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Biomedical subjects

V Kumaraswami

Publications and source records attributed to V Kumaraswami.

At least 55 records · Page 3Linked to original sources

High levels of spontaneous and parasite antigen-driven interleukin-10 production are associated with antigen-specific hyporesponsiveness in human lymphatic filariasis.

To determine whether counterregulation by interleukin (IL)-10 plays a role in the generation or maintenance of the antigen-specific hyporesponsiveness seen in asymptomatic microfilaremic (MF) patients, parasite antigen (PAg)- and nonparasite antigen (NPAg)-driven IL-10 production by peripheral blood mononuclear cells (PBMC) was studied in 10 MF patients and in ll patients with chronic lymphatic pathology (CP). PBMC from MF patients spontaneously secreted 10-fold more IL-10 than did PBMC from patients with CP. PAg also induced significantly more IL-10 production by PBMC from CP patients. There was a negative correlation between PAg driven IL-10 production by PBMC and PAg-specific T cell proliferation in the MF group. IL-10 secretion by plastic adherent cells from MF persons was higher in response to PAg than NPAg, whereas IL-6 and tumor necrosis factor-alpha secretion were equivalent for PAg and NPAg, suggesting that PAg preferentially induces IL-10 secretion in these cells. Thus, PAg-induced IL-10 likely plays an important role in down-regulating antigen-specific proliferative responses in MF patients.

Adolescent↗

A preliminary study of filariasis related acute adenolymphangitis with special reference to precipitating factors and treatment modalities.

Episodic adenolymphangitis (ADL) is one of the important clinical manifestations of lymphatic filariasis. Recurrent ADLs contribute to the progress of the disease and also have important socioeconomic implications since they cause significant loss of man days. The present study was conducted in order to identify the precipitating factors responsible for ADL attacks and also to examine the different modalities of treatment. Sixty-five individuals with filariasis related ADL attacks, who are residents of Alleppey district (endemic for Brugia malayi) were studied. All efforts were taken to identify the precipitating factors for ADLs in these individuals. They were hospitalized for a period of five days or more. All of them received symptomatic antipyretic/antiinflammatory therapy and topical antibiotic/antifungal treatment of the affected limbs. They were then randomly allocated to one of the following four regimens: group I - symptomatic alone; group II - symptomatic plus antibiotics; group III - symptomatic followed by diethylcarbamazine citrate (DEC) and group IV - symptomatic plus antibiotic followed by DEC. Patients in groups III and IV received DEC every three months up to one year. There was a significant relationship between the number of ADL attacks and the grade of edema. Presence of focus of infection in the affected limb could be identified in 28 of the 65 patients. In the majority of patients (48) response to treatment was rapid (resolution in less than five days). Neither antibiotics nor DEC (given at intervals of three months) appeared to alter the frequency of ADL attacks. On the otherhand simple hygienic measures combined with good foot care and local antibiotic/antifungal cream application (where required), were effective in reducing the number of ADL attacks.

Adolescent↗

IL-4- and IL-5-secreting lymphocyte populations are preferentially stimulated by parasite-derived antigens in human tissue invasive nematode infections.

Helminth infections in humans and animals are associated with strong T helper 2 (Th2) responses. To determine whether parasite-derived Ag preferentially expand a Th2-like cell population, a filter immunoplaque assay was used to enumerate the frequencies (F0) of PBMC and CD4(+)-enriched PBMC from individuals with helminth infections secreting selected cytokines in response to parasite-derived (PAg) and nonparasite antigens (NPAg). In 20 individuals with lymphatic filariasis, frequency analysis of PBMC secreting IL-4 and IFN-gamma indicated that the F0 of PAg-specific IL-4-secreting cells (geometric mean F0 (GM): 1/12,100) was 57-fold higher than the corresponding F0 of NPAg-reactive cells (GM: 1/692,000; p < 0.02). In marked contrast, the F0 of IFN-gamma-secreting cells responding to PAg (GM: 1/2,700) did not differ from those of cells specific for NAPg (GM: 1/3,400; p = 0.83). In another group of helminth-infected individuals, the F0 of highly enriched CD4+ cells secreting IL-4 and IL-5 in response to PAg (GMs: 1/2,600 and 1/5,600 CD4+ cells, respectively) were also found to be significantly higher than those specific for NPAg (GMs: 1/291,000 and 1/303,000 CD4+; p < 0.05 and p < 0.01, respectively), whereas the corresponding F0 of IFN-gamma- and granulocyte-macrophage-CSF-secreting cells were equivalent for PAg and NPag. Furthermore, the proportion of PAg-specific IL-4- and IL-5-secreting CD4+ cells relative to all cells secreting the given cytokine were approximately 29-fold higher than the proportion of NPAg-specific cells secreting these cytokines. Again, the corresponding proportions of Ag-specific IFN-gamma-and GM-CSF-secreting CD4+ cells were equivalent for PAg and NPAg. Thus, in this ex vivo system, a circulating population of IL-4- and IL-5-secreting (Th2-like) cells has been shown to exist in humans; PAg appears to expand these cells preferentially.

Adult↗

Lymphatic abnormalities in human filariasis as depicted by lymphangioscintigraphy.

BACKGROUND: Investigation into filarial lymphedema has been hampered by the lack of a simple, safe, and easily repeated test to image the peripheral lymphatic system. Recent refinements in radionuclide lymphangioscintigraphy have established this noninvasive technique as the initial procedure of choice for visualizing lymphatics. Accordingly, we applied lymphangioscintigraphy to patients with filariasis and, for purposes of interpretation, compared the findings with those in patients with non-filarial lymphedema. METHODS: Thirty-three patients with classic symptoms or signs consistent with acute or chronic filariasis underwent lymphangioscintigraphy, and the findings were compared with those in five patients without lymphatic dysfunction and in 50 other patients with primary or secondary lymphedema without exposure to filariasis. RESULTS: As in patients with nonfilarial lymphedema, scintigraphic abnormalities in the 33 patients with filariasis included delayed or absent tracer transport of the radiotracer (25 patients), tortuous and bizarre deep lymphatics (seven patients), dermal diffusion (15 patients), retrograde tracer flow (six patients), and faint or absent regional nodal visualization (14 patients). Even in patients with long-standing filarial lymphedema, peripheral trunks were often visualized (at least in part), and regional nodes and more central lymphatics sometimes filled after light exercise. In some of the latter patients, however, discrete lymphatic trunks were not detected. CONCLUSION: Lymphangioscintigraphy is a simple, safe, reliable, noninvasive method with which to examine the peripheral lymphatic system, including truncal and nodal abnormalities, in endemic populations with occult and overt lymphatic filariasis.

Adolescent↗

Side reactions following ivermectin therapy in high density bancroftian microfilaraemics.

Side reactions following ivermectin treatment were evaluated in sixty males with high density bancroftian microfilaremia (GM 1388/ml). Following a single oral dose of ivermectin of different strengths (20, 50, 100 or 200 micrograms/kg), microfilariae clearance and side reactions were monitored in a double blind fashion. Microfilaria levels fell rapidly after ivermectin administration in all dosage groups and 98% of pretreatment microfilariae was cleared after 12 h of treatment. The rate of microfilaria (mf) clearance was slower with 20 micrograms/kg than with the highest dose (200 micrograms/kg) administered. Forty-six patients (77%) became amicrofilaraemic within 2 weeks of treatment. Side reactions were noted in 97% of cases. The most common reactions were fever, headache, weakness, myalgia and cough which appeared by 12 h and subsided by 72 h following treatment. The frequency and intensity of side reactions were related to pretreatment mf densities and were independent of the dose administered. Unusual side reactions were noted in a few patients with high density microfilaraemia. These included intense cough, shortness of breath, blood tinged mucoid expectoration associated with patchy pneumonitis of the lung. Itchy rashes, lymphatic nodules and raised alkaline phosphatase level were also observed in some patients. These side reactions were transient, self limiting and were not serious enough to warrant any treatment. These exaggerated unusual reactions were possibly due to allergic response of the susceptible host to rapid killing of large number of microfilariae.

Adolescent↗

A comparative study of the efficacy and tolerability of single and split doses of ivermectin and diethylcarbamazine in periodic brugian filariasis.

The use of ivermectin in lymphatic filariasis (both bancroftian and brugian) has been recently explored in several studies. We report in this paper, for the first time, a direct comparison of the efficacy and tolerability of single doses of ivermectin and diethylcarbamazine (DEC) in brugian filariasis. We also present our findings on the use of split doses of ivermectin and DEC on microfilaraemia levels and the occurrence of adverse reactions. Fifty male, asymptomatic microfilaremics drawn from the Alleppey District, Kerala, India, were allocated one of the following five treatment regimens in a double blind randomized study: (1) single oral 6 mg/kg dose of DEC; (2) single oral 6 mg/kg dose of DEC preceded by 1 mg/kg DEC primer; (3) single oral 220 micrograms/kg dose of ivermectin; (4) single oral 200 micrograms/kg dose of ivermectin preceded by a 20 micrograms/kg ivermectin primer; or (5) a single oral 400 micrograms/kg dose of ivermectin preceded by a 20 micrograms/kg ivermectin primer. The kinetics of microfilaria clearance differed in the two (DEC/ivermectin) groups in the first month post-treatment. At the end of 1 year there were no differences in the microfilaria levels in the two DEC-tested groups and the 420 micrograms/kg ivermectin group. The safety of the 400 micrograms/kg dose of ivermectin was established in this study which has also shown that, currently, this dose would be the best choice for brugian filariasis. Patients in the ivermectin groups had significantly lower adverse reaction scores than patients who had received DEC. There was no advantage in splitting the dose of either DEC or ivermectin, either in terms of efficacy or tolerability.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Kinetics of serum and cellular interleukin-5 in posttreatment eosinophilia of patients with lymphatic filariasis.

Peripheral blood eosinophil counts and serum levels and in vitro production of eosinophilopoietic cytokines were assessed before and at frequent intervals after diethylcarbamazine treatment of Bancroftian filariasis. Eosinophil counts peaked at day 7 after the start of treatment (359% +/- 118% of pretreatment levels) and declined to pretreatment levels by day 17. Serum interleukin (IL)-5, undetectable in 14 of 15 patients before treatment, rose sharply but transiently, with peak levels (32 +/- 7 pg/mL) 2 days after diethylcarbamazine treatment. Granulocyte-macrophage colony-stimulating factor and IL-3 were not detectable in serum at any time. In vitro mitogen-induced IL-5 levels decreased significantly in 7 of 9 patients 3 days after treatment when serum IL-5 was at near-peak levels. By day 10 IL-5 values increased in 8 of 9 patients compared with treatment values (P < .02). These data define the temporal relation between serum IL-5 levels and the subsequent development of eosinophilia and suggest that lymphocytes are the source of IL-5.

Adolescent↗

Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset.

The immunological mechanisms involved in maintenance of an asymptomatic microfilaremic state (MF) in patients with lymphatic filariasis remain undefined. MF patients have impaired filarial antigen (Ag)-specific lymphocyte proliferation and decreased frequencies (Fo) of Ag-specific T cells, and yet elevated serum IgE and antifilarial IgG4. To investigate the mechanism of Ag-specific anergy in MF patients in contrast to amicrofilaremic individuals with chronic lymphatic obstruction (CP), the Fo of Ag-specific lymphocytes from peripheral blood mononuclear cells secreting either IL-4 or IFN-gamma were assessed by filter spot enzyme-linked immunosorbent assay, and IL-10 and transforming growth factor-beta (TGF-beta) mRNA transcript levels were assessed by a semiquantitative reverse transcriptase polymerase chain reaction technique. The Fo of filaria-specific IL-4-secreting lymphocytes were equivalent in both MF (geometric mean [GM] = 1:11,700) and CP (GM = 1:29,300 P = 0.08), whereas the Fo of IFN-gamma-secreting lymphocytes were lower in MF (GM = 1:39,300) than in CP (GM = 1:4,200, P < 0.01). When the ratio of IL-4/IFN-gamma (T helper type 2 [Th2]/Th1)-secreting cells was examined, MF subjects showed a predominant Th2 response (8:1) compared with a Th1 response in CP individuals (1:4). mRNA transcript levels of IL-10 were also significantly elevated in MF compared with CP individuals (P < 0.01). Further, IL-10 and TGF-beta were shown to have a role in modulating the Ag-specific anergy among MF subjects, in that neutralizing anti-IL-10 or anti-TGF-beta significantly enhanced lymphocyte proliferation response (by 220-1,300%) to filarial Ags in MF individuals. These findings demonstrate that MF subjects respond to parasite antigen by producing a set of suppressive cytokines that may facilitate persistence of the parasite within humans while producing little clinical disease.

Adult↗

Ivermectin in the treatment of bancroftian filarial infection in Orissa, India.

Ivermectin treatment was evaluated for its efficacy and side reactions in sixty patients of Orissa with Bancroftian filarial infection and microfilaremia. Ivermectin was administered as a single oral dose at four dosage levels (20, 50, 100 and 200 micrograms/kg), and both microfilarial clearance and associated side reactions were monitored in a double blind fashion. Blood microfilariae were cleared in all patients at all dosages within 1 to 14 days. In most patients microfilariae reappeared by third month. The microfilaria appearance by third and sixth month averaged 12.2 to 44 percent of pretreatment values in the four study groups. Side reactions were encountered in almost all patients, the commonest being fever, headache, weakness, myalgia and cough which occurred most prominently 12 to 72 hours after treatment. Side reactions were more frequent and severe in patients with high microfilaria counts. Clinical reaction scores for each group were independent of the dose administered. The 200 micrograms dose group showed significantly more rapid microfilariae clearance and its delayed reappearance as compared with the other dosage groups and without inducing significantly greater clinical reaction scores.

Adult↗

Ivermectin for the treatment of periodic malayan filariasis: a study of efficacy and side effects following a single oral dose and retreatment at six months.

Ivermectin, a new antifilarial drug and currently the drug of choice for the treatment of onchocerciasis, has been shown to be effective in bancroftian filariasis. We report here, for the first time, the efficacy and safety of the drug in the treatment of filariasis caused by periodic Brugia malayi. Sixty male, asymptomatic microfilaraemics of Alleppey district, Kerala, South India, received single oral doses of ivermectin in a double blind study. Four dosages were used: 20, 50, 100 and 200 micrograms kg-1 body weight. Clearance of microfilariae, which was not complete, began as early as 12 hours post-treatment and was maximal at the end of one month. Microfilaria levels began to rise thereafter and reached 20-50% of pretreatment levels at six months. The two higher doses (100 and 200 micrograms kg-1) were more effective in suppressing microfilaraemia at six months (P < 0.05). After six months, 32 patients were retreated using the same dose of ivermectin that they had received initially. The pattern of clearance was essentially similar to that seen during the first treatment phase and microfilaria levels were 10-35% of pretreatment levels at the end of the next six months. Twenty-eight individuals who were not retreated at six months continued to have increasing levels of microfilariae, reaching 60% of pretreatment levels at the end of the next six months. Side effects (such as fever, headache, myalgia), which were mild to moderate, were seen in most patients and were unrelated to the dose (P > 0.05) or pretreatment levels of microfilariae.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Immunologic tolerance in lymphatic filariasis. Diminished parasite-specific T and B lymphocyte precursor frequency in the microfilaremic state.

To explore the mechanisms of antigen-specific immune unresponsiveness seen in microfilaremic patients with bancroftian filariasis, T and B cell precursor frequency analysis was performed using PBMC from individuals with either asymptomatic microfilaremia (MF, n = 7) or chronic lymphatic obstruction (CP, n = 20). Highly purified CD3+ cells were partially reconstituted with adherent cells and their proliferative response to parasite antigens determined in cultures of T cells by limiting dilution analysis. A filter immunoplaque assay also assessed the frequency of both total and parasite-specific Ig-producing B cells. While the lymphocyte proliferation to mitogens and to a nonparasite antigen (Streptolysin-O, [SLO]) were similar in all groups of patients, the frequency of parasite-specific CD3+ T cells was significantly lower (geometric mean [GM], 1/3,757) in MF patients when compared to that in CP patients (GM 1/1,513; P less than 0.001). Similarly, the proportion of lymphocytes producing parasite-specific IgE or IgG was significantly lower in MF patients (IgE mean, 0.2%; IgG mean, 0.33%) compared with CP patients (IgE mean, 3.2%; IgG mean, 1.76%; P less than 0.05 for both comparisons). These observations imply that low numbers of parasite-specific T and B lymphocytes may be partially responsible for the severely diminished capacity of lymphocytes from patients with MF to produce parasite-specific antibody and to proliferate to parasite antigen in vitro. Such differences in parasite-specific lymphocyte responses suggest that tolerance by clonal anergy may be a critical mechanism for maintaining the microfilaremic state.

Animals↗

Salivary cortisol in the assessment of adrenocortical function in patients with pulmonary tuberculosis.

Adrenocortical function was assessed on the basis of changes in salivary cortisol in patients with pulmonary tuberculosis and the findings compared with those in healthy subjects. A method of direct radioimmunoassay of salivary cortisol was standardized and the sensitivity was 0.8 nmol/l. Cortisol levels in saliva were significantly higher in the patients than in the healthy subjects (P less than 0.001). The diurnal rhythm of cortisol secretion was disturbed in the patients with a significant increase in salivary cortisol beyond 1800 h. While dexamethasone caused an appreciable suppression (87%), stimulation with ACTH (tetracosactrin) resulted in a marked increase in salivary cortisol, the increase being significantly higher in the healthy subjects than in the patients (P less than 0.001). Attempts to classify subjects as positive or negative responders to tetracosactrin based on increases in salivary cortisol in relation to plasma cortisol changes were however not successful, as the agreement between the two methods ranged from 73 to 80 per cent with various criteria used.

Adrenal Cortex↗

A controlled trial of ivermectin and diethylcarbamazine in lymphatic filariasis.

Ivermectin is a new antifilarial drug that can be given in a single oral dose. To compare the efficacy and side effects of ivermectin with those of diethylcarbamazine, the standard antifilarial treatment, we conducted a randomized, double-blind trial in 40 South Indian men with lymphatic filariasis caused by Wuchereria bancrofti. Patients were randomly assigned to one of three treatments: a single low dose of ivermectin (mean [+/- SE], 21.3 +/- 0.7 micrograms per kilogram of body weight; n = 13) followed by placebo for 12 days; a single high dose of ivermectin (mean, 126.2 +/- 3.7 micrograms per kilogram; n = 13) followed by placebo for 12 days; or diethylcarbamazine for 13 days (6 mg per kilogram per day for 12 days preceded by 3 mg per kilogram for 1 day; n = 14). Eleven patients were initially assigned to receive placebo and after five days were reassigned to one of the three treatment groups. At day 12 there was complete clearance of microfilariae from the blood in all 26 men who took ivermectin and in 11 of the 14 men who took diethylcarbamazine. At six months the numbers of detectable microfilariae (as a percentage of the pretreatment values) were 18.3 percent after low-dose ivermectin and 19.5 percent after high-dose ivermectin, as compared with 6.0 percent after diethylcarbamazine (P less than 0.05). The side effects were confined to the first five days and were similar in the three treatment groups. We conclude that in lymphatic filariasis, the clinical response to a single dose of ivermectin compares favorably with that after the standard 12-day course of diethylcarbamazine. Given the practical advantages of single-dose administration, ivermectin should become a useful medication for the control of bancroftian filariasis.

Adult↗

Adrenocortical function in patients with pulmonary tuberculosis.

Adrenocortical function was studied in patients with pulmonary tuberculosis and the findings compared with those in healthy subjects. Plasma cortisol levels in newly diagnosed patients were appreciably higher than in the healthy subjects (P less than 0.001). A normal (positive) response to ACTH (tetracosactrin) stimulation was observed in 35 (97%) of 36 healthy subjects, 15 (56%) of 27 newly diagnosed patients with tuberculosis and 5 (42%) of 12 chronic cases (i.e. those who had had the disease for more than 3 years); the difference between the healthy subjects and the two groups of tuberculosis patients was highly significant (P less than 0.001). Dexamethasone caused an appreciable decrease in the plasma cortisol levels of tuberculosis patients. Considering the diurnal variation of cortisol secretion, there was a steady decline in the cortisol levels between 08:00 and 20:00 in the healthy subjects (P = 0.02); in the tuberculosis patients, however, there was a decrease up to 16:00 followed by a significant increase (P = 0.05), and the mean value at 20:00 was similar to that at 08:00.

Adrenal Cortex↗

Persistent lower respiratory tract inflammation associated with interstitial lung disease in patients with tropical pulmonary eosinophilia following conventional treatment with diethylcarbamazine.

Tropical pulmonary eosinophilia (TPE) presents as an acute syndrome with dyspnea, fluffy infiltrates, and rounded opacities on the chest radiograph, reduced lung function, marked eosinophilia in the blood and lower respiratory tract, and high titers of specific IgE and IgG antifilarial antibodies. The standard therapy for TPE is a 3-wk course of diethylcarbamazine (DEC) following which there is almost always a marked improvement in all parameters. However, clinical observations suggest that the disease can persist despite DEC therapy and lead to chronic dyspnea with restrictive lung impairment. To evaluate the concept that DEC therapy is not completely "curative" for TPE, but rather leaves most individuals with a mild, chronic form of TPE defined by persistent inflammation of the lower respiratory tract, we evaluated 23 individuals an average of 12 +/- 2 months following a standard 3-wk course of diethylcarbamazine for acute TPE. In the majority there were mild, persistent symptoms referrable to the lung, chest X-ray abnormalities, blood eosinophilia, and elevated serum IgE and filarial specific IgG. On the average, lung function was consistent with the presence of chronic, mild interstitial lung disease. When the inflammatory cells from the lower respiratory tract were examined, there was a persistent eosinophilic alveolitis (TPE/post-DEC 1769 +/- 376 eosinophils/microliters epithelial lining fluid; normal subjects 256 +/- 38, p less than 0.02). Evaluation of the lower respiratory tract inflammatory cells recovered from the TPE/post-DEC-treated individuals demonstrated spontaneous release of exaggerated amounts of O2-. and H2O2 compared to normal subjects (p less than 0.05, both comparisons).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

Phosphocholine-containing antigens of Brugia malayi nonspecifically suppress lymphocyte function.

The immunosuppressive effect of Brugia malayi antigen (BmA) on phytohemagglutinin (PHA) driven T cell proliferation was evaluated in patients with filariasis (n = 14) and compared to control individuals (n = 12). When peripheral blood lymphocytes were co-cultured with BmA and PHA, BmA markedly suppressed the T cell proliferative response to PHA in both filarial patients and control individuals in a dose-dependent manner. The suppression resulted neither from any direct toxicity of BmA nor from nonspecific absorption of the PHA mitogenic activity by BmA. The major suppressive component appears to be phosphocholine (PC), an immunodominant molecule present in abundance on filarial parasites and on circulating filarial antigen. Both purified PC as well as PC-containing antigens affinity purified from BmA were capable of suppressing the proliferative responses of co-cultured autologous lymphocytes to PHA. The suppressive activity was not abolished by mitomycin-C treatment and was greater in patients with filariasis than in normal controls, suggesting that levels of PC-containing antigens determines the magnitude of the suppressive effect of PC-antigen. Further, as induction of the suppressive activity was completely abrogated when antigen pre-treated cells were T cell-depleted, the suppressive effect appears to be mediated primarily by T cells.

Adult↗

Selective up-regulation of endothelial cell class I MHC expression by cytokines from patients with lymphatic filariasis.

Local host immune responses to the lymphatic-dwelling filarial parasite Wuchereria bancrofti are important in the pathogenesis of the lymphangitis that leads to filarial elephantiasis. That the lymphatic endothelial cells may be important in this inflammatory process was shown by the ability of supernatants generated from filarial Ag-driven PBMC of individuals with filarial elephantiasis caused by W. bancrofti infection to up-regulate class I MHC expression on human umbilical vein endothelial cells when compared to unstimulated control supernatants from the same individual (relative fluorescence intensity = 159% +/- 13.5; p less than 0.001). In contrast, individuals with the same filarial infection but manifesting no lymphatic disease were unable to generate, in response to filarial Ag the cytokines required for this activation (relative fluorescence intensity = 93% +/- 2.6). Supernatants induced by a non-filarial Ag (purified protein derivative) were able to effect class I MHC up-regulation in both patient groups. The same filarial Ag-driven supernatants did not cause detectable class II MHC staining on human umbilical vein endothelial cells. These results suggest a likely role for parasite Ag-driven, cytokine-mediated endothelial cell activation in the pathogenesis of lymphatic inflammatory/obstructive filarial disease.

Adult↗