Pharmacological intervention in young adolescents rescues synaptic physiology and behavioural deficits in Syngap1+/- mice.

Haploinsufficiency in SYNGAP1 is implicated in intellectual disability (ID) and autism spectrum disorder (ASD) and affects the maturation of dendritic spines. The abnormal spine development has been suggested to cause a disbalance of excitatory and inhibitory (E/I) neurotransmission at distinct developmental periods. In addition, E/I imbalances in Syngap1+/- mice might be due to abnormalities in K+-Cl- co-transporter function (NKCC1, KCC2), in a maner similar to the murine models of Fragile-X and Rett syndromes. To study whether an altered intracellular chloride ion concentration represents an underlying mechanism of modified function of GABAergic synapses in Dentate Gyrus Granule Cells of Syngap1+/- recordings were performed at different developmental stages of the mice. We observed depolarised neurons at P14-15 as illustrated by decreased Cl- reversal potential in Syngap1+/- mice. The KCC2 expression was decreased compared to Wild-type (WT) mice at P14-15. The GSK-3ß inhibitor, 6-bromoindirubin-3'-oxime (6BIO) that crosses the blood-brain barrier, was tested to restore the function of GABAergic synapses. We discovered that the intraperitoneal administration of 6BIO during the critical period or young adolescents [P30 to P80 (4-week to 10-week)] normalised an altered E/I balance, the deficits of synaptic plasticity, and behavioural performance like social novelty, anxiety, and memory of the Syngap1+/- mice. In summary, altered GABAergic function in Syngap1+/- mice is due to reduced KCC2 expression leading to an increase in the intracellular chloride concentration that can be counteracted by the 6BIO, which restored cognitive, emotional, and social symptoms by pharmacological intervention, particularly in adulthood.

Critical aspects of neurodevelopment.

Organisms have the unique ability to adapt to their environment by making use of external inputs. In the process, the brain is shaped by experiences that go hand-in-hand with optimisation of neural circuits. As such, there exists a time window for the development of different brain regions, each unique for a particular sensory modality, wherein the propensity of forming strong, irreversible connections are high, referred to as a critical period of development. Over the years, this domain of neurodevelopmental research has garnered considerable attention from many scientists, primarily because of the intensive activity-dependent nature of development. This review discusses the cellular, molecular, and neurophysiological bases of critical periods of different sensory modalities, and the disorders associated in cases the regulators of development are dysfunctional. Eventually, the neurobiological bases of the behavioural abnormalities related to developmental pathologies are discussed. A more in-depth insight into the development of the brain during the critical period of plasticity will eventually aid in developing potential therapeutics for several neurodevelopmental disorders that are categorised under critical period disorders.

Interface Dominated Dielectric Response of PS-Fe3O4 Patchy Microspheres.

Polymeric-inorganic interface plays a vital role in enhancing dielectric properties of patchy microspheres, Janus particles, and nanocomposites. We performed the computational modeling and simulations along with experiments to understand the phenomena behind the improved dielectric permittivity of polystyrene-iron oxide (PS-Fe3O4) patchy microspheres. We addressed the fundamental insights into the role of the interfacial region on the dielectric properties. Based on the experimental outcomes and computational simulations on dielectric behavior including polarization and electric field formation, we propose a new mechanism of charge buildup at the interface. Computational results reveal that the creation of interface bound-charges at the inorganic-polymeric interface is responsible for the improved dielectric properties. We also fabricated PS-Fe3O4 patchy microspheres by Pickering emulsion polymerization using Fe3O4 particles as a solid stabilizer. The microstructure, composition, morphology, dielectric, and thermal properties of the synthesized patchy PS-Fe3O4 particles were investigated. The dielectric permittivity (k) of the neat PS increased from ∼2.9 to ∼14.8 after decorating with Fe3O4 particles. Impedance response of the patchy microspheres shows that the interface of PS-Fe3O4 stores more charges than bulk PS-Fe3O4. The dielectric behavior of patchy microspheres can be engineered by tuning the shape and position of the patches. The present studies on polymer-inorganic interface provide some insights into the mechanisms that control dielectric permittivity and nonlinear conduction in an applied electric field.

Role of antigen presenting cell invariant chain in the development of hepatic steatosis in mouse model.

The role of Invariant chain (CD74 or Ii) in antigen presentation via Antigen Presenting Cells (APC), macrophage recruitment as well as survival, T cell activation and B cell differentiation has been well recognized. However, the aspect of CD74 which is involved in the development of hepatic steatosis and the pathways through which it acts remain to be studied. In this study, we investigated the role of CD74 in the inflammatory pathway and its contribution to development of hepatic steatosis. For this, wild type C57BL/6J and CD74 deficient mice (Ii(-/-) mice) were fed with high fat high fructose (HFHF) diet for 12 weeks. Chronic consumption of this feed did not develop hepatic steatosis, glucose intolerance or change in the level of immune cells in Ii(-/-) mice. Moreover, there was relatively delayed expression of genes involved in development of non alcoholic fatty liver disease (NAFLD) in HFHF fed Ii(-/-) mice as compared to that of C57BL/6J phenotype. Taken together, the data suggest that HFHF diet fed Ii(-/-) mice fail to develop hepatic steatosis, suggesting that Ii mediated pathways play a vital role in the initiation and propagation of liver inflammation.

Potency and pharmacokinetics of broad spectrum and isoform-specific p110γ and δ inhibitors in cancers.

Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110γ and p110δ catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110δ structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2 ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110γ and p110δ, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, molecular phylogeny revealed that p110γ and p110δ are evolutionarily divergent; they probably need separate strategies for drug development.

Susceptible and protective associations of HLA DRB1*/DQB1* alleles and haplotypes with ischaemic stroke.

Stroke has emerged as the second commonest cause of mortality worldwide and is a major public health problem. For the first time, we present here the association of human leucocyte antigen (HLA)-DRB1*/DQB1* alleles and haplotypes with ischaemic stroke in South Indian patients. Ischaemic stroke (IS) cases and controls were genotyped for HLA-DRB1*/DQB1* alleles by polymerase chain reaction sequence-specific primers (PCR-SSP) method. The frequencies of HLA class II alleles such as DRB1*04, DRB1*07, DRB1*11, DRB1*12, DRB1*13, DQB1*02 and DQB1*07 were high in IS patients than in the age- and gender-matched controls, suggesting that the individuals with these alleles are susceptible to ischaemic stroke in South India. The frequencies of alleles such as DRB1*03, DRB1*10, DRB1*14, DQB1*04 and DQB1*05 were less in IS cases than in the controls, suggesting a protective association. Haplotypes DRB1*04-DQB1*0301, DRB1*07-DQB1*02, DRB1*07-DQB1*0301, DRB1*11-DQB1*0301 and DRB1*13-DQB1*06 were found to be high in IS patients conferring susceptibility. The frequency of haplotype DRB1*10-DQB1*05 was high in controls conferring protection. IS-LVD and gender-stratified analysis too confirmed these susceptible and protective associations. Thus, HLA-DRB1*/DQB1* alleles and haplotypes strongly predispose South Indian population to ischaemic stroke. Further studies in different populations with large sample size or the meta-analysis are needed to explain the exact mechanism of associations of HLA gene(s) with IS.

Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin.

Tumor metastasis refers to spread of a tumor from site of its origin to distant organs and causes majority of cancer deaths. Although >30 metastasis suppressor genes (MSGs) that negatively regulate metastasis have been identified so far, two issues are poorly understood: first, which MSGs oppose metastasis in a tumor type, and second, which molecular function of MSG controls metastasis. Herein, integrative analyses of tumor-transcriptomes (n=382), survival data (n=530) and lymph node metastases (n=100) in lung cancer patients identified non-metastatic 2 (NME2) as a key MSG from a pool of >30 metastasis suppressors. Subsequently, we generated a promoter-wide binding map for NME2 using chromatin immunoprecipitation with promoter microarrays (ChIP-chip), and transcriptome profiling. We discovered novel targets of NME2 which are involved in focal adhesion signaling. Importantly, we detected binding of NME2 in promoter of focal adhesion factor, vinculin. Reduced expression of NME2 led to enhanced transcription of vinculin. In comparison, NME1, a close homolog of NME2, did not bind to vinculin promoter nor regulate its expression. In line, enhanced metastasis of NME2-depleted lung cancer cells was found in zebrafish and nude mice tumor models. The metastatic potential of NME2-depleted cells was remarkably diminished upon selective RNA-i-mediated silencing of vinculin. Together, we demonstrate that reduced NME2 levels lead to transcriptional de-repression of vinculin and regulate lung cancer metastasis.

G-quadruplexes and associated proteins in aging and Alzheimer's disease.

Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer's disease (AD). Alzheimer's disease is characterized by progressive cognitive decline, memory loss, and neuropsychiatric and behavioral symptoms, accounting for most of the reported dementia cases. This disease is now becoming a major challenge and burden on modern society, especially with the aging population. Over the last few decades, a significant understanding of the pathophysiology of AD has been gained by studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, and neuroinflammation. This review focuses on the role of non-canonical secondary structures of DNA/RNA G-quadruplexes (G4s, G4-DNA, and G4-RNA), G4-binding proteins (G4BPs), and helicases, and their roles in aging and AD. Being critically important for cellular function, G4s are involved in the regulation of DNA and RNA processes, such as replication, transcription, translation, RNA localization, and degradation. Recent studies have also highlighted G4-DNA's roles in inducing DNA double-strand breaks that cause genomic instability and G4-RNA's participation in regulating stress granule formation. This review emphasizes the significance of G4s in aging processes and how their homeostatic imbalance may contribute to the pathophysiology of AD.

Effect of dietary ß carotene on cerebral aneurysm and subarachnoid haemorrhage in the brain apo E-/- mice.

Atherosclerosis will lead to stenosis/occlusion in the lumen of various arteries of living body. This can lead various conditions including myocardial infarction, cerebral infarction/aneurysm and peripheral artery disease. Ang II is believed to be an important regulatory peptide involved in maintaining cardiovascular homeostasis and pathogenesis of various cardiovascular diseases. Matrix metalloproteinase's (MMPs), adhesion molecules and plasminogen systems are involved in the inflammatory reaction of various blood vessels as well as pathogenesis of cerebro vasuclar disease in apo E(-/-) mice during angiotensin II injection. The present study analyses the role of ang II in development of cerebral aneurysm and also evaluated the mRNA levels of MMPs, adhesion molecules, plasminogen systems and peroxisome proliferators-associated receptors in the brain of apo E(-/-) mouse during the progression of cerebral aneurysm and ischemic conditions. Also, this study evaluates the role of dietary ß carotene on cerebrovascular disease. Serum total cholesterol (TC), Low density lipoprotein (LDL) and triglyceride (TG) levels were significantly increased in angiotensin II treated animals and further ß carotene supplementation reduces TC but does not affect the triglyceride and LDL levels. Circulating levels of macrophages were significantly increased in angiotensin treated animals and further beta carotene supplementation significantly reduced the circulating macrophages. Cerebro meningeous aneurysm, subarachnoid haemorrhage, multiple foci of infarction, necrosis and infiltration of inflammatory cells were observed in the cerebral hemispheres of ang II treated animals, however, infarction size were reduced and no aneurysm, inflammatory foci was observed in ß carotene treated animals. Real time analysis showed down regulation of mRNA levels of MMP 2, uPA, PAI, PPAR-A, MCSF1 and up regulation of tPA and MCP-1 in the brain during the progression of cerebral aneurysm and ß carotene supplementation to bring to normal expression levels of all the candidate genes for cerebrovascular diseases. Based on above results, Ang II may induced cerebral aneurysm, ischemia/infarction on brain through RAS system by down regulating the mRNA levels of MMP 2, uPA, PAI, PPAR-A, MCSF1 and up regulating tPA and MCP-1 and ß carotene attenuates the disease condition and bring down to normal expression levels of above genes.

Spatiotemporal analysis of soluble aggregates and autophagy markers in the R6/2 mouse model.

Maintenance of cellular proteostasis is vital for post-mitotic cells like neurons to sustain normal physiological function and homeostasis, defects in which are established hallmarks of several age-related conditions like AD, PD, HD, and ALS. The Spatio-temporal accumulation of aggregated proteins in the form of inclusion bodies/plaques is one of the major characteristics of many neurodegenerative diseases, including Huntington's disease (HD). Toxic accumulation of HUNTINGTIN (HTT) aggregates in neurons bring about the aberrant phenotypes of HD, including severe motor dysfunction, dementia, and cognitive impairment at the organismal level, in an age-dependent manner. In several cellular and animal models, aggrephagy induction has been shown to clear aggregate-prone proteins like HTT and ameliorate disease pathology by conferring neuroprotection. In this study, we used the mouse model of HD, R6/2, to understand the pathogenicity of mHTT aggregates, primarily focusing on autophagy dysfunction. We report that basal autophagy is not altered in R6/2 mice, whilst being functional at a steady-state level in neurons. Moreover, we tested the efficacy of a known autophagy modulator, Nilotinib (Tasigna™), presently in clinical trials for PD, and HD, in curbing mHTT aggregate growth and their potential clearance, which was ineffective in both inducing autophagy and rescuing the pathological phenotypes in R6/2 mice.

High fat diet containing cholesterol induce aortic aneurysm through recruitment and proliferation of circulating agranulocytes in apoE knock out mice model.

We studied and compared the efficiency of induction aneurysm in apo E mice by using high fat diet and Ang II. Aneurysm induced in 6 week old male apo E -/- mice by subcutaneous release of Ang II injection for 45 days. Also, aneurysm was induced in three month old male apo E by administration of high fat diet for a period of three months. No difference in body weight in Ang II treated mice. But, increase in body weight and mean arterial blood pressure observed in high fat diet group animals. Highly significant increase in total cholesterol, TG, LDL and significant decrease in HDL level were observed in Ang II treated animals. Significant increase in total cholesterol, but no changes in TG, LDL, HDL levels were observed in high fat diet group. Higher percentage of circulating monocytes was observed in ang II treated group but more number of circulating lymphocytes were observed in high fat diet group in FACS analysis. In histopathology, intimal layer of abdominal aorta was completely replaced by chronic inflammatory cells particularly macrophages (80%) which appeared as foam cells and lymphocytes (20%) in ang II treated animals. Degradation of elastin, infiltration of lymphocytes, chondrocytes and cellular migration towards media were observed in the abdominal aorta of high fat diet group. Real time analysis and immunofluorescence assay supports over expression of Vcam 1 Icam1, MCP 1and MMP2 genes were observed in Ang II treated animals. In immunofluorescence assay, over expression of Mac 3 protein specific for macrophages was observed in abdominal aorta of ang II treated animals, but over expression of CD45.1 & 45.2 proteins specific to lymphocytes were observed in high fat diet group. Based on our observations, Ang II induced aortic aneurysm by recruiting/ proliferating circulating monocytes by up regulating Icam-1, Vcam -1 and MCP-1. Also, ang II involved in degradation of elastin in the abdominal aorta by up regulation of MMP2 to promote agranulocytes migration in the intimal layers. Epithelial cell hyperplasia with accumulation of fatty fluids (cyst) was observed in seminal vesicle and ventral prostate of high fat treated animals. Fatty degeneration, germ cell apoptosis and infiltration giant cells were observed in the testes of high fat diet group. As per available literature these observations were not reported with high fat diet treatments with apo E models. High fat diet induced aneurysm prominently in abdominal, thoracic aorta and extensive plaque formation was observed in femoral and renal arteries. Administration of high fat diet containing cholesterol induced aneurysm in apo E mice model also efficient method to rule out the pathogenesis of aortic aneurysm when compared with angiotensin.

Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen.

Acute liver failure (ALF) is a clinical condition caused by various etiologies resulting in the loss of metabolic, biochemical, synthesizing, and detoxifying functions of the liver. In most irreversible liver damage cases, orthotropic liver transplant (OLT) remains the only available treatment. To study the therapeutic potential of a treatment for ALF, its prior testing in an animal model of ALF is essential. In the current study, an ALF model in rats was developed by combining 70% partial hepatectomy (PHx) and injections of acetaminophen (APAP) that provides a therapeutic window of 48 h. The median and left lateral lobes of the liver were removed to excise 70% of the liver mass and APAP was given 24 h postsurgically for 2 days. Survival in ALF-induced animals was found to be severely decreased. The development of ALF was confirmed by altered serum levels of the enzymes alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP); changes in prothrombin time (PT); and assessment of the international normalized ratio (INR). Study of the gene expression profile by qPCR revealed an increase in expression levels of genes involved in apoptosis, inflammation, and in the progression of liver injury. Diffused degeneration of hepatocytes and infiltration of immune cells was observed by histological evaluation. The reversibility of ALF was confirmed by the restoration of survival and serum levels of ALT, AST, and ALP after intrasplenic transplantation of syngeneic healthy rat hepatocytes. This model presents a reliable alternative to the available ALF animal models to study the pathophysiology of ALF as well as to evaluate the potential of a novel therapy for ALF. The use of two different approaches also makes it possible to study the combined effect of physical and drug-induced liver injury. The reproducibility and feasibility of current procedure is an added benefit of the model.

Inducible alterations of glutathione levels in adult dopaminergic midbrain neurons result in nigrostriatal degeneration.

Parkinson's disease is a neurodegenerative disorder characterized by the preferential loss of midbrain dopaminergic neurons in the substantia nigra (SN). One of the earliest detectable biochemical alterations that occurs in the Parkinsonian brain is a marked reduction in SN levels of total glutathione (glutathione plus glutathione disulfide), occurring before losses in mitochondrial complex I (CI) activity, striatal dopamine levels, or midbrain dopaminergic neurodegeneration associated with the disease. Previous in vitro data from our laboratory has suggested that prolonged depletion of dopaminergic glutathione results in selective impairment of mitochondrial complex I activity through a reversible thiol oxidation event. To address the effects of depletion in dopaminergic glutathione levels in vivo on the nigrostriatal system, we created genetically engineered transgenic mouse lines in which expression of gamma-glutamyl cysteine ligase, the rate-limiting enzyme in de novo glutathione synthesis, can be inducibly downregulated in catecholaminergic neurons, including those of the SN. A novel method for isolation of purified dopaminergic striatal synaptosomes was used to study the impact of dopaminergic glutathione depletion on mitochondrial events demonstrated previously to occur in vitro as a consequence of this alteration. Dopaminergic glutathione depletion was found to result in a selective reversible thiol-oxidation-dependent mitochondrial complex I inhibition, followed by an age-related nigrostriatal neurodegeneration. This suggests that depletion in glutathione within dopaminergic SN neurons has a direct impact on mitochondrial complex I activity via increased nitric oxide-related thiol oxidation and age-related dopaminergic SN cell loss.

A mouse model for luminal epithelial like ER positive subtype of human breast cancer.

BACKGROUND: Generation of novel spontaneous ER positive mammary tumor animal model from heterozygous NIH nude mice. METHODS: Using brother-sister mating with pedigree expansion system, we derived a colony of heterozygous breeding females showing ER-Positive tumors around the age of 6 months. Complete blood picture, differential leukocyte count, and serum levels of Estrogen, Alanine amino transferase (SGPT), Aspartate amino transferase (SGOT), total protein and albumin were estimated. Aspiration biopsies and microbiology were carried out. Gross pathology of the tumors and their metastatic potential were assessed. The tumors were excised and further characterized using histopathology, cytology, electron microscopy (EM), molecular markers and Mouse mammary Tumor Virus - Long Terminal Repeats (MMTV LTR) specific RT-PCR. RESULTS: The tumors originated from 2nd or 5th or both the mammary glands and were multi-nodulated with variable central necrosis accompanied with an accumulation of inflammatory exudate. Significant increases in estrogen, SGPT, SGOT and neutrophils levels were noticed. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and subcutaneous tissue. Metastatic spread through hematogenous and regional lymph nodes, into liver, lungs, spleen, heart and dermal lymphatics was observed. EM picture revealed no viral particles and MMTV-negativity was confirmed through MMTV LTR-specific RT-PCR. High expression of ER alpha, moderate to high expression of proliferating cell nuclear antigen (PCNA), moderate expression of vimentin and Cytokeratin 19 (K19) and low expression of p53 were observed in tumor sections, when compared with that of the normal mammary gland. CONCLUSION: Since 75% of human breast cancer were classified ER-positive and as our model mimics (in most of the characteristics, such as histopathology, metastasis, high estrogen levels) the ER-positive luminal epithelial-like human breast cancer, this model will be an attractive tool to understand the biology of estrogen-dependant breast cancer in women. To our knowledge, this is the first report of a spontaneous mammary model displaying regional lymph node involvement with both hematogenous and lymphatic spread to liver, lung, heart, spleen and lymph nodes.

Diagnosis Delayed but not Denied - Sheehan's syndrome.

Sheehan's syndrome is a rare complication of postpartum hemorrhage. With advancement in obstetric care, Sheehan's syndrome has become uncommon except in developing countries. Here, we report a patient with Sheehan's syndrome who escaped diagnosis for 22 years and presented with life threatening complications. This patient also had certain unusual features of Sheehan's syndrome like pancytopenia and renal failure. A high index of suspicion is necessary in diagnosing such patients.

Interleukin-18-induced atherosclerosis involves CD36 and NF-κB crosstalk in Apo E-/- mice.

OBJECTIVE: Interleukin (IL)-18 is a pleotropic cytokine involved in various inflammatory disorders. The transcription factor, nuclear factor kappa-B (NF-κB), is thought to play an important role in IL-18 signaling. The present study proposes a novel role for IL-18 in cholesterol efflux and plaque stability and demonstrates that pyrrolidine dithiocarbamate (PDTC), a NF-κB inhibitor blocks IL-18 signaling in apolipoprotein (Apo) E-/- mice. METHODS: Three groups of normal chow-diet-fed, male Apo E-/- mice, aged 12 weeks (n=6/group) were employed: Gp I, PBS (2mo); Gp II, recombinant (r)IL-18 (1mo) followed by PBS (1mo); Gp III, rIL-18 (1mo) followed by PDTC (1mo). RESULTS: Significantly augmented expression of IL-18 receptor (R)α by fluorescence-activated cell sorting analysis and plasma IL-18 was observed in Gp II. There was a significant increase in total cholesterol and low-density lipoprotein cholesterol whereas high-density lipoprotein cholesterol was significantly decreased in Gp II. However, this pattern was reversed in Gp III. Significantly augmented mRNA expression of IL-18, CD36, matrix metalloproteinase (MMP)-9, and NF-κB was observed in Gp II but liver X receptor alpha (LXR-α) gene was significantly reduced. A significant increase in frequency of atherosclerotic lesions was observed in Gp II animals, whereas there was a significant decrease in the Gp III. CONCLUSION: IL-18 administration initiates inflammatory cascade by binding with IL-18 Rα via NF-κB which is involved in progression and destabilization of atherosclerotic plaques in Apo E-/- mice. This study also reveals that NF-κB blockade with PDTC, blocks IL-18 signaling through down-regulation of IL-18, IL-18 Rα, CD36, and MMP-9, thus reducing inflammation and restoring plaque instability via upregulation of LXR-α.

Neuroacanthocytosis misdiagnosed as Huntington's disease: a case report.

A patient with the typical features of neuroacanthocytosis is reported. Chorea, tics, personality changes and caudate atrophy on cranial MRI resulted in an erroneous diagnosis of Huntington's disease elsewhere. Attention to other features viz., absence of ocular motility disturbances, amyotrophy, areflexia, EMG evidence of axonopathy, raised serum creatinine phosphokinase (CPK) levels and the typical erythrocytic acanthocytosis enabled us to establish the correct diagnosis. The typical features of the disease as seen in the patient are discussed. In view of the implications for genetic counseling, careful clinical and laboratory evaluation is always warranted to exclude neuroacanthocytosis in all suspected cases of Huntington's disease.

Mapping of artificial neural networks onto message passing systems.

Various Artificial Neural Networks (ANNs) have been proposed in recent years to mimic the human brain in solving problems involving human-like intelligence. Efficient mapping of ANNs comprising of large number of neurons onto various distributed MIMD architectures is discussed in this paper. The massive interconnection among neurons demands a communication efficient architecture. Issues related to the suitability of MIMD architectures for simulating neural networks are discussed. Performance analysis of ring, torus, binary tree, hypercube, and extended hypercube for simulating artificial neural networks is presented. Our studies reveal that the performance of the extended hypercube is better than those of ring, torus, binary tree, and hypercube topologies.

Essential oil of Tridax procumbens L induces apoptosis and suppresses angiogenesis and lung metastasis of the B16F-10 cell line in C57BL/6 mice.

BACKGROUND: To determine the effect of essential oil obtained from a traditionally used medicinal plant Tridax procumbens L, on lung metastasis developed by B16F-10 melanoma cells in C57BL/6 mice. MATERIALS AND METHODS: Parameters studied were toxicity, lung tumor nodule count, histopathological features, tumor directed capillary vessel formation, apoptosis and expression levels of P53 and caspase-3 proteins. RESULTS: In vitro the MTT assay showed cytotoxicity was found to be high as 70.2% of cancer cell death within 24 hrs for 50 µg. In vivo oil treatment significantly inhibited tumor nodule formation by 71.7% when compared with untreated mice. Formation of tumor directed new blood vessels was also found to be inhibited to about 39.5%. TUNEL assays also demonstrated a significant increase in the number of apoptotic positive cells after the treatment. P53 and caspase-3 expression was also found to be greater in the essential oil treated group than the normal and cancer group. CONCLUSIONS: The present investigation showed significant effects of the essential oil of Tridax procumbens L in preventing lung metastasis by B16F-10 cell line in C57BL/6 mice. Its specific preventive effect on tumor directed angiogenesis and inducing effect on apoptosis warrant further studies at the molecular level to validate the significance of Tridax procumbens L for anticancer therapy.

Modifiable risk factors for acute lower respiratory tract infections.

OBJECTIVE: Acute respiratory infection is a leading cause of morbidity and mortality in under five children in developing countries. Hence, the present study was undertaken to identify various modifiable risk factors for acute lower respiratory tract infections (ALRI) in children aged 1 mth to 5 yr. METHODS: 104 ALRI cases fulfilling WHO criteria for pneumonia, in the age group of 1 mth to 5 yr were interrogated for potential modifiable risk factors as per a predesigned proforma. 104 healthy control children in the same age group were also interrogated. RESULTS: The significant sociodemographic risk factors were parental illiteracy, low socioeconomic status, overcrowding and partial immunization, [p value < 0.05 in all]. Significant nutritional risk factors were administration of prelacteal feeds, early weaning, anemia, rickets and malnutrition, [p value < 0.05 in all]. Significant environmental risk factors were use of kerosene lamps, biomass fuel pollution and lack of ventilation [p value < 0.05 in all]. On logistic regression analysis, partial immunization, overcrowding and malnutrition were found to be significant risk factors. CONCLUSION: The present study has identified various socio-demographic, nutritional and environmental modifiable risk factors for ALRI which can be tackled by effective education of the community and appropriate initiatives taken by the government.