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Biomedical subjects

S Iyer

Publications and source records attributed to S Iyer.

At least 37 records · Page 2Linked to original sources
PubMed2001

Neuropathy in rheumatoid arthritis.

BACKGROUND: Paucity of Indian literature on rheumatoid neuropathy creates a lacuna in the critical evaluation and discussion of the subject. We did this study to find out the incidence and pattern of neuropathy and to correlate it with disease parameters and other extra-articular involvement. MATERIAL AND METHODS: We studied 31 patients of rheumatoid arthritis (RA) classified by ACR criteria. Electromyography and nerve conduction studies (EMG/NCV) were done in all the patients apart from routine laboratory and radiological investigations. Electrocardiograph (ECG), pulmonary function tests (PFT) and ophthalmological examination were also carried out to ascertain extra-articular involvement. RESULTS: Ten out of 31 RA patients had neuropathy of which five each were overt and subclinical respectively. Only one patient had entrapment neuropathy. Four of the ten patients had pure motor neuropathy whereas the other six were sensori-motor neuropathies. Four patients had mononeuritis multiplex and five had symmetrical peripheral neuropathy. Nine of the ten neuropathic patients had RA for more than 2 years. Seven patients had other extra-articular features along with neuropathy. CONCLUSIONS: One-third of patients with RA have evidence of neuropathy. Disease parameters such as activity, rheumatoid factor and functional and radiological grade do not correlate with neuropathy. Non-entrapment sensori-motor type of neuropathy is the most common type.

Adult↗
PubMed2000

The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 A resolution.

The angiogenic molecule placenta growth factor (PlGF) is a member of the cysteine-knot family of growth factors. In this study, a mature isoform of the human PlGF protein, PlGF-1, was crystallized as a homodimer in the crystallographic asymmetric unit, and its crystal structure was elucidated at 2.0 A resolution. The overall structure of PlGF-1 is similar to that of vascular endothelial growth factor (VEGF) with which it shares 42% amino acid sequence identity. Based on structural and biochemical data, we have mapped several important residues on the PlGF-1 molecule that are involved in recognition of the fms-like tyrosine kinase receptor (Flt-1, also known as VEGFR-1). We propose a model for the association of PlGF-1 and Flt-1 domain 2 with precise shape complementarity, consider the relevance of this assembly for PlGF-1 signal transduction, and provide a structural basis for altered specificity of this molecule.

Amino Acid Sequence↗
PubMed2000

Telomere fusions caused by mutating the terminal region of telomeric DNA.

Mutations in the template region of a telomerase RNA gene can lead to the corresponding sequence alterations appearing in newly synthesized telomeric repeats. We analyzed a set of mutations in the template region of the telomerase RNA gene (TER1) of the budding yeast Kluyveromyces lactis that were predicted to lead to synthesis of mutant telomeric repeats with disrupted binding of the telomeric protein Rap1p. We showed previously that mutating the left side of the 12-bp consensus Rap1p binding site led to immediate and severe telomere elongation. Here, we show that, in contrast, mutating either the right side of the site or both sides together leads initially to telomere shortening. On additional passaging, certain mutants of both categories exhibit telomere-telomere fusions. Often, six new Bal-31-resistant, telomere repeat-containing bands appeared, and we infer that each of the six K. lactis chromosomes became circularized. These fusions were not stable, appearing occasionally to resolve and then reform. We demonstrate directly that a linear minichromosome introduced into one of the fusion mutant strains circularized by means of end-to-end fusions of the mutant repeat tracts. In contrast to the chromosomal circularization reported previously in Schizosaccharomyces pombe mutants defective in telomere maintenance, the K. lactis telomere fusions retained their telomeric DNA repeat sequences.

DNA, Fungal↗
PubMed2000

Inhibition of tumor necrosis factor mRNA translation by a rationally designed immunomodulatory peptide.

Based on sequences of immunomodulatory peptides derived from the heavy chain of HLA Class I, novel immunomodulatory peptides with increased potency were developed by computer-aided rational design. Allotrap 1258 was characterized in detail and shown to inhibit cell-mediated immune responses in vitro and in vivo. Immunomodulatory activity was associated with the capability of the peptides to modulate heme oxygenase (HO) activity. In this study we analyzed the effect of Allotrap 1258 on cytokine expression. Allotrap 1258 inhibited concanavalin A- and lipopolysaccharide-induced human and mouse tumor necrosis factor (TNF) production in vitro and in vivo but had no effect on interleukin (IL)-1, IL-2, IL-4, IL-6, or IL-10 expression. Experiments with HO-1/KO and iNOS/KO mice showed that Allotrap 1258-mediated inhibition of TNF was independent of HO-1 and iNOS. Quantitation of TNF protein expression and mRNA steady state levels demonstrated that Allotrap 1258-mediated inhibition occurred at the translational level. Deletion of the AU-rich element in the 3'-untranslated region (UTR) of TNF mRNA, a region known to be involved in TNF mRNA translation, had minimal effect on Allotrap 1258-mediated inhibition. However, replacement of the TNF 3'-UTR with the human globin 3'-UTR rendered the peptide inactive. This demonstrates that besides AU-rich elements, other sequences in the 3'-UTR of TNF mRNA are involved in translational control of TNF expression. Such sequences are necessary for Allotrap 1258-mediated inhibition of TNF production.

3' Untranslated Regions↗
PubMed2000

Genomic structure of murine Rab11 family members.

Rab11a, Rab11b, and Rab25 in mammals are thought to comprise a subfamily of Rab proteins, although Rab25 has two amino acid differences in its effector domain. We have isolated and characterized the genomic sequences of murine Rab11a and Rab25 and compared them with those of previously characterized mammalian Rab genes. The Rab11a gene spans 29 kb and Rab25 spans 9 kb. The genes have TATA-less promoters, but contain GC-rich areas in their upstream 5' regions. Both genes have 5 exons, with the introns containing characteristic repeats. Rab11a has an unusually long 8. 5-kb fourth intron. The Rab11a and Rab25 genes are localized to chromosomes 9C and 3E3/F1, respectively. The overall organization of the Rab11a, Rab11b, and Rab25 genes is similar, with homologous exon-intron boundaries, and differs markedly from those of Rab3A and Rab1A. These results confirm that Rab11A, Rab11b, and Rab25 represent a closely related gene family.

Amino Acid Sequence↗
PubMed2000

Alleviation of graft-versus-host disease after conditioning with cobalt-protoporphyrin, an inducer of heme oxygenase-1.

BACKGROUND: Recently, we demonstrated that elevated expression of heme oxygenase-1 (HO-1 or Hsp-32) resulted in the modulation of several immune effector functions. Here we evaluated whether induction of HO-1 after administration of cobalt protoporphyrin (CoPP) can prevent the development of acute graft-versus-host-disease (GVHD). METHODS: Acute GVHD was initiated by injection of unfractionated spleen cells from C57BL/6 into B6D2/F1 mice. RESULTS: Administration of CoPP resulted in increased survival: 85% of CoPP-treated animals survived for >100 days compared with only 29% of saline-treated control animals (P<0.05). In contrast, administration of ZnPP, a well-known inhibitor of HO, accelerated GVHD development. The protective effect of CoPP therapy seemed to be caused by immunomodulation of donor cells, because treatment of cell donors prevented development of acute GVHD in 80% of recipients compared with 0% in control animals. Spontaneous lymphocyte proliferation could be measured with splenocytes harvested from animals developing GVHD but not with splenocytes from recipients of CoPP-treated donor cells. CoPP-treatment had no effect on interleukin-2 or interleukin-4 synthesis but inhibited interferon-gamma production. Mice with active GVHD demonstrated a defective lympho-proliferative response to alloantigens or concanavalin A. However, spleen cells isolated from survivors (on day 100) responded normally. Flow cytometric analysis of splenic T cell populations revealed a severe reduction in recipient type (H-2b,d) cells in mice with active GVHD, whereas in protected mice the number of cells remained normal. CONCLUSION: The results from this study confirmed our previous observation that up-regulation of HO-1 activity is associated with down-regulation of several immune effector functions. This resulted in protection from acute GVHD in a parent into F1 mouse model.

Animals↗
PubMed2000

Procedural costs of digital vs. analog archiving of diagnostic cardiac catheterizations.

The use of digital technology in the cardiac catheterization laboratory is expanding at a rapid pace. The cost-effectiveness of this new technology is yet to be proven. The aims of this study were to determine the direct cost differences of digital versus analog media (CDs) for the storage of diagnostic cardiac catheterizations and to explore the factors influencing these differences. Procedural costs of all diagnostic angiograms (n = 109), from three physicians, performed in an analog catheterization laboratory (room A) and a digital catheterization laboratory (room C) were compared during a 9-month period. The mean procedural cost was higher in room A than in room C ($1,102 vs. $1,087, P < 0.001). This cost difference was eliminated when recording media costs were excluded from analysis ($1,079 vs. $1,080, P = 0.931). Therefore, we conclude there is a procedural cost savings in a cardiac catheterization room that uses digital CDs versus cineangiogram film as the archival media. Cathet. Cardiovasc. Intervent. 49:246-250, 2000.

Cardiac Catheterization↗
PubMed2000

Calmodulin, poly(ADP-ribose)polymerase and p53 are targets for modulating the effects of sulfur mustard.

We describe two pathways by which the vesicating agent sulfur mustard (HD) may cause basal cell death and detachment: induction of terminal differentiation and apoptosis. Following treatment of normal human epidermal keratinocytes (NHEK) with 10 or 100 microM HD, the differentiation-specific keratin pair K1/K10 was induced and the cornified envelope precursor protein, involucrin, was cross-linked by epidermal transglutaminase. Fibronectin levels were reduced in a time- and dose-dependent manner. The rapid increase in p53 and decrease in Bcl-2 levels was consistent not only with epidermal differentiation but with apoptosis as well. Further examination of biochemical markers of apoptosis following treatment of either NHEK or human papillomavirus (HPV)-immortalized keratinocytes revealed a burst of poly(ADP-ribose) synthesis, specific cleavage of poly(ADP-ribose)polymerase (PARP) in vivo and in vitro into characteristic 89 and 24 kDa fragments, processing of caspase-3 into its active form and the formation of DNA ladders. The intracellular calcium chelator BAPTA suppressed the differentiation markers, whereas antisense oligonucleotides and chemical inhibitors specific for calmodulin blocked both markers of differentiation and apoptosis. Modulation of p53 levels utilizing retroviral constructs expressing the E6, E7 or E6 + E7 genes of HPV-16 revealed that HD-induced apoptosis was partially p53-dependent. Finally, immortalized fibroblasts derived from PARP -/- 'knockout mice' were exquisitely sensitive to HD-induced apoptosis. These cells became HD resistant when wild-type PARP was stably expressed in these cells. These results indicate that HD exerts its effects via calmodulin, 3 and PARP-sensitive pathways.

Apoptosis↗
PubMed2000

Impact of heparin bonding on pediatric cardiopulmonary bypass: a prospective randomized study.

BACKGROUND: Heparin-coated circuits reduce the inflammatory response to cardiopulmonary bypass in adult patients; however, little is known about its effects in the pediatric population. Two studies were performed to assess this technology's impact on inflammation and clinical outcomes. METHODS: In a pilot study, complement and interleukins were measured in 19 patients who had either uncoated cardiopulmonary bypass circuits or heparin-bonded circuits. Subsequently, 23 additional patients were studied in a randomized fashion. Respiratory function and blood product utilization were recorded. RESULTS: In the pilot study, heparin-bonded circuit patients had less complement 3a (p < 0.001) and interleukin-8 (p < 0.05) compared with uncoated cardiopulmonary bypass circuit patients. The randomized study revealed that the heparin-bonded circuit was associated with reduced complement 3a (p = 0.02). Multiple variable analysis revealed that the following postoperative variables were increased with bypass time (p = 0.01) and diminished with heparin-bonded circuits: interleukins (p = 0.01), peak airway pressures (p = 0.05), and prothrombin time (p = 0.03). CONCLUSIONS: Heparin-bonded circuits significantly reduce cytokines and complement during cardiopulmonary bypass and lower interleukin levels postbypass; they were also associated with improved pulmonary and coagulation function. Heparin-bonded circuits ameliorate the systemic inflammatory response in pediatric patients from cardiopulmonary bypass.

Cardiopulmonary Bypass↗
PubMed2000

Tyrosine phosphorylation of PNS myelin P(0) occurs in the cytoplasmic domain and is maximal during early development.

P(0), the major protein of PNS myelin, is considered to play a critical role in the compaction and stabilization of myelin lamellae. The protein undergoes extensive posttranslational modifications, including phosphorylation at multiple serine moieties in the cytoplasmic region. Recently, we demonstrated that P(0) is phosphorylated on one or more tyrosine residues in rat nerve homogenates after incubation. In this study, we show that P(0) phosphorylated on tyrosine is also present in the intact animal. The proportion of P(0) molecules phosphorylated on tyrosine is highest during the first postnatal week, a period that coincides with the most rapid period of myelin deposition in the PNS. A peptide that constitutes the cytoplasmic domain was isolated from purified P(0) and shown by immunochemical and chemical means to be phosphorylated on the tyrosine corresponding to Y(191) in the intact protein. No evidence was obtained supporting the possibility that P(0) is phosphorylated on other tyrosine residues. The sequence of amino acids surrounding Y(191) resemble known substrate phosphorylation sites for some nonreceptor cytoplasmic tyrosine kinases, as well as tyrosine-based recognition signals associated with clathrin vesicle-mediated cndocytosis.

Aging↗
PubMed1999

Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells.

An early transient burst of poly(ADP-ribosyl)ation of nuclear proteins was recently shown to be required for apoptosis to proceed in various cell lines (Simbulan-Rosenthal, C., Rosenthal, D., Iyer, S., Boulares, H., and Smulson, M. (1998) J. Biol. Chem. 273, 13703-13712) followed by cleavage of poly(ADP-ribose) polymerase (PARP), catalyzed by caspase-3. This inactivation of PARP has been proposed to prevent depletion of NAD (a PARP substrate) and ATP, which are thought to be required for later events in apoptosis. The role of PARP cleavage in apoptosis has now been investigated in human osteosarcoma cells and PARP -/- fibroblasts stably transfected with a vector encoding a caspase-3-resistant PARP mutant. Expression of this mutant PARP increased the rate of staurosporine and tumor necrosis factor-alpha-induced apoptosis, at least in part by reducing the time interval required for the onset of caspase-3 activation and internucleosomal DNA fragmentation, as well as the generation of 50-kilobase pair DNA breaks, thought to be associated with early chromatin unfolding. Overexpression of wild-type PARP in osteosarcoma cells also accelerated the apoptotic process, although not to the same extent as that apparent in cells expressing the mutant PARP. These effects of the mutant and wild-type enzymes might be due to the early and transient poly(ADP-ribose) synthesis in response to DNA breaks, and the accompanying depletion of NAD apparent in the transfected cells. The accelerated NAD depletion did not seem to interfere with the later stages of apoptosis. These results indicate that PARP activation and subsequent cleavage have active and complex roles in apoptosis.

Apoptosis↗
PubMed1999

Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation.

BACKGROUND: Ticlopidine has been shown to reduce the incidence of stent thrombosis compared with warfarin, but it may cause serious hematological side effects. Clopidogrel, a new thienopyridine derivative, may be a safe alternative to ticlopidine. The aim of this study was to compare the safety and efficacy of clopidogrel and aspirin with those of ticlopidine and aspirin in patients undergoing coronary stent implantation. METHODS AND RESULTS: The population of this study consisted of 2 groups: patients who underwent coronary stenting and were treated with ticlopidine and aspirin (TA group, n=1406), and patients who underwent coronary stenting followed by treatment with clopidogrel and aspirin (CA group, n=283). At 1-month follow-up, there was no difference in stent thrombosis (1.5% versus 1.4%, P=1.0) or major adverse cardiac events (3.1% versus 2.4%, P=0. 85) between the TA and CA groups, respectively. The probability of any side effect (neutropenia, diarrhea, rash) was significantly higher in the TA group (10.6% versus 5.3%, P=0.006; relative risk, 0. 53; CI, 0.32 to 0.86). CONCLUSIONS: These data suggest that clopidogrel may be an effective pharmacological regimen after coronary stent implantation. Furthermore, the simpler dosing regimen, the absence of neutropenia, and the lower frequency of other side effects make it a safe alternative to ticlopidine.

Aged↗
PubMed1999

The effect of acetabular cup orientations on limiting hip rotation.

The orientation of the acetabular cup and position of lip augmentation (if present) may improve postoperative total hip replacement stability by decreasing dislocation caused by hip prosthesis impingement during rotation. To determine how these cup parameters affect dislocation, the range and amount of rotation for two standard femoral components was determined in a Sawbones hemipelvis model. The parameters that allowed for maximal range of rotation were a cup angle of inclination between 35 degrees and 45 degrees and cup anteversion between 0 degrees and 10 degrees. Cup anteversion angles greater than 20 degrees and cup angles of inclination greater than 45 degrees significantly limited internal and external rotation, particularly for hip flexion greater than 60 degrees. The position of the cup lip augmentation did not affect the amount of rotation except when the hip was flexed and the lip superiorly oriented. Although there are currently devices to facilitate a particular cup position, hip stem type and orientation are other important factors affecting range of rotation that must be considered.

Acetabulum↗
PubMed1999

Treatment with inverse agonists enhances baseline atrial contractility in transgenic mice with chronic beta2-adrenoceptor activation.

In this study, we investigate whether chronic treatment with beta-adrenoceptor (betaAR) ligands with inverse agonist activity enhances myocardial beta2AR-mediated atrial tension more than neutral antagonists in transgenic mice (TG35). These mice exhibit chronic adrenoceptor activation because they possess a greater number of constitutively active receptors than wild type mice due to cardiac-specific overexpression of human betaARs. TG35 and wild type mice were chronically treated for 90 h with three inverse agonists, ICI-118,551, propranolol, and carvedilol, and one neutral antagonist, alprenolol. After 96 h, we compared the basal and isoprenaline-stimulated (10 microM) increase in atrial tension in treated or untreated TG35 mice and wild type mice. In parallel, to determine the effect of chronic betaAR ligand treatment on the amounts of G protein receptor kinase-2 (GRK-2) and G proteins, we performed Western blotting on myocardial cytosolic and membrane proteins. Atria from the TG35 mice treated with inverse agonists showed increases in the baseline tension compared to those from alprenolol/vehicle-treated mice. ICI-118,551 and propranolol treatment restored the elevated myocardial G-inhibitory protein (Gialpha) levels to that of wild type. Also, treatment with inverse agonists upregulated G-stimulatory protein (Gsalpha) levels and GRK2 above those levels in vehicle-treated TG35 or wild type mice. The increased baseline atrial tension was reversed by the addition of ICI-118,551. Overall, our data suggests that inverse agonists enhance baseline atrial tension more than neutral antagonists. Based on this, we propose that upregulation of the active conformation of the beta2ARs, Gsalpha protein and restoration of Gialpha as three possible mechanisms to explain this enhanced receptor activity. Therefore, the favourable effects of some ligands used in pathological conditions involving chronic adrenoceptor activation may be due to the inverse agonist activity of the ligand.

Adrenergic beta-Agonists↗
PubMed1999

Influence of age upon complications of carotid artery stenting. UAB Neurovascular Angioplasty Team.

PURPOSE: To examine the impact of age upon the development of neurological and major systemic complications during or after carotid artery stenting. METHODS: We reviewed the complications that occurred in patients undergoing elective carotid stent implantation between September 1994 and August 1996. The study population was then divided into 3 groups according to age: > or = 80 (group A), 75 to 79 (group B), and < or = 74 (group C) years. The rates of death, major and minor stroke, and myocardial infarction were compared among the groups, as well as with the rates reported by the major carotid endarterectomy (CEA) trials. RESULTS: During the study period, 182 patients (216 vessels) were treated with carotid stenting. There were 19 (10.4%) complications: 1 (0.5%) death, 2 (1.1%) major strokes, 15 (8.2%) minor strokes, and 1 (0.5%) myocardial infarction. Neurological complications were clearly related to increased age with rates of 25.0% in group A versus 8.6% in group C (p = 0.042). The overall per patient rate of death or major stroke was 1.6% (1.4% per vessel). CONCLUSIONS: Increasing age has a negative impact on the rate of complications in carotid stent patients. However, the majority of those complications are minor. The relative roles of medical therapy, stenting, and CEA in patients > 80 years of age must await the results of randomized trials.

Age Factors↗
PubMed1999

Neurological monitoring during carotid artery stenting: the Duck Squeezing Test.

PURPOSE: To examine the usefulness of a novel method for neurological monitoring during carotid artery stenting (CAS). METHODS: The records of patients who underwent elective CAS between June 1996 and October 1998 were reviewed to identify those who had neurological changes during the procedure. We examined whether the neurological change had been detected by a change in the ability of the patient to respond to predetermined commands involving a small rubber duck placed in the contralateral hand. RESULTS: hundred seventy patients (320 vessels) underwent monitoring using the Duck Squeezing Test; 10 suffered neurological events during the procedure. Four of these were transient and temporally related to balloon inflation. Another 6 were tentatively ascribed to distal embolism. All instances were accompanied by a change in the patient's ability to perform the Duck Squeezing Test, which allowed the identification of the abnormal clinical situation. In addition, there were 4 false-positive tests secondary to the patient accidentally dropping the rubber duck. CONCLUSIONS: The Duck Squeezing Test is a sensitive and specific method for monitoring patients during elective CAS. Its practical applicability is based on sound neurophysiological concepts, which underscore the clinical importance of the test.

Adult↗
PubMed1999

In vitro and in vivo immunomodulatory effects of RDP1258, a novel synthetic peptide.

Peptides derived from certain regions of human class I MHC molecules are known to have immunomodulatory effects. In particular, amino acid residues 75-84 of the HLA-B7 and HLA-B2702 molecules have demonstrated allele nonspecific immunosuppression in several animal transplant models. There is evidence that these effects are mediated by binding to intracellular heat shock proteins, including heme oxygenase-1. A new derivative of these peptides, RDP1258, was developed using a novel computer-assisted rational design technique. In vitro, RDP1258 peptide inhibited rat heme oxygenase activity in a dose-dependent manner. Similar to observations made with other in vitro heme oxygenase inhibitors, in vivo administration of RDP1258 peptide to naive rats resulted in upregulation of splenic heme oxygenase activity. The effects of the peptide on alloimmune responses were then tested. Addition of RDP1258 to rat and human mixed leukocyte reactions inhibited proliferation in a dose-dependent manner. In a rat renal transplantation model, peptide therapy combined with a sub-therapeutic dose of cyclosporin A significantly prolonged allograft survival. These data provide further evidence that modulation of the heat shock protein heme oxygenase by rationally designed peptides affects immune effector functions and may allow the development of novel immunomodulatory strategies in organ transplantation.

Adjuvants, Immunologic↗