two patients for lateral meniscus and one patient for both in the same knee. All patients were functionally evaluated by Lysholm functional knee scores over an average follow-up of 1 year and 5 months (range: 0.5-7 years). RESULTS: The mean Lysholm score was 84 out of a maximum of 100. Functional outcome was excellent in 6 patients, good in 5, fair in 2 and poor in one patient. The patient with poor outcome was young with a chronic tear; she had concomitant ipsi-lateral radiculopathy and also had signs of reflex sympathetic dystrophy. One 64 year old patient with fair outcome developed a post-operative flexion contracture of 15 degrees. She also had moderate osteoarthritis of the medial compartment. One patient developed saphenous nerve neuralgia which was relieved spontaneously after a few months. CONCLUSION: All patients with excellent results were relatively younger with an acute tear. Elderly patients with concomitant osteoarthritis of the knee joint did not have a satisfactory outcome even if the tear was acute.