Polypharmacological repurposing approach identifies approved drugs as potential inhibitors of Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M. tb), the causative pathogen of tuberculosis (TB) remains the leading cause of death from single infectious agent. Furthermore, its evolution to multi-drug resistant (MDR) and extremely drug-resistant (XDR) strains necessitate de novo identification of drug-targets/candidates or to repurpose existing drugs against known targets through drug repurposing. Repurposing of drugs has gained traction recently where orphan drugs are exploited for new indications. In the current study, we have combined drug repurposing with polypharmacological targeting approach to modulate structure-function of multiple proteins in M. tb. Based on previously established essentiality of genes in M. tb, four proteins implicated in acceleration of protein folding (PpiB), chaperone assisted protein folding (MoxR1), microbial replication (RipA) and host immune modulation (S-adenosyl dependent methyltransferase, sMTase) were selected. Genetic diversity analyses in target proteins showed accumulation of mutations outside respective substrate/drug binding sites. Using a composite receptor-template based screening method followed by molecular dynamics simulations, we have identified potential candidates from FDA approved drugs database; Anidulafungin (anti-fungal), Azilsartan (anti-hypertensive) and Degarelix (anti-cancer). Isothermal titration calorimetric analyses showed that the drugs can bind with high affinity to target proteins and interfere with known protein-protein interaction of MoxR1 and RipA. Cell based inhibitory assays of these drugs against M. tb (H37Ra) culture indicates their potential to interfere with pathogen growth and replication. Topographic assessment of drug-treated bacteria showed induction of morphological aberrations in M. tb. The approved candidates may also serve as scaffolds for optimization to future anti-mycobacterial agents which can target MDR strains of M. tb.

Effects of Exercise Training in Patients with Lung Cancer during Chemotherapy Treatment.

Background: Cancer is the second greatest cause of death and disability after cardiovascular disease. Objective: To determine the effects of exercise training in patients with lung cancer during chemotherapy treatment. Methods: A randomised clinical trial was conducted in Shaukat Khanum Memorial Cancer Hospital and Institute of Radiotherapy and Nuclear Medicine (IRNUM) Peshawar. A total of 40 participants were randomly divided into two groups: i) the Experimental group (EG, n = 20) and ii) Control group (CG, n = 20). Both groups received exercise training for 4 weeks, with five sessions per week. The EG received pulmonary rehabilitation and aerobic training. The CG received only pulmonary rehabilitation. Both groups were evaluated at baseline and after 6 weeks through Mindful Attention Awareness Scale (MAAS) Urdu version, Six Minute Walk Test (6MWT), digital spirometry, Borgs scale, Hospital Anxiety and Depression Scale (HADs) and Visual Analogue Scale (VAS). Results: Both the EG and CG showed significant improvement in MAAS scores at post-study with a (P < 0.001). The scores of 6MWT were improved significantly in both groups after intervention with a (P = 0.001). The patient's anxiety scores were significantly improved in both groups after intervention with a (P < 0.001), while depression scores were also improved considerably between the two groups at post-level with a (P < 0.001). Regarding spirometry value, both groups showed significant improvement after intervention for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC (P < 0.001). Both groups show significant differences in patient pain intensity and dyspnea at post-level with P < 0.001. Conclusion: This study concluded that pulmonary rehabilitation along with aerobic training can be more effective than pulmonary rehabilitation alone for patients with lung cancer during chemotherapy treatment.

The exploitation of host autophagy and ubiquitin machinery by Mycobacterium tuberculosis in shaping immune responses and host defense during infection.

Intracellular pathogens have evolved various efficient molecular armaments to subvert innate defenses. Cellular ubiquitination, a normal physiological process to maintain homeostasis, is emerging one such exploited mechanism. Ubiquitin (Ub), a small protein modifier, is conjugated to diverse protein substrates to regulate many functions. Structurally diverse linkages of poly-Ub to target proteins allow enormous functional diversity with specificity being governed by evolutionarily conserved enzymes (E3-Ub ligases). The Ub-binding domain (UBD) and LC3-interacting region (LIR) are critical features of macroautophagy/autophagy receptors that recognize Ub-conjugated on protein substrates. Emerging evidence suggests that E3-Ub ligases unexpectedly protect against intracellular pathogens by tagging poly-Ub on their surfaces and targeting them to phagophores. Two E3-Ub ligases, PRKN and SMURF1, provide immunity against Mycobacterium tuberculosis (M. tb). Both enzymes conjugate K63 and K48-linked poly-Ub to M. tb for successful delivery to phagophores. Intriguingly, M. tb exploits virulence factors to effectively dampen host-directed autophagy utilizing diverse mechanisms. Autophagy receptors contain LIR-motifs that interact with conserved Atg8-family proteins to modulate phagophore biogenesis and fusion to the lysosome. Intracellular pathogens have evolved a vast repertoire of virulence effectors to subdue host-immunity via hijacking the host ubiquitination process. This review highlights the xenophagy-mediated clearance of M. tb involving host E3-Ub ligases and counter-strategy of autophagy inhibition by M. tb using virulence factors. The role of Ub-binding receptors and their mode of autophagy regulation is also explained. We also discuss the co-opting and utilization of the host Ub system by M. tb for its survival and virulence.Abbreviations: APC: anaphase promoting complex/cyclosome; ATG5: autophagy related 5; BCG: bacille Calmette-Guerin; C2: Ca2+-binding motif; CALCOCO2: calcium binding and coiled-coil domain 2; CUE: coupling of ubiquitin conjugation to ER degradation domains; DUB: deubiquitinating enzyme; GABARAP: GABA type A receptor-associated protein; HECT: homologous to the E6-AP carboxyl terminus; IBR: in-between-ring fingers; IFN: interferon; IL1B: interleukin 1 beta; KEAP1: kelch like ECH associated protein 1; LAMP1: lysosomal associated membrane protein 1; LGALS: galectin; LIR: LC3-interacting region; MAPK11/p38: mitogen-activated protein kinase 11; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MAPK8/JNK: mitogen-activated protein kinase 8; MHC-II: major histocompatibility complex-II; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; NFKB1/p50: nuclear factor kappa B subunit 1; OPTN: optineurin; PB1: phox and bem 1; PE/PPE: proline-glutamic acid/proline-proline-glutamic acid; PknG: serine/threonine-protein kinase PknG; PRKN: parkin RBR E3 ubiquitin protein ligase; RBR: RING-in between RING; RING: really interesting new gene; RNF166: RING finger protein 166; ROS: reactive oxygen species; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TNF: tumor necrosis factor; TRAF6: TNF receptor associated factor 6; Ub: ubiquitin; UBA: ubiquitin-associated; UBAN: ubiquitin-binding domain in ABIN proteins and NEMO; UBD: ubiquitin-binding domain; UBL: ubiquitin-like; ULK1: unc-51 like autophagy activating kinase 1.

Double Stab Excision Arteriotomy-A Novel Technique For A Better Outcome.

BACKGROUND: This study was carried out to introduce a new technique of excision arteriotomy and to compare it with standard excision arteriotomy in terms of achieving desired size, shape and margins with minimal technical problems. METHODS: This was a comparative study carried out at the Vascular Surgery Unit of Combined Military Hospital Peshawar between January and September 2022. A total of 150 patients of chronic renal failure undergoing Arteriovenous access fulfilling the inclusion criteria were enrolled in our study. The patients were randomized into two groups, 75 in each group: Group A consisted of patients who underwent Conventional excision arteriotomy and Group B underwent Double Stab excision Arteriotomy. The endpoint of the study was to achieve an appropriate arteriotomy of the desired size and shape by having regular margins without intimal dissection during its formation or otherwise inappropriate arteriotomy if any of the criteria is not met. RESULTS: Among the total 150 patients included in our study, Ages ranged between 30-60 years and a mean age of 52.5 years. There were 82 (54.66%) males and 68 (45.33%) females with a male-to-female ratio of 1.2:1. In group A (Conventional Excision arteriotomy) there were 30 (40%) inappropriate arteriotomies and 45 (60%) appropriate arteriotomies. Among the total 30(40%) inappropriate arteriotomies in group A, larger than desired size arteriotomies were 10 cases (33.33%) followed by smaller than desired size arteriotomies; 6 (20%), irregular margins 9 (30%), intimal dissection 3(10%) & lateral tear 2 (6.66%) respectively. In group B of double stab excision arteriotomies, appropriate arteriotomies were achieved in 69 (92%) while the rest had inappropriate arteriotomies in 6 (8%). Among the total 6 (8%) inappropriate arteriotomies in group B, larger than desired size arteriotomies were 2 (33.33%), smaller than desired size arteriotomy; 1 (16.66%), irregular margins 1 (16.66%), intimal dissection;2 (33.33%) & no lateral tear respectively. CONCLUSIONS: This study concluded that the Double stab excision arteriotomy technique is superior to the conventional excision arteriotomy technique. The advantages of our technique are; its reliability with a short learning curve and can be performed precisely and safely.

Treatment Outcomes Of Patients With Hairy Cell Leukaemia; A 16-Year Experience At A Tertiary Care Center In Pakistan.

BACKGROUND: Hairy cell leukaemia (HCL) is an uncommon neoplasm of mature B-lymphoid cells which is characterized by cytopenias, commonly of all three cell lines, with typical hairy cells on peripheral smear and/or bone marrow along with organomegaly. Objective was to document the outcomes of HCL patients treated at a tertiary care hospital in Pakistan. METHODS: Medical records of patients from 2004 to 2020 were reviewed and data was collected to assess patient's demographics, symptomatology, remission rate and overall survival. The record flies of all patients presenting to AFBMTC with HCL were included in the study. The record file with insufficient data were excluded. RESULTS: 26 patients with a mean age of 48.12±11.43 years were diagnosed with HCL and treated at AFBMTC. Out of these, 23 (88.4%) were male and 03 (11.5%) females. The main presenting complaints were generalized body aches (34.6%), fever (15.4%), incidental finding of cytopenias (11.5%) and abdominal discomfort (26.9%). Splenomegaly was found in 76.92% while hepatomegaly was found in 46.15% of patients. A total of 12 (46.15%) patients received Cladribine (either intravenous or subcutaneous) and splenectomy was done in 7 (26.92%) as 1st line treatment. Eleven patients out of 12 (83.33%) who received Cladribine and 05 (71.42%) patients out of seven who underwent splenectomy; achieved complete remission (CR) after 1 st line of treatment. One patient received Cladribine as 1st line of treatment but did not respond and CHOP regimen was given as second line. Out of the 26 patients, 5 patients (19.23%) relapsed at a median interval of 5.83±6.6 years. Two patients received Cladribine + Rituximab while 03 patients received cladribine as their salvage therapy. Disease free survival (DFS) of 71.4% among the patients underwent splenectomy while 75.0% among the patients received Cladribine. DFS for combination therapy (included CHOP and CVP) was 66.7% while OS was calculated among patients who received cladribine, splenectomy and combination chemotherapy as 100%, 85.7%, 66.7% respectively. CONCLUSIONS: Cladribine has a significant efficacy and encouraging acute and long-term benefits when administered to patients with HCL. A single course of cladribine was able to induce CR in a vast majority of patients. At a median follow up of 4.6 years the OS was 100% with cladribine and 85% with splenectomy. Those who relapsed were successfully retreated with cladribine + Rituximab.

Clinical Practice Guidelines For The Management Of Colorectal Cancer, A Consensus Statement By The Society Of Surgeons® And Surgical Oncology Society Of Pakistan®.

A joint effort by the Society of Surgeons Pakistan and Society of Surgical Oncology Pakistan, these guidelines provide a framework for the practicing surgeons involved in care and management of patients with colorectal cancer. The guidelines take into account the issues related to our local circumstances and provide a minimum standard of care that must be given to these patients. The Guideline Committee had members from all disciplines, including surgery, surgical oncology, medical oncology and radiation oncology. The guidelines have attempted to simplify things to understand and follow for the practicing surgeons. With these guidelines we wish to eliminate disparities in treatment among institutions and prevent any under treatment of patients.

Duodenal Perforation due to Ingested Partial Denture.

Ingestion of foreign bodies including dentures can be a cause of morbidity and mortality. We report a case of poor-fit denture in an elderly male with pulmonary and musculoskeletal comorbidities, who presented as an acute abdomen. The pin attached to the denture caused perforation of first part of duodenum. The only positive finding prior to surgery was a radiopaque density in the abdominal radiograph of the patient and air under the diaphragm. It is important for all the surgeons dealing with acute care patients to be aware of different designs and constructions of dentures.

Effectiveness of Ultrasound Shear for Clipless Laparoscopic Cholecystectomy Versus Conventional Unipolar Electrocautery in Patients with Cholelithiasis.

OBJECTIVE: To determine the efficacy of ultrasound shear in laparoscopic cholecystectomy in terms of total operative time, postoperative bile leaks, gall bladder perforation rate, and postoperative bleeding from cystic artery and collateral injury to bowel and duodenum. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Mayo Hospital, Lahore, from June 2013 to May 2014. METHODOLOGY: 150 cases (75 in each group) were randomized into two groups, i.e. harmonic scalpel clipless group (HSG) versus conventional laparoscopic cholecystectomy (CLC) with electrocautery group. The above stated variables were documented. The data for age, blood loss, and drain output were positively skewed as calculated using the Shapiro-Wilk test. The histograms, Q-Q plots and box plots were analyzed for all the dependent variables. Skewed qualitative continuous data was analyzed using the Mann-Whitney U-Test. RESULTS: Operative time was significantly lower in HSG as compared to CLC. Median operative times were 30 minutes (IQR 10) versus 35 minutes (IQR 10) (p<0.001). HSG group had perforation rate of 5/75 (6.67%) as compated to 16/75 (21.33%) in CLC (p=0.010). Intraoperative blood loss in group Awas significantly lower than in group B (p=0.001). Postoperative median pain score was 3 (IQR 2) versus 3 (IQR 3) in HSG versus CLC, respectively. CONCLUSION: All the primary outcomes showed improved results in the ultrasound shear group as compared to the group for conventional electrocautery.

Penile Shaft Strangulation with Wrought Iron Metallic Pipe.

Penile strangulation due to any solid encircling ornament or metal is rarely reported. Venous outflow obstruction due to any constricting item around the shaft leads to venous congestion, urinary obstruction, and rarely gangrene of the penile shaft skin. We report a case presenting with penile near-strangulation due to iron-lead metallic junction pipe which was cut using a heavy electric metal cutter.

The efficiency, accuracy and acceptability of smartphone-delivered data collection in a low-resource setting - A prospective study.

Smartphones are increasingly used in healthcare, yet little is known about their utility in medical research as a means of data collection in low- and middle-income countries (LMIC). In this letter, we discuss results from our experiences with data collection on smartphones in an LMIC setting. Our experience found smartphones a secure and reliable data collection tool for medical research that can empower researchers in countries to participate in surgical studies.

Pregnant Lady With Undiagnosed Hodgkin's Disease Presenting As Secondary Sclerosing Cholangitis.

Hodgkin's lymphoma. A 25 years old lady, 34 weeks primigravida was referred from the Emergency Department to the Medical Unit Khyber Teaching Hospital-MTI, Peshawar with four weeks of fever, progressive jaundice, pruritus, night sweats and weight loss. LFTs showed cholestatic picture, ERCP showed scanty intrahepatic giving beading and autumn tree appearance typical of sclerosing cholangitis. CBD was normal. Doppler U/S of hepatic and portal vein reported normal. She was started on steroids, ursodeoxycholic acid and antibiotics 3rd generation cephalosporins to which she did not respond well. This prompted a Liver biopsy which showed Hodgkin's disease having mixed cellularity. She was shifted to specialized oncology unit for further management where she died of irreversible liver damage. This is a rare case of secondary sclerosing cholangitis in Hodgkin's lymphoma of liver and the first case reported to our Hospital.

Stray bullet in inferior vena cava.

A young boy presented in emergency with history of being hit by a stray bullet injuring the right hypochondrium. Ultrasound of abdomen showed hemoperitoneum and the radiograph showed bullet in the pelvis. Exploratory laparotomy showed injuries to liver and cystic duct with tract leading retroperitoneally into the inferior vena cava. The bullet was found wandering inside the vena caval lumen. Stray bullets are presumed to remain limited to the soft tissues. However, the trajectory, impact velocity and the involved region ultimately determine the outcome and influence management.

Duodenal perforation in a 14-year-old boy with abdominal tuberculosis despite being on antituberculous treatment.

We are presenting a case of a 14-year-old male patient with known history of abdominal tuberculosis on medication for 4 months with frank peritonitis and air under the diaphragm found to have primary perforation of the duodenum due to tuberculosis. Tuberculosis is common in the third world but affects iliocaecal junction commonly. Cases with tuberculous duodenal are rarely reported in the literature.

Transhiatal esophageal surgery for malignancy--a 7-year experience at a tertiary care hospital.

OBJECTIVE: The aim of this study was to determine the outcomes of transhiatal esophagectomy for dysphagia for esophageal malignancy in terms of short and long-term morbidity and mortality and to determine the survival series. STUDY DESIGN: Case series study. PLACE AND DURATION OF STUDY: South and West Surgical Ward, Mayo Hospital, Lahore, from January 2001 to December 2007. METHODOLOGY: All patients referred electively or admitted through OPD presenting with features of progressive dysphagia due to malignancy were included in the study. The patients were investigated for site of stricture and extent of growth into the surrounding structures. All underwent transhiatal esophagectomy and gastric tube or colon was used as the conduit to restore continuity. Patients with squamous cell variety were referred to oncology department for chemoradiotherapy postoperatively. Morbidity and in-hospital mortality were recorded. RESULTS: A total of 42 patients were operated electively for malignant stricture esophagus through transhiatal approach. Site of lesion were 5 (11.9%) upper, 13 (31%) middle and 24 (58%) at lower end of esophagus. The TNM staging were stage I, IIa, IIb, III and IV in zero (0), 5 (11%), 10 (22%), 24 (57.8%) and 3 (7.1%) respectively. Mean operating time was 154 minutes and average blood loss of 371 ml. Postoperative complications included pneumothorax 16.7%, pulmonary complication (16.7%), anastomotic leakage (9.5%), wound infection (3.4%), recurrent laryngeal nerve injury (4.8%) and stricture formation (4.8%). Only 3 (7.1%) 30-day in-hospital mortality was recorded. CONCLUSION: Transhiatal esophagectomy is the surgical treatment of choice for resection of carcinoma esophagus specifically at the lower and mid-esophageal levels. The frequency of complications is lower as compared to transthoracic approach and the early stage of presentation can lead to high 5-year survival ratios.

Comparative study of ultrasound guided fine needle aspiration cytology with open/laparoscopic biopsy for diagnosis of carcinoma gallbladder.

OBJECTIVE: To determine the accuracy of Fine Needle Aspiration Cytology (FNAC) in cases of gallbladder mass. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Surgical Units of Mayo Hospital, Lahore and Lahore General Hospital, Lahore in collaboration with the Department of Radiology, Sir Ganga Ram Hospital, Lahore and Department of Pathology of PGMI, Lahore, from September 2006 to September 2007. METHODOLOGY: Ultrasound guided fine needle aspiration cytology was done in all cases and histopathological findings were confirmed with open/laparoscopic biopsies. The results of these two modalities were compared. RESULTS: Fifty cases with mean age 60.71+11.073 years presented with mass gallbladder underwent FNAC. Smears showed adenocarcinoma 23, undifferentiated carcinoma in 7, dysplasia and suspicion of malignancy in 5, hemorrhagic background without malignant cells in 12 and inflammatory cells with no malignancy in 3 cases. Results compared with open/ laparoscopic biopsy showed a sensitivity, specificity and Positive Predictive Value (PPV) of 72.91%, 100% and 100% respectively. CONCLUSION: Ultrasound guided FNAC is a safe and less invasive diagnostic modality for diagnosing carcinoma gall bladder preventing the patient to undergo major surgery and helps in better quality of life.