Chitosan-grafted folic acid decorated one-dimensional GONS: A biocompatible drug cargo for targeted co-delivery of anticancer agents.

In conventional chemotherapy, the cancer cells can become highly resilient due to a phenomenon known as multi-drug resistance (MDR). The co-delivery of chemotherapeutic agents assisted with novel nanocarrier-based targeted DDS may counter the MDR issues and subsequently improve their therapeutic efficacy. In line with this, the present work deals with the development of 1D graphene oxide nanoscrolls (GONS)-based nano delivery system for co-delivery of chemosensitizer along with the chemotherapeutic agent. Herein, the 1D GONS nanocarrier was initially functionalized with chitosan (CS) biopolymer and folic acid (FA) further to enhance their biocompatibility and target-specific co-delivery. The resultant GONS-CS-FA (GCF) nanocarriers were co-loaded with doxorubicin (DOX) and caffeic acid (CA) at different weight proportions with respect to nanocarrier and drug composition. The optimum loading efficiency of 51.14 ± 1.47 % (DOX) and 49.70 ± 1.19 % (CA) was observed for GCF: drug ratio of 2.5 with drug composition of 1:1. In vitro release at pH 5 yielded ~83 % DOX and 75 % CA, compared to ~71 % DOX and 61 % CA at pH 7.4 over 7 days, suggesting a higher and targeted drug release in the cancer microenvironment. Cytotoxicity tests revealed selective apoptosis in cancer cells (A549) while maintaining cytocompatibility with normal cells (HEK293).

Modified 5-Item Frailty Index: A Useful Tool for Assessing the Impact of Frailty on Postoperative Morbidity and Mortality Following Surgical Fixation of Thoracolumbar Fractures.

OBJECTIVES: The modified 5-item frailty index (mFI-5) is a comorbidity-based risk stratification tool to predict adverse events following various neurologic surgeries. This study aims to quantify the association between increased mFI-5 and postoperative complications and mortality following surgical fixation of traumatic thoracolumbar fractures. METHODS: The 2011-2021 American College of Surgeons - National Surgical Quality Improvement Program (ACS-NSQIP) dataset was used to identify patients undergoing fusion surgeries for thoracolumbar spine fractures. The mFI-5 score was calculated based on the presence of 5 major comorbidities: congestive heart failure within 30 days before surgery, insulin-dependent or noninsulin-dependent diabetes mellitus, chronic obstructive pulmonary disease, partially dependent or totally dependent functional health status at the time of surgery, and hypertension requiring medication. Multivariate analysis assessed the independent impact of increasing mFI-5 scores on postoperative 30-day morbidity and mortality while controlling for baseline clinical characteristics. RESULTS: A total of 66,904 patients were included in our analysis (54.2% female, mean age 62.27 ± 12.93 years). On univariate analysis, higher mFI-5 score was significantly associated with increased risks of superficial surgical site infection, deep surgical site infection, wound dehiscence, unplanned reoperation, pneumonia, unplanned intubation, postoperative ventilator use, progressive renal insufficiency, acute renal failure, urinary tract infection, stroke, myocardial infarction, cardiac arrest, pulmonary embolism, deep vein thrombosis, bleeding requiring transfusion, sepsis, septic shock, and longer hospital length of stay (LOS). On multivariate logistic regression, increasing mFI-5 score versus a mFI-5 score of zero was associated with higher odds of overall complications (mFI-5 ≥2: odds ratio [OR] 1.38 CI: 1.24-1.54, P < 0.001; mFI-5 = 1: OR 1.18 CI: 1.11-1.24, P < 0.001) and 30-day mortality (mFI-5 ≥2: OR 2.33 CI: 1.60-3.38, P < 0.001). CONCLUSION: This study demonstrates that frailty, when measured using the mFI-5, independently predicts postoperative complications, hospital LOS, and 30-day mortality after surgical repair of thoracolumbar fractures. These findings are important for risk stratification in patients undergoing thoracolumbar fusion surgery and for standardization in reporting outcomes after those procedures.

Doxorubicin induces phosphorylation of lamin A/C and loss of nuclear membrane integrity: A novel mechanism of cardiotoxicity.

Lamin A/C, essential inner nuclear membrane proteins, have been linked to progeria, a disease of accelerated aging, and many other diseases, which include cardiac disorder. Lamin A/C mutation and its phosphorylation are associated with altering nuclear shape and size. The role of lamin A/C in regulating normal cardiac function was reported earlier. In the present study, we hypothesized that Doxorubicin (Dox) may alter total lamin A/C expression and phosphorylation, thereby taking part in cardiac injury. An in vitro cellular injury model was generated with Dox (0.1-10.0 µM) treatment on cardiomyoblast cells (H9c2) to prove our hypothesis. Increased size and irregular (ameboid) nucleus shape were observed in H9c2 cells after Dox treatment. Similarly, we have observed a significant increase in cell death on increasing the Dox concentration. The expression of lamin A/C and its phosphorylation at serine 22 significantly decreased and increased, respectively in H9c2 cells and rat hearts after Dox exposure. Phosphorylation led to depolymerization of the lamin A/C in the inner nuclear membrane and was evidenced by their presence throughout the nucleoplasm as observed by immunocytochemistry techniques. Thinning and perforation on the walls of the nuclear membrane were observed in Dox-treated H9c2 cells. LMNA-overexpression in H9c2 protected the cells from Dox-induced cell death, reversing all changes described above. Further, improvement of lamin A/C levels was observed in Dox-treated H9c2 cells when treated with Purvalanol A, a CDK1 inhibitor and N-acetylcysteine, an antioxidant. The study provides new insight regarding Dox-induced cardiac injury with the involvement of lamin A/C and alteration of inner nuclear membrane structure.

On-Arrival Lumbar Epidural Analgesia for Lower Limb Trauma Pain in Emergency Care: A Superiority Randomized Controlled Trial.

BACKGROUND: Lower limb trauma in emergency settings often leads to pain management challenges. Traditional methods, primarily non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, have limitations. This study explores the efficacy of epidural analgesia in emergency for lower limb trauma patients (ELETRA) as an alternative for managing pain in lower limb trauma patients upon arrival in emergency care. OBJECTIVES:  This study primarily focuses on determining ELETRA's effectiveness in reducing pain for patients with lower limb trauma upon arrival. It also aims to evaluate ELETRA's influence on decreasing stress and shortening hospital stays compared to traditional pain management approaches. METHODS: This study was executed as a prospective, parallel-design, randomized controlled trial in the emergency department of a tertiary care teaching hospital. The interventions were performed in a dedicated induction room adjacent to the emergency operating theater. The trial was registered in the Clinical Trial Registry of India with registration number CTRI/2022/08/044699 dated 16/08/2022. Participants were 18- to 50-year-old patients with lower limb injuries, classified under American Society of Anesthesiologists (ASA) class 1 or 2. Participants were randomized into two groups: one receiving ELETRA and the other standard pain control treatment. The effectiveness of pain relief was measured through a visual analog scale (VAS), and hemodynamic parameters, adverse effects, levels of acute phase reactants, and stress hormones were also measured along with patient satisfaction. RESULTS: The study enrolled 356 participants with lower limb injuries. After excluding participants lost following the intervention, data from 157 individuals in Group A and 160 in Group B were analyzed. Group A's success rate for analgesia (VAS < 2) was 92.35% (n = 145), significantly higher than Group B's 75.62% (n = 121) (p < 0.001). The commonest side effect was hypotension (5.73%) in Group A and nausea in Group B (7.5%). C-reactive protein (CRP) levels rose to 104.71 ± 8.99 mg/dL in Group A and 192.58 ± 9.23 mg/dL in Group B; the difference was statistically significant. Serum cortisol levels were also higher in Group B (67.18 ± 9.21) compared to Group A (44.72 ± 6.14) at one week. Group B had a longer hospital stay, averaging 12.24 ± 4.81 days, against Group A's 10.19 ± 4.91 days. CONCLUSION: ELETRA is a safe and effective alternative for pain management in lower limb trauma patients in emergency settings. It reduces pain, improves patient satisfaction, and has a favorable impact on stress responses.

Comparison between Different Combinations of Alendronate, Platelet-rich Fibrin, Hydroxyapatite in Bone Regeneration in Endodontic Surgeries Using Cone-beam Computed Tomography.

AIM: To compare different combinations of alendronate, platelet-rich fibrin (PRF), and hydroxyapatite in bone regeneration in endodontic surgeries using cone-beam computed tomography (CBCT). METHODS AND SUBJECTS: During this study, 28 patients were selected who were found to have pathology in the periapical area in the anterior region, The study subjects were categorized into four categories, each consisting of seven subjects, Category one-there was no placement of any material; category two-PRF; category three-hydroxyapatite along with PRF; category four-alendronate along with PRF, Root canal treatment followed by endodontic surgery in each patient was carried out, Volumetric analysis of the lesions was carried out before surgery and 12 months after surgery using CBCT, Analysis of variance (ANOVA) test and Tukey post-hoc test were used for statistical analysis. RESULTS: There was a maximum change in the volume of lesions in the study subjects in which PRF was used along with hydroxyapatite in comparison to other combination of materials, There was no significant difference when PRF was placed along with alendronate in comparison to study subjects when PRF was placed alone, The difference was not significant when PRF was placed in defects of bone in comparison to study subjects when no materials were placed in the defects of bone. CONCLUSION: It can be concluded from the current research that PRF along with hydroxyapatite is a better option for the healing of defects of bone in surgeries performed in the area around the root apex in endodontic patients, But further studies should be carried out with a large sample size and for a longer duration. CLINICAL SIGNIFICANCE: It is a very important consideration that there should be healing of the lesion after surgery around the root apex by actual bone regeneration, The healing of the larger lesions does not take place easily as compared with the lesions having a small size, This is because there is healing by secondary intention where there is formation of scar instead of actual healing by formation of bone, There are several methods by which proper bone regeneration can be obtained.

Young Male With Seizure Disorder and Intracranial Calcification: A Case of Fahr's Syndrome.

Fahr's syndrome is a neurodegenerative disorder characterized by abnormal deposition of calcium in the brain, especially in basal ganglia. The term Fahr's disease is used when primary familial brain calcification is present, and the term Fahr's syndrome is used for secondary causes. Our patient is a 35-year-old male who presented to our hospital with complaints of two episodes of generalized tonic-clonic seizures. He had a history of recurrent episodes of seizures since the age of 15 and they all were generalized tonic-clonic seizures. He did not have a family his-tory of epilepsy. Lab investigations showed a normal hemogram, and liver and renal function were within normal limits. Serum electrolyte levels showed hypocalcemia, but other electrolyte levels were normal. He had low parathyroid hormone levels and normal levels of vitamin D. Brain imaging studies with non-contrast CT and a contrast-enhanced MRI showed bilaterally symmetrical dense calcifications. The etiology in our patient was the primary hypoparathyroidism and was treated accordingly. He reported symptomatic improvement with treatment and had no episodes of seizures after the commencement of the treatment. So, in cases of Fahr's syndrome, treatable etiologies must be ruled out as they can delay the progression of the disease.

Deciphering the Role of Aberrant Protein Post-Translational Modification in the Pathology of Neurodegeneration.

Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington's Disease (HD), are characterized by progressive neuronal dysfunction and death. Recent studies have established detrimental modifications in the structure and function of brain proteins, which stimulate their aggregation, misfolding and deposition in and around the neurons an important hallmark of neurodegenerative diseases. Post-Translational Modification (PTM) of proteins, including phosphorylation, acetylation, glycosylation, palmitoylation, SUMOylation, and ubiquitination, are important regulators of protein characteristics, including stability, intracellular distribution, activity, interactions, aggregation and clearance. Despite clear evidence that altered protein modifications emerging from impromptu chemical modifications to side chains of amino acid are associated with neurodegeneration, the underlying mechanisms that promote aberrant PTM remain poorly understood. Therefore, elucidating PTM of specific disease-associated proteins can prove to be a significant step in evaluating the functional alteration of proteins and their association with neurodegeneration. This review describes how aberrant PTM of various proteins is linked with the neurodegenerative disease pathogenesis, as well as molecular strategies targeting these modifications for treating such diseases, which are yet incurable.

Observational Study to Evaluate the Effect of Epidural Steroid Injection on Bone Mineral Density and Bone Turnover Markers.

BACKGROUND: Epidural steroid injection (ESI) is widely used to manage low back pain. ESIs are commonly performed to treat pain accompanying intervertebral disc prolapse, spinal stenosis, facet joint pathologies, and other degenerative spinal pathologies. Corticosteroids for musculoskeletal conditions, regardless of the route of administration, can reduce bone mineral density (BMD) and increase the risk of fracture. With paraspinal administration of steroids, the severity of risk is enhanced as the steroid is being deposited in close proximity to bone. BMD and molecular markers of bone metabolism are the standard methods to assess the effect of any insult on bone strength and bone metabolism. Carboxy terminal crosslinked telopeptides of type 1 collagen (sCTX) and serum Procollagen Type I N-terminal propeptide (P1NP) are the reference markers of bone resorption and formation, respectively. OBJECTIVE: We conducted this study to determine the effect of ESI on BMD and bone turnover markers. STUDY DESIGN: This was a prospective observational cohort study, involving a cohort of 264 patients between the ages of 40 to 60 years who were advised to undergo ESI at L3-4 or L4-5 by their pain physician. SETTING: Research was conducted at a tertiary care teaching hospital pain clinic in collaboration with the department of orthopaedics and radiodiagnosis. METHODS: Serum CTX-1, P1NP, and pre-ESI BMD of the spine, femur neck, and dual femur were evaluated at baseline; these same parameters were serially evaluated post ESI on follow-ups at 1, 3, and 6 months. Additional follow-up at 10 days post ESI was called for evaluation of bone turnover markers (BTMs). A paired t test was used to analyze changes in BMD and BTMs vs baseline within the group. Cumulative incidence and relative risk of moderate to markedly low BMD were calculated using standard formulas. Any fractures sustained during follow-ups were also evaluated thoroughly and quantified separately. A P value less than .05 was considered statistically significant. RESULTS: The proportion of pre-ESI moderately to markedly low BMD was 10.22% in the study population. There was a statistically significant increase in serum CTX 10 days post ESI which persisted at the one-month and 3-month follow-ups. There was no significant change in serum P1NP level post ESI after 7 days and at the one-month follow-up. The mean value of serum P1NP was, however, significantly higher at the 3-month follow-up. Statistical comparison of the mean BMD value at the spine and femur neck revealed statistically significant decline 3 months post ESI. There was no significant impact of ESI on the total femur BMD. The cumulative incidence of moderately low to markedly low BMD over a period of 6 months in the study population was 45 out of 223, i.e., 20.17%. LIMITATIONS: The study's primary limitations included its high dropout rate, a larger reference range for BTMs, making them a less specific tool for comparison, and the absence of a control group. ESI has a negative impact on the BMD of the hip and spine. Reduced BMD should be considered as a potential side effect of ESI.

Secondary Metabolites in the Treatment of Diabetes Mellitus: A Paradigm Shift.

Diabetes mellitus (DM) is a chronic, polygenic and non-infectious group of diseases that occurs due to insulin resistance or its low production by the pancreas and is also associated with lifelong damage, dysfunction and collapse of various organs. Management of diabetes is quite complex having many bodily and emotional complications and warrants efficient measures for prevention and control of the same. As per the estimates of the current and future diabetes prevalence, around 425 million people were diabetic in 2017 which is anticipated to rise up to 629 million by 2045. Various studies have vaguely proven the fact that several vitamins, minerals, botanicals and secondary metabolites demonstrate hypoglycemic activity in vivo as well as in vitro. Flavonoids, anthocyanin, catechin, lipoic acid, coumarin metabolites, etc. derived from herbs were found to elicit a significant influence on diabetes. However, the prescription of herbal compounds depend on various factors, including the degree of diabetes progression, comorbidities, feasibility, economics as well as their ADR profile. For instance, cinnamon could be a more favorable choice for diabetic hypertensive patients. Diabecon®, Glyoherb® and Diabeta Plus® are some of the herbal products that had been launched in the market for the favorable or adjuvant therapy of diabetes. Moreover, Aloe vera leaf gel extract demonstrates significant activity in diabetes. The goal of this review was to inscribe various classes of secondary metabolites, in particular those obtained from plants, and their role in the treatment of DM. Recent advancements in recognizing the markers which can be employed for identifying altered metabolic pathways, biomarker discovery, limitations, metabolic markers of drug potency and off-label effects are also reviewed.

Comparative analysis of contextual bias around the translation initiation sites in plant genomes.

Nucleotide distribution around translation initiation site (TIS) is thought to play an important role in determining translation efficiency. Kozak in vertebrates and later Joshi et al. in plants identified context sequence having a key role in translation efficiency, but a great variation regarding this context sequence has been observed among different taxa. The present study aims to refine the context sequence around initiation codon in plants and addresses the sampling error problem by using complete genomes of 7 monocots and 7 dicots separately. Besides positions -3 and +4, significant conservation at -2 and +5 positions was also found and nucleotide bias at the latter two positions was shown to directly influence translation efficiency in the taxon studied. About 1.8% (monocots) and 2.4% (dicots) of the total sequences fit the context sequence from positions -3 to +5, which might be indicative of lower number of housekeeping genes in the transcriptome. A three base periodicity was observed in 5' UTR and CDS of monocots and only in CDS of dicots as confirmed against random occurrence and annotation errors. Deterministic enrichment of GCNAUGGC in monocots, AANAUGGC in dicots and GCNAUGGC in plants around TIS was also established (where AUG denotes the start codon), which can serve as an arbiter of putative TIS with efficient translation in plants.

Analyses of methyltransferases across the pathogenicity spectrum of different mycobacterial species point to an extremophile connection.

Tuberculosis is a devastating disease, taking one human life every 20 seconds globally. We hypothesize that professional pathogens such as M.tb have acquired specific features that might assist in causing infection, persistence and transmissible pathology in their host. We have identified 121 methyltransferases (MTases) in the M.tb proteome, which use a variety of substrates - DNA, RNA, protein, intermediates of mycolic acid biosynthesis and other fatty acids - that are involved in cellular maintenance within the host. A comparative analysis of the proteome of the virulent strain H37Rv and the avirulent strain H37Ra identified 3 MTases, which displayed significant variations in terms of N-terminal extension/deletion and point mutations, possibly impacting various physicochemical properties. The cross-proteomic comparison of MTases of M.tb H37Rv with 15 different Mycobacterium species revealed the acquisition of novel MTases in a MTB complex as a function of evolution. Phylogenetic analysis revealed that these newly acquired MTases showed common roots with certain extremophiles such as halophilic and acidophilic organisms. Our results establish an evolutionary relationship of M.tb with halotolerant organisms and also the role of MTases of M.tb in withstanding the host osmotic stress, thereby pointing to their likely role in pathogenesis, virulence and niche adaptation.

An in vivo evaluation of different methods of working length determination.

OBJECTIVE: The purpose of this in vivo study was to compare the ability of digital tactile, digital radiographic and electronic methods to determine reliability in locating the apical constriction. MATERIALS AND METHODS: Informed consent was obtained from patients scheduled for orthodontic extraction. The teeth were anesthetized, isolated and accessed. The canals were negotiated, pulp chamber and canals were irrigated and pulp was extirpated. The working length was then evaluated for each canal by digital tactile sensation, an electronic apex locator (The Root ZX) and digital radiography. The readings were then compared with post-extraction working length measurements. RESULTS: The percentage accuracy indicated that EAL method (Root ZX) shows maximum accuracy, i.e. 99.85% and digital tactile and digital radiographic method (DDR) showed 98.20 and 97.90% accuracy respectively. CLINICAL SIGNIFICANCE: Hence, it can be concluded that the EAL method (Root ZX) produced most reliable results for determining the accurate working length.

Possible modulation of FAS and PTP-1B signaling in ameliorative potential of Bombax ceiba against high fat diet induced obesity.

BACKGROUND: Bombax ceiba Linn., commonly called as Semal, is used in various gastro-intestinal disturbances. It contains Lupeol which inhibits PTP-1B, adipogenesis, TG synthesis and accumulation of lipids in adipocytes and adipokines whereas the flavonoids isolated from B. ceiba has FAS inhibitory activity. The present study was aimed to investigate ameliorative potential of Bombax ceiba to experimental obesity in Wistar rats, and its possible mechanism of action. METHODS: Male Wistar albino rats weighing 180-220 g were employed in present study. Experimental obesity was induced by feeding high fat diet for 10 weeks. Methanolic extract of B. ceiba extract 100, 200 and 400 mg/kg and Gemfibrozil 50 mg/kg as standard drug were given orally from 7th to 10th week. RESULTS: Induction with HFD for 10 weeks caused significant (p < 0.05) increase in % body wt, BMI, LEE indices; serum glucose, triglyceride, LDL, VLDL, cholesterol, free fatty acid, ALT, AST; tissue TBARS, nitrate/nitrite levels; different fat pads and relative liver weight; and significant decrease in food intake (g and kcal), serum HDL and tissue glutathione levels in HFD control rats. Treatment with B. ceiba extract and Gemfibrozil significantly attenuated these HFD induced changes, as compared to HFD control. The effect of B. ceiba 200 and 400 mg/kg was more pronounced in comparison to Gemfibrozil. CONCLUSION: On the basis of results obtained, it may be concluded that the methanolic extract of stem bark of Bombax ceiba has significant ameliorative potential against HFD induced obesity in rats, possibly through modulation of FAS and PTP-1B signaling due to the presence of flavonoids and lupeol.

The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARß/δ. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ causes insulin sensitization and enhances glucose metabolism, whereas activation of PPAR-ß/δ enhances fatty acids metabolism. Thus, PPAR family of nuclear receptors plays a major regulatory role in energy homeostasis and metabolic function. The present review critically analyzes the protective and detrimental effect of PPAR agonists in dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity.