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BACKGROUND: Vascular parkinsonism (VP) is an atypical Parkinsonian syndrome that is believed to have a temporal association with cerebrovascular disease. However, now it is evolving as a heterogeneous entity with no clear consensus on the definition and diagnostic criteria. AIM AND OBJECTIVES: This study aimed at evaluating the clinico-radiological profile of patients with VP and Parkinson’s disease (PD). MATERIALS AND METHODS: The present study was conducted at a tertiary care university hospital. A total of 80 patients, with a diagnosis of probable VP (40) and PD (40), were evaluated and compared with Unified Parkinson’s Disease Rating Scale (UPDRS) part III, gait scale, Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and MRI brain. RESULTS: Significantly older age of onset (P = 0.005), higher vascular risk factors (P < 0.001), and motor scores in UPDRS part III (P < 0.001), gait scale (P < 0.001), and modified Hoehn and Yahr (P < 0.001) were seen in the VP as compared with the PD. On the cognitive scales, patients with VP scored significantly lower in MMSE (19.92 ± 6.0 vs. 24.90 ± 3.34; P < 0.001) and FAB (7.75 ± 4.27 vs. 11.22 ± 2.75; P < 0.001); on the modified Hachinski scale (7.77 ± 3.19 vs. 3.30 ± 1.97; P < 0.001), they scored higher compared with patients with PD. Periventricular ischemic changes, generalized brain atrophy, and multiple lacunar infarcts were the most common radiological abnormality found significantly more in patients with VP. CONCLUSION: An older age, worse cognitive scores and motor scores, and more profound periventricular and subcortical lesions on MRI favored VP.

BACKGROUND: There is a paucity of literature in patients with focal dystonia from our country with certain differences in the clinical characteristics as compared to the Western population. OBJECTIVES: The aim of this study was to evaluate the clinical spectrum of patients with focal dystonia attending the neurology outpatient department and of admitted patients in neurology ward of a tertiary care hospital. MATERIALS AND METHODS: All consecutive patients of focal dystonia from October 2017 to September 2019, fulfilling the inclusion criteria were enrolled. Patients were subjected to a detailed history and thorough examination as per a predesigned pro forma. RESULTS: Of a total of 88 patients with focal dystonia, 62.5% were male. Majority of the focal dystonia (51.1%) had late adulthood onset (>40 years). Writer’s cramp was the most common type of focal dystonia (n = 38; 43.2%), but in patients older than 40 years, focal cranial dystonias (n = 28 of 43, 65.1%) were the most common. Oromandibular dystonia and blepharospasm had significantly older mean age of onset compared to focal upper limb (57.0 ± 14.05, 44.9 ± 13.83 vs. 31.5 ± 17.67; P < 0.001, P = 0.032, respectively). Most of the focal dystonias were isolated (87.5%, n = 77) and idiopathic (66%). Among the acquired causes, drugs were the most common (n = 9; 10.1%), followed by perinatal birth insult (n = 4; 4.5%). All of the drug-induced focal dystonias were oromandibular. CONCLUSION: Focal dystonia was more prevalent in males, and it had an earlier age of onset by a decade as compared to the Western population. Writer’s cramp was the most common type of focal dystonia, but in patients older than 40 years, cranial dystonias were the most common. In patients presenting with oromandibular dystonia, a drug history should be carefully sought.

Abstract Warburg effect is an emerging hallmark of cancer cells with pyruvate kinase M2 (PKM2) as its key regulator. Curcumin is an extensively-studied anti-cancer compound, however, its role in affecting cancer metabolism remains poorly understood. Herein, we show that curcumin inhibits glucose uptake and lactate production (Warburg effect) in a variety of cancer cell lines by down-regulating PKM2 expression, via inhibition of mTOR-HIF1α axis. Stable PKM2 silencing revealed that PKM2 is required for Warburg effect and proliferation of cancer cells. PKM2 over-expression abrogated the effects of curcumin, demonstrating that inhibition of Warburg effect by curcumin is PKM2-mediated. High PKM2 expression correlated strongly with poor overall survival in cancer, suggesting the requirement of PKM2 in cancer progression. The study unravels novel PKM2-mediated inhibitory effect of curcumin on metabolic capacities of cancer cells. To the best of our knowledge, this is the first study linking curcumin with PKM2-driven cancer glycolysis, thus, providing new perspectives into the mechanism of its anticancer activity.

The topological characteristics of biological networks enable us to identify the key nodes in terms of modularity. However, due to a large size of the biological networks with many hubs and functional modules across intertwined layers within the network, it often becomes difficult to accomplish the task of identifying potential key regulators. We use for the first time a generalized formalism of Hamiltonian Energy (HE) with a recursive approach. The concept, when applied to the Apoptosis Regulatory Gene Network (ARGN), helped us identify 11 Motif hubs (MHs), which influenced the network up to motif levels. The approach adopted allowed to classify MHs into 5 significant motif hubs (S-MHs) and 6 non-significant motif hubs (NS-MHs). The significant motif hubs had a higher HE value and were considered as high-active key regulators; while the non-significant motif hubs had a relatively lower HE value and were considered as low-active key regulators, in network control mechanism. Further, we compared the results of the HE analyses with the topological characterization, after subjecting to the three conditions independently: (i) removing all MHs, (ii) removing only S-MHs, and (iii) removing only NS-MHs from the ARGN. This procedure allowed us to cross-validate the role of 5 S-MHs, NFk-B1, BRCA1, CEBPB, AR, and POU2F1 as the potential key regulators. The changes in HE calculations further showed that the removal of 5 S-MHs could cause perturbation at all levels of the network, a feature not discernible by topological analysis alone.

Cancer cells rewire metabolism to meet biosynthetic and energetic demands. The characteristic increase in glycolysis, i.e., Warburg effect, now considered as a hallmark, supports cancer in various ways. To attain such metabolic reshuffle, cancer cells preferentially re-express the M2 isoform of pyruvate kinase (PKM2, M2-PK) and alter its quaternary structure to generate less-active PKM2 dimers. The relatively inactive dimers cause the accumulation of glycolytic intermediates that are redirected into anabolic pathways. In addition, dimeric PKM2 also benefits cancer cells through various non-glycolytic moonlight functions, such as gene transcription, protein kinase activity, and redox balance. A large body of data have shown that several distinct posttranslation modifications (PTMs) regulate PKM2 in a way that benefits cancer growth, e.g., formation of PKM2 dimers. This review discusses the recent advancements in our understanding of various PTMs and the benefits they impart to the sustenance of cancer. Understanding the PTMs in PKM2 is crucial to assess their therapeutic potential and to design novel anticancer strategies.

Role of, 29-non-synonymous, 15-intronic, 3-close to UTR, single nucleotide polymorphisms (SNPs) and 2 mutations of Human Pyruvate Kinase (PK) M2 were investigated by in-silico and in-vitro functional studies. Prediction of deleterious substitutions based on sequence homology and structure based servers, SIFT, PANTHER, SNPs&GO, PhD-SNP, SNAP and PolyPhen, depicted that 19% emerged common between all the mentioned programs. SNPeffect and HOPE showed three substitutions (C31F, Q310P and S437Y) in-silico as deleterious and functionally important. In-vitro activity assays showed C31F and S437Y variants of PKM2 with reduced activity, while Q310P variant was catalytically inactive. The allosteric activation due to binding of fructose 1-6 bisphosphate (FBP) was compromised in case of S437Y nsSNP variant protein. This was corroborated through molecular dynamics (MD) simulation study, which was also carried out in other two variant proteins. The 5 intronic SNPs of PKM2, associated with sporadic breast cancer in a case-control study, when subjected to different computational analyses, indicated that 3 SNPs (rs2856929, rs8192381 and rs8192431) could generate an alternative transcript by influencing splicing factor binding to PKM2. We propose that these, potentially functional and important variations, both within exons and introns, could have a bearing on cancer metabolism, since PKM2 has been implicated in cancer in the recent past.

Gemcitabine, an effective agent in treatment of cancer of pancreas, has undergone failures in many instances after multiple cycles of therapy due to emergence of drug resistance. Combination of dietary compounds with clinically validated drugs has emerged as an effective therapeutic approach to treat pancreatic tumors, refractory to gemcitabine therapy. In order to optimize a possible synergistic combination of Gemcitabine (GCB) with dietary molecules, Betuilnic acid (BA) and Thymoquinone (TQ), stand-alone IC50 dose of GCB, BA and TQ was calculated for pancreatic cancer cell lines. Fixed IC50 dose ratio of the dietary molecules in combination with reduced IC50 dose of GCB was tested on GCB resistant PANC-1 and sensitive MIA PaCa-2 cells for synergism, additive response and antagonism, using calcusyn. Combination index (CI) revealed that pre-treatment of BA and TQ along with GCB synergistically inhibited the cancer cell proliferation in in-vitro experiments. Pyruvate kinase (PK) M2 isoform, a promising target involved in cancer cell metabolism, showed down-regulation in presence of TQ or BA in combination with GCB. GCB with BA acted preferentially on tumor mitochondria and triggered mitochondrial permeability transition. Pre-exposure of the cell lines, MIA PaCa-2 and PANC-1, to TQ in combination with GCB induced apoptosis. Thus, the effectiveness of BA or TQ in combination with GCB to inhibit cell proliferation, induce apoptosis and down-regulate the expression of PKM2, reflects promise in pancreatic cancer treatment.

Leprosy is a chronic infectious disease caused by Mycobacterium Leprae, where the host genetic background plays an important role toward the disease pathogenesis. Various studies have identified a number of human genes in association with leprosy or its clinical forms. However, non-replication of results has hinted at the heterogeneity among associations between different population groups, which could be due to differently evolved LD structures and differential frequencies of SNPs within the studied regions of the genome. A need for systematic and saturated mapping of the associated regions with the disease is warranted to unravel the observed heterogeneity in different populations. Mapping of the PARK2 and PACRG gene regulatory region with 96 SNPs, with a resolution of 1 SNP per 1 Kb for PARK2 gene regulatory region in a North Indian population, showed an involvement of 11 SNPs in determining the susceptibility towards leprosy. The association was replicated in a geographically distinct and unrelated population from Orissa in eastern India. In vitro reporter assays revealed that the two significantly associated SNPs, located 63.8 kb upstream of PARK2 gene and represented in a single BIN of 8 SNPs, influenced the gene expression. A comparison of BINs between Indian and Vietnamese populations revealed differences in the BIN structures, explaining the heterogeneity and also the reason for non-replication of the associated genomic region in different populations.

Type 2 diabetes (T2D) is a syndrome of multiple metabolic disorders and is genetically heterogeneous. India comprises one of the largest global populations with highest number of reported type 2 diabetes cases. However, limited information about T2D associated loci is available for Indian populations. It is, therefore, pertinent to evaluate the previously associated candidates as well as identify novel genetic variations in Indian populations to understand the extent of genetic heterogeneity. We chose to do a cost effective high-throughput mass-array genotyping and studied the candidate gene variations associated with T2D in literature. In this case-control candidate genes association study, 91 SNPs from 55 candidate genes have been analyzed in three geographically independent population groups from India. We report the genetic variants in five candidate genes: TCF7L2, HHEX, ENPP1, IDE and FTO, are significantly associated (after Bonferroni correction, p

Metabolism of cancer cells with pyruvate kinase M2 (PKM2) at its centre stage has assumed a prime significance in cancer research in recent times. Cancer cell metabolism, characterized by enhanced glucose uptake, production of lactate and anabolism is considered an ideal target for therapeutic interventions. Expression of PKM2 switches metabolism in favor of cancer cells, therefore, the present study was designed to investigate the hitherto unknown effect of resveratrol, a phytoalexin, on PKM2 expression and resultant implications on cancer metabolism. We observed that resveratrol down-regulated PKM2 expression by inhibiting mTOR signaling and suppressed cancer metabolism, adjudged by decreased glucose uptake, lactate production (aerobic glycolysis) and reduced anabolism (macromolecule synthesis) in various cancer cell lines. A contingent decrease in intracellular levels of ribose-5-phosphate (R5P), a critical intermediate of pentose phosphate pathway, accounted for a reduced anabolism. Consequently, the state of suppressed cancer metabolism resulted in decreased cellular proliferation. Interestingly, shRNA-mediated silencing of PKM2 inhibited glucose uptake and lactate production, providing evidence for the critical role of PKM2 and its mediation in the observed effects of resveratrol on cancer metabolism. Further, an over-expression of PKM2 abolished the observed effects of resveratrol, signifying the role of PKM2 downregulation as a critical function of resveratrol. The study reports a novel PKM2-mediated effect of resveratrol on cancer metabolism and provides a new dimension to its therapeutic potential.

Our previous studies have implicated genes mainly involved in the activity of pancreatic β cells in type 2 diabetes (T2D) susceptibility in the North Indian population. Recent literature on the role of SIRT1 as a potential master switch modulating insulin secretion and regulating gene expression in pancreatic β cells has warranted an evaluation of SIRT1 promoter region polymorphisms in the North Indian population, which is the main focus of the present study. 1542 samples (692 T2D patients and 850 controls) were sequenced for the 1.46 kb region upstream the translation start site of the SIRT1 gene. We performed a functional characterization of the SIRT1 promoter region polymorphisms using luciferase assay and observed a single-nucleotide polymorphism (SNP), rs12778366, in association with SIRT1 expression. We propose that TT, the high-expressing genotype of SNP rs12778366 in the SIRT1 promoter region and present in >80% of the North Indian population, was favored under conditions of feast-famine cycles in evolution, which has turned out to be a cause of concern in the present sedentary lifestyle under ad libitum conditions. Case-control association analysis did not implicate rs12778366 in T2DM per se in the studied population. However, our earlier reported risk genotype combinations of mt-ND3, PGC1α, and UCP2-866, when compared with the protective genotype combinations, in the background of the high-expressing TT genotype of SIRT1 SNP rs12778366, showed a very high additive risk [corrected odd ratio (OR) = 8.91; p = 6.5×10(-11)]. The risk level was considerably low in the genotype backgrounds of TX (OR = 6.68; p = 2.71×10(-12)) and CX (OR = 3.74; p = 4.0×10(-3)). In addition, we screened other reported T2D-associated polymorphisms: PIK3R1 rs3730089, IRS1 rs1801278, and PPP1R3 rs1799999, which did not show any significant association in North Indian population. The present paper emphasizes the importance of gene interactions in the biological pathways of T2D, a complex lifestyle disease.

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7 x 10(-8), OR = 0.31, 95% CI = 0.20-0.48, and HLA-DQA1 rs1071630, case-control P = 4.9 x 10(-14), OR = 0.43, 95% CI = 0.35-0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.

The article focuses on a rare case of Donnai–Barrow syndrome (DBS) presenting with spastic paraparesis, a feature not previously documented in the literature. Topics include the unique neurological manifestation of spastic paraparesis in DBS, the importance of reporting atypical symptoms for early diagnosis and genetic counseling, and the use of whole exome sequencing to confirm the diagnosis.

Neurorehabilitation is the major pathway for motor recovery, but its effect on biomarkers of stroke has rarely been considered. Only brain-derived neurotrophic factor and matrix metalloproteinase are related to the rehabilitation process. Radiological and inflammatory biomarkers need to be correlated with the neurorehabilitation process. The clinical and physiological effects of neurorehabilitation on biomarkers and motor recovery should be established, to maximise the effect of neurorehabilitation. In this systematic review with narrative synthesis we provide the current state and understanding of neurorehabilitation and its effect on biomarkers for motor recovery in acute ischaemic stroke patients.

Background: Post-stroke pain is common after a stroke and might be underreported. We describe Persistent Facial Pain (PFP) developed in post-stroke patients. Method: ology: This was a prospective hospital-based cohort study of stroke patients, and patients were followed up. Out of 415 stroke patients, 26 developed PFP. Result: Out of all PFP patients, six patients had an ischemic stroke, and 20 had a hemorrhagic stroke. 57.7% of patients had hypertension, while 34.6 patients had diabetes. The stroke location was left-sided in 12 patients and right-sided in 14 patients. 46.15% of patients responded to venlafaxine, 30.77% responded to amitriptyline, and 23.08% responded to pregabalin. Conclusion: Persistent facial pain is a pain syndrome that might be missed in patients post-stroke. It might be more common in hemorrhagic stroke patients than in ischemic stroke patients. It responds adequately to antidepressants. A high index of suspicion is required to diagnose and appropriately manage these patients.