Design, synthesis, and evaluation of benzofuran-based chromenochalcones for antihyperglycemic and antidyslipidemic activities.

A series of benzofuran-based chromenochalcones (16-35) were synthesized and evaluated for in vitro and in vivo antidiabetic activities in L-6 skeletal muscle cells and streptozotocin (STZ)-induced diabetic rat models, respectively, and further in vivo dyslipidemia activity of the compounds was evaluated in a Triton-induced hyperlipidemic hamster model. Among them, compounds 16, 18, 21, 22, 24, 31, and 35 showed significant glucose uptake stimulatory effects in skeletal muscle cells and were further evaluated for in vivo efficacy. Compounds 21, 22, and 24 showed a significant reduction in blood glucose levels in STZ-induced diabetic rats. Compounds 16, 20, 21, 24, 28, 29, 34, 35, and 36 were found active in antidyslipidemic studies. Furthermore, compound 24 effectively improved the postprandial and fasting blood glucose levels, oral glucose tolerance, serum lipid profile, serum insulin level, and the HOMA-index of db/db mice, following 15 days of successive treatment.

Tinosporaside from Tinospora cordifolia Encourages Skeletal Muscle Glucose Transport through Both PI-3-Kinase- and AMPK-Dependent Mechanisms.

The stem of Tinospora cordifolia has been traditionally used in traditional Indian systems of medicine for blood sugar control, without the knowledge of the underlying mechanism and chemical constitution responsible for the observed anti-diabetic effect. In the present study, Tinosporaside, a diterpenoid isolated from the stem of T. cordifolia, was investigated for its effects on glucose utilization in skeletal muscle cells, which was followed by determining the anti-hyperglycemic efficacy in our diabetic db/db mice model. We found that tinosporaside augmented glucose uptake by increasing the translocation of GLUT4 to the plasma membrane in L6 myotubes, upon prolonged exposure for 16 h. Moreover, tinosporaside treatment significantly increased the phosphorylation of protein kinase B/AKT (Ser-473) and 5' AMP-activated protein kinase (AMPK, Thr-172). These effects were abolished in the presence of the wortmannin and compound C. Administration of tinosporaside to db/db mice improved glucose tolerance and peripheral insulin sensitivity associated with increased gene expression and phosphorylation of the markers of phosphoinositide 3-kinases (PI3Ks) and AMPK signaling in skeletal muscle tissue. The findings revealed that tinosporaside exerted its antidiabetic efficacy by enhancing the rate of glucose utilization in skeletal muscle, mediated by PI3K- and AMPK-dependent signaling mechanisms.

Complex spinal dysraphism: myelomenigocele associated with dorsal bony spur, split cord malformation type I, syringomyelia, lipoma and tethered cord.

Variations in split cord malformation (SCM) are known. However, association of SCM type I with myelomeningocele along with same level dorsal bony spur has not been described previously. We report a 1-year old male child who presented with these findings with associated syringomyelia, lipoma and tethered cord.

Serum cytokines in astrocytic brain tumors: a prospective study.

BACKGROUND: Gliomas are the most aggressive form of brain tumors responsible for the majority of brain cancer related deaths. Interleukin (IL)-6, 10 and tumor necrosis factor (TNF)- α are tumor specific proteins that are expressed in gliomas. This study aims to estimate the pre- and postoperative levels of serum markers of these cytokines to evaluate any bearing with its grade and volume. METHODS: Prospective analysis of 80 patients of newly-diagnosed gliomas of any grade was carried out. Pre- and postoperative blood samples day one, one month and at 3rd month of surgery was taken and levels of IL-6, 10 and TNF- α measured and matched with 20 healthy controls. RESULTS: Of the 80 patients, 3 patients had pilocytic astrocytoma, 4 had ganglioglioma, 9 had oligodendroglioma, 17 had diffuse astrocytoma, 5 had anaplastic astrocytoma while 43 had glioblastoma. Preoperative levels of IL-6 and TNF- α was found to be markedly raised in high grade gliomas. Positive correlation was seen between IL-6 with the grade of tumor and high-grade tumors were seen to be more significantly correlated with IL-6. However, preoperative IL-10 in both low and high grade of gliomas did not show any correlation with the volume and grade of tumor. CONCLUSION: High level of IL-6 and TNF-α in peripheral blood in patients of high-grade gliomas provides clue to the invasiveness of the disease which can be useful for understanding the premorbid development of tumor and perhaps extrapolating to ongoing tumor response to treatment.

Treatment Dilemma of Latrogenic Pseudoaneurysm of the Intracavernous Internal Carotid Artery in Young Girl Following Transnasal Transsphenoidal Surgery: A Case Report.

Epistaxis following transnasal transsphenoidal (TNTS) removal of pituitary adenoma can be massive and life-threatening. The intracranial source of bleeding is usually the intracavernous segment of the internal carotid artery (ICA) or adjacent branches. Injury to the cavernous ICA can lead to pseudoaneurysm (PA) or fistula formation. Management of PA is different from saccular aneurysms. A timely diagnosis and adequate management can restore vessel integrity and prevent associated morbidity. A young patient of growth hormone-secreting pituitary adenoma, who underwent microscopic TNTS excision of the tumour, presented with massive epistaxis. Pseudoaneurysm of the cavernous ICA was initially not seen on computed tomography angiography and was later diagnosed on digital subtraction angiography. The attempted management of PA with coils without stent could not stop aneurysm recurrence. The management of such complicated PAs is discussed, and a literature review is done regarding epistaxis in growth hormone secreting adenoma.

Viscosity Reduction and Stability Enhancement of Monoclonal Antibody Formulations Using Derivatives of Amino Acids.

Monoclonal antibodies are complex molecules that often require high concentration formulations to meet clinical requirement and bulk drug substance storage. Stability is a common concern in both high and low concentration formulations, however, high concentration formulations are further complicated by an increase in viscosity, leading to manufacturing and administration challenges. To manage stability and viscosity, drug developers typically use salt, amino acids, sugars, polyols, and surfactant. It is possible that excipients control some of the product quality attributes (CQAs), at the cost of several others. In this paper, we have evaluated several amino acid derivatives and identified bis acetyl lysine and propionyl serine to be efficient and superior to commonly used parenteral excipients for minimizing antibody solution viscosity, as well as mitigating physical and chemical degradation by controlling protein-protein interactions and deamidation.

Maxwell-Wagner Relaxation-Driven High Dielectric Constant in Al2O3/TiO2 Nanolaminates Grown by Pulsed Laser Deposition.

Multilayer nanolaminates (NLs) of alternate ultrathin sublayers of Al2O3 and TiO2 (ATA) with the thickness ranging ∼2 to 0.5 nm were fabricated by optimized pulsed laser deposition (PLD). Maxwell-Wagner (M-W) relaxation-induced interfacial polarization was realized and engineered by precisely controlling the sublayer thicknesses and the number of interfaces. X-ray reflectivity and cross-sectional transmission electron microscopy measurements of ATA NLs revealed an artificial periodicity with well-defined uniformly thick amorphous sublayers with chemically and physically distinct interfaces down to a sublayer thickness of ∼0.8 nm. The dielectric constants and loss of ATA NLs were found to increase from ∼60 to 670 and decrease from ∼0.9 to 0.16, respectively, as sublayer thicknesses reduced from ∼2 to 0.8 nm. However, for a sublayer thickness below 0.8 nm, the trend was reversed. Furthermore, temperature-dependent impedance spectroscopy studies revealed two distinct thermally activated relaxation processes, corresponding to TiO2 and Al2O3 sublayers, corroborating the M-W relaxation. The conductivity contrast between the sublayers of ATA NLs enhanced with reducing sublayer thickness and plateaued at a sublayer thickness of ∼0.8 nm, resulting in dominant M-W interfacial polarization and a high cut-off frequency of ∼50 kHz. These results demonstrate that ATA NLs grown by PLD may find application as potential high-k materials for next-generation nanoelectronic devices.

In vitro, In vivo and In silico Antihyperglycemic Activity of Some Semi-Synthetic Phytol Derivatives.

BACKGROUND: Due to the prevalence of type-2 diabetes across the globe, there is an unmet need to explore new molecular targets for the development of cost-effective and safer antihyperglycemic agents. OBJECTIVE: Structural modification of phytol and evaluation of in vitro, in vivo and in silico antihyperglycemic activity of derivatives establishing the preliminary structure activity relationship (SAR). METHODS: The semi-synthetic derivatives of phytol were prepared following previously described methods. The antihyperglycemic potential was measured in vitro in terms of increase in 2- deoxyglucose (2-DG) uptake by L-6 rat skeletal muscle cells as well as in vivo in sucrose-loaded (SLM) and streptozotocin (STZ)-induced diabetic rat models. The blood glucose profile was measured at 30, 60, 90, 120, 180, 240, 300 and 1440 min post administration of sucrose in rats. The in silico docking was performed on peroxisome proliferator-activated receptor gamma (PPARγ) as antidiabetic target along with absorption, distribution, metabolism, excretion and toxicity (ADMET) studies. RESULTS: Nine semi-synthetic ester derivatives: acetyl (1), lauroyl (2), palmitoyl (3), pivaloyl (4), trans-crotonyl (5), benzoyl (6), m-anisoyl (7), 3,4,5-trimethoxy benzoyl (8) cinnamoyl (9) along with bromo derivative (10) of phytol were prepared. The derivatives 9, 8 and 2 caused 4.5, 3.2 and 2.7 times more in vitro uptake of 2-DG respectively than rosiglitazone (ROSI). The derivatives showed significant improvement in oral glucose tolerance both in SLM (29.6-21%) as well as STZ-induced diabetic (30.8-19.0%) rats. The in silico ADMET, docking studies showed non-toxicity and high binding affinity with PPARγ. CONCLUSION: The potent antihyperglycemic activity with favorable pharmacokinetics supports phytol derivatives as a suitable antidiabetic lead.

Nasopharyngeal rhinosporidiosis with intracranial extension masquerading as juvenile angiofibroma: an unusual entity.

Rhinosporidiosis is a chronic fungal inflammatory disease prevalent in India and Sri Lanka. Its manifestations are mostly nasal and extranasal lesions are relatively rare. Occasional atypical presentations of this disease lead to diagnostic dilemma. Herein we report on a case of nasopharyngeal rhinosporidiosis having extensive involvement of paranasal sinuses along with intracranial extension which mimicked radiologically as juvenile nasopharyngeal angiofibroma. To our knowledge, this is the first reported case of rhinosporidiosis having intracranial extension. We discuss the pathology, treatment and briefly review the literature of this rare disease.

Pregnane-Oximino-Alkyl-Amino-Ether Compound as a Novel Class of TGR5 Receptor Agonist Exhibiting Antidiabetic and Anti-Dyslipidemic Activities.

INTRODUCTION: The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. METHODS: The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic db/db mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. RESULTS: From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 14b) improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic db/db mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 14b treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 14b decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 14b were associated with the activation of the G-protein-coupled bile acid receptor TGR5. CONCLUSION: Compound 14b exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.

Occipital transtentorial approach for pineal region lesions: Addressing the controversies in conventional teaching.

BACKGROUND: The occipital transtentorial (OT) approach is well-established approach for pineal region tumors and can be of choice for the lesions located around the suboccipital part of tentorium such as the quadrigeminal plate, posterior part of thalamus, tentorial surface of cerebellum, splenial region, posterior falx, and lesions around the tentorial incisura. However, it is not very much extensively used in the above-mentioned locations other than the pineal region. METHODS: Thirty-one patients of pineal region lesions were operated by OT approach, the role of conventional preoperative evaluation of the anatomy of the venous sinuses, deep venous system, and tentorial angle was investigated. RESULTS: A variety of lesions were operated using this approach achieving gross and near total resection in majority of the cases (76.6%), with acceptable postoperative mean modified Rankin scales (1.8). CONCLUSION: The OT is a preferable approach for pineal region lesions for patients of all ages and can be tailored for achieving high resectability rates irrespective of the status of the deep venous system and tentorial angle, with reasonable postoperative surgical outcome.

Posterior ischemic optic neuropathy with acute monocular vision loss following clipping of anterior communicating artery aneurysm. A case report and review of literature.

BACKGROUND: The acute postoperative monocular vision loss following anterior communicating artery aneurysm clipping secondary to posterior ischemic optic neuropathy (PION) a rare presentation. CASE DESCRIPTION: A 32-year old patient presented with a spontaneous holocranial thunderclap headache for 7 days, associated with vomiting. The SAH was diagnosed with a tiny saccular aneurysm arising from the anterior communicating artery. A left pterional craniotomy and clipping of aneurysm were done. On the 3rd postoperative day, he complained of left-sided complete blindness, and on the 5th postoperative day, his GCS dropped to E4V1M5 with right-sided hemiplegia. MRI brain showed normal optic apparatus with bilateral ACA and left MCA territory infarct. CONCLUSION: The PION must be kept in the differential diagnosis of post-clipping sudden visual deterioration, especially following anterior communicating artery aneurysm rupture.

An analysis of neurocognitive dysfunction in brain tumors.

BACKGROUND: Neurocognitive dysfunction is an important issue in patients with frontal lobe lesions. These patients who may be in good neurological status may succumb to neurocognitive dysfunction, affecting their daily living and hampering the quality of life. This study aims to correlate pre- and post-operative neurocognitive dysfunction in patients with frontal lobe lesions. MATERIALS AND METHODS: A prospective analysis of 50 patients of newly-diagnosed frontal lobe tumors of any grade deemed suitable for surgical resection was carried out. All patients underwent neurocognitive testing using frontal assessment battery (FAB), mini mental state examination, and verbal learning and memory test pre- and post-operatively. RESULTS: In this study, 22 patients had right frontal lobe lesion, whereas in 24 patients, it was located in the left frontal lobe, and 4 patients had bilateral lesions. Only 12 patients were found to be in good FAB score preoperatively, and all of them had symptom duration of less than 3 months. 1-week postsurgery, 26 patients achieved a good score, which increased to 44 at 3rd month. Patients who had psychological dysfunction for more than 3 months had average-to-bad preoperative FAB scores, while at 3rd month postoperatively, only six patients were in average score and none in bad score. CONCLUSION: Frontal lobe lesion should be kept in mind in patients with neurocognitive dysfunction. FAB is a simple bedside test that should be included in routine neurological examination in daily neurosurgical practice to assess long-term functional outcome in patients with frontal lobe lesions.

Intra-operative cerebral blood flow assessment by indocyanine green video-angiography after temporary arterial occlusion in aneurysm surgery and its clinical implications: a prospective study.

OBJECTIVE: Indocyanine green video angiography (ICG-VA) is a routine while performing vascular surgery to assess patency of perforators, completeness of clipping and/or to assess patency of anastomosis. Its usefulness in assessing cerebral blood flow and perfusion is not well studied. This study is aimed to assess the cerebral blood flow and perfusion after temporary clipping and to correlate with the risk of ischemia. METHODS: Prospective analysis of intra-operative ICG-VA performed during temporary arterial occlusion in 38 patients from January 2014 to December 2018 was conducted. Co-relation with post-operative MR diffusion weighted imaging (MR DWI) in terms of vascular territory of interest within 48 hours of surgery was performed. Clinical outcome was assessed using modified Rankin Scale (mRS) score 1-month post-surgery. RESULTS: 43 aneurysms in 38 patients clipped using ICG-VA were included in this study. No side effect of ICG dye was seen in any patients. The number of times temporary clips applied had a direct relationship to the delay in appearance of ICG in the surgical field which became statistically significant after application of 3rd temporary clip. Nine (23.7%) patients developed ischemia following the procedure confirmed by post-operative MR DWI and all the ischemic cases had visible decrease in ICG fluorescence post-temporary clipping. CONCLUSIONS: No previous study had tried to assess the intraoperative cerebral blood flow and perfusion during temporary clipping of parent vessels during aneurysm surgery. The use of ICG-VA can be extended to assess perfusion in desired territory by merely assessing the degree of opacification.

Microvascular Decompression for Trigeminal Neuralgia: Experience of a Tertiary Care Center in India and a Brief Review of Literature.

BACKGROUND: Trigeminal neuralgia (TN) is a devastating condition causing significant patient discomfort and morbidity hampering quality of life. Of the many treatment options available, microvascular decompression (MVD) of the trigeminal nerve is widely performed. However, the procedure is not risk-free. OBJECTIVE: The study aimed to describe our experience of treating TN via MVD and long-term follow-up of the patients treated by this modality. MATERIALS AND METHODS: It is a 5-year retrospective analysis of the database of patients with idiopathic TN treated with MVD at our institute. A total of 106 patients fulfilling the criteria of idiopathic TN by International Classification of Headache Disorders, 3rd ed.ition and available for follow-up for at least 1-year post-procedure were included in the study. RESULTS: Of the 106 patients, 58 (54.7%) were female and 48 (45.3%) were male with a mean age of 55 years (range 22-75 years). Vascular compression of the trigeminal nerve was seen in all cases; arterial compression in 82%, both artery and vein 14.5% while unidentified vessels were the culprit in 3.8% of the patients. There were no intra- or post-operative deaths. The best response was achieved at 1 month following the procedure where 85% of the patients achieved excellent outcomes. CONCLUSION: In experienced hands, MVD is still a safe and cost-effective modality over a myriad of treatment options available for TN in patients of all ages. The absence of adhesions, indentations, and distortion of the trigeminal nerve are positive predictors of excellent outcomes in the long run.

Endovascular management of large and giant intracranial aneurysms: Experience from a tertiary care neurosurgery institute in India.

OBJECTIVE: With the development of endovascular technique and devices, large and giant intracranial aneurysms are increasingly being managed by this less invasive method. Here we discuss our experience on managing such aneurysms via endovascular technique. METHODS: Retrospective data on 42 patients with large and giant intracranial aneurysms managed by endovascular techniques between September 2015 to December 2017 at our neurosurgery institute were included in this analysis. RESULTS: There were a total 42 patients with 9 giant and 33 large aneurysms in this study. Eight aneurysms were treated by parent vessel occlusion, 22 aneurysms with coils and rest 12 aneurysms were treated with stent assisted coiling. Following the procedure, Raymond class I occlusion was accomplished in 31 (73.8%) patients while class Ⅱ in 9 (21.4%) and class Ⅲ in 2 (4.8%) patients. Overall morbidity and mortality were 9.5% and 14.3% respectively and favorable outcome was seen in 80.9% patients. Significant correlation was observed with clinical outcome and initial neurological status. CONCLUSIONS: The study indicates that endovascular intervention is a safe and effective method in managing large and giant intracranial aneurysms with lesser morbidity and mortality.

Manufacturing Challenges and Rational Formulation Development for AAV Viral Vectors.

Adeno-associated virus (AAV) has emerged as a leading platform for gene delivery for treating various diseases due to its excellent safety profile and efficient transduction to various target tissues. However, the large-scale production and long-term storage of viral vectors is not efficient resulting in lower yields, moderate purity, and shorter shelf-life compared to recombinant protein therapeutics. This review provides a comprehensive analysis of upstream, downstream and formulation unit operation challenges encountered during AAV vector manufacturing, and discusses how desired product quality attributes can be maintained throughout product shelf-life by understanding the degradation mechanisms and formulation strategies. The mechanisms of various physical and chemical instabilities that the viral vector may encounter during its production and shelf-life because of various stressed conditions such as thermal, shear, freeze-thaw, and light exposure are highlighted. The role of buffer, pH, excipients, and impurities on the stability of viral vectors is also discussed. As such, the aim of this review is to outline the tools and a potential roadmap for improving the quality of AAV-based drug products by stressing the need for a mechanistic understanding of the involved processes.

Sub-nanograin metal based high efficiency multilayer reflective optics for high energies.

The present finding illuminates the physics of the formation of interfaces of metal based hetero-structures near layer continuous limit as an approach to develop high-efficiency W/B4C multilayer (ML) optics with ML periodicity varying d = 1.86-1.23 nm at a fixed number of layer pairs N = 400. The microstructure of metal layers is tailored near the onset of grain growth to control the surface density of grains resulting in small average sizes of grains to sub-nanometers. This generates concurrently desirable atomically sharp interfaces, high optical contrast, and desirable stress properties over a large number of periods, which have evidence through the developed ML optics. We demonstrate significantly high reflectivities of ML optics measured in the energy range 10-20 keV, except for d = 1.23 nm due to quasi-continuous layers. The reflectivities at soft gamma-rays are predicted.

Craniosynostosis: To Study the Spectrum and Outcome of Surgical Intervention at a Tertiary Referral Institute in India.

AIMS AND OBJECTIVES: This study aimed to analyze the spectrum and surgical outcome of cases of craniosynostosis operated at a tertiary referral institute in India. DESIGN: This was a cross-sectional study. MATERIALS AND METHODS: We retrospectively examined 60 cases of craniosynostosis operated at our institute from 2008 to 2014 (with a minimum follow-up of 2 years). Data was collected including name, age, gender, involved sutures, other medical conditions, whether syndromic craniosynostosis or not, whether symptoms and signs of intracranial hypertension were present or not, associated findings on magnetic resonance imaging of brain and cervico-medullary junction, type of surgery performed, age at which surgery was performed, perioperative complications (if any), and findings on follow-up. To be able to analyze the surgical results, we used the seven category classification system used by Sloan et al. RESULTS: Craniosynostosis affected more men than women. The incidence of syndromic craniosynostosis was 11.67%. Mean age at first surgery was 3.85 years. Chiari malformation was present in 80% of the Crouzon's syndrome cases, 62.5% of the oxycephaly cases, and 4.44% of the non-syndromic, non-oxycephaly cases. Intracranial hypertension was present in 80% of the Crouzon's syndrome cases, 75% of the oxycephaly cases, and 6.67% of the non-syndromic, non-oxycephaly cases. Perioperative complications were present in 42.86% of the syndromic craniosynostosis cases, 50% of the oxycephaly cases, and 15.56% of the non-syndromic, non-oxycephaly cases. Compromised overall correction was present in 4 of 7 cases of syndromic craniosynostosis, 3 of 8 cases of oxycephaly, and 2 of 45 cases of non-syndromic, non-oxycephaly group. CONCLUSION: The study highlights the importance of educating the masses so that cases of craniosynostosis present early. The incidence of Chiari malformation, intracranial hypertension, and perioperative complications was significantly higher in the syndromic craniosynostosis and oxycephaly groups than in single-suture craniosynostosis. The best surgical outcome and the least perioperative complications were seen in the trigonocephaly group. Compromised overall correction and reoperations were more common in the syndromic and complex craniosynostosis groups than in single-suture craniosynostosis.