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Biomedical subjects

S P Rao

Publications and source records attributed to S P Rao.

At least 19 recordsLinked to original sources
PubMed2004

Is Chlamydia pneumoniae infection associated with stroke in children with sickle cell disease?

BACKGROUND: Stroke is often a devastating complication of sickle cell disease (SCD). Most children with SCD-related stroke have stenotic and occlusive disease of cerebral blood vessels due to intimal hyperplasia. This hyperplasia is hypothesized to result from an inflammatory response similar to that in atherosclerosis and has been attributed to infection by Chlamydia pneumoniae. OBJECTIVE: To determine whether C pneumoniae infection is associated with stroke and cerebrovascular disease, including transient ischemic attacks and abnormal transcranial Doppler examinations, in children with SCD. METHODS: Children with SCD on chronic transfusion due to a history of stroke, transient ischemic attack, or abnormal transcranial Doppler; children with SCD without stroke; healthy controls; and children being transfused for other reasons were enrolled. Peripheral blood and nasopharyngeal (NP) swab specimens were collected from all patients. In patients on transfusion, pretransfusion specimens and samples from the unit of packed red blood cells being transfused were obtained. Peripheral blood monocytic cells (PBMCs) and NP swab specimens were cultured for C pneumoniae in HEp-2 cells. C pneumoniae polymerase chain reaction was performed on PBMCs with a nested touch-down method with primers from the omp-1gene (in duplicate) and a second real-time polymerase chain reaction by using 16S ribosomal RNA primers. RESULTS: C pneumoniae DNA was detected in the PBMCs of 1 of 14 (7.1%) children with SCD on chronic transfusion, 1 of 10 (10%) sickle cell controls, 1 of 10 (10%) healthy controls, and none of the 5 children receiving chronic transfusion for other reasons. It was not detected in specimens from transfusion units. One child with SCD and stroke, 1 sickle cell control, and 1 transfusion control had positive NP cultures for C pneumoniae. C pneumoniae DNA was not detected in their PBMCs, and all 3 children were asymptomatic. C pneumoniae was not detected by culture of PBMCs from any of the patients after 7 passages. CONCLUSION: Stroke in children with SCD does not seem to be associated with C pneumoniae infection in our population.

Adolescent↗
PubMed2003

A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion.

Luminal acidification provides the strongest physiological stimulus for duodenal HCO3- secretion. Various neurohumoral mechanisms are believed to play a role in acid-stimulated HCO3- secretion. Previous studies in the rat and human duodenum have shown that guanylin and Escherichia coli heat-stable toxin, both ligands of the transmembrane guanylyl cyclase receptor [guanylate cyclase C (GC-C)], are potent stimulators for duodenal HCO3- secretion. We postulated that the GC-C receptor plays an important role in acid-stimulated HCO3- secretion. In vivo perfusion studies performed in wild-type (WT) and GC-C knockout (KO) mice indicated that acid-stimulated duodenal HCO3- secretion was significantly decreased in the GC-C KO animals compared with the WT counterparts. Pretreatment with PD-98059, an MEK inhibitor, resulted in attenuation of duodenal HCO3- secretion in response to acid stimulation in the WT mice with no further effect in the KO mice. In vitro cGMP generation studies demonstrated a significant and comparable increase in cGMP levels on acid exposure in the duodenum of both WT and KO mice. In addition, a rapid, time-dependent phosphorylation of ERK was observed with acid exposure in the duodenum of WT mice, whereas a marked attenuation in ERK phosphorylation was observed in the KO animals despite equivalent levels of ERK in both groups of animals. On the basis of these studies, we conclude that transmembrane GC-C is a key mediator of acid-stimulated duodenal HCO3- secretion. Furthermore, ERK phosphorylation may be an important intracellular mediator of duodenal HCO3- secretion.

Acids↗
PubMed2003

Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic-pituitary-adrenal axis activity: interaction with serotonergic systems.

The mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) produces anxiolytic or antidepressant effects in several rodent models through incompletely described mechanisms. Anxiolytics and antidepressants share several neuroendocrine features, including acute activation of the hypothalamic-pituitary-adrenal (HPA)-axis, desensitization of neuroendocrine responses with repeated dosing, and desensitization of the HPA axis to 5-HT1A agonist stimulation. We characterized these neuroendocrine parameters in rats treated systemically with MPEP and compared them to those induced by the anxiolytic buspirone. Acutely, MPEP dose-dependently (0.1-10 mg/kg i.p.) increased plasma corticosterone concentrations. These responses were blocked by 50% with the 5-HT1A antagonist WAY100635. The corticosterone responses to both 3 mg/kg MPEP and buspirone were decreased by 80% after 5 days of twice-daily injections. Repeated injection with MPEP decreased HPA-axis sensitivity to buspirone challenge by 75%. This desensitization was not associated with changes in mGluR5 or 5-HT1A receptor binding properties, expression of G-protein subunits coupled to these receptors, or in 5-HT-stimulated binding of [(3)H]-GTPgammaS to membranes. We conclude that MPEP acutely disinhibits the HPA axis, in part through uncharacterized changes in serotonergic signaling. Desensitization of 5-HT1A responses after repeated MPEP administration may indicate that, like other anxiolytics and antidepressants, plasticity in 5-HT signal transduction pathways has occurred.

Animals↗
PubMed2003

Treatment of acute lymphoblastic leukemia-induced extreme hypercalcemia with pamidronate and calcitonin.

OBJECTIVE: To describe extreme hypercalcemia as the presenting feature of acute lymphoblastic leukemia in an 8-yr-old girl and the combined use of pamidronate and calcitonin for its treatment. DESIGN: Case report. SETTING: Pediatric intensive care unit. PATIENT: An 8-yr-old girl with 20.0 mg/dL serum calcium (reference range, 8.8-10.4 mg/dL) and 2.66 mmol/L ionized calcium (reference range, 1.13-1.32 mmol/L). INTERVENTION: Intravenous pamidronate and subcutaneous calcitonin. MEASUREMENTS AND MAIN RESULTS: Our patient presented with nausea, vomiting, lethargy, weight loss, fatigue, and weakness but, remarkably, did not exhibit electrocardiographic changes. Initial treatment with hydration at 8 mL x kg(-1) x hr(-1) and furosemide was ineffective. A single dose of 1 mg/kg intravenous pamidronate given over 24 hrs complemented by three doses of 5 units/kg subcutaneous calcitonin over 36 hrs lowered serum calcium to a normal range within 3 days. Side effects noted were hypocalcemia, hypomagnesemia, and hypophosphatemia. They were most pronounced 7-9 days after treatment, stabilized with supplementation, and returned to acceptable ranges by 1 month without need for ongoing electrolyte supplements. A renal computed tomographic scan did not show nephrocalcinosis. The patient remained free from recurrence of hypercalcemia 6 wks after initiating chemotherapy for acute lymphoblastic leukemia. CONCLUSIONS: Extreme hypercalcemia can be a presenting feature of acute lymphoblastic leukemia, but it may not result in life-threatening organ dysfunction. Combined treatment with pamidronate and calcitonin should be considered for treating hypercalcemia that does not respond to conventional therapy with hydration and furosemide.

Antineoplastic Agents↗
PubMed2003

Clinical and epidemiological correlation of Leptospirosis among patients attending KMCH, Manipal.

Leptospirosis is one of the most widespread zoonotic diseases in the world. Infection may range from sub clinical infection to death of the patient. It may also occur endemically in tropical countries, showing seasonal incidences following heavy rainfall. As the diagnosis is difficult due to vague clinical symptoms, laboratory investigations are essential for the confirmation of the disease. This study was undertaken to correlate the clinical findings, occupation and behavioural pattern in seropositive cases of Leptospirosis. A total of 733 patients suspected of Leptospirosis were tested for specific IgM ELISA and clinical findings, occupation and behavioural pattern were noted.

Antibodies, Bacterial↗
PubMed2001

The T cell-dependent B cell immune response and germinal center reaction are intact in A-myb-deficient mice.

Expression of the protooncogene A-myb is restricted to the developing CNS, adult testes, breasts in late pregnancy, and germinal centers of secondary B cell follicles. The functional relevance of A-myb expression at three of these sites has been demonstrated previously via the generation and analysis of A-myb-deficient mice, which display behavioral abnormalities, male sterility, and perturbed breast development during pregnancy. In contrast, here we show that the germinal center response driven by T cell-dependent Ag immunization and the associated processes of Ab V gene somatic hypermutation, affinity maturation, and heavy chain class switching are overtly normal in A-myb-deficient mice. Nonetheless, these mice display mild splenic white pulp hypoplasia and blunted primary serum Ab responses, suggesting that although A-myb is not directly involved in the regulation of the memory B cell response, it may play a role in enhancing peripheral B cell survival or proliferative capacity.

Animals↗
PubMed2001

Hemophagocytosis and granulomas in the bone marrow of a child with Down syndrome.

Persistent fever with pancytopenia and hepatomegaly with negative blood cultures and no obvious focus of infection in a child with Down syndrome should arouse a suspicion of leukemia. Bone marrow examination and clot biopsy from one such patient revealed hemophagocytosis and granulomas, with serologic evidence of recent Epstein-Barr virus infection. Bone marrow granulomas are not a feature of Epstein-Barr infection. Later, bone marrow culture and repeat blood culture grew Salmonella typhi. Thus, in a febrile child, when performing a bone marrow aspirate, a clot biopsy and culture for infectious etiology may be helpful, even when leukemia is strongly suspected.

Bacteremia↗
PubMed2001

Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase.

Bacterial DNA and its synthetic immunostimulatory oligodeoxynucleotide analogs (ISS-ODN) activate innate immunity and promote Th1 and cytotoxic T-lymphocyte immune responses. Based on these activities, we investigated whether ISS-ODN could modify the course of Mycobacterium avium infection. M. avium growth in vitro was significantly inhibited by ISS-ODN treatment of human and mouse macrophages, and M. avium growth in vivo was similarly inhibited in C57BL/6 mice treated with ISS-ODN. This protective effect of ISS-ODN was largely independent of tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), nitric oxide, NADPH oxidase, alpha/beta interferon (IFN-alpha/beta), and IFN-gamma. In contrast, we found that the induction of indoleamine 2,3-dioxygenase (IDO) was required for the antimycobacterial effect of ISS-ODN. To evaluate the potential for synergism between ISS-ODN and other antimycobacterial agents, treatment with a combination of ISS-ODN and clarithromycin (CLA) was tested in vitro and in vivo. ISS-ODN significantly enhanced the therapeutic effect of CLA in both human and mouse macrophages and in C57BL/6 mice. This study newly identifies IDO as being involved in the antimicrobial activity of ISS-ODN and suggests the usefulness of ISS-ODN when used in combination with conventional chemotherapy for microbial infections.

Adjuvants, Immunologic↗
PubMed2001

Active learning of respiratory physiology improves performance on respiratory physiology examinations.

Active involvement in the learning process has been suggested to enhance creative thinking, judgement, interpretation, and problem-solving skills. Therefore, educators are encouraged to create an active-learning environment by incorporating active-learning strategies into the class. However, there is very little documentation of the effectiveness of active-learning strategies. Furthermore, faculty are often reluctant to incorporate new strategies without documentation of the effectiveness of these strategies. To address this concern, we compared the performance of two individual classes on an identical respiratory physiology examination. One class was taught respiratory physiology using active-learning strategies. The other class was taught respiratory physiology using the traditional lecture format. The results document that students who learned using active-learning strategies did significantly better (P < 0.05) on the respiratory physiology examination than students who learned by the traditional lecture format (61 +/- 2.2 vs. 86 +/- 1.0). Thus, by actively involving students in the learning process, academic performance is enhanced.

Education, Graduate↗
PubMed2000

Release of monocyte chemoattractant protein (MCP)-1 by a human alveolar epithelial cell line in response to mycobacterium avium.

Clinical strains of Mycobacterium avium isolated from patients with acquired immunodeficiency syndrome, but not a non-clinical laboratory strain (ATCC 25291), were found to stimulate the human alveolar epithelial cell line A549, to produce monocyte chemoattractant protein (MCP)-1. A549 cells were also found to produce elevated levels of MCP-1 in response to sonicates of the clinical strains of M. avium, and surprisingly, the non-clinical strain as well. However, sonic extracts of the clinical strains were found to induce significantly higher levels of MCP-1 production compared to extracts of the non-clinical strain (P < 0.001). These data suggest the existence of strain-related differences in antigen expression by M. avium. The clinical and non-clinical strains of M. avium were found to attach and invade, but not replicate in A549 cells indicating that MCP-1 production by A549 cells does require the presence of viable, replicating organisms. Activation of alveolar epithelial cells by exposure to M. avium resulting in the production of chemokines which recruit inflammatory cells to the site of infection may be an important regulatory pathway for the activation of pulmonary host defense.

Chemokine CCL2↗
PubMed2000

Peer instruction improves performance on quizzes.

Peer instruction is a cooperative-learning technique that promotes critical thinking, problem solving, and decision-making skills. Benson's think-pair-share and Mazur's peer-instruction techniques are simple cooperative exercises that promote student's participation in class and increase student's interaction with each other and with the instructor in a large classroom. We borrowed concepts from Benson and Mazur and applied these concepts to enhance student involvement during the respiratory component of the medical physiology class. The medical physiology class consisted of 256 first-year medical students. The peer-instruction technique was used for 10 classes. Each class of 50 min was divided into three or four short presentations of 12-20 min. Each presentation was followed by a one-question, multiple-choice quiz on the subject discussed. Questions ranged from simple recall to those testing complex intellectual activities. Students were given 1 min to think and to record their first answer. Subsequently, students were allowed 1 min to discuss their answers with their classmates and possibly correct their first response. The percentage of correct answers increased significantly (P < 0.05) after discussion for both recall and intellectual questions. These data demonstrate that pausing three to four times during a 50-min class to allow discussion of concepts enhanced the students level of understanding and ability to synthesize and integrate material.

Education, Medical↗
PubMed2000

Interferon-alpha-2b immunoconjugate for improving immunoscintigraphy and immunotherapy.

UNLABELLED: A pretreatment with a single dose of an immunoconjugate (IC) that promises to enhance tumor uptake and decrease liver uptake of radiolabeled monoclonal antibodies (MAbs) might be of use in radioimmunodetection and radioimmunotherapy (RIT). We have shown previously that an interferon (IFN)-MAb (1:1) immunoconjugate (IC) enhances tumor uptake by a factor of 2 or more and reduces liver uptake by 50% in nude mice bearing human tumors. The aim of this study was to determine whether IFN modulates antigenic expression and to ascertain the most effective route of its administration, the optimal quantity to be administered, and the optimal duration of time to lapse between the administration of IC and the radiolabeled MAb. METHODS: IFN-alpha-2b and anticarcinoembryonic antigen-F6 (IgG2a) MAb were conjugated (1:1), and F(ab')2 of the MAb was labeled with 99mTc. Human colorectal tumors were grown in nude mice by implanting 5 x 10(6) LS174T confluent cells grown in culture. Mice, 5 in each group, received 20 x 10(3) IU intravenously, intramuscularly, or intraperitoneally and 40 x 10(3), 60 x 10(3), and 80 x 10(3) IU intravenously 30 min before the intravenous administration of 25.9 MBq 99mTc/20 microg F(ab')2. Mice in the control groups received 99mTc-F(ab')2 but not the conjugate. Twenty-four hours later mice were killed and imaged, and tissues were removed for quantitative (percentage injected dose/g [% ID/g]) distribution of 99mTc. RESULTS: In all conjugate-receiving mice, the tumor uptake was higher and the liver uptake was lower (P < 0.01) than that in the control mice with the exception of liver uptake, which was not significantly different in mice receiving 80 x 10(3) IU conjugate. The optimal results were apparent in mice pretreated with 40 x 10(3) IU conjugate in which tumor uptake was enhanced by a factor of 2.3 (4.8 +/- 0.5 %ID/g versus 11 +/- 0.7 %ID/g; P < 0.01). The renal uptake remained unchanged, and the tumor-to-muscle ratios increased from 11.5 +/- 6.8 to 14.6 +/- 3.9, and the tumor-to-blood ratios increased from 4.4 +/- 1.8 to 8.3 +/- 2.4. The liver uptake decreased from 9.5% +/- 1% to 5% +/- 1.6%. Results were attributed to enhanced tumor blood flow, increased antigenic expression, and blocking of hepatic nonspecific Fc receptors. CONCLUSION: A pretreatment with IFN-MAb conjugate is a worthwhile approach to consider in radioimmunoscintigraphy and RIT.

Animals↗
PubMed1999

Biased VH gene usage in early lineage human B cells: evidence for preferential Ig gene rearrangement in the absence of selection.

Certain VH genes are predominantly expressed in mature B cells. We hypothesized that several, mutually nonexclusive VH-dependent mechanisms operating at distinct stages during B cell development may be responsible for overrepresentation of these VH genes. In the present study, we have assessed whether one of the mechanisms involves preferential rearrangement at the pro-B cell stage. The frequency of individual VH4 and VH3 genes in rearrangement libraries from FACS-purified human CD34+/CD19+ pro-B and CD34-/CD19+ pre-B cells was assessed. The in-frame and out-of-frame rearrangements from both cell populations were analyzed using a high resolution PAGE system. The frequencies of individual VH gene segments among out-of-frame rearrangements from pro-B cells were determined, because these frequencies should reflect only processes before the translation of the mu-heavy chain and should not be biased by selection mechanisms. Our results demonstrate that, at the pro-B cell stage, the V4-34, V4-39, and V4-59 gene segments are the most frequently rearranged VH4 family genes, and the V3-23 and V3-30 gene segments are the most frequently rearranged VH3 family genes. This finding suggests that the predominant expression of these VH genes in peripheral mature B cells is determined to a significant degree by their preferential rearrangement during V-DJ recombination.

Adult↗
PubMed1999

2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist.

In the present paper we describe 2-methyl-6-(phenylethynyl)-pyridine (MPEP) as a potent, selective and systemically active antagonist for the metabotropic glutamate receptor subtype 5 (mGlu5). At the human mGlu5a receptor expressed in recombinant cells, MPEP completely inhibited quisqualate-stimulated phosphoinositide (PI) hydrolysis with an IC50 value of 36 nM while having no agonist or antagonist activities at cells expressing the human mGlu1b receptor at concentrations up to 30 microM. When tested at group II and III receptors, MPEP did not show agonist or antagonist activity at 100 microM on human mGlu2, -3, -4a, -7b, and -8a receptors nor at 10 microM on the human mGlu6 receptor. Electrophysiological recordings in Xenopus laevis oocytes demonstrated no significant effect at 100 microM on human NMDA (NMDA1A/2A), rat AMPA (Glu3-(flop)) and human kainate (Glu6-(IYQ)) receptor subtypes nor at 10 microM on the human NMDA1A/2B receptor. In rat neonatal brain slices, MPEP inhibited DHPG-stimulated PI hydrolysis with a potency and selectivity similar to that observed on human mGlu receptors. Furthermore, in extracellular recordings in the CA1 area of the hippocampus in anesthetized rats, the microiontophoretic application of DHPG induced neuronal firing that was blocked when MPEP was administered by iontophoretic or intravenous routes. Excitations induced by microiontophoretic application of AMPA were not affected.

Animals↗
PubMed1999

Human B cells accumulate immunoglobulin V gene somatic mutations in a cell contact-dependent manner in cultures supported by activated T cells but not in cultures supported by CD40 ligand.

The acquisition of somatic mutations in the rearranged immunoglobulin V regions in B cells occurs within the tightly regulated microenvironment of a germinal centre. The precise mechanism responsible for turning on the mutational process is unknown. To dissect the role of different components of the germinal centre in this mechanism, we have used in vitro cultures of normal human IgD+ peripheral blood B lymphocytes co-cultured with activated CD4+ T cells, or with resting CD4+ T cells, or with CD40 ligand and IL-4. We observed that if the cultures included activated CD4+ T cells, then up to 100% of VH transcripts on day 14 were somatically mutated. Transcripts were found to carry from one to 36 substitutions (median five). In contrast, in the absence of activated T cells, transcripts contained only background levels of somatic mutation irrespective of the presence of resting T cells or CD40 ligand and IL-4. Cell-cell contact was required for mutation because mutations were not detected when B cells were separated from activated T cells by a membrane.

Animals↗
PubMed1999

Role of CD40 ligand in Mycobacterium avium infection.

Mycobacterium avium is a common opportunistic pathogen in immunocompromised patients such as those infected with human immunodeficiency virus. Although M. avium is an intracellular organism replicating predominantly in macrophages, disseminated M. avium infection is seen in AIDS patients with CD4(+) cell counts of <50 cells/microliters, suggesting a possible involvement of a T cell-macrophage interaction for the elimination of M. avium. To determine whether CD40-CD40 ligand (CD40L) interactions play a role in M. avium infection, we studied the ability of CD40L to restrict M. avium replication in human monocyte-derived macrophages (MDM) in vitro. MDM were infected with M. avium and cocultured with CD40L-transfected 293 cells for 7 days. Intracellular growth of M. avium in these MDM was assessed by colony counting. CD40L-expressing cells inhibited growth of M. avium in MDM by 86.5% +/- 4.2% compared to MDM cultured with control cells. These findings were verified by assays using purified, soluble recombinant human CD40L (CD40LT). CD40LT (5 micrograms/ml) inhibited intracellular growth of M. avium by 76.9% +/- 18.0% compared to cells treated with medium alone. Inhibition by CD40LT was reduced by monoclonal antibodies (MAbs) against CD40 and CD40L. The inhibitory effect of CD40LT was not accompanied by enhancement of interleukin-12 (IL-12) production by M. avium-infected MDM, while CD40L-expressing cells stimulated IL-12 production by these cells. Treatment of M. avium-infected mice with MAb against murine CD40L resulted in recovery of larger numbers of organisms (0.8 to 1.0 log) from the spleens, livers, and lungs of these animals compared to infected mice which received normal immunoglobulin G. These results indicate that CD40-CD40L signaling may be an important step in host immune response against M. avium infection.

Animals↗