mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1.

The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission/fusion, ATP production, metabolite biogenesis, and apoptosis, are not well understood. Here, we demonstrate that the nutrient-sensing mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase dynamin-related protein 1 (DRP1). Potent active-site mTOR inhibitors engender mitochondrial hyperfusion due to the diminished translation of MTFP1, which is mediated by translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Uncoupling MTFP1 levels from the mTORC1/4E-BP pathway upon mTOR inhibition blocks the hyperfusion response and leads to apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic. These data provide direct evidence for cell survival upon mTOR inhibition through mitochondrial hyperfusion employing MTFP1 as a critical effector of mTORC1 to govern cell fate decisions.

4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold.

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)-induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb ) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

A short report on the current landscape of Artificial Intelligence (AI) in vascular surgery in Pakistan.

This study focuses on the current applications, potential, and challenges to Artificial Intelligence (AI) integration in vascular surgery with specific emphasis on its relevance in Pakistan. Despite the benefits of AI in vascular surgery, there is a substantial gap in its adoption in Pakistan compared to global standards. In our context with limited resources and a scarcity of vascular surgeons, AI can serve as a promising solution. It can enhance healthcare accessibility, improve diagnostic accuracy, and alleviate the workload on vascular surgeons. However, hurdles including the absence of a comprehensive vascular surgery database, a shortage of AI experts, and potential algorithmic biases pose significant challenges to AI implementation. Despite these obstacles, the study underscores the imperative for continued research, collaborative efforts, and investments to unlock the full potential of AI and elevate vascular healthcare standards in Pakistan.

A systematic review of simulation training for lower extremity bypass procedures.

OBJECTIVES: Simulation is used across surgical specialties for skill enhancement. The choice and assessment method of a simulator varies across literature. In the age of endovascular approach, trainees have limited exposure to open lower limb bypass procedures which needs attention. This review aims to assess the utility of simulation training in lower limb bypass surgery using Kirkpatrick's model. METHODS: Using PRISMA statement, we included all the studies done on simulators in lower limb bypass surgical procedures for this systematic review. The primary outcome was to assess the effectiveness of different types of simulation used for lower limb bypass surgery using the Kirkpatrick's model for training evaluation. RESULTS: An initial search identified 295 articles out of which 7 articles were found to be eligible for this systematic review. A variety of simulators were used including cadavers and synthetic models. Most studies (n=5) found the use of simulation as an effective tool in achieving technical competence. All the five studies we found at level 2 on Kirpatrick's model evaluation. CONCLUSION: Most of the existing studies are at level 2 of Kirkpatrick's model which reflects learning changes in trainees after simulation. Feedback mechanism needs to be evolved where the improvement after simulation training can be gauged by its replication in clinical practice and improved patient care practices corresponding to the highest level of Kirkpatrick's model.

Pyrazole scaffold-based derivatives: A glimpse of α-glucosidase inhibitory activity, SAR, and route of synthesis.

The α-glucosidase is a validated target to develop drugs for treating type 2 diabetes mellitus. The existing α-glucosidase inhibitors have certain shortcomings related to side effects and route of synthesis. Accordingly, it is inevitable to develop new chemical templates as α-glucosidase inhibitors. Pyrazole derivatives have a special place in medicinal chemistry because of various biological activities. Recently, pyrazole-based heterocyclic compounds have emerged as a promising scaffold to develop α-glucosidase inhibitors. This study focuses on the recently reported pyrazole-based α-glucosidase inhibitors, including their biological activity (in vivo, in vitro, and in silico), structure-activity relationship, and ways of synthesis. The literature revealed the development of several promising pyrazole-based α-glucosidase inhibitors and new synthetic routes for their preparation. The encouraging α-glucosidase inhibitory results of the pyrazole-based heterocyclic compounds make them an attractive target for further research. The authors also foresee the arrival of the pyrazole-based α-glucosidase inhibitors in clinical practice.

Insight into Structure Activity Relationship of DPP-4 Inhibitors for Development of Antidiabetic Agents.

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, ß-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC50) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future.

Role of stem cells in arteriovenous access: perspective from Lower Middle Income Countries.

Adequately created well functional haemodialysis access is an important part for the physical and mental wellbeing of renal failure patients. Every effort should be made to enhance the patency of these accesses. Recently, stem cell treatment modalities have opened new avenues in the better patency of arteriovenous fistula. Use of mesenchymal stromal cells (MSC) to prevent venous neointimal hyperplasia have been studied with good success rates. Adopting such costly treatment modalities in low middle income class country like Pakistan is associated with significant challenges. This short report discusses the current role of stem cells in arteriovenous access and how this exciting modality can be utilized in our country.

How do plants remember drought?

MAIN CONCLUSION: Plants develop both short-term and transgenerational memory of drought stress through epigenetic regulation of transcription for a better response to subsequent exposure. Recurrent spells of droughts are more common than a single drought, with intermittent moist recovery intervals. While the detrimental effects of the first drought on plant structure and physiology are unavoidable, if survived, plants can memorize the first drought to present a more robust response to the following droughts. This includes a partial stomatal opening in the watered recovery interval, higher levels of osmoprotectants and ABA, and attenuation of photosynthesis in the subsequent exposure. Short-term drought memory is regulated by ABA and other phytohormone signaling with transcriptional memory behavior in various genes. High levels of methylated histones are deposited at the drought-tolerance genes. During the recovery interval, the RNA polymerase is stalled to be activated by a pause-breaking factor in the subsequent drought. Drought leads to DNA demethylation near drought-response genes, with genetic control of the process. Progenies of the drought-exposed plants can better adapt to drought owing to the inheritance of particular methylation patterns. However, a prolonged watered recovery interval leads to loss of drought memory, mediated by certain demethylases and chromatin accessibility factors. Small RNAs act as critical regulators of drought memory by altering transcript levels of drought-responsive target genes. Further studies in the future will throw more light on the genetic control of drought memory and the interplay of genetic and epigenetic factors in its inheritance. Plants from extreme environments can give queues to understanding robust memory responses at the ecosystem level.

Availability of Operative Surgical Experience and Supervision for Competency-Based Education: A Review of A General Surgery Program at A Tertiary Care Teaching Hospital in Pakistan.

BACKGROUND: In view of importance for competency-based education (CBE), we undertook a self-study to elicit the available operative surgical workload and supervision for residents in the general surgical residency program at the teaching hospital in Karachi. METHODOLOGY: This was a cross-sectional study spanning a 5-year period between January 2015 and December 2019. The numbers of surgical residents during this period were identified. Five procedures were selected as core general surgical procedures: incision and drainage of superficial abscess, laparoscopic appendectomy, laparoscopic cholecystectomy, open inguinal hernia repair, and perianal procedures. Trends of the number of residents per year and the numbers of procedures per year were determined. The mean number of core procedures per eligible resident during their entire training was calculated to represent potential operative surgical experience and were benchmarked. The ratio of the average number of residents rotating in general surgery per year to the number of attending surgeons was determined as a measure of available supervision. RESULT: The mean total number of general surgical residents per year was 31.2 (range 28-35). The numbers of core general surgical procedures were consistent over the years of study. Potential exposure of eligible residents to each core procedure during their entire training was: 19.5 cases for incision and drainage of superficial abscess; 89 cases for laparoscopic appendectomy; 113.6 for inguinal hernia repair, 267.5 for laparoscopic cholecystectomy and 64.5 for perianal procedures. The average yearly residents to full-time attending surgeons' ratio was 2.5. The workload of core general surgical procedures at AKUH was higher than the Accreditation Council for Graduate Medical Education (ACGME) recommended volumes for operative surgical experience for residents in the US. CONCLUSION: This method of assessing the potential of a surgical program for transitioning to CBE appears practical and can be generalized.

Hepatic posttranscriptional network comprised of CCR4-NOT deadenylase and FGF21 maintains systemic metabolic homeostasis.

Whole-body metabolic homeostasis is tightly controlled by hormone-like factors with systemic or paracrine effects that are derived from nonendocrine organs, including adipose tissue (adipokines) and liver (hepatokines). Fibroblast growth factor 21 (FGF21) is a hormone-like protein, which is emerging as a major regulator of whole-body metabolism and has therapeutic potential for treating metabolic syndrome. However, the mechanisms that control FGF21 levels are not fully understood. Herein, we demonstrate that FGF21 production in the liver is regulated via a posttranscriptional network consisting of the CCR4-NOT deadenylase complex and RNA-binding protein tristetraprolin (TTP). In response to nutrient uptake, CCR4-NOT cooperates with TTP to degrade AU-rich mRNAs that encode pivotal metabolic regulators, including FGF21. Disruption of CCR4-NOT activity in the liver, by deletion of the catalytic subunit CNOT6L, increases serum FGF21 levels, which ameliorates diet-induced metabolic disorders and enhances energy expenditure without disrupting bone homeostasis. Taken together, our study describes a hepatic CCR4-NOT/FGF21 axis as a hitherto unrecognized systemic regulator of metabolism and suggests that hepatic CCR4-NOT may serve as a target for devising therapeutic strategies in metabolic syndrome and related morbidities.

The evolving role of digital media in medical education.

Within the last decade, social media has progressed from a form of mere entertainment to a medium for solution of complex issues in our daily lives. During the last few years, social media has gained value in medical education and the diversity in the use of digital media has given new dimensions to medical education while facing the Covid pandemic. Digital media helps in creating virtual communities which not only bring more harmony between teachers and students but has also shown to have reduced anxiety and stress among students. Common social media platforms such as Facebook and WhatsApp have recently gained popularity as platforms which are being actively used in various ways to enhance learning. Social media in medical education is also utilised to enhance communication skills, professionalism and better patient care, but this should be addressed with caution as violation of patient's privacy and confidentiality remains a threat.

Role of simulation in open varicose veins surgery: A systematic review.

OBJECTIVE: To assess the types and effectiveness of simulators present for open varicose vein surgery. METHODS: The systematic review was conducted at The Aga Khan University Hospital Karachi and comprised studies published from 1st January 2000 to 30th June 2020 related to open varicose vein surgical procedures done on simulators. Databases searched were PubMed, Medline, Google Scholar, Cochrane and Scopus using appropriate key words. The primary outcome of the review was to assess the effectiveness of different types of simulators used for varicose vein surgery. RESULTS: Of the 286 articles found, 6(2%) were included. A variety of simulators ranging from animal models, homemade simulators and commercially designed models with high fidelity options had been used. Technical competence was the major domain assessed in most of the studies 5(83.3%), while 1(16.6%) study focussed on self-assessment. Blinding was done in 4(66.6%) studies for assessment purpose, and videorecording of the trainees' performance was done in 5(83.3%) studies. Most studies 4(66.6%) found the use of simulation to be an effective tool in achieving technical competence. CONCLUSION: The use of simulation in the training of surgical residents for open varicose vein surgery was found to be beneficial, but most studies were heterogeneous in terms of design, simulator types and study participants. This makes it difficult to establish the superiority of any one type of simulator over the rest. Further research is needed to develop and validate simulators in open varicose vein surgery procedures.

Barriers in surgical research: A perspective from the developing world.

Research in surgery has led to significant advances over the last century in terms of how medicine is practised in and outside the operating rooms today. Surgical research in the developed countries is responsible for most of this advancement, but it is often inapplicable in resource-limited settings in the developing world. Lower- and middle-income countries are in a unique position to take this work further, but they are limited by certain barriers. These barriers could broadly be classified under social and cultural, infrastructure, financial, ethical, and personal categories. These barriers are often not fully realised, but can potentially be addressed with concerted efforts to continue the advancement of medicine for everyone.

Clinicians as Leaders: Impact and Challenges.

Healthcare has always been a complex system phenomenon which needs accountability from the leading clinical and management roles. Adequate and competent leadership is recognized as a driving point for a successful healthcare division. Medical professionals taking charge for quality improvement are well placed yet the style to deliver their leadership qualities bears a massive significance. While exceptional clinical prowess is of tremendous importance, harmonious teamwork, inefficiency reduction and patient communication and safety lead to noteworthy health management outcomes. Explores not explains the importance of leadership, qualities and styles of a leader, various leadership theories, the impact of leadership in medical education and the current issues related to medical leadership.

Pharmacophore based drug design and synthesis of oxindole bearing hybrid as anticancer agents.

Dual TK inhibitors have shown significant clinical effects against many tumors, but with unmanageable side effects. Design approach and selectivity of these inhibitors plays substantial role in their potency and side-effects. Understanding the homology of binding sites in targeted receptors, and involvement of signaling proteins after the inhibition might help in producing less toxic but effective inhibitors. Herein, we designed benzylideneindolon-2-one derivatives based on homology modeling in binding sites of VEGFR-2 and EGFR receptors as dual- inhibitor potent anticancer compounds with high selectivity. The benzylideneindolon-2-one derivatives were found to possess conformational switch in form of oxindole, substituted at 2-benzimidazole. Within synthesized compounds, 5b was found most active in in-vitro enzyme inhibition assay against VEGFR-2 and EGFR with highest IC50 value of 6.81 ± 2.55 and 13.04 ± 4.07 nM, respectively. Interestingly, cytotoxicity studies revealed selective toxicity of compound 5b against proliferation of A-431 cell lines (over expressed VEGFR-2 and EGFR) with GI50 value of 0.9 ± 0.66 µM. However, the compounds showed mild to moderate activity in all other cancer cell line in the range of 0.2-100 µM. Further mode of action studies by flow cytometry and western blot on A-431 indicated that they work via apoptosis at S- phase following Bcl/Bax pathway, and cell migration via MMP9. 5b not only suppressed tumor growth but also improved vandetanib associated with weight loss toxicity. Moreover, 5b was found safer than sunitinib and erlotinib with LD50 of 500 mg/kg body weight. These results propose 5b as potential anti-tumor drug with safer profile of conventional inhibitors of VEGFR-2 and EGFR for solid tumors.

Recent progress of 1,3,4-oxadiazoles as anticonvulsants: Future horizons.

Epilepsy is the most common neurological disorder, which affects more than 50 million people worldwide. Despite the development and use of several antiepileptic drugs (AEDs), attempted seizure control fails in almost 30% of the individuals treated. Other patients benefit from seizure control by drug therapy at the expense of dose-related toxicity and side effects. These drawbacks with conventional AEDs demand the need for developing more effective and safer antiseizure agents. As a result, extensive efforts are devoted to design and develop new effective molecules as antiepileptics. This area of research to find more effective and safer AEDs is important and challenging. This review describes the future perspective of various 1,3,4-oxadiazole derivatives as anticonvulsant agents and focuses on the design and development of the new effective molecule.

3'-(4-(Benzyloxy)phenyl)-1'-phenyl-5-(heteroaryl/aryl)-3,4-dihydro-1'H,2H-[3,4'-bipyrazole]-2-carboxamides as EGFR kinase inhibitors: Synthesis, anticancer evaluation, and molecular docking studies.

Pyrazoline-linked carboxamide derivatives were designed, synthesized, and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer activity, and apoptotic and cardiomyopathy toxicity. Compounds 6m and 6n inhibit EGFR kinase at a concentration of 6.5 ± 2.91 and 3.65 ± 0.54 µM, respectively. Some of these compounds showed effects on proliferation, which were also then evaluated against four different human cancer cell lines, that is, MCF-7 (breast cancer), A549 (non-small-cell lung tumor), HCT-116 (colon cancer), and SiHa cells (cancerous tissues of the cervix uteri). The results showed that certain synthetic compounds showed significant inhibitor activity; compounds 6m and 6n were more cytotoxic than doxorubicin against A549 cancer cells, with IC50 values of 10.3 ± 1.07 and 4.6 ± 0.57 µM, respectively. Additionally, compounds 6m and 6n induced apoptosis in A549 cancer cells, as evidenced by 4',6-diamidino-2-phenylindole (DAPI) staining and phase-contrast microscopy. Potency to induce apoptosis by compound 6n was further confirmed by fluorescence-activated cell sorting using Annexin V-FITC and propidium iodide labeling. Compound 6n showed normal cardiomyocytes with no marked sign of pyknotic nuclei in cardiomyopathy and also normal histological appearance of the renal cortex when compared with that of control. Results of molecular docking studies suggested that compounds 6m and 6n can bind to the hinge region of the adenosine triphosphate-binding site of EGFR kinase, like the standard drug erlotinib. Therefore, the present study suggests that compounds 6m and 6n have potent in vitro antitumor activities against the human non-small-cell lung tumor cell line A549, which can be further explored in other cancer cell lines and in animal studies.

Non-operative treatment of hepatic trauma: A changing paradigm. A Six year review of liver trauma patient in a single institute.

OBJECTIVE: To review the managing strategies of adult patients with liver trauma in a tertiary care hospital during a six years period. METHODS: The medical records of all patients admitted with a diagnosis of liver trauma from January 2012 to December 2017 in the Aga Khan University Hospital were retrospectively reviewed. The details of demographic, clinical, and outcome variables including morbidity and mortality rates were noted. RESULTS: A total of 182 patients were admitted at AKUH with liver trauma between January 2012 and December 2017. Twenty-two patients were excluded according to our study criteria. Of 160 patients, 139 were male and 21 were female. One hundred twenty seven (79.4%) patients were less than 45 years of age. Most patients (89.4%) had no comorbids and 48 (44%) arrived at the hospital within 4 hours of injury. Majority, 101 (63.1%) of the patients had blunt trauma and 142 (89%) met with road accidents. A total of 109 (68.1%) patients were stable at arrival and 77 (48.1%) had abdominal signs present on examination. FAST ultrasound was done on 75 (46.9%) patients and CT scan abdomen on 145 (90.6 %) patients. Liver injuries were associated with other abdominal or systemic injuries in 139 (86.6%) patients. Low grade (Grade I & II) liver injuries were found in only 41 (25.6%) patients, with the remainder being high grade (Grade III- 41 patients, Grade IV-42 patients and Grade V-2 patients). Conservative treatment was offered to 68 (41.9%) patients, of which 57 (85.1%) remained stable and were eventually discharged. Of these, 2 expired and 3 required intervention. There were a total of 92 (57.2%) interventions done of which 60 patients were cured, 14 expired and 18 readmitted. Interventions included perihepatic packing (n=18), hepatorraphy (n=3), angioembolization (n=12) and hepatectomy (n=1). There were 16(10%) deaths in which liver haemorrhage and sepsis were the most common cause of mortality. Mean hospital stay in our study population was 8.9 days. Second admission was observed in 28 (17.5%) patients (n=28). Morbidity rate in our patients was 17.5% (n=28). The most common complication noted was that of a liver abscess, developing in 2 (1.3%) patients. Other significant problems were intra-abdominal collections (n=2) and biliary complications (n=3). Unstable haemodynamic status at arrival and prolonged stay in high dependency unit were noted to be independent risk factors for mortality. CONCLUSIONS: Conservative treatment was found successful in most of our patients with an intervention rate of 57.5% and overall mortality rate of 10%. So, NOMLI can be safely offered to liver trauma patients, even in high grade injuries.

Changing face of trauma and surgical training in a developing country: A literature review.

Trauma continues to be the major cause of disability and death globally and surgeons are often involved in immediate care. However there has been an exponential decrease in the number of the trained trauma surgeons. The purpose of the current review article is to summarize the published literature pertaining to trauma education in postgraduate surgical training programmes internationally and in a developing country as Pakistan. Several electronic databases like MEDLINE, PubMed, Google scholar and PakMediNet were searched using the keywords 'trauma education' or 'trauma training' AND 'postgraduate medical education', 'surgery residency training', 'surgery residents' and 'surgeons'. The current training in most surgical residency programmes, locally and globally, is suboptimal. Change in trauma management protocols, and decrease in volume of trauma cases results in variable and/ or inadequate exposure and hands-on experience of the surgical trainees in operative and non-operative management of trauma. This warrants collaborative measures for integration of innovative educational interventions at all levels of the surgical educational programmes.

Novel 9-(2-(1-arylethylidene)hydrazinyl)acridine derivatives: Target Topoisomerase 1 and growth inhibition of HeLa cancer cells.

A series of 9-(2-(1-arylethylidene)hydrazinyl)acridine and its analogs were designed, synthesized and evaluated for biological activities. Various biochemical assays were performed to determine the free radical scavenging capacity of synthesized compounds (4a-4j). Anticancer activity of these compounds was assessed against two different human cancer cell lines viz cervical cancer cells (HeLa) and liver cancer cells (HepG2) as well as normal human embryonic kidney cell line (HEK 293). Compounds 4b, 4d and 4e showed potential anti-proliferative effects on HeLa cells. Based on results obtained from antioxidant and cytotoxicity studies, 4b, 4d and 4e were further studied in detail for different biological activities. 4b, 4d and 4e reduced the cell growth, inhibited metastatic activity and declined the potential of cell migration in HeLa cell lines. Topoisomerase1 (Top1) treated with compounds 4b, 4d and 4e exhibited inhibition of Top1 and prevented DNA replication. Molecular docking results validate that interaction of compounds 4b, 4d and 4e with Top1-DNA complex, which might be accountable for their inhibitory effects. Further it was concluded that compounds 4b, 4d and 4e arrests the cells at S phase and consequently induces cell death through DNA damage in HeLa cells.