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Biomedical subjects

P Chaturvedi

Publications and source records attributed to P Chaturvedi.

At least 19 recordsLinked to original sources
PubMed2001

Effect of neurophilin ligands on motor units in mice with SOD1 ALS mutations.

BACKGROUND: Mice with trangenes that express mutations in the gene for cytosolic copper/zinc superoxide dismutase (SOD1) develop motor neuron degeneration resembling human ALS. Neurophilin ligands are small molecules that promote neurite outgrowth. OBJECTIVE: To test the hypothesis that treatment with two neurophilin ligands increases survival in these ALS mice by slowing the loss of motor neurons and increasing the sizes of motor units. METHODS: Transgenic mice hemizygous for the G93A mutation were untreated or treated from 30 days of age with one of two doses of two neurophilin ligands (V-13,670; V-10,367, Vertex Pharmaceuticals, Boston, MA). Onset of behavioral abnormalities and survival were recorded. Motor unit number estimation (MUNE) was performed every 21 days starting at age 60 days. RESULTS: In control animals, disease onset occurred at 77.0 days of age and death occurred at 137 days of age. Neither neurophilin ligand affected the disease course. In control animals, MUNE declined with time beginning before behavioral abnormalities were noted, and motor unit size increased concomitantly. There was no effect of drug on motor unit loss as assessed by MUNE; however, motor unit size increased more rapidly and to a greater degree in animals treated with V-13,670. CONCLUSION: As in human ALS, the transgenic ALS mice show physiologic changes in the motor unit prior to the development of clinical signs: MUNE declines as motor unit size increases. Although neither neurophilin ligand significantly affected survival, one produced an increase in motor unit size. The fact that survival was not altered by the increase in motor unit size may reflect the rapid disease course in this animal model.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Modified Glasgow Coma Scale to predict mortality in febrile unconscious children.

A prospective hospital based study was conducted in the Department of Pediatrics of the Kasturba Hospital, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha to predict the mortality in children admitted with fever and unconsciousness using the Modified Glasgow Coma Scale (MGCS) score. Forty eight children were admitted with fever and unconsciousness; cases of febrile convulsions, epilepsy and cerebral palsy were excluded. MGCS scores were assessed on admission and repeated at 12 hours, 24 hours, 48 hours and 72 hours after admission in each case. Diagnosis in each case was confirmed by history, examinations and investigations. All the cases were regularly followed up till death/discharge. The overall mortality was 29.1% (14/48) out of which 85% (12/14) died within the first 24 hours. Mortality was highest in the toddler age group and in patients with pyogenic meningitis. There was a significant association between death and MGCS scores on admission with a post test probability for discharge being only 10% with a score of less than 5 and 99% with a score of more than 10 respectively. MGCS scores on admission can be used to predict mortality in patients hospitalized with fever and unconsciousness. The scale is simple, easy, can be applied at bed side and does not need any investigations. Its application in developing countries with limited investigative and intensive care facilities can help the treating physician decide regarding referral and counseling the parents regarding the probable clinical outcome.

Analysis of Variance↗
PubMed2001

Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease.

Slowing or halting the progressive dopaminergic (DA) degeneration in Parkinson's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug-induced side-effects. We tested the potential of two orally administered novel immunophilin ligands to protect against DA degeneration in two animal models of PD. First, in an MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model, we compared an immunophilin ligand (V-10,367) documented to bind the immunophilin FKBP12 with V-13,661, which does not bind FKBP12. Both molecules could prevent the loss of striatal DA innervation in a dose-dependent fashion during 10 days of oral administration. Second, to determine whether an immunophilin ligand can protect against progressive and slow DA degeneration typical of PD, an intrastriatal 6-hydroxydopamine-infusion rat model was utilized. Oral treatment with the FKBP12-binding immunophilin ligand began on the day of lesion and continued for 21 days. At this time point, post mortem analyses revealed that the treatment had prevented the progressive loss of DA innervation within the striatum and loss of DA neurons within the substantia nigra, related to functional outcome as measured by rotational behaviour. Notably, DA fibres extending into the area of striatal DA denervation were observed only in rats treated with the immunophilin ligand, indicating neuroprotection or sprouting of spared DA fibres. This is the first demonstration that immunophilin ligands can prevent a slow and progressive DA axonal degeneration and neuronal death in vivo. The effects of orally administered structurally related immunophilin ligands in acute and progressive models of DA degeneration are consistent with the idea that these compounds may have therapeutic value in PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Fucosylated human milk oligosaccharides vary between individuals and over the course of lactation.

Specific human milk oligosaccharides, especially fucosylated neutral oligosaccharides, protect infants against specific microbial pathogens. To study the concentrations of individual neutral oligosaccharides during lactation, a total of 84 milk samples were obtained from 12 women at 7 time periods during weeks 1-49 postpartum. The neutral oligosaccharides from each sample were isolated, perbenzoylated, resolved, and quantified by reversed-phase high-performance liquid chromatography. The resultant oligosaccharide peaks, identified by co-elution with authentic standards and mass spectrometry, ranged in size from tri- to octasaccharides. The total concentration of oligosaccharides declined over the course of lactation; the mean concentration at 1 year was less than half that in the first few weeks postpartum. One of the 12 donors produced milk fucosyloligosaccharides that were essentially devoid of alpha1,2 linkages (but contained alpha1,3- and alpha1,4-linked fucose) until late in lactation, consistent with the nonsecretor phenotype. In milk samples from the remaining 11 donors, fucosyloligosaccharides containing alpha1,2-linked fucose were prevalent, and their profiles were distinct from those of fucosyloligosaccharides devoid of alpha1,2-linked fucose. The ratio of alpha1,2-linked oligosaccharide concentrations to oligosaccharides devoid of alpha1,2-linked fucose changed during the first year of lactation from 5:1 to 1:1. Furthermore, the absolute and the relative concentrations of individual oligosaccharides varied substantially, both between individual donors and over the course of lactation for each individual. The patterns of milk oligosaccharides among individuals suggest the existence of many genotype subpopulations. This variation in individual oligosaccharide concentrations suggests that the protective activities of human milk could also vary among individuals and during lactation.

Carbohydrate Conformation↗
PubMed2001

Regulation of monocyte chemoattractant protein (MCP)-1 transcription by interferon-gamma (IFN-gamma) in human astrocytoma cells: postinduction refractory state of the gene, governed by its upstream elements.

Monocyte chemoattractant protein (MCP)-1 is expressed by astrocytes in diverse inflammatory states and is a key regulator of monocyte recruitment to the central nervous system (CNS). In the current study, we addressed mechanisms by which transcription of the human MCP-1 gene (hMCP-1) was terminated, after induction by interferon (IFN)-gamma. Our results demonstrated that IFN-gamma-induced transcription of hMCP-1 was followed by a refractory state, during which hMCP-1 was resistant to restimulation by either IFN-gamma or heterologous activators such as TNF-alpha. This refractory state affected the hMCP-1 gene selectively, as other IFN-gamma-inducible genes remained responsive to restimulation. The IFN-gamma-induced hMCP-1 refractory state was governed at the transcriptional level and was sensitive to protein synthesis inhibitors, suggesting a requirement for newly expressed components. A minimal 213 base pair hMCP-1 regulatory element directed both IFN-gamma-mediated transcription and the subsequent refractory state. We previously demonstrated that IFN-gamma treatment resulted in coordinate protein occupancy in vivo of two hMCP-1 promoter elements, a gamma-activated site (GAS) and a GC-rich element. During the refractory state, IFN-gamma treatment failed to induce protection of either the hMCP-1 GAS element or the GC box. These results furnish insight into the expression of hMCP-1 during CNS inflammation and provide the first delineation of an IFN-gamma-induced transcriptional refractory state.

Astrocytoma↗
PubMed2001

Tumor necrosis factor alpha increases human cerebral endothelial cell Gb3 and sensitivity to Shiga toxin.

Hemolytic uremic syndrome (HUS) is associated with intestinal infection by enterohemorrhagic Escherichia coli strains that produce Shiga toxins. Globotriaosylceramide (Gb3) is the functional receptor for Shiga toxin, and tumor necrosis factor alpha (TNF-alpha) upregulates Gb3 in both human macrovascular umbilical vein endothelial cells and human microvascular brain endothelial cells. TNF-alpha treatment enhanced Shiga toxin binding and sensitivity to toxin. This upregulation was specific for Gb3 species containing normal fatty acids (NFA). Central nervous system (CNS) pathology in HUS could involve cytokine-stimulated elevation of endothelial NFA-Gb3 levels. Differential expression of Gb3 species may be a critical determinant of Shiga toxin toxicity and of CNS involvement in HUS.

Blood-Brain Barrier↗
PubMed2001

Autoamputation of the tongue.

Autoamputation is an uncommon phenomenon that has been reported for the fingers, toes, appendix, ovary, spleen, etc. Autoamputation of the tongue has never been reported. An elderly man with carcinoma of lateral pharyngeal wall and tonsil presented with an autoamputated tongue that was attached to the oral cavity with a thin band. The patient required detachment of the tongue and tracheostomy followed by radiotherapy for the primary tumour.

Aged↗
PubMed2000

A self MHC class II beta-chain peptide prevents diabetes in nonobese diabetic mice.

We explored T cell responses to the self class II MHC (I-Ag7) beta-chain-derived peptides in diabetic and prediabetic nonobese diabetic (NOD) mice. We found that one of these immunodominant epitopes of the beta-chain of I-Ag7 molecule, peptide 54-76, could regulate autoimmunity leading to diabetes in NOD mice. T cells from prediabetic young NOD mice do not respond to the peptide 54-76, but T cells from diabetic NOD mice proliferated in response to this peptide. T cells from older nondiabetic mice or mice protected from diabetes do not respond to this peptide, suggesting a role for peptide 54-76-specific T cells in pathogenesis of diabetes. We show that this peptide is naturally processed and presented by the NOD APCs to self T cells. However, the peptide-specific T cells generated after immunization of young mice regulate autoimmunity in NOD mice by blocking the diabetogenic cells in adoptive transfer experiments. The NOD mice immunized with this peptide are protected from both spontaneous and cyclophosphamide-induced insulin-dependent diabetes mellitus. Immunization of young NOD mice with this peptide elicited T cell proliferation and production of Th2-type cytokines. In addition, immunization with this peptide induced peptide-specific Abs of IgG1 isotype that recognized native I-Ag7 molecule on the cell surface and inhibited the T cell proliferative responses. These results suggest that I-Abetag7(54-76) peptide-reactive T cells are involved in the pathogenesis of diabetes. However, immunization with this peptide at young age induces regulatory cells and the peptide-specific Abs that can modulate autoimmunity in NOD mice and prevent spontaneous and induced diabetes.

Adoptive Transfer↗
PubMed2000

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled.

Hematopoiesis is the cumulative result of intricately regulated signal transduction cascades that are mediated by cytokines and their cognate receptors. Proper culmination of these diverse signaling pathways forms the basis for an orderly generation of different cell types and aberrations in these pathways is an underlying cause for diseases such as cancer. Over the past several years, downstream events initiated upon cytokine/growth factor stimulation have been a major focus of biomedical research. As a result, several key concepts have emerged allowing a better understanding of the complex signaling processes. A group of novel transcription factors, termed signal transducers and activators of transcription (STATs) appear to orchestrate the downstream events propagated by cytokine/growth factor interactions with their cognate receptors. Until recently, the JAK proteins were considered to be the tyrosine kinases, which dictated the levels of phosphorylation and activation of STAT proteins, forming the basis of the JAK-STAT model. However, over the past few years, increasing evidence has accumulated which indicates that at least some of the STAT protein activation may be mediated by members of the Src gene family following cytokine/growth factor stimulation. Studies have demonstrated that the Src-family of tyrosine kinases can phosphorylate and activate certain STAT proteins, in lieu of JAK kinases. In such a scenario, JAK kinases may be more crucial to phosphorylation of the cytokine/growth factor receptors and in the process create docking sites on the receptors for binding of SH2-containing proteins such as STATs, Src-kinases and other signaling intermediates. Tyrosine phosphorylation and activation of STAT proteins can be achieved either by JAKs or Src-kinases depending on the nature of STAT that is being activated. This forms the basis for the JAK-Src-STAT model proposed in this review. The concerted action of JAK kinases, members of the Src-kinase family and STAT proteins, leads to cell proliferation and cell survival, the end-point of the cytokine/growth factor stimulus. Oncogene (2000).

Animals↗
PubMed2000

Caffeine abolishes the mammalian G(2)/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity.

Recent evidence indicates that arrest of mammalian cells at the G(2)/M checkpoint involves inactivation and translocation of Cdc25C, which is mediated by phosphorylation of Cdc25C on serine 216. Data obtained with a phospho-specific antibody against serine 216 suggest that activation of the DNA damage checkpoint is accompanied by an increase in serine 216 phosphorylated Cdc25C in the nucleus after exposure of cells to gamma-radiation. Prior treatment of cells with 2 mM caffeine inhibits such a change and markedly reduces radiation-induced ataxia-telangiectasia-mutated (ATM)-dependent Chk2/Cds1 activation and phosphorylation. Chk2/Cds1 is known to localize in the nucleus and to phosphorylate Cdc25C at serine 216 in vitro. Caffeine does not inhibit Chk2/Cds1 activity directly, but rather, blocks the activation of Chk2/Cds1 by inhibiting ATM kinase activity. In vitro, ATM phosphorylates Chk2/Cds1 at threonine 68 close to the N terminus, and caffeine inhibits this phosphorylation with an IC(50) of approximately 200 microM. Using a phospho-specific antibody against threonine 68, we demonstrate that radiation-induced, ATM-dependent phosphorylation of Chk2/Cds1 at this site is caffeine-sensitive. From these results, we propose a model wherein caffeine abrogates the G(2)/M checkpoint by targeting the ATM-Chk2/Cds1 pathway; by inhibiting ATM, it prevents the serine 216 phosphorylation of Cdc25C in the nucleus. Inhibition of ATM provides a molecular explanation for the increased radiosensitivity of caffeine-treated cells.

Ataxia Telangiectasia↗
PubMed2000

Ellis-Van Creveld syndrome associated with nodular sclerosing Hodgkin's disease and nephrotic syndrome.

An 11-year-old male child presented with multiple congenital anomalies, gradually increasing swelling on the left side of neck for one month along with generalized swelling of body and passage of scanty urine for fifteen days. On examination, the child had multiple congenital anomalies and cervical lymphadenopathy. Cardiac examination revealed a pansystolic murmur grade III/VI in left lower parasternal area. Laboratory evaluation revealed significant hypoalbuminemia and hypercholesterolemia, 24 hours urinary protein was 116 mg/hour/m2. Histopathological examination of left cervical lymphnode revealed Hodgkin's disease (Nodular Sclerosing type), 2D echocardiography revealed presence of a single atrium. A diagnosis of Ellis-van Creveld syndrome with nodular sclerosing Hodgkin's disease and nephrotic syndrome was kept. This association, to the best of our knowledge has not been previously reported.

Child↗
PubMed2000

Knowledge and attitude regarding breast-feeding, in mothers attending antenatal clinics.

A hospital based study included 600 mothers who delivered at Kasturba Hospital Sevagram during 1996-97, to assess their knowledge and attitude regarding breastfeeding. The mothers were attending antenatal clinics of a Baby Friendly Hospital (BFH). The obstetric staff was trained regarding the practices following which mothers admitted to the hospital were interviewed within 24 hours of the delivery. Mothers were interrogated by a single interviewer regarding knowledge and attitude of breastfeeding within 24 hours of delivery by using a pretested semistructured open and close ended questionnaire. Three hundred and three mothers (50.5%) had attended antenatal clinics of KHS (booked), whereas 276 (46%) had antenatal check-ups at other health centres and 21 (3.5%) did not have any check-ups. Only 54.5% booked mothers and 30.3% unbooked mothers were informed regarding benefits of breastfeeding during antenatal visits. This difference was statistically significant. The booked mothers wanted to initiate breastfeeding early and did not want to give water supplementation, and were also significantly more knowledgeable as compared to unbooked mothers regarding benefits of breastfeeding, feeding of colostrum, avoiding prelacteal feeds, additional nutritional requirements during lactation and continuation of breastfeeding during maternal illnesses, child illness, pregnancy and maternal drug intake. Breast examination during antenatal check-ups was lacking in both the groups. Only 21 (6.9%) booked and 9 (3%) unbooked mothers had breast examination done during antenatal visits. The data shows that subjects receiving antenatal care at KHS had varied ideas in regard to knowledge and attitude towards breast feeding, thereby suggesting that BFHI activities are useful, at least, to some extent. However, it was disheartening that despite including the obstetricians in the training of BFHI approach, nearly half the booked cases did not get information regarding benefits of breastfeeding and breast examination was not done in most during the antenatal visits. Systematic efforts must be made to ensure that all mothers attending antenatal clinics be managed as per WHO/UNICEF guidelines pertaining to promotion of breastfeeding.

Breast Feeding↗
PubMed2000

The functional role of class II-associated invariant chain peptide (CLIP) in its ability to variably modulate immune responses.

During the process of class II MHC assembly and cell surface expression, the class II-associated invariant chain peptide (CLIP) is removed from the peptide-binding groove of MHC, a task mediated by H-2M. This allows binding and presentation of peptide epitopes. We have previously shown that exogenously added CLIP interferes with this process and down-regulates the cell surface expression of class II molecules. In this study, we explored the effect of exogenously added CLIP on antigen-specific immune responses. In vivo studies with CLIP and various peptide and protein antigens with different affinities for I-A(d) molecules demonstrated that CLIP variably affects the T cell-mediated immune responses. Immunization with CLIP along with the antigen induced a shift from a T(h)1- to T(h)2-like response as determined by the cytokine profile and antibody isotype. These results suggest that the presence of exogenous CLIP can significantly influence the presentation of antigen by class II MHC molecules to CD4 T cells and thereby modulate immune responses. Exogenously added CLIP rapidly localized into the subcellular compartment of antigen-presenting cells where MHC class II molecules are present. We suggest that exogenous CLIP reduces the loading of peptides on the class II molecules, thus down-regulating MHC-peptide complexes on the cell surface. Alternatively, CLIP may bind to cell surface class II molecules and this complex is rapidly internalized resulting in reduced cell surface MHC class II expression. The reduced level of MHC-peptide complexes favors the activation of T(h)2 cells over T(h)1 cells. These results have implications in the regulation of immune responses, particularly the prevention of certain autoimmune diseases where T(h)1-type responses are pathogenic and T(h)2-type responses are protective.

Animals↗
PubMed2000

Maximum-likelihood approach to strain imaging using ultrasound

A maximum-likelihood (ML) strategy for strain estimation is presented as a framework for designing and evaluating bioelasticity imaging systems. Concepts from continuum mechanics, signal analysis, and acoustic scattering are combined to develop a mathematical model of the ultrasonic waveforms used to form strain images. The model includes three-dimensional (3-D) object motion described by affine transformations, Rayleigh scattering from random media, and 3-D system response functions. The likelihood function for these waveforms is derived to express the Fisher information matrix and variance bounds for displacement and strain estimation. The ML estimator is a generalized cross correlator for pre- and post-compression echo waveforms that is realized by waveform warping and filtering prior to cross correlation and peak detection. Experiments involving soft tissuelike media show the ML estimator approaches the Cramer-Rao error bound for small scaling deformations: at 5 MHz and 1.2% compression, the predicted lower bound for displacement errors is 4.4 microns and the measured standard deviation is 5.7 microns.

Journal Article↗