Formulation and Development of Novel Sulfasalazine Bilayer Tablets for The Treatment of Arthritis Associated With IBD: In-vitro and In-vivo Investigations.

Sulfasalazine needs frequent daily dosing and the administration of numerous tablets per day pose challenges to patient compliance, contributing to increased adverse effects and difficulties in disease control. These inconveniences result in less effective treatment for arthritis associated with inflammatory bowel disease i.e. ulcerative colitis etc. To improve drug bioavailability, a delayed-release mechanism that releases the drug at the colon is necessary. To develop and optimize colon-targeted controlled release bilayer tablets coated with pH-dependent polymers. The bilayer tablets containing the immediate release part and sustained release part were developed. The tablets were coated with enteric-coated with Eudragit® S-100 and l-100 to achieve release in the colon. Granule properties and tablets were evaluated. The physicochemical parameters of the tablets were evaluated including, stability study, and drug release in 0.1 N HCl (pH 1.2), pH 6.8 phosphate buffer, pH 7.4 phosphate buffer for 2, 1, and up to 24 h respectively. Radiographic imaging and in vivo pharmacokinetic studies were also done in Rabbits. The bilayer tablets containing immediate and sustained release were successfully developed for the colon targeting. The granule properties were found within the acceptable range indicating good flow properties. The physicochemical properties of the tablets were also found acceptable. The tablets did not show release in 0.1 N HCl and 6.8 phosphate buffer but drug release was found under control in the 7.4 pH buffer. Sulfasalazine coated bilayer tablets were found stable and no significant changes were observed in the stability studies. Based on the X-ray studies, the formulated tablet remained discernible in the stomach, small intestine, and colon for a duration of up to 24 h. Finally, by the 32nd hour, the tablet was no longer visible in the X-ray examination, leading to the conclusion of complete drug release. The drug concentration in plasma remained within the therapeutic range for up to 24 h in vivo. These novel formulations present substantial advantages, providing prolonged targeted drug release and reducing systemic adverse effects. The results suggest promising potential for treating arthritis in Inflammatory bowel disease (IBD) patients, offering a solution to current delivery systems.

Effect of electric field direction on neuronal activity: an ex-vivo study.

The effect of electrical stimulation on neurons depends on the spatiotemporal properties of the applied electric field as well as on the biophysical properties of the neural tissue, which includes geometric and electrical characteristics of the cells, and the neural circuit dynamics. In this work, we characterize the effect of electric field direction on neural response in cortical layers. This can, for instance, enable more efficient (e.g., with reduced currents) and/or more selective stimulation. We stimulated mice brain slices using a recently developed brain slice platform to study transcranial currents in an ex-vivo model, where electrodes are separated from the brain slice to inject electric fields at a distance. By rotating the electrode array with respect to the slice, we changed the direction of electric field with respect to the cortical column. Our results demonstrate that in somatosensory cortex, the maximum local field potential (LFP) response is attained when the electric field is oriented parallel to the cortical column. For the same field intensity, when the field is oriented perpendicular to the cortical column, the LFP response is absent. This confirms that electric field direction is an important quantity to determine the effect of neuronal stimulation.

Distinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement.

Malaria parasite lacks canonical pathways for amino acid biosynthesis and depends primarily on hemoglobin degradation and extracellular resources for amino acids. Interestingly, a putative gene for glutamine synthetase (GS) is retained despite glutamine being an abundant amino acid in human and mosquito hosts. Here we show Plasmodium GS has evolved as a unique type I enzyme with distinct structural and regulatory properties to adapt to the asexual niche. Methionine sulfoximine (MSO) and phosphinothricin (PPT) inhibit parasite GS activity. GS is localized to the parasite cytosol and abundantly expressed in all the life cycle stages. Parasite GS displays species-specific requirement in Plasmodium falciparum (Pf) having asparagine-rich proteome. Targeting PfGS affects asparagine levels and inhibits protein synthesis through eIF2α phosphorylation leading to parasite death. Exposure of artemisinin-resistant Pf parasites to MSO and PPT inhibits the emergence of viable parasites upon artemisinin treatment.

Focused Epicranial Brain Stimulation by Spatial Sculpting of Pulsed Electric Fields Using High Density Electrode Arrays.

Transcranial electrical neuromodulation of the central nervous system is used as a non-invasive method to induce neural and behavioral responses, yet targeted non-invasive electrical stimulation of the brain with high spatial resolution remains elusive. This work demonstrates a focused, steerable, high-density epicranial current stimulation (HD-ECS) approach to evoke neural activity. Custom-designed high-density (HD) flexible surface electrode arrays are employed to apply high-resolution pulsed electric currents through skull to achieve localized stimulation of the intact mouse brain. The stimulation pattern is steered in real time without physical movement of the electrodes. Steerability and focality are validated at the behavioral, physiological, and cellular levels using motor evoked potentials (MEPs), intracortical recording, and c-fos immunostaining. Whisker movement is also demonstrated to further corroborate the selectivity and steerability. Safety characterization confirmed no significant tissue damage following repetitive stimulation. This method can be used to design novel therapeutics and implement next-generation brain interfaces.

Therapeutic potential and novel formulations of ursolic acid and its derivatives: an updated review.

Plants produce biologically active metabolites that have been utilised to cure a variety of severe and persistent illnesses. There is a possibility that understanding how these bioactive molecules work would allow researchers to come up with better treatments for diseases including malignancy, cardiac disease and neurological disorders. A triterpene called ursolic acid (UA) is a pentacyclic prevalent triterpenoid found in fruits, leaves, herbs and blooms. The biological and chemical aspects of UA, as well as their presence, plant sources and biosynthesis, and traditional and newer technologies of extraction, are discussed in this review. Because of its biological function in the creation of new therapeutic techniques, UA is a feasible option for the evolution and medical management of a wide range of medical conditions, including cancer and other life threatening diseases. Despite this, the substance's poor solubility in aquatic environments makes it unsuitable for medicinal purposes. This hurdle was resolved in many different ways. The inclusion of UA into various pharmaceutical delivery approaches was found to be quite effective in this respect. This review also describes the properties of UA and its pharmacokinetics, as well as therapeutic applications of UA for cancer, inflammatory and cardiovascular diseases, in addition to its anti-diabetic, immunomodulatory, hepatoprotective and anti-microbial properties. Some of the recent findings related to novel nano-sized carriers as a delivery system for UA and the patents related to the applications of UA and its various derivatives are covered in this review. The analytical study of UA, oleanolic acid and other phytoconstituents by UV, HPLC, high-performance thin-layer chromatography and gas chromatography is also discussed. In the future, UA could be explored in vivo using various animal models and, in addition, the regulatory status regarding UA needs to be explored. © 2023 Society of Chemical Industry.

Pulley Reconstruction Following Surgical Release of DC1 Pulley in De Quervain's Tenosynovitis: Surgical Technique and Case Series.

De Quervain's disease (DQD) is tenosynovitis of the first dorsal compartment (DC1) of the wrist between the osteofibrous tunnel and the tendons involving the APL and EPB sheaths at the radial styloid. Surgical intervention is indicated when pain does not resolve despite 3 to 6 months of conservative management. Release of the first dorsal compartment is an effective treatment of DQD. In addition to surgical release, we performed pulley reconstruction using a new technique in the present series of 20 patients which has not been previously described with a followup of over 1 year. All patients showed a consistent improvement in VAS score at over one year followup with resolution of Finkelstein, Eichoff and WHAT test. Only one temporary neuropraxia was encountered due to stretching/scar entrapment of superficial branch of radial nerve. Our innovative technique of pulley reconstruction is not only easy to understand and perform but has shown consistent result in the 20 cases operated with this technique with a follow up of at least 1 year. The technique has the distinct advantage of having a quick learning curve and gives reliable, lasting results without complications or recurrence.

Expanding Indications of Primary Arthrodesis in Selected Individuals for Managing Complex Hindfoot Trauma During COVID-19 Pandemic.

Background: During the COVID-19 pandemic, public health measures to encourage social distancing have been implemented, including cancellation of outdoor activities, organized sports, and schools/colleges. Neglected hindfoot fractures have emerged as a consequence with increased frequency. Similarly, complex ankle and pilon fractures that require staged management, prolonged hospital stay, and soft-tissue care have emerged as a potential concern as prolonged exposure to healthcare setting adds to risk of acquiring as well as transmitting COVID-19 infection. The authors present their experience with expanding these indications for hindfoot arthrodesis as they encounter a greater number of neglected ankle and hindfoot trauma. Methods: This was a retrospective observational study of collected data from the trauma unit of our hospital. Inclusion criteria included all trauma classified by the AO/OTA as occurring at locations 43, and who underwent subtalar and ankle arthrodesis. This included distal tibia, malleolar, talus, and calcaneus fractures. These patients were followed up to at least 6 months till complete fracture union. Results: A total of 18 patients underwent arthrodesis of either the ankle or subtalar joint between March and October 2020. Mean age of patients undergoing arthrodesis of the hindfoot was 69.2 years (43-84 years). Indications for the procedure included Displaced and comminuted intra-articular distal tibia fractures in elderly (6 patients), Malunited ankle fractures (2 patients), Neglected Ankle fractures managed conservatively (3 patients), Calcaneus fractures (5 patients), and neglected Talus body fracture (2 patients). All patients were followed up to at least 6 months and everyone went onto successful painless union between 3 and 6 months of the arthrodesis procedure without any significant complications. Conclusion: In summary, COVID-19 pandemic has led to a change in paradigm of trauma management and foot and ankle management is no different than other musculoskeletal trauma systems. The authors propose an expansion of indications for hindfoot arthrodesis in managing complex hindfoot trauma in pandemic situation.

Flexible optoelectric neural interfaces.

Understanding the neural basis of brain function and dysfunction and designing effective therapeutics require high resolution targeted stimulation and recording of neural activity. Optical methods have been recently developed for neural stimulation as well as functional and structural imaging. These methods call for implantable devices to deliver light into the neural tissue at depth with high spatiotemporal resolution. To address this need, rigid and flexible neurophotonic implants have been recently designed. This article reviews the state-of-the-art flexible passive and active penetrating optical neural probes developed for light delivery with minimal damage to the tissue. Passive and active flexible neurophotonic implants are compared and insights about future directions are provided.

A Potentially Dangerous Industrial Projectile Lodged in the Leg of a Steel Factory Worker.

Penetrating injuries due to fragments energized by an explosive event are life/limb-threatening and are associated with poor clinical and functional outcomes. Penetrating injuries are commonly inflicted in attacks with explosive devices. The extremities, especially the leg, are the most commonly affected body areas, presenting a high risk of infection, slow recovery, and the threat of amputation. This report presents a case of a young factory worker who sustained an injury to the leg with a foreign body lodged near the neuro-vascular bundle. A 44-year-old gentleman sustained a projectile injury while working in a stainless steel factory from the rula (steel rolling) machine with a foreign body getting lodged in the leg in March 2019. He was initially managed with wound care and didn't report any functional impairment. Gradually patient developed numbness and claudication symptoms of the foot over the next couple of years. He was subsequently operated on in 2021 for removal of the stainless steel foreign body encased in dystrophic calcification close to the tibial nerve and posterior tibial vessels. Interestingly the entry point of the foreign body was on the anterolateral aspect of the leg. The foreign body was removed using the postero-lateral approach to the tibia with careful dissection close to the neurovascular bundle. At a follow-up of 3 months, the patient is symptom-free with significant improvement of limb function. The authors propose that the foreign body crossed the interosseous membrane to get lodged close to the posterior tibial neurovascular bundle. In such a scenario, the patient was extremely lucky to have survived an amputation or significant functional injury of the limb. Proper protective equipment is needed not only for the torso but also for extremities to protect industrial workers from such limb-threatening injuries. Moreover, primary care physicians should be sensitised for the proper management of such injuries.

Periodontal health of the geriatric population in old-age homes of Delhi, India.

BACKGROUND: Periodontal disease is one of the leading causes of tooth loss in the geriatric population. Assessment of periodontal disease in a population is an important step in planning effective prevention and control programs for periodontal disease. Therefore, a study was carried out in old-age homes of Delhi to assess the periodontal status of 65-74-year-old elderly and recommend interventions to improve their periodontal health. MATERIALS AND METHODS: A cross-sectional study was conducted among 464 elderly from old-age homes of Delhi. Periodontal health status of the participants was determined using the WHO oral health assessment form. Community Periodontal Index (CPI) and loss of attachment (LOA) were recorded. Collected data were analyzed using SPSS version 23. Chi-square test was used to determine statistically significant difference among CPI scores and LOA according to age and gender. P ≤ 0.05 was considered statistically significant. RESULTS: The result of the study showed that 25.4% of the elderly had healthy periodontium, 71.1% had a periodontal pocket of 6 mm or more, and 2.40% had a pocket depth of 4-5 mm. Around 36% had 6-8 mm LOA and 34.70% had 9-11 mm LOA. The difference between CPI scores among gender and age group was not significant (P = 0.20, P = 0.096). However, the difference among gender for LOA was found significant (P = 0.014). CONCLUSION: The results from this study show that periodontal health of elderly residing in old-age homes is very poor. The periodontal status of this population can be enhanced by special collaborative efforts from the government and various nongovernmental organizations toward preventive and curative periodontal health services.

Ginkgo biloba L. Prevents Hypobaric Hypoxia-Induced Spatial Memory Deficit Through Small Conductance Calcium-Activated Potassium Channel Inhibition: The Role of ERK/CaMKII/CREB Signaling.

Hypobaric hypoxia (HH) is a stressful condition, which is more common at high altitudes and can impair cognitive functions. Ginkgo biloba L. leaf extract (GBE) is widely used as herbal medicine against different disorders. Its ability to improve cognitive functions, reduce oxidative stress, and promote cell survival makes it a putative therapeutic candidate against HH. The present study has been designed to explore the effect of GBE on HH-induced neurodegeneration and memory impairment as well as possible signaling mechanisms involved. 220-250 gm (approximately 6- to 8-week-old) Sprague Dawley rats were randomly divided into different groups. GBE was orally administered to respective groups at a dose of 100 mg/kg/day throughout the HH exposure, i.e., 14 days. Memory testing was performed followed by hippocampus isolation for further processing of different molecular and morphological parameters related to cognition. The results indicated that GBE ameliorates HH-induced memory impairment and oxidative damage and reduces apoptosis. Moreover, GBE modulates the activity of the small conductance calcium-activated potassium channels, which further reduces glutamate excitotoxicity and apoptosis. The exploration of the downstream signaling pathway demonstrated that GBE administration prevents HH-induced small conductance calcium-activated potassium channel activation, and that initiates pro-survival machinery by activating extracellular signal-regulated kinase (ERK)/calmodulin-dependent protein kinase II (CaMKII) and the cAMP response element-binding protein (CREB) signaling pathway. In summary, the current study demonstrates the beneficial effect of GBE on conditions like HH and provides various therapeutic targets involved in the mechanism of action of GBE-mediated neuroprotection.

HDAC inhibition prevents hypobaric hypoxia-induced spatial memory impairment through PΙ3K/GSK3ß/CREB pathway.

Hypobaric hypoxia at higher altitudes usually impairs cognitive function. Previous studies suggested that epigenetic modifications are the culprits for this condition. Here, we set out to determine how hypobaric hypoxia mediates epigenetic modifications and how this condition worsens neurodegeneration and memory loss in rats. In the current study, different duration of hypobaric hypoxia exposure showed a discrete pattern of histone acetyltransferases and histone deacetylases (HDACs) gene expression in the hippocampus when compared with control rat brains. The level of acetylation sites in histone H2A, H3 and H4 was significantly decreased under hypobaric hypoxia exposure compared to the control rat's hippocampus. Additionally, inhibiting the HDAC family with sodium butyrate administration (1.2 g/kg body weight) attenuated neurodegeneration and memory loss in hypobaric hypoxia-exposed rats. Moreover, histone acetylation increased at the promoter regions of brain-derived neurotrophic factor (BDNF); thereby its protein expression was enhanced significantly in hypobaric hypoxia exposed rats treated with HDAC inhibitor compared with hypoxic rats. Thus, BDNF expression upregulated cAMP-response element binding protein (CREB) phosphorylation by stimulation of PI3K/GSK3ß/CREB axis, which counteracts hypobaric hypoxia-induced spatial memory impairment. In conclusion, these results suggested that sodium butyrate is a novel therapeutic agent for the treatment of spatial memory loss associated with hypobaric hypoxia, and also further studies are warranted to explore specific HDAC inhibitors in this condition.

Cross-cultural adaptation and psychometric properties of the Hindi version of Child Perception Questionnaire (CPQ11-14 ) in school children.

BACKGROUND: There is a need to validate OHRQoL measures in Hindi to assess the OHRQoL of Indian children. AIM: To develop a Hindi version of the CPQ11-14 and to appraise its validity and reliability for use among North Indian children aged 11-14 years. DESIGN: The cross-culturally adapted Hindi version of CPQ11-14 was achieved by forward translation, backward translation, committee review, and pretesting. A total of 1000 children were recruited from schools, chosen by two-stage cluster random sampling technique. After completing the self-administered questionnaire CPQ11-14 by the child, oral examination was conducted using decayed/missing/filled teeth (DMFT) index, malocclusion index, and Dean's fluorosis index. Test-retest reliability was checked on 100 participants after one week. RESULTS: The floor effect was present in 3.6% individuals, and there was no ceiling effect. Cronbach's alpha for the overall CPQ11-14 scale was 0.963. Intra-class correlation (ICC) coefficient was 0.952 for the entire scale. Cronbach's alpha value for test-retest was 0.918. There was a non-significant change in domain-level and overall median CPQ11-14 scores with an increase in DMFT scores. For malocclusion and fluorosis, there was a statistically significant increase in overall and domain-level scores with increased severity scores. CPQ11-14 and individual domains significantly correlated with both the global questions. CONCLUSION: Hindi version of CPQ11-14 is a reliable scale to assess OHRQoL in Hindi speaking 11- to 14-year-old children.

Recent Advances in Lipid-based Nanodrug Delivery Systems in Cancer Therapy.

Cancer is the second leading cause of death globally, with every sixth death being attributable to cancer. Nevertheless, the efficacy of conventional chemotherapeutic drugs is often limited due to their poor solubility, unfavorable pharmacokinetic profile, and lack of tumor selectivity. The use of nanotechnology provides an opportunity to enhance the efficacy of a chemotherapeutic drug by improving its bioavailability and pharmacokinetic profile while facilitating preferential accumulation at the tumor tissue. To date, a variety of platforms have been investigated as nanocarriers in oncology, which include lipid-based, polymer-based, inorganic materials, and even viruses. Among different nanocarriers, lipid-based delivery systems have been extensively used in oncology because of their biocompatibility, biodegradability, ability to encapsulate diverse drug molecules, high temporal and thermal stability, and offer prolonged and controlled drug release. This review discusses the current status of the lipid-based nanocarriers and their applications in cancer treatment as well as an overview of the different liposomal formulations commercially available for cancer therapy.

Intranasal Lipid Particulate Drug Delivery Systems: An Update on Clinical Challenges and Biodistribution Studies of Cerebroactive Drugs in Alzheimer's disease.

BACKGROUND: Alzheimer's is the primary cause of death in the various countries that affect wide strata of the population. The treatment of it is restricted to a few conventional oral medications that act only superficially. It is evident that the delivery of a drug to the brain across the blood-brain barrier is challenging as the BBB is armed with several efflux transporters like the P-glycoprotein as well as nasal mucociliary clearance adds up leading to decreased concentration and reduced therapeutic efficacy. Considering these, the intranasal IN route of drug administration is emerging as an alternative route for the systemic delivery of a drug to the brain. The intranasal (IN) administration of lipid nanoparticles loaded with cerebroactive drugs showed promise in treating various neurodegenerative diseases, since the nasal route allows the direct nose to brain delivery by means of solid lipid nanoparticles (SLN's). The tailoring of intranasal lipid particulate drug delivery systems is a pleasing approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when a free drug has poor pharmacokinetics/ biodistribution (PK/BD) or significant off-site toxicities. OBJECTIVES: 1) In this review, key challenges and physiological mechanisms regulating intranasal brain delivery in Alzheimer's disease, ex vivo studies, pharmacokinetics parameters including brain uptake and histopathological studies are thoroughly discussed. 2) A thorough understanding of the in vivo behaviour of the intranasal drug carriers will be the elusive goal. 3) The article emphasizes to drag the attention of the research community working in the intranasal field towards the challenges and hurdles of the practical applicability of intranasal delivery of cerebroactive drugs. METHOD: Various electronic databases, journals like nanotechnology and nanoscience, dove press are reviewed for the collection and compilation of data. RESULTS: From in vivo biodistribution studies, pharmacokinetics parameters, and gamma scintigraphy images of various drugs, it is speculated that intranasal lipid particulates drug delivery system shows better brain targeting efficiency for various CNS disorders in comparison to other routes. CONCLUSION: Various routes are explored for the delivery of drugs to increase bioavailability in the brain for CNS disorders but the intranasal route shows better results that pave the way for success in the future if properly explored.

Osmolytes: A Possible Therapeutic Molecule for Ameliorating the Neurodegeneration Caused by Protein Misfolding and Aggregation.

Most of the neurological disorders in the brain are caused by the abnormal buildup of misfolded or aggregated proteins. Osmolytes are low molecular weight organic molecules usually built up in tissues at a quite high amount during stress or any pathological condition. These molecules help in providing stability to the aggregated proteins and protect these proteins from misfolding. Alzheimer's disease (AD) is the uttermost universal neurological disorder that can be described by the deposition of neurofibrillary tangles, aggregated/misfolded protein produced by the amyloid ß-protein (Aß). Osmolytes provide stability to the folded, functional form of a protein and alter the folding balance away from aggregation and/or degradation of the protein. Moreover, they are identified as chemical chaperones. Brain osmolytes enhance the pace of Aß aggregation, combine with the nearby water molecules more promptly, and avert the aggregation/misfolding of proteins by providing stability to them. Therefore, osmolytes can be employed as therapeutic targets and may assist in potential drug design for many neurodegenerative and other diseases.

Perceptions of a university's faculty members on organ donation.

Background: . Availability of donated organs may save lives of people with end-stage disease. However, multiple barriers exist for obtaining donated organs such as insufficient knowledge and lack of a positive attitude towards organ donation. We assessed the knowledge and attitude regarding organ donation among faculty members of a university in India. Methods: . We did this observational, cross-sectional study from December 2017 to January 2018. A structured, close-ended questionnaire consisting of 20 items was used to assess knowledge, attitude and practices regarding organ donation. Data for 170 participants were analysed using SPSS version 21. Unpaired t-test was used to compare the knowledge and attitude score among different variables. Results: . A statistically significant difference was found between the attitude score of graduate and postgraduate faculty (p=0.003), as well as between graduate and doctoral faculty (p=0.001). We found that 5.3% of participants had already donated organs, 12.9% had pledged to donate and 63.5% of participants had expressed willingness to donate organs. Conclusions: . There is a need to increase the knowledge regarding organ donation as most people have a good attitude towards organ donation, but their knowledge was insufficient and at times inaccurate.

Triple Outlet Right Ventricle, With Duplication of the Aortic Root and Intrapericardial Ascending Aorta.

We present a case of a highly unusual congenital cardiac malformation, namely, triple outlet right ventricle with duplication of the aortic root and the intrapericardial component of the ascending aorta. A girl, aged five, presented with complaints of cyanosis and effort intolerance and was diagnosed with double-outlet right ventricle and subpulmonary infundibular stenosis. Intraoperatively, we noted that the aortic root was guarded by two separate aortic valves, oriented anteroposteriorly relative to each other, and separated within the right ventricle by a muscle bar. Postoperative interrogation by both echocardiography and computed tomography confirmed the surgical findings. To the best of our knowledge, our case is the first example of duplication of the aortic root to produce triple outlet right ventricle.