Evaluation of three different 99mTc-based mock-venom agents for lymphoscintigraphy studies in preclinical models of peripheral snakebite envenomation.

Snakebite envenomation is one of the major public health concerns across many countries; with the WHO designating it as a 'priority neglected tropical disease' and stressing for a need to develop novel therapeutic strategies to reduce death and disability rate by end of 2030. Since a major component of venom; the high molecular weight (HMw) toxins enter the bloodstream through lymphatic system, research is focusing on modulating the lymphatic flow rate after topical application of suitable drug candidates. Present study compared the suitability of three radiopharmaceutical agents, namely 99mTc-Sulfur colloid (SC), 99mTc-Phytate (Phy) and 99mTc-Human serum albumin (HSA), to be used as mock-venom agent in studying modulation in lymphatic flow rate in preclinical models of peripheral snakebite envenomation using lymphoscintigraphy studies. The study was performed in 72 Sprague Dawley rats; divided into six groups of 12 rats each. Control groups were given intradermal injection (1.29-1.48 MBq in 100 µl normal saline) of either 99mTc-Phy/ 99mTc-SC/ 99mTc-HSA into the tail as 'mock-venom'. In respective test groups, commercially available topical formulation (Anobliss® Cream) containing Nifedipine (Nif; 0.3% w/w) and Lidocaine (Lid; 1.5% w/w) was applied topically over the animals' lower body (tail and hind limbs) immediately within 20s of administering intradermal injection of the radiopharmaceutical. Any modulation in lymph transit time from periphery to systemic circulation was assessed using lymphoscintigraphy by taking dynamic gamma-scintigraphy images of 60s each till 1 h post-injection of the test radiopharmaceuticals. Significant difference in movement of the three radiopharmaceuticals was noted in terms of their lymphatic movement. 99mTc-Phy did not show significant travel through the lymphatics and the liver was faintly visualized in control as well as test intervention groups. In case of 99mTc-SC, significant changes in movement of the radiotracer after topical application of Nif/Lid in the test intervention groups were clearly noted in comparison to control (P < 0.05). Multiple numbers of lymph nodes (LNs) could be clearly visualized in control (5 ± 1 LNs) and test intervention groups (3 ± 1 LNs). Liver uptake was more prominent in control animals and it reduced significantly in test intervention groups. On the other hand, 99mTc-HSA showed lesser number of lymph nodes and higher accumulation in liver as compared to 99mTc-SC, suggesting very fast movement of this radiopharmaceutical. Results indicates that 99mTc-SC could be used as a suitable agent to mimic lymphatic transit behavior of HMw toxin components of snake venom and could therefore be used as a model in studying the effect of any test pharmacological intervention in modulating lymphatic transit rate. Additional advantage could be a significant reduction in the need for sacrificing large number of animals, particularly during initial screening phase of drug development cycle.

Advanced multifunctional nano-lipid carrier loaded gel for targeted delivery of 5-flurouracil and cannabidiol against non-melanoma skin cancer.

Non-melanoma skin cancer is one of the most common malignancies reported around the globe. Current treatment therapies fail to meet the desired therapeutic efficacy due to high degree of drug resistance. Thus, there is prominent demand in advancing the current conventional therapy to achieve desired therapeutic efficacy. To break the bottleneck, nanoparticles have been used as next generation vehicles that facilitate the efficient interaction with the cancer cells. Here, we developed combined therapy of 5-fluorouracil (5-FU) and cannabidiol (CBD)-loaded nanostructured lipid carrier gel (FU-CBD-NLCs gel). The current investigation has been designed to evaluate the safety and efficacy of developed 5-Flurouracil and cannabidiol loaded combinatorial lipid-based nanocarrier (FU-CBD NLCs) gel for the effective treatment of skin cancer. Initially, confocal microscopy study results showed excellent uptake and deposition at epidermal and the dermal layer. Irritation studies performed by IR camera and HET cam shows FU-CBD NLCs was much more tolerated and less irritant compared to conventional treatment. Furthermore, gamma scintigraphy evaluation shows the skin retention behavior of the formulation. Later, in-ovo tumor remission studies were performed, and it was found that prepared FU-CBD NLCs was able to reduce tumor volume significantly compared to conventional formulation. Thus, obtained results disclosed that permeation and disposition of 5-FU and CBD into different layers of the skin FU-CBD NLCs gel could be more potential carrier than conventional gel. Furthermore, prepared formulation showed greater tumor remission, better survival rate, reduction in tumor number, area, and volume with improved biochemical profile. Thus, prepared gel could serve as a promising formulation approach for the skin cancer treatment.

Efficacy of Physiotherapy Rehabilitation for Proximal Femur Fracture.

A diaphysis fracture that occurs between 5 cm distal to the lesser trochanter and 5 cm proximal to the adductor tubercle is recognized as a femoral shaft fracture and is prevalent in runners and military personnel. A patient's ability to carry out activities of daily living effectively and efficiently post-surgery is hampered by a variety of obstacles. We present a case of a 21-year-old male who came to the hospital with a complaint of pain and swelling in his right leg. The patient was diagnosed with a proximal femur fracture. Physiotherapy procedures commenced with the purpose of alleviating pain and establishing a normal range of motion. As a result of the physiotherapy regimens, the patient was aided in his recovery.

Physical Therapy Rehabilitation for a Chronic Alcoholic Patient With Loculated Pleural Effusion.

Pleural effusion is the accumulation of extra fluid between the layers of the pleura outside the lungs, also known as water on the lungs. Pleura are thin membranes that lubricate and aid breathing by lining the lungs and the inside of the chest cavity. The pleural space typically contains only a few teaspoons of watery fluid, which enables the lungs to move easily inside the chest cavity when breathing. Several barriers limited the patient's capacity to carry out daily activities successfully and efficiently. Loculated effusions are most frequently associated with diseases such as empyema, hemothorax, or tuberculosis that result in severe pleural inflammation. Hence, a physiotherapy program is started to help improve the patient's symptoms. A 59-year-old male presented to the hospital with the chief complaint of left-sided chest pain, fever, and breathlessness. On the Modified Medical Research Council dyspnea scale, breathlessness was grade 3.

Multidisciplinary Approach Towards Hypertensive and Chronic Alcoholic Patient With Intracerebral Bleed.

Intracerebral haemorrhage, the most lethal form of stroke, accounts for almost a third of all strokes. The brain receives and expels blood through blood arteries. Veins or arteries may rupture due to trauma, improper development, or excessive pressure. Blood itself has the potential to harm brain tissue. Here, we discuss the case of a 36-year-old individual who experienced giddiness, two to three seizure episodes, and left extremity weakness. Investigation revealed an intracerebral bleed. Physiotherapy was necessary to enable the patient to carry out his everyday activities comfortably in addition to medical management. The patient's condition was improved with the help of a physiotherapy protocol.

Effect of temperature on CO oxidation over Pt(111) in two-dimensional confinement.

Confined catalysis between a two-dimensional (2D) cover and metal surfaces has provided a unique environment with enhanced activity compared to uncovered metal surfaces. Within this 2D confinement, weakened adsorption and lowered activation energies were observed using surface science experiments and density functional theory (DFT) calculations. Computationally, the role of electronic and mechanical factors responsible for the improved activity was deduced only from static DFT calculations. This demands a detailed investigation on the dynamics of reactions under 2D confinement, including temperature effects. In this work, we study CO oxidation on a 2D graphene covered Pt(111) surface at 90 and 593 K using DFT-based ab initio molecular dynamics simulations starting from the transition state configuration. We show that CO oxidation in the presence of a graphene cover is substantially enhanced (2.3 times) at 90 K. Our findings suggest that 2D confined spaces can be used to enhance the activity of chemical reactions, especially at low temperatures.

Fabrication, characterization and evaluation of the efficacy of gelatin/hyaluronic acid microporous scaffolds suffused with aloe-vera in a rat burn model.

Burn induced injuries are commonly encountered in civilian and military settings, leading to severe morbidity and mortality. Objective of this study was to construct microporous bioactive scaffolds of gelatin-hyaluronic acid suffused with aloe-vera gel (Gela/HA/AvG), and to evaluate their efficacy in healing partial-thickness burn wounds. Scaffolds were characterized using Fourier transform-infrared spectroscopy, Scanning electron microscopy, and Thermo-gravimetric analysis to understand intermolecular interactions and morphological characteristics. In-vitro fluid uptake ability and hemolytic index of test scaffolds were also determined. In-vitro collagenase digestion was done to assess biodegradability of scaffolds. Wound retraction studies were carried out in Sprague Dawley rats inflicted with partial-thickness burn wounds to assess and compare efficacy of optimized scaffolds with respect to negative and positive control groups. In-vivo gamma scintigraphy using Technetium-99m labeled Immunoglobulin-G (99mTc-IgG) as imaging agent was also performed to validate efficacy results. Histological and immunohistochemical comparison between groups was also made. Scaffolds exhibited mircoporous structure, with pore size getting reduced from 41.3 ± 4.3 µm to 30.49 ± 5.7 µm when gelatin conc. was varied from 1% to 5%. Optimized test scaffolds showed sustained in-vitro swelling behavior, were biodegradable and showed hemolytic index in range of 2.4-4.3%. Wound retraction study along with in-vivo gamma scintigraphy indicated that Gela/HA/AvG scaffolds were not only able to reduce local inflammation faster but also accelerated dermis regeneration. Immunohistochemical analysis, in terms of expression levels of epidermal growth factor and fibroblast growth factor-2 also corroborated in-vivo efficacy findings. Gela/HA/AvG scaffolds, therefore, can potentially be developed into an effective dermal regeneration template for partial-thickness burn wounds.

Biophysical Investigation of the Interplay between the Conformational Species of Domain-Swapped GB1 Amyloid Mutant through Real-Time Monitoring of Amyloid Fibrillation.

Mutant polypeptide GB1HS#124F26A, which is known to aggregate into amyloid-like fibrils, has been utilized as a model in this study for gaining insights into the mechanism of domain-swapped aggregation through real-time monitoring. Size exclusion with UV monitoring at 280 nm and dynamic light scattering (DLS) profiles through different time points of fibrillation reveal that the dimer transitions into monomeric intermediates during the aggregation, which could further facilitate domain swapping to form amyloid fibrils. The 1D 1H and 2D 1H-13C HSQC nuclear magnetic resonance (NMR) spectra profiling through different time points of fibrillation reveal that there may be some other species present along with the dimer during aggregation which contribute to different trends for the intensity of protons in the spectral peaks. Diffusion NMR reveals changes in the mobility of the dimeric species during the process of aggregation, indicating that the dimer gives rise to other lower molecular weight species midway during aggregation, which further add up to form the oligomers and amyloid fibrils successively. The present work is a preliminary study which explores the possibility of utilizing biophysical methods to gain atomistic level insights into the different stages of aggregation.

In vivo wound-healing and antioxidant activity of aqueous extract of Roylea elegans leaves against physically induced burn model in Wistar albino rats.

Roylea elegans Wall. ex Benth. is a lemon-scented hoary shrub belonging to the mint family (Lamiaceae). Traditionally, a local tribe of the Himalayan region uses leaves for scabs and skin infections. The aerial parts and leaves are widely used to cure various skin ailments. The plant is well known for two furanoid diterpenes, royeleganin and royelegafuran. The aqueous extract of Roylea elegans (AERE) leaves was investigated for wound-healing effects in rats using a physically induced burn model by assessing different parameters. Animals were divided into four groups (six rats in each group). Group I animals were considered as disease control and topically given base cream. Group II was considered as standard control and treated topically with Framycetin sulphate cream (1% w/w). Group III and IV animals were treated topically with creams containing 5 or 10% of AERE, respectively. Several parameters such as wound contraction rate, epithelialization period, and enzymatic and non-enzymatic antioxidant markers along with pro- and anti-inflammatory cytokines were studied followed by histopathological studies. The animals treated with AERE cream exhibited significant declination in the wound area and increased collagen content as compared to the disease control group. The results showed that the lower dose (5%) of AERE produced a significant decrease in the epithelialization period, wound contraction rate, and collagen content. Increased levels of cytokine production may be one of the mechanisms in accelerating the wound-healing process. The study established the traditional claim as an antioxidant and wound-healing potential of Roylea elegans by promoting the accelerated wound-healing activity against the physically induced burn model.

Health data from diaries used in low-income communities, north India.

OBJECTIVE: To determine the acceptability of keeping a self-written health diary among members of low-income communities, with the aim of generating needed health data. METHODS: We identified three different types of impoverished communities (tribal, inner-city slum and rural) in north India, and conducted a baseline survey to establish the sociodemographic properties of the members of 595 (tribal), 446 (slum) and 51 (rural) households. We designed health diaries with a single page to fill in per month, each with a carbon duplicate, and distributed diaries to willing participants. Health volunteers visited households each month to assist with diary completion and to collect duplicate pages for a period of one year. We compared the frequency of illnesses reported in health diaries with baseline survey data. FINDINGS: A total of 4881 diary users (tribal: 2205; slum: 2185; rural: 491) participated in our project. In terms of acceptability, 49.6% (1093/2205), 64.7% (1413/2185) and 79.0% (388/491) at the tribal, slum and rural sites, respectively, expressed satisfaction with the scheme and a willingness to continue. In the tribal and slum areas, we observed increased reporting of illnesses from health diaries when compared with baseline data. We observed that influenza-like illnesses were reported with the highest frequency of 58.9% (2972/5044) at the tribal site. CONCLUSION: We observed high levels of acceptability and participation among the communities. From our initial field studies, we have observed the benefits to both our study participants (timely preventive education and referrals) and to service providers (obtaining health data to allow improved planning).

Synthesis of pH-sensitive crosslinked guar gum-g-poly(acrylic acid-co-acrylonitrile) for the delivery of thymoquinone against inflammation.

The present work aims to synthesize the pH-sensitive crosslinked guar gum-g-poly(acrylic acid-co-acrylonitrile) [guar-g-(AA-co-ACN)] via microwave-assisted technique for the sustained release of thymoquinone. The synthesized material [guar-g-(AA-co-ACN)] was optimized by varying synthetic parameters viz. monomer concentration, reaction time, and microwave power to obtain the maximum yield of the crosslinked guar gum grafted product as well as maximum encapsulation of thymoquinone. The synthesized material [guar-g-poly(AA-co-ACN)] was characterized by FT-IR, SEM, XRD, NMR, zeta potential, and thermal techniques. This synthesized material was used to encapsulate thymoquinone (TQ) for effective nanotherapeutic delivery. In-vitro thymoquinone release behavior of guar-g-poly(AA-co-ACN) based nanoparticles (NpTGG) was investigated. The maximum thymoquinone release (78%) was achieved at pH 7.4 and time (6 h). The NpTGG also exhibited better antioxidant activity and hemocompatibility as compared to thymoquinone. Cytotoxicity of uar-g-(AA-co-ACN) and NpTGG was also evaluated against the human kidney VERO cell line and found to be nontoxic. Current research provides a cost-effective and green approach for the synthesis of guar-g-(AA-co-ACN) and NpTGG for sustained release of thymoquinone.

Dysregulation of Multiple Signaling Neurodevelopmental Pathways during Embryogenesis: A Possible Cause of Autism Spectrum Disorder.

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like "novel drugs for ASD" and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling pathways, their significance, and implications for ASD.

Mechanistic Insights into the Structural Stability of Collagen-Containing Biomaterials Such as Bones and Cartilage.

Structural stability of various collagen-containing biomaterials such as bones and cartilage is still a mystery. Despite the spectroscopic development of several decades, the detailed mechanism of collagen interaction with citrate in bones and glycosaminoglycans (GAGs) in the cartilage extracellular matrix (ECM) in its native state is unobservable. We present a significant advancement to probe the collagen interactions with citrate and GAGs in the ECM of native bones and cartilage along with specific/non-specific interactions inside the collagen assembly at the nanoscopic level through natural-abundance dynamic nuclear polarization-based solid-state nuclear magnetic resonance spectroscopy. The detected molecular-level interactions between citrate-collagen and GAG-collagen inside the native bone and cartilage matrices and other backbone and side-chain interactions in the collagen assembly are responsible for the structural stability and other biomechanical properties of these important classes of biomaterials.

Experimental Rodent Models of Vascular Dementia: A Systematic Review.

Vascular Dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of Vascular Cognitive Impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small Vessel Disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), and Cerebral Amyloid Angiopathy (CAA), which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as Diabetes Mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.

Probing short and long-range interactions in native collagen inside the bone matrix by BioSolids CryoProbe.

Solid-state nuclear magnetic resonance is a promising technique to probe bone mineralization and interaction of collagen protein in the native state. However, many of the developments are hampered due to the low sensitivity of the technique. In this article, we report solid-state nuclear magnetic resonance (NMR) experiments using the newly developed BioSolids CryoProbe™ to access its applicability for elucidating the atomic-level structural details of collagen protein in native state inside the bone. We report here approximately a fourfold sensitivity enhancement in the natural abundance 13 C spectrum compared with the room temperature conventional solid-state NMR probe. With the advantage of sensitivity enhancement, we have been able to perform natural abundance 15 N cross-polarization magic angle spinning (CPMAS) and two-dimensional (2D) 1 H-13 C heteronuclear correlation (HETCOR) experiments of native collagen within a reasonable timeframe. Due to high sensitivity, 2D 1 H/13 C HETCOR experiments have helped in detecting several short and long-range interactions of native collagen assembly, thus significantly expanding the scope of the method to such challenging biomaterials.

Novel ß-Coronavirus (SARS-CoV-2): Current and future aspects of pharmacological treatments.

The novel coronavirus outbreak has reported to be rapidly spreading across the countries and becomes a foremost community health alarm. At present, no vaccine or specific drug is on hand for the treatment of this infectious disease. This review investigates the drugs, which are being evaluated and found to be effective against nCOVID-19 infection. A thorough literature search was performedon the recently published research papers in between January 2020 to May 2020, through various databases like "Science Direct", "Google Scholar", "PubMed","Medline", "Web of Science", and "World Health Organization (WHO)". We reviewed and documented the information related with the current and future aspects for the management and cure of COVID-19. As of 21st July 2020 a total of 14,562,550 confirmed cases of coronavirus and 607,781 deaths have been reported world-wide. The main clinical feature of COVID-19 ranges from asymptomatic disease to mild lower respiratory tract illness to severe pneumonia, acute lung injury, acute respiratory distress syndrome (ARDS), multiple organ dysfunction, and death. The drugs at present used in COVID-19 patients and ongoing clinical trials focusing on drug repurposing of various therapeutic classes of drug e.g. antiviral, anti-inflammatory and/or immunomodulatory drugs along with adjuvant/supportive care. Many drugs on clinical trials shows effective results on preliminary scale and now used currently in patients. Adjuvant/supportive care therapy are used in patients to get the best results in order to minimize the short and long-term complications. However, further studies and clinical trials are needed on large scale of population to reach any firm conclusion in terms of its efficacy and safety.

Self healable neuromorphic memtransistor elements for decentralized sensory signal processing in robotics.

Sensory information processing in robot skins currently rely on a centralized approach where signal transduction (on the body) is separated from centralized computation and decision-making, requiring the transfer of large amounts of data from periphery to central processors, at the cost of wiring, latency, fault tolerance and robustness. We envision a decentralized approach where intelligence is embedded in the sensing nodes, using a unique neuromorphic methodology to extract relevant information in robotic skins. Here we specifically address pain perception and the association of nociception with tactile perception to trigger the escape reflex in a sensorized robotic arm. The proposed system comprises self-healable materials and memtransistors as enabling technologies for the implementation of neuromorphic nociceptors, spiking local associative learning and communication. Configuring memtransistors as gated-threshold and -memristive switches, the demonstrated system features in-memory edge computing with minimal hardware circuitry and wiring, and enhanced fault tolerance and robustness.

Role of inflammatory markers in corona virus disease (COVID-19) patients: A review.

IMPACT STATEMENT: In late 2019, a novel virus called SARS-CoV-2, expanded globally from Wuhan, China and was declared a pandemic on 11 March 2020 by the WHO. The mechanism of virus entry inside the host cell depends upon the cellular proteases including cathepsins, HAT, and TMPRSS2, which splits up the spike protein and causes further penetration. MERS coronavirus uses DPP4, while coronavirus HCoV-NL63 and SARS-CoV and SARS-CoV-2 employ ACE-2 as the key receptor. Cytokine storm syndrome was analyzed in critically ill nCOVID-19 patients and it is presented with high inflammatory mediators, systemic inflammation, and multiple organ failure. Among various inflammatory mediators, the level of interleukins (IL-2, IL-7, IL-10), G-CSF, MIP1A, MCP1, and TNF-α was reported to be higher in critically ill patients. Understanding this molecular mechanism of ILs, T cells, and dendritic cells will be helpful to design immunotherapy and novel drugs for the treatment of nCOVID-19 infection.

Cerebral palsy: Aetiology, pathophysiology and therapeutic interventions.

Cerebral palsy (CP) is the most common non-progressive neurodevelopmental disorder in which the impairment of motor and posture functions occurs. This condition may be present in many different clinical spectra. Various aetiological and risk factors play a crucial role in the causation of CP. In various cases, the causes of CP may not be apparent. Interruption in the supply of oxygen to the fetus or brain asphyxia was considered to be the main causative factor explaining CP. Antenatal, perinatal, and postnatal factors could be involved in the origin of CP. Understanding its pathophysiology is also crucial for developing preventive and protective strategies. A major advancement in the brain stimulation techniques has emerged as a promising status in diagnostic and interventional approaches. This review provides a brief explanation about the various aetiological factors, pathophysiology, and recent therapeutic approaches in the treatment of cerebral palsy.