Breaking barriers to remain healthy and fit during a residency in anaesthesiology.

Anaesthesiology is a high-demand speciality of medicine in terms of long and unpredictable work hours, stressful work requirements, pressure for a cent per cent productivity in academics, clinical work and research. Higher stress levels can cause non-communicable diseases like hypertension, obesity and depressed immunity, among many others. In the journey as a trainee anaesthetist, vigorous and diligent efforts are needed to gain perfection in knowledge and skills ultimately. While this path is being transversed, it is essential to address physical and mental fitness by exercising it to the recommended benefits, to ward away stress and burnout. In this special article, the authors will discuss the barriers young anaesthesia trainees face to staying healthy and fit during their training and practical and appropriate measures to mitigate the same through intervention at various levels of hierarchy.

COVID-19 pneumonia in kyphoscoliosis: The success stories.

Coronavirus disease (COVID-19) pandemic has led to millions of deaths worldwide. Old age, immunocompromised state and multiple comorbidities are described as risk factors. Kyphoscoliosis (KS) is the most common spine abnormality and a risk factor of respiratory failure. Management of pneumonia in a patient with severe kyphoscoliosis is challenging to the intensivist. We report successful management of two patients with severe kyphoscoliosis who developed severe COVID-19 pneumonia.

Structural insights on binding mechanism of CAD complexes (CPSase, ATCase and DHOase).

Pyrimidine biosynthetic pathway enzymes constitute an important target for the development of antitumor drugs. To understand the role of binding mechanisms underlying the inborn errors of pyrimidine biosynthetic pathway, structure and function of enzymes have been analyzed. Pyrimidine biosynthetic pathway is initiated by CAD enzymes that harbor the first three enzymatic activities facilitated by Carbamoyl Phosphate Synthetase (CPSase), Aspartate Transcarbamoylase (ATCase) and Dihydroorotase (DHOase). While being an attractive therapeutic target, the lack of data driven us to study the CPSase (CarA and CarB) and its mode of binding to ATCase and DHOase which are the major limitation for its structural optimization. Understanding the binding mode of CPSase, ATCase and DHOase could help to identify the potential interface hotspot residues that favor the mechanism behind it. The mechanistic insight into the CAD complexes were achieved through Molecular modeling, Protein-Protein docking, Alanine scanning and Molecular dynamics (MD) Studies. The hotspot residues present in the CarB region of carboxy phosphate and carbamoyl phosphate synthetic domains are responsible for the assembly of CAD (CPSase-ATCase-DHOase) complexes. Overall analysis suggests that the identified hotspot residues were confirmed by alanine scanning and important for the regulation of pyrimidine biosynthesis. MD simulations analysis provided the prolonged stability of the interacting complexes. The present study reveals the novel hotspot residues such as Glu134, Glu147, Glu154, Asp266, Lys269, Glu274, Asp333, Trp459, Asp526, Asp528, Glu533, Glu544, Glu546, Glu800, Val855, Asp877, Tyr884 and Gln919 which could be targeted for structure-based inhibitor design to potentiate the CAD mediated regulation of aggressive tumors.Communicated by Ramaswamy H. Sarma.

Structural and functional insights of STAT2-NS5 interaction for the identification of NS5 antagonist - An approach for restoring interferon signaling.

Dengue is a mosquito-borne viral infection caused by Dengue virus (DENV) and is an emerging concern in public health affecting billions of people worldwide annually with no effective drugs available till now. Immunogenic and highly conserved properties of Non-Structural Protein 5(NS5) in DENV makes it a potent marker to identify DENV infection. DENV interfere in the innate immune signaling and thereby decreases antiviral responses and favors viral replication. Viral recognition by host pathogen recognition receptors facilitates binding of interferon (IFN) to the interferon receptors that further activates both the Signal Transducer and Activator of Transcription-2 (STAT-2) a factor producing an antiviral response. The most debilitating factor of DENV infection is emaciation of human immune system by DENV- NS5. NS5 counters the antiviral response by STAT2 degradation impeding the transcriptional activation of interferon stimulated genes through interferon stimulated response elements. The present study aims to identify inhibitors for NS5 Methyl Transferase (MTase) domain and to provide an insight into the mechanism of STAT2 degradation in the host infected with DENV. Virtual screening and molecular docking studies identified five potential inhibitors ZINC84154300, ZINC08762321, ZINC08762323, ZINC12659408 and ZINC12285470 with docking scores of -10.55, -10.53, -10.78, -11.28 and -10.78 kcal/mol respectively. To further investigate the stability of the complexes, we have used Molecular Dynamics Simulations (MD). Besides, the binding free energy of top 5 docked ligands were estimated through Molecular Mechanics Generalized Born and Surface Area Solvation (MM/GBSA) methods. This study also provides an insight on the mechanism of immunological processes involved in alleviating the antiviral immune response and computational identification of potent inhibitors for viral NS5 protein.

Insights into Exogenous Tryptophan-Mediated Allosteric Communication and Helical Transition of TRP Protein for Transcription Regulation.

In this study, the binding recognition and allosteric mechanism of tryptophan-responsive regulatory protein (TRP)-DNA and bound exogenous tryptophan (Trp) amino acid complexes for transcriptional regulation were explained through the molecular docking, molecular dynamics (MD), free-energy landscape (FEL), binding free energy (molecular mechanics Poisson-Boltzmann surface area, MMPBSA), and protein structural network (PSN) analyses. The domain transition of helix-turn-helix (HTH) and effector binding domain (EBD) of TRP protein is the vital process for allosteric network communication, DNA recognition, and transcription. TRP protein consists of four putative active site pockets (Act1, Act2, Act3, and Act4) with the binding specificity of exogenous Trp amino acid, which modulates the binding energy of TRP-DNA complexes by conferring the specific residual network and internal helical orientation of DNA-binding domain (DBD) for regulatory mechanism. In the TRP-DNA complex, interaction of Arg28 (helix-1) and Arg36 (helix-2) with the DNA molecule plays a vital role in DNA recognition. As a consequence, allosteric induction of exogenous Trp in the Act3 binding site retains the structural integrity and is quite comfortable with DNA major groove; therefore, it produces less binding energy for complex formation and may involve in oligomeric association for transcription regulation. Meanwhile, Trp in the Act1 binding site induces high helical orientation and fluctuations, leading to dissociation of DNA from the TRP protein. The remaining two complexes of Trp with Act2 and Act4 are predicted to partially affect the transcription mechanism. The present study aims to unravel the role of exogenous Trp amino acid in TRP protein for transcriptional regulatory mechanism.

Comparative Study of Oral Midazolam Syrup and Intranasal Midazolam Spray for Sedative Premedication in Pediatric Surgeries.

INTRODUCTION: Midazolam is a water-soluble benzodiazepine which is frequently administered by intravenous and oral routes. Its nasal spray has become recently available. MATERIALS AND METHODS: In this study, after obtaining clearance from the ethical committe, 66 patients between the age group of 4 and 10 years comparable in demographic variables were randomly allocated into two groups of 33 each. Group "O" received oral midazolam (0.5 mg/kg) 20 min before induction. Group "N" received intranasal midazolam (0.2 mg/kg) 20 min before induction. The heart rate and blood pressure (systolic, diastolic, and mean) and oxygen saturation (SPO2) were recorded. STATISTICAL ANALYSIS USED: The statistical analysis was done using SPSS (Statistical Package for the Social Sciences) version 15.0 software. The values were represented in number (%) and mean±sd. RESULTS: Satisfactory sedation scores were better in nasal spray group than oral group. Satisfactory ease of induction scores, recovery times, and postanesthesia recovery scores were better in the nasal spray group than in the oral group. CONCLUSION: Nasal midazolam spray is acceptable and is a good alternative to oral midazolam as premedication in the pediatric population.

Comparison of Epidural Bupivacaine and Dexmedetomidine with Bupivacaine and Fentanyl for Postoperative Pain Relief in Lower Limb Orthopedic Surgery.

CONTEXT: Different trials have shown that multimodal analgesia through different techniques is associated with superior pain relief. Opioids as epidural adjunct to local anesthetics have been in use for long and α2 agonists are being increasingly used for same. The present study aims at comparing the hemodynamic, sedative, and analgesic effects of epidurally administered fentanyl and dexmedetomidine when combined with bupivacaine. AIMS: The aim of this study was to compare the efficacy of epidural dexmedetomidine with bupivacaine versus epidural fentanyl with bupivacaine for postoperative pain relief. SUBJECTS AND METHODS: In this ongoing randomized double-blind study, 70 patients with ASA physical status classes I and II of either sex between 20 and 60 years scheduled for lower limb orthopedic surgeries under epidural block were randomly divided into two Groups (n = 35). After epidural block with 15 ml of 0.5% bupivacaine, Group I received 1 µg/kg of fentanyl and Group II received 1 µg/kg of dexmedetomidine. Onset and duration of sensory block, motor block, and time to request for the first postoperative analgesia were recorded. STATISTICAL ANALYSIS USED: The statistical analysis was performed using SPSS (Statistical Package for the Social Sciences) Version 15.0 Statistical Analysis Software, Mann-Whitney U-test and Chi-square test. RESULTS: The time to achieve T10 sensory block was early in Group I (dexmedetomidine) (8.10 + 1.03 min) as compared to Group II (15.03 + 1.67 min). Onset of motor was earlier in Group I (15.10 + 1.49 min) as compared to Group II (22.77 + 1.41 min). In Group I (dexmedetomidine), the majority of patients required 2-3 rescue doses, while in Group II (fentanyl), the majority of patients required 3-4 rescue doses. CONCLUSIONS: Dexmedetomidine seems to be a better alternative to fentanyl as an epidural adjuvant due to early onset of sensory anesthesia, prolonged postoperative analgesia, and lower consumption of rescue analgesia.

Molecular dynamics and quantum chemistry-based approaches to identify isoform selective HDAC2 inhibitor - a novel target to prevent Alzheimer's disease.

Histone deacetylase 2 (HDAC2) is an emerging target of Alzheimer's disease. Four featured pharmacophore model (ADRR) with one H-bond acceptor (A), one H-bond donor (D), and two aromatic rings (R) was generated using experimentally reported compounds, ((E-5[3-benzenesulfonamido) phenyl]-N-hydroxypent-2-en-4-ynamide)) and (N'-hydroxy-N-phenyloctanediamide) with IC50 values of 0.16 ± 0.11 nM and 62 ± 0.15 nM, respectively. Quantum Polarized Ligand Docking and Binding Free Energy calculation was performed for the top three identified leads RH01652, JFD02573, and HTS00800 from HitFinder database. RH01652 (methyl 2-[({5-[(benzoylamino) methyl]-2-thienyl} sulfonyl) amino]-3-(1H-indol-3-yl) propanoate) with docking score (-12.62 kcal/mol) and binding free energy (-75.27 kcal/mol), shows good binding affinity. RH01652 interacts with Gly154, His183, Glu208, and Phe210 with four H-bonds and stabilized by π-π interactions with His146, Tyr209, and Phe210. DFT studies at B3LYP level with 6-31G* basis set for the lead RH01652 reveals low band gap/ΔE (EHOMO-ELUMO) of -0.16 eV, which illustrates good reactivity of the lead. MD simulation studies (40 ns) was performed to confirm the stability of lead binding. Comparative molecular docking studies of the lead RH01652 with class I HDACs (HDAC1, HDAC2, HDAC3, and HDAC8) shows higher binding affinity towards HDAC2. Thus, lead RH01652 could serve as template to design novel and potent inhibitor of HDAC2.

Preemptive Epidural Analgesia for Postoperative Pain Relief Revisited: Comparison of Combination of Buprenorphine and Neostigmine with Combination of Buprenorphine and Ketamine in Lower Abdominal Surgeries, A Double-blind Randomized Trial.

CONTEXT: Postoperative pain relief provides subjective comfort to patient in addition to blunting of autonomic and somatic reflex responses to pain, subsequently enhancing restoration of function by allowing the patient to breathe, cough, and move easily. AIMS: The aim is to evaluate and compare the effects of neostigmine + buprenorphine and ketamine + buprenorphine for preemptive epidural analgesia for postoperative pain relief in patients undergoing abdominal surgeries under general anesthesia (GA). SETTINGS AND DESIGN: A double-blind randomized trial. SUBJECTS AND METHODS: A total of 60 American Society of Anesthesiologists physical status Classes I and II patients undergoing abdominal surgeries under GA were taken up for the study. They were randomly allocated into two groups, Group A and Group B of thirty patients each. Preemptive epidural analgesia for postoperative pain relief was provided by a combination of neostigmine 1 µg/kg + buprenorphine 2 µg/kg in Group A patients and ketamine 1 mg/kg + buprenorphine 2 µg/kg in Group B patients after induction of GA but before surgical incision. Postoperatively, vital parameters, pain score, requirement of top up doses, and side effects in the two groups were observed and recorded at 2, 4, 6, 10, 18, and 22 h. STATISTICAL ANALYSIS USED: Mean values within each of the Group A and Group B were compared using one-way analysis of variance (one-way ANOVA). Mean values between Group A and Group B were compared using double analysis of variance (two-way ANOVA). RESULTS: Group A patients had a significant analgesia (visual analog scale [VAS] pain scores reduced significantly from 54.6 ± 6.3 at 2 h to 8.1 ± 8.9 at 22 h postoperatively). Group B patients had significant analgesia too (VAS pain scores reduced significantly from 36 ± 12.5 at 2 h to 5.3 ± 10.9 at 22 h postoperatively). There was however no significant difference between the two groups with respect to the degree of postoperative analgesia on comparison of VAS scores, effect on vital parameters, and incidence of side effects. CONCLUSIONS: Either of the two combinations, neostigmine 1 µg/kg + buprenorphine µg/kg or ketamine 1 mg/kg + buprenorphine 2 µg/kg can be safely used for preemptive epidural analgesia for postoperative pain relief in patients undergoing abdominal surgeries under GA.

To Evaluate the Efficacy of Intravenous Infusion of Dexmedetomidine as Premedication in Attenuating the Rise of Intraocular Pressure Caused by Succinylcholine in Patients Undergoing Rapid Sequence Induction for General Anesthesia: A Randomized Study.

CONTEXT: Laryngoscopy and intubation performed during RSI lead to choroidal blood volume increase and an eventual rise in intraocular pressure (IOP). Use of succinylcholine (SCh) causes an undesirable rise in IOP which is further aggravated by laryngoscopy and endotracheal intubation. Dexmedetomidine is a highly selective centrally acting α2 adrenergic agonist that has IOP lowering properties. AIMS: This study aims to evaluate the efficacy of intravenous (i.v.) infusion of dexmedetomidine (0.5 µg/kg) as premedication in attenuating the rise of IOP and adverse effect if any caused by SCh in patients undergoing RSI for general anesthesia. SETTINGS AND DESIGN: This was a double-blind, randomized trial. SUBJECTS AND METHODS: Sixty adult patients in the age group of 20-50 years scheduled for elective surgeries under general anesthesia. Group I (dexmedetomidine group) (n = 30) received i.v. infusion of dexmedetomidine (0.5 µg/kg) and Group II (control group) (n = 30) received i.v. infusion of 50 ml normal saline as premedication. STATISTICAL ANALYSIS USED: The analysis was done using Statistical Package for Social Sciences Version 15.0 statistical Analysis Software. RESULTS: It was observed that Group I (dexmedetomidine group) had a better attenuating effect over the increases in IOP in patients undergoing RSI for general anesthesia using SCh. An increase in IOP was seen in Group II (control group) patients with RSI. CONCLUSIONS: The findings in the present study indicate that i.v. dexmedetomidine effectively attenuates the increases in IOP with an additional advantage of control on hemodynamic responses following RSI.

Efficacy of Oral Transmucosal Fentanyl Citrate for Premedication in Patients for Surgery under General Anesthesia.

BACKGROUND: Oral transmucosal fentanyl citrate (OTFC), a water soluble salt when mixed in saliva is 80% nonionized; making it the only opioid suitable for transmucosal absorption. OTFC has rapid onset of action (3-5 min) with peak effect at 20-40 min and total duration of activity is 2-3 h. AIMS: This study aims to determine the efficacy of OTFC as premedicant in patients scheduled for surgery under general anesthesia (GA) and to assess the effects of OTFC on anxiety, sedation. SETTINGS AND DESIGN: A prospective randomized study. SUBJECTS AND METHODS: Patients between 21 and 60 years of age in American Society of Anesthesiologists physical status Classes I and II scheduled for elective surgery under GA were randomly assigned to three groups of 30 each: OTFC, placebo, and control. Mean arterial blood pressure (MAP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO2) along with anxiety and sedation scores were recorded as baseline and upon entering the operation theater. Adverse effects were also recorded. STATISTICAL ANALYSIS USED: Statistical analysis was done using Statistical Package for Social Sciences Version 15.0 Statistical Analysis Software. RESULTS: No significant differences were found in MAP, HR, RR, or SpO2 among the groups. OTFC group demonstrated significantly higher levels of anxiolysis than the control group (P < 0.05). No significant difference in sedation score was found. No remarkable adverse effects were observed. CONCLUSIONS: OTFC is an effective anxiolytic in adult with minimal risks and side effects. It is readily acceptable by the patients in its given form.

A Comparative Study of Dexmedetomidine and Diltiazem for Attenuating Pressor Responses to Laryngoscopy and Endotracheal Intubation: A Double-blind, Randomized Study.

CONTEXT: Endotracheal intubation has been suggested to be one of the most invasive stimuli in anesthesia, particularly during induction and after tracheal intubation. The present study aims to evaluate the efficacy of dexmedetomidine as compared to diltiazem on hemodynamic response to laryngoscopy and intubation. AIMS: To assess and compare the hemodynamic response of dexmedetomidine as compared to diltiazem in patients undergoing laryngoscopy and intubation and rate and type of side effects of the drugs if any. SETTINGS AND DESIGN: This study design was a prospective, randomized, and double-blind trial. SUBJECTS AND METHODS: The patients were randomly allocated into three groups: Group I (control), Group II (dexmedetomidine), and Group III (diltiazem) of 45 patients each. Group I (n = 45): 0.9% NaCl 10 ml was given to the patients over 10 min before intubation in Group I (control). Group II (n = 45): injection dexmedetomidine (0.5 µg/kg) in 10 ml normal saline was given to the patients over 10 min before intubation. Group III (n = 45): injection diltiazem (0.3 mg/kg) in 10 ml normal saline was given to the patients over 10 min before intubation. STATISTICAL ANALYSIS USED: The data so collected were subjected to statistical analysis using Statistical Package for the Social Sciences version 15.0. RESULTS: Mean percentage increase in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) following intubation was 17.90%, 19.96%, and 19.04%, respectively, in control group, 9.04%, 6.32%, and 7.53%, respectively, in dexmedetomidine group, and 12.30%, 10.32%, and 11.14%, respectively, in diltiazem groups. Statistically, there was a significant difference in postintubation SBP, DBP, and MAP of the three groups (P < 0.001). Dexmedetomidine at a dose of 0.5 µg/kg showed to have a better attenuation of pressor response as compared to diltiazem at a dose of 0.3 µg/kg. CONCLUSIONS: Both dexmedetomidine and diltiazem were safe and effective in attenuating the hemodynamic response following laryngoscopy and endotracheal intubation; however, between two trial drugs, dexmedetomidine had a better response.

To Evaluate the Efficacy of Fentanyl and Dexmedetomidine as Adjuvant to Ropivacaine in Brachial Plexus Block: A Double-blind, Prospective, Randomized Study.

CONTEXT: Anesthesia and analgesia for surgeries to the upper extremity are commonly provided using brachial plexus anesthesia. There are limited or almost no studies comparing the use of ropivacaine with fentanyl to ropivacaine with dexmedetomidine. AIMS: To compare the efficacy of fentanyl and dexmedetomidine as adjuvants to ropivacaine for brachial plexus block among patients undergoing upper limb orthopedic surgeries. SETTINGS AND DESIGN: This was a prospective, randomized, double-blinded study. SUBJECTS AND METHODS: The patients were randomly divided into three groups of 35 each using computerized randomization table. Group I patients received 3 mg/kg of 0.75% ropivacaine with 1 µg/kg of fentanyl diluted with normal saline (NS) to make a total volume of 35 ml. Group II patients received 3 mg/kg of 0.75% ropivacaine with 1 µg/kg of dexmedetomidine diluted with NS to make a total volume of 35 ml. Group III patients received 3 mg/kg of 0.75% ropivacaine with NS making a total volume of 35 ml. STATISTICAL ANALYSIS USED: Statistical analysis was performed using Statistical Package for Social Sciences, version 15.0. Analysis of variance followed by independent samples t-test was performed for parametric data, and Kruskal-Wallis test followed by Mann-Whitney U-test was performed for nonparametric data. RESULTS: Mean motor and sensory block onset time was minimum in Group I and maximum in Group III while mean duration of sensory and motor block was maximum in Group I and minimum in Group III. Time taken for first rescue analgesic dose was also maximum in Group I and minimum in Group III. CONCLUSIONS: It can be concluded that 3 mg/kg of 0.75% ropivacaine along with 1 µg/kg of fentanyl diluted with NS to make a total volume of 35 ml was the most efficacious regimen for brachial plexus block among patients undergoing upper limb orthopedic surgeries.

Molecular modeling, dynamics studies and density functional theory approaches to identify potential inhibitors of SIRT4 protein from Homo sapiens : a novel target for the treatment of type 2 diabetes.

Type 2 diabetes is one of the biggest health challenges in the world and WHO projects it to be the 7th leading cause of death in 2030. It is a chronic condition affecting the way our body metabolizes sugar. Insulin resistance is high risk factor marked by expression of Lipoprotein Lipases and Peroxisome Proliferator-Activated Receptor that predisposes to type 2 diabetes. AMP-dependent protein kinase in AMPK signaling pathway is a central sensor of energy status. Deregulation of AMPK signaling leads to inflammation, oxidative stress, and deactivation of autophagy which are implicated in pathogenesis of insulin resistance. SIRT4 protein deactivates AMPK as well as directly inhibits insulin secretion. SIRT4 overexpression leads to dyslipidimeia, decreased fatty acid oxidation, and lipogenesis which are the characteristic features of insulin resistance promoting type 2 diabetes. This makes SIRT4 a novel therapeutic target to control type 2 diabetes. Virtual screening and molecular docking studies were performed to obtain potential ligands. To further optimize the geometry of protein-ligand complexes Quantum Polarized Ligand Docking was performed. Binding Free Energy was calculated for the top three ligand molecules. In view of exploring the stereoelectronic features of the ligand, density functional theory approach was implemented at B3LYP/6-31G* level. 30 ns MD simulation studies of the protein-ligand complexes were done. The present research work proposes ZINC12421989 as potential inhibitor of SIRT4 with docking score (-7.54 kcal/mol), docking energy (-51.34 kcal/mol), binding free energy (-70.21 kcal/mol), and comparatively low energy gap (-0.1786 eV) for HOMO and LUMO indicating reactivity of the lead molecule.

Comparison of ropivacaine with levobupivacaine under epidural anesthesia in the lower limb orthopedic surgeries: A randomized study.

CONTEXT: Epidural anesthesia is nowadays considered as the gold standard anesthetic technique for lower limb orthopedic surgeries, and the present study was conducted to evaluate the efficacy of levobupivacaine and ropivacaine in terms of onset, duration of sensory and motor block with duration of postoperative analgesia in patients undergoing lower limb orthopedic surgeries under epidural anesthesia. AIMS: To compare the efficacy of 15 mL of levobupivacaine 0.5% with that of 15 mL of ropivacaine 0.75% in patients undergoing lower limb orthopedic surgeries under epidural anesthesia and to determine the better of the two agents with respect to onset, duration of sensory and motor blockade, postoperative analgesia, and adverse effects; if any. SETTINGS AND DESIGN: A double-blind randomized study. SUBJECTS AND METHODS: A total of seventy patients planned to undergo elective lower limb orthopedic surgeries fulfilling the criteria were enrolled in the study. Group I (n = 35): Received 15 mL 0.5% levobupivacaine epidurally. Group II (n = 35): Received 15 mL 0.75% ropivacaine epidurally. STATISTICAL ANALYSIS: Statistical Analysis was done by Statistical Package for Social Sciences (SPSS Version 15.0) statistical analysis software. The values were represented in number (%) and mean ± standard deviation. RESULTS: Time to achieve sensory onset and motor onset were significantly lower in Group II (17.86 ± 2.51 and 23.14 ± 2.73) as compared to Group I (26.14 ± 2.45 and 31.43 ± 2.59) while the duration of sensory block was significantly higher in Group II (173.29 ± 6.29 min) as compared to Group I (156.71 ± 6.96 min). Although motor block duration of Group I (142.43 ± 8.43 min) was higher than that of Group II (141.43 ± 12.81 min), but this difference was not found to be statistically significant. CONCLUSIONS: The inference drawn from this discussion, in general, indicated that both the drugs are comparable for block onset, quality, and duration along with similar hemodynamic profile when given in same concentration. However, relatively better response of ropivacaine for block onset and duration as obtained in the present study coupled with higher but statistically.

A mechanistic approach to explore novel HDAC1 inhibitor using pharmacophore modeling, 3D- QSAR analysis, molecular docking, density functional and molecular dynamics simulation study.

Deregulated epigenetic activity of Histone deacetylase 1 (HDAC1) in tumor development and carcinogenesis pronounces it as promising therapeutic target for cancer treatment. HDAC1 has recently captured the attention of researchers owing to its decisive role in multiple types of cancer. In the present study a multistep framework combining ligand based 3D-QSAR, molecular docking and Molecular Dynamics (MD) simulation studies were performed to explore potential compound with good HDAC1 binding affinity. Four different pharmacophore hypotheses Hypo1 (AADR), Hypo2 (AAAH), Hypo3 (AAAR) and Hypo4 (ADDR) were obtained. The hypothesis Hypo1 (AADR) with two hydrogen bond acceptors (A), one hydrogen bond donor (D) and one aromatics ring (R) was selected to build 3D-QSAR model on the basis of statistical parameter. The pharmacophore hypothesis produced a statistically significant QSAR model, with co-efficient of correlation r2=0.82 and cross validation correlation co-efficient q2=0.70. External validation result displays high predictive power with r2 (o) value of 0.88 and r2 (m) value of 0.58 to carry out further in silico studies. Virtual screening result shows ZINC70450932 as the most promising lead where HDAC1 interacts with residues Asp99, His178, Tyr204, Phe205 and Leu271 forming seven hydrogen bonds. A high docking score (-11.17kcal/mol) and lower docking energy -37.84kcal/mol) displays the binding efficiency of the ligand. Binding free energy calculation was done using MM/GBSA to access affinity of ligands towards protein. Density Functional Theory was employed to explore electronic features of the ligands describing intramolcular charge transfer reaction. Molecular dynamics simulation studies at 50ns display metal ion (Zn)-ligand interaction which is vital to inhibit the enzymatic activity of the protein.

Mechanical insights of oxythiamine compound as potent inhibitor for human transketolase-like protein 1 (TKTL1 protein).

Transketolase is a connecting link between glycolytic and pentose phosphate pathway, which is considered as the rate-limiting step due to synthesis of large number of ATP molecule and it can be proposed as a plausible target facilitating the growth of cancerous cells suggesting its potential role in cancer. Oxythiamine, an antimetabolite has been proved to be an efficient anticancerous compound in vitro, but its structural elucidation of the inhibitory mechanism has not yet been done against the human transketolase-like 1 protein (TKTL1). The three-dimensional (3D) structure of TKTL1 protein was modeled and subjected for refinement, stability and validation. Based on the reported homologs of transketolase (TKT), the active site residues His46, Ser49, Ser52, Ser53, Ile56, Leu82, Lys84, Leu123, Ser125, Glu128, Asp154, His160, Thr216 and Lys218 were identified and considered for molecular-modeling studies. Docking studies reveal the H-bond interactions with residues Ser49 and Lys218 that could play a major role in the activity of TKTL1. Molecular dynamics (MD) simulation study was performed to reveal the comparative stability of both native and complex forms of TKTL1. MD trajectory at 30 ns, confirm the role of active site residues Ser49, Lys84, Glu128, His160 and Lys218 in suppressing the activity of TKTL1. Glu128 is observed to be the most important residue for deprotonation state of the aminopyrimidine moiety and preferred to be the site of inhibitory action. Thus, the proposed mechanism of inhibition through in silico studies would pave the way for structure-oriented drug designing against cancer.

A comparative study between intrathecal dexmedetomidine and fentanyl as adjuvant to intrathecal bupivacaine in lower abdominal surgeries: A randomized trial.

CONTEXT: Spinal anesthesia is preferred choice of anesthesia in lower abdominal surgeries since long time. However problem with this is limited duration of action, so for long duration surgeries alternative are required. Dexmedetomidine is a highly selective alpha-2-adrenergic agonist has property to potentiate the action of local anesthetic used in spinal anesthesia. Fentanyl is an opioid and it has also the same property. AIMS: To compare the efficacy, analgesic effects, and side-effects of dexmedetomidine and fentanyl as adjuvant to bupivacaine for lower abdominal surgery. SETTINGS AND DESIGN: The type of this study was double-blind randomized trial. SUBJECTS AND METHODS: A total of 80 patients were randomly allocated in two Group D and Group F. Group D were injected injection bupivacaine 0.5% heavy × 3.0 ml + 0.5 ml of preservative free normal saline containing 5 µg dexmedetomidine. Group F were received injection bupivacaine 0.5% heavy × 3.0 ml + 0.5 ml fentanyl equivalent to 25 µg. STATISTICAL ANALYSIS USED: The statistical analysis was performed using SPSS (Statistical Package for Social Sciences) version 15.0 statistical analysis software. RESULTS: The results show that highest sensitivity level of T6 and T8 was achieved by higher proportion of subjects from Group D when compared to Group F and sensitivity level T7 was achieved by higher proportion of subjects of Group F when compared to Group D. Duration of analgesic properties was significantly higher in Group D when compared to Group F. CONCLUSION: The findings in the present study suggested that intrathecal adjuvant use of dexmedetomidine as compared to fentanyl provides a longer sensory and motor blockade and also prolongs the postoperative analgesic effect.