Comparison of the Efficacy of Macintosh Laryngoscope Versus Airtraq Videolaryngoscope for Visualization of Laryngeal Structures at the End of Thyroidectomy: A Randomized Control Study.

To compare the efficacy of conventional Macintosh laryngoscope with Airtraq videolaryngoscope for visualization of laryngeal structures to rule out recurrent laryngeal nerve injury at the end of thyroidectomy. This randomized double-blind control study was conducted following IEC-Human approval, prospective CTRI registration and written informed consent from participants. Patients of either sex, aged 18-65 years, ASA grade I/II, scheduled for thyroidectomy under GA were included. Group DL underwent direct laryngoscopy using Macintosh blade whereas group VL underwent laryngoscopy using Airtraq® videolaryngoscope. CL(Cormack-Lehane) grade of laryngeal view, time taken to achieve optimal view, haemodynamic parameters, Patient reactivity score(PRS) and complications were noted. Unpaired t-test, chi-square test were used. A total of 73 patients were included for study with 38 in group DL and 35 in group VL. The grade of laryngeal view was found to be significantly better with Airtraq® VL compared to Macintosh laryngoscope without the application of BURP (p < 0.05). In the DL group, 34.2% (n = 13) had a CL grade I, 36.8% (n = 14) had CL grade 2A, 13.2% had CL grade 2B (n = 5) and 15.8% (n = 6) had CL Grade 3 at the end of thyroidectomy. On the contrary, in the VL Group, 71.5% (n = 25) of the participants had a CL Grade I; whereas, 20% (n = 7) had a CL Grade 2A, 5.7% (n = 2) had CL grade 2B and 2.8% (n = 1) of participants had CL grade 3. The mean "time taken to achieve optimal view' was comparable between the two groups (DL = 39.16 ± 105.53 s vs. VL = 38.89 ± 20.69 s) (p = 0.988).The haemodynamic parameters, Patient reactivity score and complications were comparable between the two groups. The performance of Airtraq® videolaryngoscope, a channelled VL is better than conventional Macintosh laryngoscope in terms of the optimal glottic view obtained to rule out recurrent laryngeal nerve palsy at the end of thyroidectomy.

The 2022 FASEB Virtual Catalyst Conference on the Cardiac Interatrial Septum and Stroke Risk, December 7, 2022.

There is emerging evidence that the cardiac interatrial septum has an important role as a thromboembolic source for ischemic strokes. There is little consensus on treatment of patients with different cardiac interatrial morphologies or pathologies who have had stroke. In this paper, we summarize the important background, diagnostic, and treatment considerations for this patient population as presented during the Federation of American Societies for Experimental Biology (FASEB) Virtual Catalytic Conference on the Cardiac Interatrial Septum and Stroke Risk, held on December 7, 2022. During this conference, many aspects of the cardiac interatrial septum were discussed. Among these were the embryogenesis of the interatrial septum and development of anatomic variants such as patent foramen ovale and left atrial septal pouch. Also addressed were various mechanisms of injury such as shunting physiologies and the consequences that can result from anatomic variants, as well as imaging considerations in echocardiography, computed tomography, and magnetic resonance imaging. Treatment options including anticoagulation and closure were addressed, as well as an in-depth discussion on whether the left atrial septal pouch is a stroke risk factor. These issues were discussed and debated by multiple experts from neurology, cardiology, and radiology.

Negative-pressure pulmonary edema after upper airway obstruction during transesophageal echocardiogram.

Negative-pressure pulmonary edema (NPPE) has become a well-recognized, though uncommon, complication of acute upper airway obstruction. While initially described in the setting of peri-operative endotracheal intubation, NPPE has been increasingly observed in numerous other clinical scenarios. In this report, we describe a case of NPPE that occurred after a scheduled cardioversion and transesophageal echocardiogram (TEE). We suspect the attempt at TEE probe placement inadvertently led to tracheal insertion as suggested by excessive resistance, poor visualization, stridor, and subsequent acute pulmonary edema. While supportive treatment when recognized can lead to rapid improvement, it is important to recognize NPPE as a possible complication of this commonly indicated procedure. Learning objective: Excessive resistance is a common challenge during the transesophageal echocardiogram (TEE) procedure and may be the result of incidental tracheal insertion. Negative-pressure pulmonary edema (NPPE) may result from this acute upper airway obstruction. Thus, NPPE should be on the differential for patients who present with unexplained non-cardiogenic pulmonary edema and should be recognized as a possible complication of the TEE procedure.

Cancer induced bone pain: current management and future perspectives.

Recent improvements in the therapeutic armamentarium of oncology by the addition of targeted and immunotherapeutic agents have led to an increase in the life expectancy of advanced-stage cancer patients. This has led to an increased number of patients presenting with bone metastasis and experiencing episodes of cancer-induced bone pain (CIBP). CIBP is a crippling, chronic, morbid state interfering significantly with the functional capacity and the quality of life (QoL). CIBP is characterized by a complex multifactorial pathophysiological mechanism involving tumor cells, bone cells, inflammatory microenvironment, and the neuronal tissue. It may not be possible to mitigate pain completely; therefore, the aim should be to reach the lowest possible level of pain that allows for an acceptable QoL to the patient. Multimodality approach of surgical, radiation, medical and behavioral techniques is thus recommended to manage CIBP. This review discusses the pathogenesis and pathophysiological mechanism accompanying bone metastasis and CIBP, currently approved therapies for the management of CIBP, and the future perspective.

The Left Atrial Septal Pouch: A New Stroke Risk Factor?

The left atrial septal pouch (LASP) occurs due to incomplete fusion of septa primum and secundum at the inter-atrial septum, creating an open flap that may serve as a thromboembolic source. Prior studies have demonstrated increased prevalence of LASP in cryptogenic strokes. The aim of the current study was to validate the above findings in a separate, larger group of stroke and non-stroke patients. We examined transesophageal echocardiograms (TEEs) performed between July 2011 and December 2018. LASP prevalence was determined in TEEs referred for ischemic stroke or transient ischemic attack ("stroke") and compared with LASP prevalence in patients undergoing TEEs for other reasons ("non-stroke"). Stroke subtyping was performed using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. There were 306 TEEs from 144 non-stroke and 162 stroke patients. Mean age and sex distribution were 56 ± 1 (mean ± SE) and 65% male in the non-stroke group and 58 ± 1 and 54% male in the stroke group. The overall prevalence of LASP was 31%. The prevalence of LASP was 28% (41/144) in non-stroke patients, 25% (24/95) in non-cryptogenic stroke patients, and 43% (29/67) in cryptogenic stroke patients. LASP prevalence was significantly higher in the cryptogenic subgroup compared with the non-cryptogenic subgroup (p = 0.02). These findings demonstrate a significant association of LASP with risk of cryptogenic stroke, suggesting that LASP may serve as a thromboembolic nidus. Additional studies are needed to determine the generalizability of these findings, and their therapeutic implications, supporting LASP as a stroke risk factor.

Comparison of nalbuphine versus fentanyl as intrathecal adjuvant to bupivacaine for orthopedic surgeries: A randomized controlled double-blind trial.

Background and Aims: Intrathecal adjuvants are used with local anesthetics to prolong the duration and provide postoperative pain relief while minimizing the dose of local anesthetic. Nalbuphine is an agonist-antagonist opioid and provides prolonged duration of analgesia with fewer side effects of fentanyl such as pruritus, nausea, and vomiting. The aim of this study was to evaluate and compare the onset and duration of sensory and motor blockade, hemodynamic effects, duration of postoperative analgesia, and adverse effects of nalbuphine and fentanyl given intrathecally with hyperbaric 0.5% bupivacaine in orthopedic lower limb surgeries. Material and Methods: Sixty six patients classified in American Society of Anesthesiology (ASA) classes I and II scheduled for orthopedic lower limb surgeries were enrolled. Patients were randomly allocated to receive 15 mg of hyperbaric bupivacaine with either 1 mg nalbuphine (group N), 25 µg fentanyl (group F) or 0.9% normal saline (group C) intrathecally. Results: Patients who received intrathecal nalbuphine (group N) had a significantly delayed onset of sensory and motor block as compared to patients who received fentanyl (group F). The time to two segment regression was significantly prolonged in group F (122.05 ± 10.65 minutes) as compared to group N (114.55 ± 10.90 minutes) [P < 0.05]. The mean duration of motor blockade was significantly prolonged in group F (197.73 ± 15.09 minutes) as compared to group N (180.68 ± 15.68 minutes) [P < 0.05]. Duration of spinal analgesia was comparable in group N (323.18 ± 57.39 minutes) and group F (287.05 ± 78.87 minutes), both significantly more than group C (224.32 ± 42.54 minutes). Hemodynamic effects, 24-h rescue analgesic requirements, and incidence of side effects were comparable among group N and F. Conclusion: Intrathecal nalbuphine in a dose of 1 mg is an equally useful alternative to fentanyl in a dose 25 µg when used as an intrathecal adjuvant to bupivacaine for lower limb surgeries. The prolonged duration of analgesia and no adverse effects makes it a good choice for the orthopedic procedures of lower limb.

Antidepressants are modifiers of lipid bilayer properties.

The two major classes of antidepressants, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), inhibit neurotransmitter reuptake at synapses. They also have off-target effects on proteins other than neurotransmitter transporters, which may contribute to both desired changes in brain function and the development of side effects. Many proteins modulated by antidepressants are bilayer spanning and coupled to the bilayer through hydrophobic interactions such that the conformational changes underlying their function will perturb the surrounding lipid bilayer, with an energetic cost (ΔG def) that varies with changes in bilayer properties. Here, we test whether changes in ΔG def caused by amphiphilic antidepressants partitioning into the bilayer are sufficient to alter membrane protein function. Using gramicidin A (gA) channels to probe whether TCAs and SSRIs alter the bilayer contribution to the free energy difference for the gramicidin monomer⇔dimer equilibrium (representing a well-defined conformational transition), we find that antidepressants alter gA channel activity with varying potency and no stereospecificity but with different effects on bilayer elasticity and intrinsic curvature. Measuring the antidepressant partition coefficients using isothermal titration calorimetry (ITC) or cLogP shows that the bilayer-modifying potency is predicted quite well by the ITC-determined partition coefficients, and channel activity is doubled at an antidepressant/lipid mole ratio of 0.02-0.07. These results suggest a mechanism by which antidepressants could alter the function of diverse membrane proteins by partitioning into cell membranes and thereby altering the bilayer contribution to the energetics of membrane protein conformational changes.

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels.

Drugs do not act solely by canonical ligand-receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure-activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT's membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported.

"Peripherally inserted central catheters: our experience from a cancer research centre".

Peripherally inserted central catheter (PICC) is a modern drug delivery system utilised in oncology practice. The purpose of this study was to determine the complications associated with PICCs within a one year study period. PICCs inserted in patients registered at Dharamshila Cancer Hospital and research centre from 1st July 2012 to 30th June 2013 were studied. Data was retrieved from the procedure room records, medical records department, department of radiology and department of microbiology. Data was collected by oncology residents and procedure team. A total of 246 PICCs were inserted during the one year period. Complete data was not available in 23 patients. 223 results were included in the final analysis. USG guidance was required in 14 patients (6.3%). Optimal PICC duration was achieved in 151 patients (67.7%). 28 patient developed culture positive infective complications (12.5%). 44 patients developed mechanical complications (19.7%). Our study shows a relatively higher rate of infective complications. PICC is an acceptable means of drug delivery system.

Gramicidin-based fluorescence assay; for determining small molecules potential for modifying lipid bilayer properties.

Many drugs and other small molecules used to modulate biological function are amphiphiles that adsorb at the bilayer/solution interface and thereby alter lipid bilayer properties. This is important because membrane proteins are energetically coupled to their host bilayer by hydrophobic interactions. Changes in bilayer properties thus alter membrane protein function, which provides an indirect way for amphiphiles to modulate protein function and a possible mechanism for "off-target" drug effects. We have previously developed an electrophysiological assay for detecting changes in lipid bilayer properties using linear gramicidin channels as probes. Gramicidin channels are mini-proteins formed by the transbilayer dimerization of two non-conducting subunits. They are sensitive to changes in their membrane environment, which makes them powerful probes for monitoring changes in lipid bilayer properties as sensed by bilayer spanning proteins. We now demonstrate a fluorescence assay for detecting changes in bilayer properties using the same channels as probes. The assay is based on measuring the time-course of fluorescence quenching from fluorophore-loaded large unilamellar vesicles due to the entry of a quencher through the gramicidin channels. We use the fluorescence indicator/quencher pair 8-aminonaphthalene-1,3,6-trisulfonate (ANTS)/Tl(+) that has been successfully used in other fluorescence quenching assays. Tl(+) permeates the lipid bilayer slowly but passes readily through conducting gramicidin channels. The method is scalable and suitable for both mechanistic studies and high-throughput screening of small molecules for bilayer-perturbing, and potential "off-target", effects. We find that results using this method are in good agreement with previous electrophysiological results.

Lipid bilayer regulation of membrane protein function: gramicidin channels as molecular force probes.

Membrane protein function is regulated by the host lipid bilayer composition. This regulation may depend on specific chemical interactions between proteins and individual molecules in the bilayer, as well as on non-specific interactions between proteins and the bilayer behaving as a physical entity with collective physical properties (e.g. thickness, intrinsic monolayer curvature or elastic moduli). Studies in physico-chemical model systems have demonstrated that changes in bilayer physical properties can regulate membrane protein function by altering the energetic cost of the bilayer deformation associated with a protein conformational change. This type of regulation is well characterized, and its mechanistic elucidation is an interdisciplinary field bordering on physics, chemistry and biology. Changes in lipid composition that alter bilayer physical properties (including cholesterol, polyunsaturated fatty acids, other lipid metabolites and amphiphiles) regulate a wide range of membrane proteins in a seemingly non-specific manner. The commonality of the changes in protein function suggests an underlying physical mechanism, and recent studies show that at least some of the changes are caused by altered bilayer physical properties. This advance is because of the introduction of new tools for studying lipid bilayer regulation of protein function. The present review provides an introduction to the regulation of membrane protein function by the bilayer physical properties. We further describe the use of gramicidin channels as molecular force probes for studying this mechanism, with a unique ability to discriminate between consequences of changes in monolayer curvature and bilayer elastic moduli.

Single molecule methods for monitoring changes in bilayer elastic properties.

Membrane protein function is regulated by the cell membrane lipid composition. This regulation is due to a combination of specific lipid-protein interactions and more general lipid bilayer-protein interactions. These interactions are particularly important in pharmacological research, as many current pharmaceuticals on the market can alter the lipid bilayer material properties, which can lead to altered membrane protein function. The formation of gramicidin channels are dependent on conformational changes in gramicidin subunits which are in turn dependent on the properties of the lipid. Hence the gramicidin channel current is a reporter of altered properties of the bilayer due to certain compounds.

Preparation of artificial bilayers for electrophysiology experiments.

Planar lipid bilayers, also called artificial lipid bilayers, allow you to study ion-conducting channels in a well-defined environment. These bilayers can be used for many different studies, such as the characterization of membrane-active peptides, the reconstitution of ion channels or investigations on how changes in lipid bilayer properties alter the function of bilayer-spanning channels. Here, we show how to form a planar bilayer and how to isolate small patches from the bilayer, and in a second video will also demonstrate a procedure for using gramicidin channels to determine changes in lipid bilayer elastic properties. We also demonstrate the individual steps needed to prepare the bilayer chamber, the electrodes and how to test that the bilayer is suitable for single-channel measurements.

Variant brain-derived neurotrophic factor (Val66Met) alters adult olfactory bulb neurogenesis and spontaneous olfactory discrimination.

Neurogenesis, the division, migration, and differentiation of new neurons, occurs throughout life. Brain derived neurotrophic factor (BDNF) has been identified as a potential signaling molecule regulating neurogenesis in the subventricular zone (SVZ), but its functional consequences in vivo have not been well defined. We report marked and unexpected deficits in survival but not proliferation of newly born cells of adult knock-in mice containing a variant form of BDNF [a valine (Val) to methionine (Met) substitution at position 66 in the prodomain of BDNF (Val66Met)], a genetic mutation shown to lead to a selective impairment in activity-dependent BDNF secretion. Utilizing knock-out mouse lines, we identified BDNF and tyrosine receptor kinase B (TrkB) as the critical molecules for the observed impairments in neurogenesis, with p75 knock-out mice showing no effect on cell proliferation or survival. We then localized the activated form of TrkB to a discrete population of cells, type A migrating neuroblasts, and demonstrate a decrease in TrkB phosphorylation in the SVZ of Val66Met mutant mice. With these findings, we identify TrkB signaling, potentially through activity dependent release of BDNF, as a critical step in the survival of migrating neuroblasts. Utilizing a behavioral task shown to be sensitive to disruptions in olfactory bulb neurogenesis, we identified specific impairments in spontaneous olfactory discrimination, but not general olfactory sensitivity or habituation to olfactory stimuli in BDNF mutant mice. Through these observations, we have identified novel links between genetic variant BDNF and adult neurogenesis in vivo, which may contribute to significant impairments in olfactory function.