Disease and brain region specific immune response profiles in neurodegenerative diseases with pure and mixed protein pathologies.

The disease-specific accumulation of pathological proteins has long been the major focus of research in neurodegenerative diseases (ND), including Alzheimer's disease (AD) and related dementias (RD), but the recent identification of a multitude of genetic risk factors for ND in immune-associated genes highlights the importance of immune processes in disease pathogenesis and progression. Studies in animal models have characterized the local immune response to disease-specific proteins in AD and ADRD, but due to the complexity of disease processes and the co-existence of multiple protein pathologies in human donor brains, the precise role of immune processes in ND is far from understood. To better characterize the interplay between different extracellular and intracellular protein pathologies and the brain's intrinsic immune system in ND, we set out to comprehensively profile the local immune response in postmortem brain samples of individuals with "pure" beta-Amyloid and tau pathology (AD), "pure" α-Synuclein pathology in Lewy body diseases (LBD), as well as cases with Alzheimer's disease neuropathological changes (ADNC) and Lewy body pathology (MIX). Combining immunohistochemical profiling of microglia and digital image analysis, along with deep immunophenotyping using gene expression profiling on the NanoString nCounter® platform and digital spatial profiling on the NanoString GeoMx® platform we identified a robust immune activation signature in AD brain samples. This signature is maintained in persons with mixed pathologies, irrespective of co-existence of AD pathology and Lewy body (LB) pathology, while LBD brain samples with "pure" LB pathology exhibit an attenuated and distinct immune signature. Our studies highlight disease- and brain region-specific immune response profiles to intracellular and extracellular protein pathologies and further underscore the complexity of neuroimmune interactions in ND.

Noble gas dative bonding with coinage metal carbene complexes: A theoretical study.

The structure and stability of noble gas (Ng) bound [NHCM]+ complexes (M = Cu, Ag, and Au) were investigated using Quantum chemical calculations. Dissociation energies, enthalpy, and free energy changes were computed to comprehend the stability of these Ng-bonded complexes. The nature of interactions associated to the bonding between metal and noble gas atoms was studied through the computation of electron density-based descriptors. Detailed electronic structure study revealed electron donation from the noble gas atoms towards the metal center, resulting in the formation of dative bonds.

Artificial intelligence and machine learning in aneurysmal subarachnoid hemorrhage: Future promises, perils, and practicalities.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (SAH) is a subtype of hemorrhagic stroke with thirty-day mortality as high as 40%. Given the expansion of Machine Learning (ML) and Artificial intelligence (AI) methods in health care, SAH patients desperately need an integrated AI system that detects, segments, and supports clinical decisions based on presentation and severity. OBJECTIVES: This review aims to synthesize the current state of the art of AI and ML tools for the management of SAH patients alongside providing an up-to-date account of future horizons in patient care. METHODS: We performed a systematic review through various databases such as Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, Cochrane Database of Systematic Reviews, and Embase. RESULTS: A total of 507 articles were identified. Following extensive revision, only 21 articles were relevant. Two studies reported improved mortality prediction using Glasgow Coma Scale and biomarkers such as Neutrophil to Lymphocyte Ratio and glucose. One study reported that ffANN is equal to the SAHIT and VASOGRADE scores. One study reported that metabolic biomarkers Ornithine, Symmetric Dimethylarginine, and Dimethylguanidine Valeric acid were associated with poor outcomes. Nine studies reported improved prediction of complications and reduction in latency until intervention using clinical scores and imaging. Four studies reported accurate prediction of aneurysmal rupture based on size, shape, and CNN. One study reported AI-assisted Robotic Transcranial Doppler as a substitute for clinicians. CONCLUSION: AI/ML technologies possess tremendous potential in accelerating SAH systems-of-care. Keeping abreast of developments is vital in advancing timely interventions for critical diseases.

A suspected case of Lyme disease causing complete heart block.

Carditis is a rare complication of Lyme disease and usually presents in the early dissemination phase, several weeks after exposure to a tick bite. Conduction abnormalities are the most common manifestation of Lyme carditis. The presentation can vary from atrioventricular conduction delay (first-degree atrioventricular conduction block) to life-threatening situations, such as a complete heart block. Although such manifestations occur late, our case report describes an interesting case where the patient developed a complete heart block in the setting of acute Lyme disease. An elevated IgM with negative IgG Lyme serology titer, an unusual finding, initially led us to face a diagnostic dilemma. Our suspicion of a tick bite was affirmed when we detected a positive titer for Babesia microti, an organism carried by the same tick and a common co-infection with Lyme disease. The patient improved with antibiotic therapy and temporary pacemaker support during the initial few days of admission.

Solvent Effect on the Photoinduced Intramolecular Charge-Transfer and Redox Potentials of Three Difuranones.

We report solvent-dependent excited state properties of three difuranone derivatives with a quinoidal backbone by steady-state and lifetime fluorescence measurements and theoretical calculations. Remarkable bathochromic shifts in fluorescence with diminished intensity indicate the occurrence of strong intramolecular charge-transfer transitions in high polar solvents. Cyclic voltammetric redox potentials reveal an interesting variation of biradical characters of the compounds with increasing solvent polarity. Solvent polarity also significantly modulates the energy levels of the charge-transfer (CT) states, as observed from the combined analyses of redox potentials and photophysical data via the Rehm-Weller equation. When high polar solvents favor forward CT by a more exoergic driving force and stabilize the charge-separated states, the reverse CT process diminishes. Estimated free energies of activation for CT suggest that high polar solvents lessen the activation barrier. Calculated excited state energies of the compounds at the CAM-B3LYP/6-31+G* level fulfill the primary conditions required for singlet fission, a process that can substantially increase the efficiency of solar cells, and the crystal packing for compound 1 also reveals a favorable geometry for singlet fission.

Multimodal monitoring: practical recommendations (dos and don'ts) in challenging situations and uncertainty.

With the advancements in modern medicine, new methods are being developed to monitor patients in the intensive care unit. Different modalities evaluate different aspects of the patient's physiology and clinical status. The complexity of these modalities often restricts their use to the realm of clinical research, thereby limiting their use in the real world. Understanding their salient features and their limitations can aid physicians in interpreting the concomitant information provided by multiple modalities to make informed decisions that may affect clinical care and outcomes. Here, we present a review of the commonly used methods in the neurological intensive care unit with practical recommendations for their use.

Harlequin syndrome.

A 56-year-old man presented to the clinic with episodic headaches for several years which had been worsening over a few months prior to the presentation. He described headache as sharp, stabbing pain around the left eye associated with nausea, vomiting, photophobia, and phonophobia lasting for hours associated with flushing on the left side of the face. The picture of his face during these episodes showed flushing of the left side of the face, ptosis of the right eyelid, and miosis (panel A). Flushing in his face would resolve with the abortion of the headache. At the time of presentation to the clinic, his neurological exam was only significant for mild left eye ptosis and miosis (panels B and C). Extensive workup including MRI brain, cervical spine, thoracic spine, lumbar spine, CTA head and neck, and CT maxillofacial was unremarkable. He had tried several medications in the past including valproic acid, nortriptyline, and verapamil without significant benefit. He was started on erenumab for migraine prophylaxis and was given sumatriptan for abortive therapy following which his headaches improved. The patient was diagnosed with idiopathic left Horner's syndrome and his migraines with autonomic dysfunction would present with unilateral flushing opposite to the site of Horner's presenting as Harlequin syndrome [1, 2].

Coordination of noble gases by alkali-metal-like superatom cation Be3 B.

Quantum chemical calculations were carried out to investigate the noble gas binding ability of Be3 B+ cluster. Calculations reveal that heavier noble gas atoms (ArXe) form stable complexes with this cluster. Detailed bonding analyses reveal that the noble gas atoms act as donor fragment in the formation of Ng → Be donor-acceptor bonds. Three noble gas atoms can consecutively form bonds with the Be atom of the Be3 B+ cluster.

Outcomes of Hem-o-Lok clip migration at vesico-urethral anastomotic site post-robotic-assisted laparoscopic radical prostatectomy: a single centre experience.

BACKGROUND: Robotic-assisted laparoscopic prostatectomy (RALP) is the most preferred intervention for the management of prostatic malignancy worldwide. Hem-o-Lok clips (HOLC) are widely used for haemostasis and lateral pedicle ligation. These clips are prone to migrate and lodge at the anastomotic junction as well as inside the bladder causing lower urinary tract symptoms (LUTS) secondary to bladder neck contracture (BNC) or bladder calculi. The objective of this study is to describe the incidence, clinical presentation, management, and outcome of HOLC migration. METHODOLOGY: Retrospective analysis of the database of Post RALP patients who developed LUTS secondary to HOLC migration was done. Cystoscopy findings, number of procedures required, number of HOLC removed intra-operatively, and follow-up of the patients was reviewed. RESULTS: The incidence of HOLC migration requiring intervention was 1.78% (9/505). The mean age of the patient, BMI, Pre-operative Serum PSA were 62.8 years, 27.8 kg/m2, and 9.8 ng/mL, respectively. The mean duration of appearance of symptoms due to HOLC migration was 9 months. Two patients presented with Haematuria and 7 presented with LUTS. Seven patients required a single intervention while 2 required up to 6 procedures for recurrent symptoms secondary to recurrent HOLC migration. CONCLUSION: HOLC use in RALP may present with migration and associated complications. HOLC migration is associated with severe BNC and may require multiple endoscopic interventions. Severe dysuria and LUTS not responding to medical management should be treated using an algorithmic approach and there should be a low threshold for performing cystoscopy and intervention in these cases to improve outcomes.

Leptospiral myocarditis and pancreatitis.

While Leptospira are known to cause multi-system dysfunction, cardiac involvement is uncommon. We present a case febrile myocarditis diagnosed to have leptospirosis. The patient also had pancreatitis, jaundice and renal failure but recovered well with timely management.

Closed-loop vasculature network design for bioprinting large, solid tissue scaffolds.

Vascularization is an indispensable requirement for fabricating large solid tissues and organs. The natural vasculature derived from medical imaging modalities for large tissues and organs are highly complex and convoluted. However, the present bioprinting capabilities limit the fabrication of such complex natural vascular networks. Simplified bioprinted vascular networks, on the other hand, lack the capability to sustain large solid tissues. This work proposes a generalized and adaptable numerical model to design the vasculature by utilizing the tissue/organ anatomy. Starting with processing the patient's medical images, organ structure, tissue-specific cues, and key vasculature tethers are determined. An open-source abdomen magnetic resonance image dataset was used in this work. The extracted properties and cues are then used in a mathematical model for guiding the vascular network formation comprising arterial and venous networks. Next, the generated three-dimensional networks are used to simulate the nutrient transport and consumption within the organ over time and the regions deprived of the nutrients are identified. These regions provide cues to evolve and optimize the vasculature in an iterative manner to ensure the availability of the nutrient transport throughout the bioprinted scaffolds. The mass transport of six components of cell culture media-glucose, glycine, glutamine, riboflavin, human serum albumin, and oxygen was studied within the organ with designed vasculature. As the vascular structure underwent iterations, the organ regions deprived of these key components decreased significantly highlighting the increase in structural complexity and efficacy of the designed vasculature. The numerical method presented in this work offers a valuable tool for designing vascular scaffolds to guide the cell growth and maturation of the bioprinted tissues for faster regeneration post bioprinting.

Native fauna interact differently with native and alien trees in a tropical megacity.

The negative effects of invasive alien plant species on natural ecosystems are well known. However, in rapidly growing cities, alien plants can provide native fauna with resources otherwise lost due to the biotic homogenization, which is common to urban ecosystems. Interactions of native fauna with alien flora have thus far focused largely on invertebrate pollinators in temperate cities in the northern hemisphere. Cities in tropical areas, however, are larger and are growing more rapidly, and host a variety of vertebrate pollinators. Understanding how birds and mammals interact with native and alien flora in these megacities could improve management of urban ecosystems in highly biodiverse regions while limiting invasion potential. Therefore, here we investigate whether native diurnal birds and mammals interact differently with native versus alien trees in Bengaluru, India where historical planting has led to an abundance of alien tree species. We find that tree origin alone was not an important predictor for bird species richness and abundance, but taller native trees with large floral display sizes were more species rich than alien trees of similar floral displays. As expected from their shared evolutionary history, nectarivorous birds fed from native trees more often in a manner that could facilitate pollination, but engaged in nectar theft more often with alien trees. Squirrels (the mammal observed most frequently to interact with flowers) were more likely, however, to depredate flowers of native trees. Our results suggest alien trees can be an important resource for fauna in expanding urban areas, and that nectar theft by birds could reduce the seed set of alien trees.

Beryllium bonding with noble gas atoms.

Quantum chemical calculations were carried out to investigate the nature of the bonding between a neutral Be3 ring and noble gas atom. Electronic structure calculation for these complexes was carried out at different computational levels in association with natural bond orbital, quantum theory of atoms in molecules, electron localization function, symmetry adapted perturbation theory, and molecular electrostatic potential surface analysis of Be3 complexes. The Be atoms in the Be3 moiety are chemically bonded to one another, with the BeBe bond dissociation energy being ~125 kJ mol-1 . The Be3 ring interacts with the noble gases through non-covalent interactions. The binding energies of the noble gas atoms with the Be3 ring increases with increase in their atomic number. The non-covalent interaction index, density overlap region indicator and independent gradient model analyses reveal the presence of non-covalent inter-fragment interactions in the complexes. Energy decomposition analysis reveals that dispersion plays the major role towards stabilizing these systems.

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay due to Novel Mutations in the SACS Gene.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is characterized by triad of progressive cerebellar ataxia, progressive spasticity, and axonal/demyelinating peripheral neuropathy. Other manifestations include dysarthria, weakness in lower extremities and distal muscle wasting, foot deformities, retinal striation, prolapse of the mitral valve and rarely intellectual disability, hearing loss, and myoclonic epilepsy. We describe a patient who developed peripheral sensorimotor neuropathy in the absence of spasticity on initial presentation. He had nerve root enhancement on magnetic resonance imaging (MRI) lumbar spine, and nerve conduction studies were suggestive of demyelinating polyneuropathy. Patient had mild cerebellar atrophy on MRI and some delay of motor milestones. Over the course of several months, he developed spasticity, and genetic analysis together with clinical presentation was consistent with ARSACS. He was noted to have a pathogenic mutation c.8108G>A (p. Arg2703His) inherited from mother and a variant of uncertain significance c.7216T>C (p. Ser2406Pro) inherited from his father in SACS gene. Atypical cases may present later in life or in absence of one of the classical features at the time of presentation, which may make diagnosis difficult. Our patient had such an atypical presentation of ARSACS. Young patients with neuropathy and concomitant cerebellar atrophy on MRI should raise suspicion for hereditary spastic ataxia syndrome. Follow-up examination can often reveal additional findings to aid the diagnosis.

CD8 Encephalitis: A Diagnostic Dilemma.

CD8+ encephalitis is a subacute encephalopathy associated with HIV infection. Pathophysiology is thought to be auto-reactive CD8+ cells attacking on HIV infected CD4+ cells and 'viral escape' phenomena (replication of CD8+ cells in CSF). We present a case of a 45-year-old man with well controlled HIV who developed CD8 encephalitis following Herpes simplex encephalitis. He had persistent encephalopathy for several weeks with status epilepticus and agitated delirium, and diagnosis remained elusive until a brain biopsy confirmed the diagnosis.

Clinical Evaluation of Two Different Doses of Clonidine as an Adjuvant to Bupivacaine in Ultrasound-Guided Supraclavicular Brachial Plexus Block for Pediatric Upper Limb Surgeries - A Randomized Trial.

Background: Clonidine as an adjuvant to local anesthetic for regional anesthesia in upper limb surgeries has been extensively studied in adults, but there is a paucity of data regarding the dose of clonidine which is effective and safe as an adjuvant in children. Aims: To find the dose of clonidine that prolongs the duration of analgesia without prolonging the side effects. Settings and Design: Prospective, randomized, double-blind study. Materials and Methods: After taking informed consent from the parents/guardian, 42 children aged 3-12 years who were scheduled to undergo unilateral upper limb surgeries below the elbow were randomized into two groups of 21 each. Group A was given 0.5 µg.kg-1 of clonidine in addition to 0.5 mL.kg-1 of 0.25% bupivacaine and Group B received 1 µg.kg-1 of clonidine added to the same volume and concentration of local anesthetic for supraclavicular brachial plexus block under general anesthesia using ultrasound guidance. The drug administration and the recording of the observations were done by an investigator blinded to the dose of clonidine. Statistical Analysis Used: Statistical testing was conducted with the Statistical Package for the Social Sciences system version SPSS 17.0. Results: The demographic parameters and baseline hemodynamic parameters were similar in the two groups. The block failed in one child in Group A. One patient in Group A required tramadol postoperatively while none of the patients in Group B required tramadol. The mean duration of analgesia (11.35 ± 1.54 h vs. 9.94 ± 1.04 h, P < 0.001) and the duration of motor block (8.86 ± 1.0 h vs. 7.77 ± 0.55 h, P < 0.001) were significantly higher in group B. Sedation scores were higher in the recovery room in Group B. Deep sedation, bradycardia, and respiratory depression were not observed in any of the cases. Conclusions: Clonidine 1 µg.kg-1 when added as an adjuvant to bupivacaine for pediatric supraclavicular brachial plexus block prolongs the duration of analgesia and motor block as compared to the dose of 0.5 µg.kg-1. However, this was at the cost of increased duration of motor block and sedation. Considering the clinical equivalence of the effect, a lower dose of clonidine would be preferable to avoid the undesirable effects.

Usefulness of computed tomography to predict residual mitral regurgitation after transcatheter mitral valve edge-to-edge repair.

BACKGROUND: Multidetector computed tomography (MDCT) can provide valuable information for preprocedural planning of transcatheter mitral valve interventions. However, no data exist on MDCT parameters predicting residual mitral regurgitation (MR) post-MitraClip (Abbott Laboratories, Abbott Park, IL, USA). METHODS: We analyzed preprocedural MDCTs of 78 consecutive patients with secondary MR undergoing MitraClip implantation at our institution. Moderate-or-severe mitral leaflet calcification (MLC) was defined as calcification, with-or-without mitral annular calcification, extending beyond the mitral leaflet base. Residual MR was assessed by postprocedural transesophageal echocardiography, and clinical outcomes were assessed at 1-year. RESULTS: Fifteen patients (19 %) had residual MR ≥2+. Compared to patients with none-or-mild residual MR, MDCT-derived mitral valve orifice area (MVOA) to mitral annulus area (MAA) ratio was significantly lower (0.32 ±â€¯0.06 vs. 0.39 ±â€¯0.09; p = 0.003), and the prevalence of MLC was higher (40 % vs. 18 %; p = 0.057) in those with residual MR ≥2+. Furthermore, the MVOA/MAA ratio and MLC were independent predictors of residual MR ≥2+ post-MitraClip [adjusted odds ratio (ORadj): 0.88 (0.80-0.97) and 5.50 (1.16-26.23), respectively]. On receiver-operating-characteristic-curve analysis, MVOA/MAA ratio <0.31 had a sensitivity of 87 % and a specificity of 60 % for residual MR ≥2+. When patients were classified according to the presence of MLC and an MVOA/MAA ratio <0.31, those with both parameters had significantly higher rates of postprocedural residual MR ≥2+ and mitral reintervention at 1-year than those with only one, and those without both parameters. CONCLUSIONS: In patients with secondary MR undergoing the MitraClip procedure, preprocedural MDCT parameters, specifically MVOA/MAA ratio and MLC, are useful to predict postprocedural residual MR.