Biomedical subjects

T V Rajan

Publications and source records attributed to T V Rajan.

At least 19 recordsLinked to original sources

PubMed2006

Inflammatory bowel disease: maladaptation of the vigilant genotype in a hyper-clean world?

Children born of Asian Indian parents who are raised in environmentally hygienic Western societies appear to be highly prone to two diseases, ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease or IBD. These ethnically Indian children are similar to an inbred mouse strain, NOD/Lt. Mice of this strain remain diabetes-free when raised in standard mouse colonies, but develop an autoimmune diabetes at high rates when kept in pathogen-free environments. I propose that certain human habitats have, over eons, selected for "vigilant genotypes," wherein combinations of alleles at critical loci result in aggressive immune responses to pathogens. This genetic configuration is adaptive in the selective environment but maladaptive in more hygienic environments, resulting in dysregulated immune effectors. One manifestation of such dysregulation is organ-specific autoimmunity, such as IBD.

Animals↗

PubMed2005

A double-blinded, placebo-controlled trial of garlic as a mosquito repellant: a preliminary study.

The hypothesis that the ingestion of garlic provides protection against bloodsucking pests such as mosquitoes was investigated using a randomized, double-blinded, placebo-controlled crossover study. Subjects were asked to consume either garlic (one visit) or a placebo (the other visit). They were then exposed to laboratory-reared Aedes aegypti (Linnaeus) (Diptera: Culicidae). The numbers of mosquitoes that did not feed on the subjects, the number of mosquito bites, the weights of the mosquitoes after feeding and the amounts of blood ingested were determined. The data did not provide evidence of significant systemic mosquito repellence. A limitation of the study is that more prolonged ingestion of garlic may be needed to accomplish repellence.

Aedes↗

PubMed2005

Eosinophils, but not eosinophil peroxidase or major basic protein, are important for host protection in experimental Brugia pahangi infection.

The attenuation of eosinophilia by the administration of monoclonal antibodies to CCR3 consistently correlates with impairment in worm elimination following primary intraperitoneal Brugia pahangi infections in mice. Host protection was unimpaired in mice deficient in eosinophil peroxidase (EPO) or major basic protein 1 (MBP-1), suggesting that eosinophils are essential in host protection but that neither EPO nor MBP-1 alone is.

Animals↗

PubMed2005

Murine extramedullary erythropoiesis induced by tick infestation.

Tick saliva contains molecules that modulate the haemostasis, pain/itch responses, wound healing and immune defences of the host. Using BALB/c mice that were each infested with 10 nymphs of Dermacentor andersoni Stiles (Acari: Ixodidae), an attempt has now been made to determine the influence of tick infestation on the expression of leucocyte adhesion molecules in the host. The ticks became fully engorged by the fourth to sixth day of infestation. On the fourth day of infestation, the results of flow cytometry indicated that 2% of the host's splenocytes were expressing high levels of CD49 (alpha4 integrin of VLA-4) and low levels of CD11a (alphaL subunit of the integrin LFA-1). By the eighth day of infestation, 30% of the hosts' splenocytes had this phenotype and were negative for the lineage markers CD3e (T-lymphocytes), DX5 (natural-killer cells of a BALB/c lineage), B220 (B-lymphocytes), CD11b (monocytes/macrophages, granulocytes, natural-killer cells, activated T-lymphocytes, and B-1 cells) and CD11c (myeloid and splenic dendritic cells). Histological examination of the spleens from infested mice revealed disruption of the white-pulp/red-pulp demarcations and the presence of a large number of basophilic normoblasts. The CD11a(lo) population of splenocytes from the tick-infested mice was positive for TER-119 but negative for CD3, B220, CD11b and Gr, confirming that the splenocytes were members of the erythroid lineage. These results indicate that, within 8 days of their initiation, the tick infestations induced extramedullary erythropoiesis in the spleens of their murine hosts.

Animals↗

PubMed2005

The L3 to L4 molt of Brugia malayi: real time visualization by video microscopy.

Brugia malayi and other filarial parasites have been studied in great detail, especially in the context of human disease. In common with other nematodes, these organisms molt 4 times in their life cycles, but details of this process have not been described. We have recently developed an in vitro culture system that supports the L3 to L4 molt at high efficiency. This has permitted us to visualize, for the first time, details of this molt using real-time video microscopy. Molting is preceded by a phase of altered motility during which the larva exhibits contractile, coiling movements. The earliest evidence of ecdysis is a clearing at one end, more frequently caudal, caused by the larva retracting from that end. A cleavage develops in the cuticle near the head end, forming a rostral cap, which is continuous with the pharyngeal cuticle. Simultaneously, it retracts out of the cuticle using coiling and writhing movements. This process takes 5 to 10 min. Finally, it retracts out of the cap and extrudes the pharyngeal cuticle. Detachment of the pharyngeal cuticle is the final event in the process and continues up to an hour after the rest of the cuticle has been shed.

Animals↗

PubMed2005

Natural course of lymphatic filariasis: insights from epidemiology, experimental human infections, and clinical observations.

Lymphatic filariasis has been described as a "spectral disease". Analysis of the natural course of infection in nonendemic individuals as well as experimental infections of "volunteers" suggests that the filarial parasites are not inherently aggressive infectious agents. Experimental infections of humans with infective larvae result in transient, low-level microfilaremia, if at all. Nonendemic individuals with limited exposure show no evidence of persistent infection or pathology. Nonendemic individuals exposed to repeated infections show accelerated pathology. It is tempting to speculate that normal, immunocompetent residents in an endemic area show either (a) no pathology (endemic normals) because they are subject to the relatively low levels of infection or (b) chronic pathology if they are repeatedly infected. It would appear that only those individuals rendered immunologically tolerant to filarial parasites become productively infected with the filarial parasites. The intensity of transmission may underlie the differences in clinical presentation seen in diverse global pockets of endemicity.

Elephantiasis, Filarial↗

PubMed2005

Neonatal outcome in the United Arab Emirates: the effect of changes in resources and practices.

Selective improvements in neonatal care resources and practices were instituted between 1992/1994 (period 1) and 1995/1998 (period 2) following a neonatal audit in the United Arab Emirates. We evaluated the effect of these changes on neonatal mortality rate (NNMR), birth-weight-specific mortality rates and causes of mortality. Overall there was a 17% decline in the NNMR from periods 1 to 2. Mortality rates in infants with birth weight < 1000 g and > 2500 g decreased by 36% and 35% respectively from periods 1 to 2. Modest declines in deaths from asphyxia, sepsis and complications of preterm births occurred from periods 1 to 2 but the differences were not statistically significant.

Adrenal Cortex Hormones↗

PubMed2004

Exogenous nucleosides are required for the morphogenesis of the human filarial parasite Brugia malayi.

The nematode parasites Wuchereria bancrofti, Brugia malayi, and B. timori cause a human disease known as lymphatic filariasis, which afflicts approximately 120 million people worldwide. The parasites enter the human host from the mosquito as L3 or infective larvae and subsequently differentiate through 2 molts. In this communication, I report that B. malayi and B. pahangi depend on an exogenous source of at least 1 purine and 1 pyrimidine nucleoside to complete the L3 to L4 molt. The requirement for exogenous nucleosides opens the door for possible chemotherapeutic intervention.

Animals↗

PubMed2004

Relationship of anti-microbial activity of tetracyclines to their ability to block the L3 to L4 molt of the human filarial parasite Brugia malayi.

The nematode parasites Wuchereria bancrofti, Brugia malayi, and B. timori cause a human disease known as lymphatic filariasis, which afflicts approximately 120 million people worldwide. These organisms are known to contain endosymbiotic bacteria (Wolbachia) that are related to rickettsiae. It has been previously reported that tetracycline blocks the L3 to L4 molt of the filarial parasite B. malayi, and suggested that this was related to their known anti-rickettsial activity. However, this interpretation was tempered by several observations. First, Wolbachia DNA could still be detected in nematodes from tetracycline-treated cultures. In addition, chloramphenicol, which has anti-rickettsial and anti-chlamydial activity, failed to inhibit the molt. These observations could not rule out the possibility that the anti-molting activity of tetracycline is due to pharmacologic activities unrelated to its anti-rickettsial functions. This study shows that chemically modified tetracycline, which does not to have anti-microbial activity, also blocks molting.

Animals↗

PubMed2003

Impaired clearance of primary but not secondary Brugia infections in IL-5 deficient mice.

Eosinophilia in blood and tissues has been strongly associated with helminth infections for over a century. In vivo depletion of IL-5, a cytokine crucially involved in eosinophilopoiesis with an antibody or through genetic manipulation, reproducibly abrogates helminth-induced eosinophilia, but renders mice permissive only in some models of parasite infection. In the current study, we compared the ability of IL-5(-/-) and B6(+/+) mice to clear intraperitoneal infections with Brugia pahangi L3. IL-5(-/-) mice had statistically significantly higher worm burdens than B6(+/+). This was true for primary infections, in young as well as old mice, suggesting that IL-5 deficient mice are more permissive to Brugian infections. This increase in permissiveness seemed to correlate well with the drastically reduced eosinophil numbers in the peritoneal cavity, the site of infection. In secondary infections, primed IL-5(-/-) mice cleared infections in an accelerated manner, comparable with B6(+/+) mice. These observations suggest that IL-5 induced eosinophilia is more important in the control of a primary infection in naïve mice than a secondary infection in primed mice.

Animals↗

PubMed2003

The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation.

Gell and Coombs classified hypersensitivity reactions into four 'types'. I suggest that the premise that these reactions represent 'hypersensitivity' manifestations is limiting and that they represent four major strategies that the body uses to combat infectious agents. I further propose that there is a fifth strategy that was not envisioned in the Gell and Coombs classification.

Animals↗

PubMed2003

Primed peritoneal B lymphocytes are sufficient to transfer protection against Brugia pahangi infection in mice.

Lymphatic filariasis is a tropical disease caused by the nematode parasites Wuchereria bancrofti and Brugia malayi. Whereas the protective potential of T lymphocytes in filarial infection is well documented, investigation of the role of B lymphocytes in antifilarial immunity has been neglected. In this communication, we examine the role of B lymphocytes in antifilarial immunity, using Brugia pahangi infections in the murine peritoneal cavity as a model. We find that B lymphocytes are required for clearance of primary and challenge infections with B. pahangi third-stage larvae (L3). We assessed the protective potential of peritoneal B lymphocytes by adoptive transfer experiments. Primed but not naïve peritoneal B cells from wild-type mice that had been immunized with B. pahangi L3 protected athymic recipients from challenge infection. We evaluated possible mechanisms by which B cells mediate protection. Comparisons of cytokine mRNA expression between B-lymphocyte-deficient and immunocompetent mice following B. pahangi infection suggest that B cells are required for the early production of Th2-type cytokines by peritoneal cells. In addition, B-cell-deficient mice demonstrate a defect in inflammatory cell recruitment to the peritoneal cavity following B. pahangi infection. The data demonstrate a critical role of B lymphocytes in antifilarial immunity in naïve mice and in the memory response in primed mice.

Adoptive Transfer↗

PubMed2003

Mice genetically deficient in immunoglobulin E are more permissive hosts than wild-type mice to a primary, but not secondary, infection with the filarial nematode Brugia malayi.

Primary and secondary murine and human infections with Brugia malayi are characterized by substantial increases in levels of immunoglobulin E (IgE). To investigate whether this is necessary for worm clearance, IgE(-/-) mice were subjected to primary- and secondary-infection protocols. Following a primary infection, IgE(-/-) mice displayed a profound deficit in their ability to clear an intraperitoneal injection of L3 infective-stage larvae in comparison to wild-type counterparts and maintained substantial worm burdens as late as 10 weeks postinfection. Although viable adult parasites were recovered at this late time point from IgE(-/-) mice, the majority of the mice remained free of microfilariae. IgE(-/-) cohorts subjected to a secondary-infection protocol were able to clear the challenge inoculation in an accelerated manner, with kinetics similar to that observed in the wild-type animals. Analysis of the humoral response in IgE(-/-) mice following infection demonstrates a defect in IgG1 and IgG2a production, in addition to the expected lack of IgE. The IgG1 deficiency is no longer evident following a secondary infection. These data imply that deficiencies other than IgE production (i.e., IgG1 production) deficiency may be responsible for the increased permissiveness of IgE(-/-) mice as hosts following infection with B. malayi.

Animals↗

PubMed2003

T cells are required for host protection against Brugia malayi but need not produce or respond to interleukin-4.

T cells are known to be required for host protection in mouse models of Brugia malayi infection. Several independent studies in murine models have also highlighted the rapid induction of Th2-like responses after infection with B. malayi or B. pahangi. Previous data from our laboratory have described a significant increase in permissiveness in the absence of interleukin-4 (IL-4), the "prototypical" Th2 cytokine, involved in both the induction and maintenance of Th2 responses. These observations led to our hypothesis that T cells involved in murine host protection would respond to IL-4 signaling and differentiate into cells of the "type 2" phenotype. As such, these cells would presumably also act as major sources of IL-4. To investigate these hypotheses, we performed several adoptive transfers in which we controlled the cell population(s) able to produce or respond to IL-4. We show here that, in contrast to our original hypotheses, IL-4 production and IL-4 receptor expression by T cells are both dispensable for T-cell-mediated host protection. Instead, our data imply that T cells may be required for eosinophil accumulation at the site of infection.

Animals↗

PubMed2003

Kinetics of cellular responses to intraperitoneal Brugia pahangi infections in normal and immunodeficient mice.

Filarial infections evoke exuberant inflammatory responses in the peritoneal cavities of immunocompetent mice. Clearance of infection appears to be dependent on complex interactions between B1 and B2 B lymphocytes, T cells, eosinophils, macrophages, and the products of these cells. In an earlier communication, we described the course of infection in normal immunocompetent mice. In this study, we utilize mice with well-characterized mutations that disable one or more effector components of adaptive immunity in order to determine their roles in host protection. We characterize peritoneal exudate cells by flow cytometry and determine the kinetics of accumulation of each of the different cell types following infection with Brugia pahangi. We find that (i) four-color flow-cytometric analysis of peritoneal exudate cells using anti-CD3, -CD11b, -CD19, and -Gr1 can distinguish up to six different populations of cells; (ii) an initial influx of neutrophils occurs within 24 h of infection, independent of the adaptive immune status of mice, and these cells disappear by day 3; (iii) an early influx of eosinophils is seen at the site of infection in all strains studied, but a larger, second wave occurs only in mice with T cells; (iv) the presence of T cells and eosinophils is important in causing an increase in macrophage size during the course of infection; and (v) most unexpectedly, T-cell recruitment appears to be optimal only if B cells are present, since JHD mice recruit significantly fewer T cells to the site of infection.

Animals↗

PubMed2003

Ascorbic acid is a requirement for the morphogenesis of the human filarial parasite Brugia malayi.

The nematode parasites Wuchereria bancrofti, Brugia malayi, and B. timori cause a disease in humans known as lymphatic filariasis, which afflicts approximately 120 million people worldwide. The parasites enter the human host from the mosquito either as L3 or as infective larvae and subsequently differentiate through 2 molts. In this article, we show that B. malayi depends on an exogenous source of vitamin C to complete the L3 to L4 molt, a critical morphogenic step in its life cycle. Brugia malayi apparently belongs to a small group of living organisms that depend on an exogenous source of vitamin C. This group includes only primates (including man) and guinea pigs among mammals.

Animals↗

PubMed2002

Brugian infections in the peritoneal cavities of laboratory mice: kinetics of infection and cellular responses.

Standard, immunocompetent, inbred strains of mice are non-permissive for infection with the human filarial nematode, Brugia malayi or the closely related Brugia pahangi. This non-permissiveness allows one to address the mechanism(s) that might be used by mammalian hosts to eliminate large, multicellular, metazoan, extracellular invertebrate pathogens. We describe here the time course of intraperitoneal Brugian infections in naïve and primed +/+ mice from two commonly used, inbred laboratory strains (C57BL/6J and BALB/cByJ). We believe that this documentation of the course of infection in normal mice will serve as a reference for future studies using mice with gene-targeted immunological deficits or which have been pharmacologically or immunologically manipulated to manifest such deficits. Our data show that even though both strains of mice eliminate the parasite before the onset of patency, there are significant differences in the time course of infection and in the fractions of input larvae that can be recovered at any time after infection. In a secondary infection, the time course of elimination is accelerated. We examined the cells in the peritoneal cavity, the site of infection, by flow microfluorimetry using forward and side scatter properties and cell surface antigen expression using fluorescent antibodies. These studies reveal a complex cellular pattern, predominated by B lymphocytes, macrophages, and eosinophils. The most notable gross morphological findings at necropsy during the phase of elimination of the parasite are nodules of tissue containing larvae, which appear viable in some cases and undergoing various stages of disintegration in others. These nodules, which are histologically granulomas, are primarily composed of macrophages and eosinophils, with few if any lymphocytes. Transmission electron micrographs reveal that eosinophils can penetrate under the cuticles of the larvae and be seen in close approximation with internal structures. These granulomas may represent an important mechanism by which worms are eliminated.

Animals↗

PubMed2002

Effect of ingestion of honey on symptoms of rhinoconjunctivitis.

BACKGROUND: Allergic rhinoconjunctivitis is a common disorder, affecting >20% of people of all socioeconomic strata. Despite this high prevalence, relatively few sufferers seek professional medical help, presumably because of a widespread reliance on complementary remedies. OBJECTIVE: We investigated the widely held belief among allergy-sufferers that regular ingestion of honey ameliorates the symptoms of allergic rhinoconjunctivitis. METHODS: The study was conducted at the University of Connecticut Health Center's Lowell P. Weicker General Clinical Research Center. Thirty-six participants who complained of allergic rhinoconjunctivitis were recruited. All recruits were scratch-tested at entry for common aeroallergens. The cohort was randomly assigned to one of three groups, with one receiving locally collected, unpasteurized, unfiltered honey, the second nationally collected, filtered, and pasteurized honey, and the third, corn syrup with synthetic honey flavoring. They were asked to consume one tablespoonful a day of the honey or substitute and to follow their usual standard care for the management of their symptoms. All participants were instructed to maintain a diary tracking 10 subjective allergy symptoms, and noting the days on which their symptoms were severe enough to require their usual antiallergy medication. RESULTS: Neither honey group experienced relief from their symptoms in excess of that seen in the placebo group. CONCLUSIONS: This study does not confirm the widely held belief that honey relieves the symptoms of allergic rhinoconjunctivitis.

Administration, Oral↗