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Biomedical subjects

A Kumar

Publications and source records attributed to A Kumar.

At least 703 records · Page 39Linked to original sources
PubMed1998

Blood lead levels in children with neurological disorders.

Blood lead levels were measured by atomic absorption spectrometry in 82 children suffering from various neurological disorders (cerebral palsy 42, seizure disorders 35, acute encephalopathy of unknown origin 5) and in 28 healthy children, aged 1 to 12 years. Mean blood lead levels were 11.96 +/- 10.97 micrograms/dl in control children and 19.30 +/- 17.65 micrograms/dl in children with neurological disorders. A significant number of control children as well as those who had neurological disorders were found to have blood lead concentrations of > or = 10 micrograms/dl and > or = 20 micrograms/dl, the cut-off limits for lead poisoning and medical evaluation, respectively. Blood lead levels were, statistically, elevated in children with cerebral palsy compared to controls. Children with pica behaviour exhibited higher blood lead concentrations.

Central Nervous System Diseases↗
PubMed1998

Carcinoma of the pancreas presenting as an orbital tumor: a case report.

Metastasis to the orbit from pancreatic adenocarcinoma is rare. A 38-year-old man with metastatic adenocarcinoma of the right orbit at initial examination is described. Two months later he was diagnosed with a pancreatic primary tumor. The incidence and pattern of orbital metastasis in carcinomas is briefly discussed.

Adenocarcinoma↗
PubMed1998

Variable phenotype in Kaufman-McKusick syndrome: report of an inbred Muslim family and review of the literature.

Multiple congenital anomalies (MCA) in two siblings and digit abnormalities in four related individuals from a large highly inbred Muslim family are described. The pattern of MCA is consistent with the autosomal recessive Kaufman-McKusick syndrome [MIM 236700]. The present report reviews the previously published reports on this uncommon MCA dysmorphic syndrome and draws attention to the marked variation in the phenotype.

Abnormalities, Multiple↗
PubMed1998

Structure-in vitro activity relationships of pentamidine analogues and dication-substituted bis-benzimidazoles as new antifungal agents.

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of </=0.09 microg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 microg/ml. Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential.

Antifungal Agents↗
PubMed1998

In vitro antifungal activities of a series of dication-substituted carbazoles, furans, and benzimidazoles.

Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 microg/ml, and it was the most potent compound against C. neoformans (MIC, </=0.09 microg/ml). Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents.

Antifungal Agents↗
PubMed1998

Characterization of protective epitopes in a highly conserved Plasmodium falciparum antigenic protein containing repeats of acidic and basic residues.

The delineation of putatively protective and immunogenic epitopes in vaccine candidate proteins constitutes a major research effort towards the development of an effective malaria vaccine. By virtue of its role in the formation of the immune clusters of merozoites, its location on the surface of merozoites, and its highly conserved nature both at the nucleotide sequence level and the amino acid sequence level, the antigen which contains repeats of acidic and basic residues (ABRA) of the human malaria parasite Plasmodium falciparum represents such an antigen. Based upon the predicted amino acid sequence of ABRA, we synthesized eight peptides, with six of these (AB-1 to AB-6) ranging from 12 to 18 residues covering the most hydrophilic regions of the protein, and two more peptides (AB-7 and AB-8) representing its repetitive sequences. We found that all eight constructs bound an appreciable amount of antibody in sera from a large proportion of P. falciparum malaria patients; two of these peptides (AB-1 and AB-3) also elicited a strong proliferation response in peripheral blood mononuclear cells from all 11 human subjects recovering from malaria. When used as carrier-free immunogens, six peptides induced a strong, boostable, immunoglobulin G-type antibody response in rabbits, indicating the presence of both B-cell determinants and T-helper-cell epitopes in these six constructs. These antibodies specifically cross-reacted with the parasite protein(s) in an immunoblot and in an immunofluorescence assay. In another immunoblot, rabbit antipeptide sera also recognized recombinant fragments of ABRA expressed in bacteria. More significantly, rabbit antibodies against two constructs (AB-1 and AB-5) inhibited the merozoite reinvasion of human erythrocytes in vitro up to approximately 90%. These results favor further studies so as to determine possible inclusion of these two constructs in a multicomponent subunit vaccine against asexual blood stages of P. falciparum.

Amino Acid Sequence↗
PubMed1998

Oral immunization of macaques with attenuated vaccine virus induces protection against vaginally transmitted AIDS.

The chimeric simian-human immunodeficiency virus SHIVKU-1, bearing the envelope of human immunodeficiency virus type 1 (HIV-1), causes fulminant infection with subtotal loss of CD4(+) T cells followed by development of AIDS in intravaginally inoculated macaques and thus provides a highly relevant model of sexually transmitted disease caused by HIV-1 in human beings. Previous studies using this SHIV model had shown that the vpu and nef genes were important in pathogenesis of the infection, and so we deleted portions of these genes to create two vaccines, DeltavpuDeltanefSHIV-4 (vaccine 1) and DeltavpuSHIVPPc (vaccine 2). Six adult macaques were immunized subcutaneously with vaccine 1, and six were immunized orally with vaccine 2. Both viruses caused infection in all inoculated animals, but whereas vaccine 1 virus caused only a nonproductive type of infection, vaccine 2 virus replicated productively but transiently for a 6- to 10-week period. Both groups were challenged 6 to 7 months later with pathogenic SHIVKU-1 by the intravaginal route. All four unvaccinated controls developed low CD4(+) T-cell counts (<200/microliter) and AIDS. The 12 vaccinated animals all became infected with SHIVKU-1, and two in group 1 developed a persistent productive infection followed by development of AIDS in one. The other 10 have maintained almost complete control over virus replication even though spliced viral RNA was detected in lymph nodes. This suppression of virus replication correlated with robust antiviral cell-mediated immune responses. This is the first demonstration of protection against virulent SHIV administered by the intravaginal route. This study supports the concept that sexually transmitted HIV disease can be prevented by parenteral or oral immunization.

AIDS Vaccines↗
PubMed1998

A role for CREB binding protein and p300 transcriptional coactivators in Ets-1 transactivation functions.

The Ets-1 transcription factor plays a critical role in cell growth and development, but the means by which it activates transcription are still unclear (J. C. Bories, D. M. Willerford, D. Grevin, L. Davidson, A. Camus, P. Martin, D. Stehelin, F. W. Alt, and J. C. Borles, Nature 377:635-638, 1995; N. Muthusamy, K. Barton, and J. M. Leiden, Nature 377:639-642, 1995). Here we show that Ets-1 binds the transcriptional coactivators CREB binding protein (CBP) and the related p300 protein (together referred to as CBP/p300) and that this interaction is required for specific Ets-1 transactivation functions. The Ets-1- and c-Myb-dependent aminopeptidase N (CD13/APN) promoter and an Ets-1-dependent artificial promoter were repressed by adenovirus E1A, a CBP/p300-specific inhibitor. Furthermore, Ets-1 activity was potentiated by CBP and p300 overexpression. The transactivation function of Ets-1 correlated with its ability to bind an N-terminal cysteine- and histidine-rich region spanning CBP residues 313 to 452. Ets-1 also bound a second cysteine- and histidine-rich region of CBP, between residues 1449 and 1892. Both Ets-1 and CBP/p300 formed a stable immunoprecipitable nuclear complex, independent of DNA binding. This Ets-1-CBP/p300 immunocomplex possessed histone acetyltransferase activity, consistent with previous findings that CBP/p300 is associated with such enzyme activity. Our results indicate that CBP/p300 may mediate antagonistic and synergistic interactions between Ets-1 and other transcription factors that use CBP/p300 as a coactivator, including c-Myb and AP-1.

Acetyltransferases↗
PubMed1998

c-Maf interacts with c-Myb to regulate transcription of an early myeloid gene during differentiation.

The MafB transcriptional activator plays a pivotal role in regulating lineage-specific gene expression during hematopoiesis by repressing Ets-1-mediated transcription of key erythroid-specific genes in myeloid cells. To determine the effects of Maf family proteins on the transactivation of myeloid-specific genes in myeloid cells, we tested the ability of c-Maf to influence Ets-1- and c-Myb-dependent CD13/APN transcription. Expression of c-Maf in human immature myeloblastic cells inhibited CD13/APN-driven reporter gene activity (85 to 95% reduction) and required the binding of both c-Myb and Ets, but not Maf, to the promoter fragment. c-Maf's inhibition of CD13/APN expression correlates with its ability to physically associate with c-Myb. While c-Maf mRNA and protein levels remain constant during myeloid differentiation, formation of inhibitory Myb-Maf complexes was developmentally regulated, with their levels being highest in immature myeloid cell lines and markedly decreased in cell lines representing later developmental stages. This pattern matched that of CD13/APN reporter gene expression, indicating that Maf modulation of c-Myb activity may be an important mechanism for the control of gene transcription during hematopoietic cell development.

Binding Sites↗
PubMed1998

Functional and structural organization of Brf, the TFIIB-related component of the RNA polymerase III transcription initiation complex.

Brf is the TFIIB-related component of Saccharomyces cerevisiae RNA polymerase III transcription initiation factor IIIB (TFIIIB). An extensive set of Brf fragments has been examined for the abilities to assemble the TFIIIB-DNA complex and recruit RNA polymerase III to accurately initiate transcription. The principal TFIIIB-assembly function of Brf was found to be contributed by a C-proximal segment spanning amino acids 435 to 545, while the principal transcription-directing function was contributed by a segment of its N-proximal, TFIIB-homologous half. The diverse activities of Brf were also reconstituted from combined fragments. The fragments spanning amino acids 1 to 282 and 284 to 596 were found to assemble into TFIIIB-DNA and TFIIIC-TFIIIB-DNA complexes that were very stable, transcriptionally highly active, and indistinguishable (by in vitro footprinting) from complexes formed with intact Brf. The proximities of the individual halves of split Brf to DNA were extensively mapped by photochemical cross-linking of the TFIIIB-DNA complex. We also identified sites of interaction of Brf fragments with TATA-binding protein (TBP), taking advantage of a recently completed mutational analysis of the TBP surface. The constraints established by these analyses specify a global model of the functional segments of Brf and how they fit into the structure of the TFIIIB-DNA complex.

Base Sequence↗
PubMed1998

Isolation of rat fibrillin-1 cDNA and its relevance in metanephric development.

The role of fibrillin-1 in metanephrogenesis was investigated. Fibrillin-1 cDNA was isolated from the rat kidney cDNA library and sequenced, and its spatiotemporal expression was studied. It had approximately 88% homology with human fibrillin-1 and had Ca2+ binding epidermal growth factor-like domains, transforming growth factor-beta binding protein motifs, and an RGD binding site. Northern blot analysis revealed an approximately 10-kb transcript, and fibrillin-1 expression was developmentally regulated. In situ hybridization and immunofluorescence studies indicated that at day 15 of gestation, fibrillin-1 is expressed in the metanephric mesenchyme. At day 18, its expression was confined to nascent blood vessels and glomeruli, and it increased in the newborn and neonatal kidneys. Immunoprecipitation revealed an approximately 300-kDa band by SDS-PAGE. Treatment with fibrillin-1 antisense oligodeoxynucleotide induced marked dysmorphogenesis of the embryonic metanephroi. Concomitantly, the fibrillin-1 mRNA, antibody reactivity in the metanephroi, and fibrillin-1-specific radioincorporation were reduced. These data indicate that, like alphavbeta3 integrin, a known morphogen and a putative receptor of fibrillin-1, the fibrillin-1 modulates events related to early organogenesis and possibly also the vascularization of the rat kidney.

Amino Acid Sequence↗
PubMed1998

Apoptosis and Fas expression in human fetal membranes.

Apoptosis (i.e. programmed cell death) plays a key role in maintaining reproductive function in the ovary, mammary and prostate glands, uterus, and testis. The purpose of the present report was to determine, based on biochemical and morphological parameters, whether cells in human fetal membranes undergo apoptosis and express Fas (CD95), a cell surface receptor that mediates apoptosis. Using the terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling immunohistochemical technique, apoptotic nuclei were identified in amnion epithelial, chorionic trophoblast, and decidua parietalis cell layers of human fetal membranes at term. Electron microscopy of fetal membranes revealed ultrastructural characteristics in amnion epithelium and chorion trophoblast cell layers consistent with apoptosis, including condensation of chromatin along the periphery of the nucleus and nuclear shrinkage. The apoptotic index (percentage of terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling-positive nuclei of the total nuclei) ranged from 8-29% in amnion epithelial, chorionic trophoblast, and decidual cell layers from women at 23-30, 31-36, and 37-42 weeks gestation. The apoptotic index was statistically greater in the 37-42 week group than in the 23-30 week group in chorionic trophoblast (P < 0.05) and decidual cell (P < 0.01) layers. In contrast, the apoptotic index in the amnion epithelial cell layer was statistically greater (P < 0.05) in the 23-30 week group than in the 31-36 week group, suggesting that apoptosis may be independently regulated in amnion epithelial, chorionic trophoblast, and decidual cell types. Based on the importance of Fas in mediating apoptosis, we investigated whether Fas was expressed by human fetal membrane cells. Immunohistochemical staining of fetal membranes with anti-Fas antibody localized Fas in amnion epithelial, chorionic trophoblast, and decidua parietalis cell layers. A 266-bp band corresponding to the cytoplasmic domain of Fas was detected in samples of amnion, chorion, decidua, and placenta by RT-PCR. Northern blotting revealed a molecular weight of approximately 1.9 kilobases for Fas messenger ribonucleic acid in amniotic tissue. These data suggest that apoptosis and Fas signaling may play a role in remodeling of fetal membrane architecture across gestation.

Amnion↗
PubMed1998

Replacement arthroplasty of the valgus knee. A modified lateral capsular approach with repositioning of vastus lateralis.

Total knee arthroplasty (TKR) using a medial capsular approach gives worse results in arthritic knees with valgus deformity than in those in varus, usually because of swelling, poor wound healing and stiffness, instability, recurrent valgus deformity and poor patellar tracking. A technique for replacement TKR of valgus knees using a lateral capsular approach was described several years ago, but was not routinely adopted because of the difficulties with and complexity of the procedure which included deliberate elevation of the tibial tubercle. In order to avoid this we have modified and simplified the procedure. Our preliminary results suggest that this lateral approach is safe and may give a better outcome than that through the medial capsule for the replacement of valgus knees.

Aged↗
PubMed1998

Shorter latencies of components of middle latency auditory evoked potentials in congenitally blind compared to normal sighted subjects.

A previous study which reported shorter latencies of the Nb component of AEP-MLRs in congenitally blind compared to normal sighted subjects, formed the basis for the present study. The blind subjects had received a rehabilitation program from the age of 4 years onwards, which may have influenced auditory function. Hence the present study was designed to compare the AEP MLRs of normal sighted subjects with age-matched blind subjects who had not undergone early rehabilitation. Auditory evoked potentials (0 to 100 ms. range) were recorded in 10 congenitally blind subjects (average age = 22.4 +/- 4.9 yrs.) and an equal number of age-matched subjects with normal vision. There were two repetitions per subject. The peak latencies of both the Pa (maximum positive peak between Na and 35 ms.) and Nb (maximum negative peak between 38 and 52 ms.) waves was significantly shorter in congenitally blind compared to normal sighted subjects. Since the Pa and Nb waves are believed to be generated by the superior temporal cortex (Heschl's gyrus), it appears that processing at this neural level occurs more efficiently in the blind. Also, in spite of the absence of an early rehabilitation program the present subjects showed the same auditory changes as those reported earlier.

Adaptation, Physiological↗
PubMed1998

Growth factors in metanephric development.

During embryonic life, renal morphogenesis is characterized by a defined period of intense cellular activity, inductive-transformation of undifferentiated cells to polarized epithelia, in-growth of capillaries into an intricate parenchymal epithelial-mesenchymal mass, and finally the maturation into an organ with diverse structural and biological functions. It should be emphasized that the interactions between various growth factors and their receptors, FCM glycoproteins and proto-oncogenes are required for proper epithelial: mesenchymal interactions essential to the process of nephrogenesis. A balance between the activities of these macromolecules, whether essential or redundant, is needed to orchestrate the proper cell signals and responses to assure the progression of normal organogenesis. Finally, in spite of the enormous wealth of data in the literature, the process of renal development is so complex that a clear picture has yet to emerge of the precise coordinated and sequential events that result in the formation of a mature functioning kidney.

Animals↗
PubMed1998

In vitro expression and in vivo immunogenicity of Plasmodium falciparum pre-erythrocytic stage DNA vaccines.

DNA vaccine plasmids were constructed that encoded four pre-erythrocytic antigens from the human malaria parasite Plasmodium falciparum: circumsporozoite protein (PfCSP); sporozoite surface protein 2 (PfSSP2); carboxyl terminus of liver stage antigen 1 (PfLSA-1 c-term); and, exported protein 1 (PfExp-1). Antigen expression was evaluated in vitro by immunoblot analysis of tissue culture cells following transient transfection with each plasmid. Clearly detectable levels of expression depended upon, or were markedly enhanced by, fusion of the antigen encoding sequences in-frame with the initiation complex and peptide leader sequence of human tissue plasminogen activator protein. Mice injected with these plasmids produced antigen specific antibody and cytotoxic T lymphocyte responses. However, the magnitudes of the responses were not always predicted by the in vitro expression assay. The results of this study provided the basis for further testing of these plasmids in primates and the formulation of multi-component pre-erythrocytic DNA vaccines for efficacy testing in human volunteers.

Amino Acid Sequence↗