In-Silico Aided Screening and Characterization Results in Stability Enhanced Novel Roxadustat Co-Crystal.

Roxadustat (RXD) is an approved drug substances for the treatment of renal anemia. It has poor aqueous solubility and photochemical stability. This study employs a comprehensive approach to enhance the stability and physicochemical properties RXD through coformer selection and characterization. The investigation integrates delta pKa analysis, molecular complementary assessment, molecular electrostatic potential surface analysis, and machine learning techniques to predict potential co-crystal formation and binding interactions between drug molecules and coformers. The co-crystal screening which lead to in a novel RXD-nicotinamide co-crystal (RXD-NA). Experimental characterization underscores the physical and chemical stability of the co-crystals. To elucidate the supramolecular synthons and understand the intermolecular interactions in the RXD-NA co-crystal, Hirshfeld surfaces analysis, quantum theory of atoms in molecules (QTAIM) analysis and non-covalent interaction (NCI) analysis were performed. Computational analysis of photo-isomer formation aligns with experimental observations, further enhancing our understanding of RXD-coformer interactions. RXD-NA co-crystal was found photo-chemically stable as compared to free base API drug substance. This integrated methodology provides a systematic framework for informed co-crystal design, holding promise for optimizing RXD formulations based on molecular interactions and stability considerations. Consequently, this study contributes valuable insights to the field of rational drug design and formulation optimization.

Efficacy of Siddha Therapeutics on Mantha Sanni (Autism Spectrum Disorder) Among Pediatric Patients: An Interventional Non-randomized Open-Label Clinical Trial.

BACKGROUND: Autism Spectrum Disorder (ASD) refers to a collection of neurodevelopmental disorders that affect brain development and can lead to various psychological imbalances in caregivers of affected children. Siddha formulations have been shown to have a role beyond the physical body and play a significant role in managing Mantha sannior ASD. The objective of this study was to examine the impacts of Amukkara chooranam and Yegamooli thylam in the pediatric population diagnosed with ASD. METHODS: This was a prospective, interventional, non-randomized, open clinical trial involving 30 patients who met the inclusion and exclusion criteria. Patients received Amukkara chooranam at a dose of 300 mg for ages 3-4 years, 500 mg for ages 5-7 years, and 1 gm for ages 8-12 years, twice a day with honey for 90 days, and Yegamooli thylam was administered using the Thuvalai external manipulation technique once a day for 90 days. Scoring by the Indian Scale for Assessment of Autism (ISAA) was documented at the end of the 0th day, 45th day, and 90th day. RESULTS: The scores were compared at each follow-up, and a statistically significant difference was found at the end of the 90th day of treatment with Amukkara chooranam and Yegamooli thylam (P < 0.05). The statistical analysis included calculating the mean and standard deviation of the clinical assessment, parameters both before and after the treatment were 37.66667 ±13.82485. CONCLUSION: The treatment with Amukkara chooranam and Yegamooli thylam resulted in a clinically significant improvement in clinical assessment parameters in children with ASD.

Prehabilitation for spine surgery: A scoping review.

We aimed to identify and describe the current interventions used in preoperative programs ("prehabilitation") for spine surgery. Knowledge gaps in approaches, feasibility, timing, patient experience, clinical outcomes, and health care costs were explored while describing their potential benefits on physical and psychological outcomes. An electronic search was conducted from January 2004 to February 2022 in Ovid Medline, Embase, EBSCO CINAHL, the Cochrane Database of Systematic Reviews, and PEDro to identify studies in English evaluating adults enrolled in prehabilitation before undergoing elective spine surgeries. Studies were uploaded into DistillerSR for systematic screening after removing duplicates. Four reviewers screened nested references for inclusion based on titles and abstracts, followed by their full-text review. Two reviewers subsequently extracted data and summarized the results. The results were reported using Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. Studies were rated for quality using National Health and Medical Research Council criteria. Out of 18,879 potential studies, a total of 23 studies (0.12%) met the eligibility criteria and were included in this scoping review. The prehabilitation programs included general education (n = 6, 26%), exercise (n = 6, 26%), cognitive behavioral therapy (n = 3, 13%), pain neuroscience education (n = 3, 13%), health behavior counseling (n = 3, 13%), and mindfulness (n = 2, 9%). Additional studies are needed to identify optimal patient characteristics, intervention dosage, and whether multimodal approaches using a combination of physical and psychological strategies lead to more favorable outcomes. Although studies on prehabilitation for spine surgery are limited, they seem to demonstrate that prehabilitation programs are feasible, reduce medical expenditures, and improve patients' postoperative pain, disability, self-efficacy, psychological behaviors, and satisfaction with surgical outcomes. The available literature suggests there is an opportunity to improve patient experience, clinical outcomes and reduce medical costs with the use of prehabilitation in spine surgery.

Risk factors predisposing to acute stroke in India: a prospective study.

BACKGROUND: Stroke is an important neurological disorder with significant morbidity and mortality. In India, the risk factors for stroke (obesity, diabetes mellitus, alcoholism, hypertension, and sedentary lifestyle) are mounting with economic growth and increasing the disease burden. OBJECTIVE: To assess the severity and risk factors of stroke in India and identify any new predisposing factors. METHODS: A multicentric (six tertiary care hospitals across India) prospective observational study (from September 2016 to July 2017) was conducted on 526 stroke patients, presenting within the first 24 h to examine the risk factors for ischemic and hemorrhagic strokes. Severity was determined using the National Institutes of Health Stroke Scale (NIHSS). RESULTS: Predominantly male (72.3%), 75% of the sample was >50 years old, with a mean body mass index (BMI) of 25.8 ±â€Š4.3 kg/m2 and 14.6% obese patients. Hypertension and diabetes mellitus were the commonest comorbidities, followed by a history of ischemic heart disease and familial history of stroke. 20.5% of patients had mild strokes, 57.4% had moderate, 8.4% experienced moderate-severe strokes, whereas 7.2% had severe strokes. Regarding the admission diagnoses, 56.8% were ischemic, 18.6% were hemorrhagic, 1.1% had a transient ischemic attack, 6.6% suffered recurrent strokes, and 17% were other forms. CONCLUSION: The foremost risk factors for stroke in India, hypertension and diabetes, need to be controlled and treated like other global high-risk populations for stroke prevention. The NIHSS scores highlight the relationship between risk factors and stroke severity.

Inter-examinerreliability study of physical examination procedures to assess the cervical spine.

OBJECTIVE: The objective of this study was to establish the level of inter-examiner reliability for six common cervical manual and physical examination procedures used to assess the cervical spine. MATERIALS: Reliability study that used a convenience sample of 51 patients between the ages of 16-70 years presenting with a chief complaint of neck pain. Two physical therapists independently performed the same series of cervical physical examination procedures on each of the participant. The clinicians were blinded to each other's findings and the clinical status of the patient. Kappa coefficients (κ) were calculated for levels of agreement between the clinicians for each procedure. RESULTS: When assessing for asymmetrical motion, excellent levels of reliability (κ range: 0.88-0.96) were observed for the Bilateral Modified Lateral Shear (asymmetry criterion), Bilateral C2 Spinous Kick (asymmetry criterion) and Flexion-Rotation Tests. When pain provocation was used as the indicator of a positive test during palpation of the cervical facet joints, moderate to substantial levels of reliability (κ range: 0.53-0.76) were observed. When patients were instructed not to provide feedback to the clinicians about pain provocation during facet joint palpation and clinicians relied solely on their qualitative assessment of segmental mobility, the level of reliability was lower (κ range: 0.45-0.53). Due to 100 % prevalence of negative findings, Kappa values could not be calculated for the Sharp-Purser test or the Unilateral C2 Spinous Kick Test. CONCLUSIONS: Most physical examination procedures examined in this study demonstrated moderate to excellent levels of inter-examiner reliability. Palpation for segmental mobility without pain provocation demonstrated a lower level of reliability compared to palpation for pain provocation. Correlation with clinical findings is necessary to establish validity and the applicability of these procedures in clinical practice.

γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor.

Excess plasma triglycerides (TGs) are a key component of obesity-induced metabolic syndrome. We have shown that γ-secretase inhibitor (GSI) treatment improves glucose tolerance due to inhibition of hepatic Notch signaling but found additional Notch-independent reduction of plasma TG-rich lipoproteins (TRLs) in GSI-treated, as well as hepatocyte-specific, γ-secretase knockout (L-Ncst) mice, which suggested a primary effect on hepatocyte TRL uptake. Indeed, we found increased VLDL and LDL particle uptake in L-Ncst hepatocytes and Ncst-deficient hepatoma cells, in part through reduced γ-secretase-mediated low-density lipoprotein receptor (LDLR) cleavage and degradation. To exploit this novel finding, we generated a liver-selective Nicastrin ASO, which recapitulated glucose and lipid improvements of L-Ncst mice, with increased levels of hepatocyte LDLR. Collectively, these results identify the role of hepatic γ-secretase to regulate LDLR and suggest that liver-specific GSIs may simultaneously improve multiple aspects of the metabolic syndrome.

The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation.

Recent cell culture and animal studies have suggested that expression of human apo C-III in the liver has a profound impact on the triacylglycerol (TAG)-rich VLDL1 production under lipid-rich conditions. The apoC-III Gln38Lys variant was identified in subjects of Mexican origin with moderate hypertriglyceridemia. We postulated that Gln38Lys (C3QK), being a gain-of-function mutation, promotes hepatic VLDL1 assembly/secretion. To test this hypothesis, we expressed C3QK in McA-RH7777 cells and apoc3-null mice to contrast its effect with WT apoC-III (C3WT). In both model systems, C3QK expression increased the secretion of VLDL1-TAG (by 230%) under lipid-rich conditions. Metabolic labeling experiments with C3QK cells showed an increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, and FA were increased in C3QK mice as compared with C3WT mice. Liver of C3QK mice also displayed an increase in DNL and expression of lipogenic genes as compared with that in C3WT mice. These results suggest that C3QK variant is a gain-of-function mutation that can stimulate VLDL1 production, through enhanced DNL.

Malignant Cylindroma of Post Aural Region Involving the Temporal Bone.

Dermal eccrine cylindroma is a benign adnexal tumour commonly affecting the neck, scalp and skin of elderly individuals. These are poorly circumscribed dermal or subcutaneous lesions consisting of numerous rounded ovoid or cord shaped dermal island that fit together to form a jigsaw pattern. Malignant transformation is not commonly seen. This case highlights malignant transformation of a dermal eccrine cylindroma in the post aural region extending to involve the underlying mastoid bone.

A comparative evaluation of Oratest with the microbiological method of assessing caries activity in children.

AIMS: The aim of this study is to find out whether Oratest can be used as a diagnostic tool in assessing the caries activity by evaluating its relationship to the existing caries status and the salivary streptococcus mutans level. MATERIALS AND METHODS: The study sample consists of 90 students divided into two groups. Group I (test group) and Group II (control group) consisting of 30 children for control group and 60 children for test group. The sampling of unstimulated saliva for the estimation of streptococcus mutans was done as per the method suggested by Kohler and Bratthall. The plates were then incubated. Rough surface colonies were identified as streptococcus mutans on a pre-determined area of the tip (approximately 1.5 cm(2)) were counted for each side of spatula pressed against mitis salivarius bacitracin agar using digital colony counter. The results were expressed in colony forming units (CFU). Oratest was carried out in the same patients after the collection of salivary sample for the microbiological method to evaluate the relationship between the two tests. STATISTICAL ANALYSIS USED: The tests used were ANOVA, Pearson Chi-square test, Pearson's correlation analysis, Mann-Whitney U test and Student's independent t-test. RESULTS: In the control group and test group, when the streptococcus mutans count (CFU) and Oratest time (minutes) were correlated using Pearson's correlation analysis, the streptococcus mutans counts was found to be in a statistically significant negative linear relationship with the Oratest time. When the caries status of the children, participated in the test group were correlated with mutans count (CFU) and Oratest time, caries status were found to be in a statistically significant positive linear relationship with streptococcus mutans count and in a significant negative linear relationship with Oratest time. CONCLUSIONS: The test proved to be a simple, inexpensive and rapid technique for assessing caries activity since a significant relationship exists clinically with caries status and microbiologically with the streptococcus mutans count of the individual.

Global Inactivation of the Pla2g6 Gene in Mice Does Not Cause Dyslipidemia under Chow or High-fat Diet Conditions.

BACKGROUND: Genome-wide association studies suggest that plasma triacylglyceride (TAG) in humans was associated with variation in the PLA2G6 locus, a gene that encodes calcium-independent phospholipase A2 (iPLA2 ß). The objective of the present study is to understand the impact of genetic inactivation of iPLA2 ß on hepatic TAG metabolism in C57BL/6 mice. METHODS: Male iPLA2 ß (+) (/-) mice were backcrossed with female iPLA2 ß (-/-) mice for up to 10 generations prior to experiments. Lipid and lipoprotein metabolism from plasma, hepatocytes, thigh subcutaneous adipose and thigh skeletal muscle tissues of the mice were determined under various experimental conditions. RESULTS: The iPLA2 ß (-/-) mice, either male or female as compared with iPLA2 ß (+) (/) (+) littermates, showed no change in fasted or postprandial plasma TAG or total cholesterol at young (12-15 weeks) or old (40-44 weeks) ages under chow diet or high-fat diet (HFD) conditions. However, fractionation of plasma lipoproteins showed that under HFD conditions, there was a significant increase (by 40%) in apoB-100 association with VLDL1 fractions in iPLA2 ß (-/-) mice as compared with iPLA2 ß (+) (/) (+) littermates. There was no significant difference in triglyceride or cholesterol contents in the liver, muscle, or adipose tissue between iPLA2 ß (-/-) and iPLA2 ß (+/+) littermates. Metabolic labeling experiments with cultured primary hepatocytes isolated from iPLA2 ß (-/-) mice also showed 2-fold increase in the secretion of [(35)S]methionine-labeled apoB-100 in VLDL1 fractions as compared with that from iPLA2 ß (+) (/) (+) hepatocytes. Likewise, secretion of [(3)H]palmitate-labeled TAG from the iPLA2 ß (-/-) hepatocytes was increased by 2-fold. CONCLUSIONS: Although iPLA2 ß may play a role in TAG-rich VLDL1 production from cultured hepatocytes, there is no evidence that inactivation of iPLA2 ß would lead to dyslipidemia in mice in vivo.

Acarbose improves glycemic control as add-on or monotherapy in Indian type-2 diabetes: Findings from the GlucoVIP multinational observational study.

OBJECTIVE: To investigate the efficacy and tolerability of the anti-diabetic agent acarbose (Glucobay(®)) as add-on or monotherapy in a range of patients with type-2 diabetes mellitus (T2DM), including those with cardiovascular morbidities in India. MATERIALS AND METHODS: This was a part of a prospective, non-interventional, non-controlled, multicentre, multinational, observational study. The study included patients of either gender if they were aged at least 18 years and had untreated or pre-treated type-2 diabetes mellitus (T2DM) or impaired glucose tolerance and no acarbose treatment within the 3 months before study inclusion. RESULTS: In total, 1996 Indian patients were included in the effectiveness and 2010 in the safety analysis. Patients received acarbose (25-150 mg/day). The mean age of the patients was 50.1 years and the mean BMI was 27.2 kg/m(2). Mean 2-h post-prandial plasma glucose (PPG) value and fasting blood glucose (FBG) decreased from 243.9 to 169.5 mg/dl and 158.3 to 120.4 mg/dl, respectively after the last follow-up of 12.4 weeks. The mean HbA1c value at initial visit was 8.4% and was 7.4% at the last follow-up visit. FBG, PPG and HbA1c deceased in 90.6%, 94.4% and 52.4% patients respectively, by the last follow-up visit. The mean decrease in weight and waist circumference was 1.4 kg and 1.6 cm, respectively by the last follow-up visit. Physicians assessed the efficacy of drug as positive response in "very good to good" in 91.08%, "sufficient" in 7.92% and "insufficient" in 0.90% of patients. Also, continuation of Acarbose was reported in 97.09% of patients. Adverse events were reported in 2.74% and drug-related adverse events were reported in 2.19% of patients. Majority of them were gastrointestinal adverse events but were not serious. CONCLUSION: Acarbose is effective and safe in Indian patients with T2DM. Further, it helps in weight reduction and has very good compliance in patients with T2DM.

Microsome-associated lumenal lipid droplets in the regulation of lipoprotein secretion.

PURPOSE OF REVIEW: Liver is the major organ in mammals that possesses the capacity to release triglyceride within VLDL. VLDL assembly requires apolipoprotein (apo) B-100 with the assistance of microsomal triglyceride transfer protein (MTP), which facilitates the mobilization of triglyceride into the microsomal lumen. Recent experimental evidence has suggested that the lumenal triglyceride associated with endoplasmic reticulum (ER)/Golgi may represent an entity serving as precursors for large VLDL1. RECENT FINDINGS: Under lipid-rich conditions, discrete triglyceride-rich lipidic bodies, termed lumenal lipid droplets, are accumulated in association with ER/Golgi microsomes. Formation of the microsome-associated lumenal lipid droplets (MALD) is dependent on the activity of MTP, and the resulting apoB-free lipidic body is associated with a variety of proteins including apolipoproteins that are components of VLDL. Formation and utilization of MALD during the assembly and secretion of VLDL1 have a profound influence on hepatic cell physiology, such as ER stress responses. SUMMARY: This review summarizes current understanding of hepatic triglyceride homeostasis in general, and highlights the functional significance of triglyceride compartmentalization between cytosol and microsomes in particular. Understanding of MALD metabolism may shed new light on the prevention and treatment of liver diseases associated with abnormally elevated intracellular triglycerides.

Antitumor activity of ethanol extract of Gracilaria edulis (Gmelin) Silva on Ehrlich ascites carcinoma-bearing mice.

OBJECTIVE: To evaluate antitumor activity of Gracilaria edulis in Swiss albino mice with Ehrlich ascites carcinoma (EAC). METHODS: Tumors were induced in mice by intraperitoneal injection of EAC cells. Ethanol extract of Gracilaria edulis (EEGE) was administered to the experimental animals in different doses after 24 h of tumor inoculation. The antitumor effect of the EEGE was evaluated by assessing in vitro cytotoxicity, survival time, biochemical parameters and hepatic enzyme levels. RESULTS: EEGE increased the life span of EAC-bearing mice compared with that of the model control mice (P<0.05 or P<0.01). EEGE treatment also converted the changes of biochemical parameters and hepatic enzyme levels in the EAC-bearing mice (P<0.05 or P<0.01). EEGE induced inhibition of tumor formation in EAC-bearing mice compared with that of the model control group (P<0.05 or P<0.01). CONCLUSION: The present study scientifically proved the antitumor activity of marine algae G. edulis and the effect can be correlated with doses.

Intrahepatic role of exchangeable apolipoproteins in lipoprotein assembly and secretion.

Exchangeable apolipoproteins, composed mainly of amphipathic α-helices, are associated with various plasma lipoproteins and play an important role in the metabolism of those lipoproteins to which they bind. Accumulating experimental evidence suggests that exchangeable apolipoproteins, such as apoE, apoA-IV, and apoC-III, also play a role intracellularly in facilitating lipid recruitment at different stages of very low-density lipoprotein assembly and trafficking through the endoplasmic reticulum-Golgi secretory compartments. Experimental evidence also suggests that apoA-I may become lipidated intracellularly through mechanisms dependent on or independent of ATP-binding cassette transporter A1. Thus, expression of these secretory proteins may exert an impact on hepatic triglyceride and cholesterol homeostasis during their transit from the endoplasmic reticulum through the Golgi apparatus. This review summarizes findings related to the modulation of intracellular assembly of very low-density lipoprotein and high-density lipoprotein by exchangeable apolipoproteins.

Mycotic aneurysm complicating a covered stent implanted for coarctation of the aorta in a child.

A mycotic aneurysm associated with a covered stent in the thoracic aorta of a 12-year-old child was successfully managed by excision and replacement with aortic homograft. On follow-up, there was unobstructed flow through the homograft. This case highlights the need for high index of suspicion for mycotic aneurysm and prompt surgical intervention in children with coarctation of aorta who present with features of infective endocarditis.

Cavernous hemangioma of the spinal cord: a rare case.

Cavernous hemangiomas are composed of dilated vessels which are filled with blood. Their common sites of occurrence include the skin, liver and the superficial and the deep soft tissues. We are presenting a rare case of cavernous hemangioma of the spinal cord.