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Biomedical subjects

D O Freedman

Publications and source records attributed to D O Freedman.

At least 19 recordsLinked to original sources
PubMed2001

Internet and computer-based resources for travel medicine practitioners.

The field of travel medicine is concerned primarily with ways to maintain the health of international travelers. Remaining current in this area requires up-to-date knowledge of global infectious diseases, patterns of drug resistance, advances in preventive measures, and public health regulations pertaining to the crossing of international borders. This review of off-line commercial databases and Internet sources will assist infectious disease consultants in accessing current reliable travel health information. Of the North American pretravel off-line databases, TRAVAX (United States) and The Medical Letter are the most comprehensive, whereas the Global Infectious Disease and Epidemiology Network is extraordinary in its provision of global infectious disease epidemiology for posttravel assessment. A total of 65 Web sites are listed within 9 categories, covering such areas as authoritative government travel health recommendations, commercially-oriented sites, and travel medicine listserv discussion groups. Even among reputable Web sites, contradictory information may be found that demands careful consideration by the clinician and by the traveling public.

Communicable Disease Control↗
PubMed2001

Evaluation of the effectiveness of an international diploma course in tropical medicine.

BACKGROUND: Numerous impediments to conducting continuing education (CE) courses in remote sites, particularly those courses that take place in developing countries, can include challenges associated with planning, infrastructure, and financial risk. This study reports the effectiveness of a course planned in the United States and executed in Peru, the Gorgas Course in clinical tropical medicine. METHODS: A survey was conducted of participants who had completed the Gorgas Course as recently as 6 months and as long as 3 years earlier. The questionnaire sought to determine each participant's reason for participation, whether the course was instrumental in the participant's reaching the personal goal associated with participation, and whether the participant considered the course to be worth the time and money spent to enable participation. RESULTS: Forty-nine participants responded to the questionnaire, all of whom indicated that the Gorgas Course enabled achievement of the personal goal associated with participation. Fully 100% of course participants stated that participation was worth the time and monetary expenditure, most often citing their having access to patients with tropical diseases and the personal enrichment of living overseas as reasons the course was worth its high cost. FINDINGS: It is logistically and financially feasible to conduct CE courses in developing countries, provided that the organization in the planning country has strong, pre-established relationships with the host institution(s). Continued collaboration between planning partners and frequent, rigorous course evaluations are necessary to enable an international CE course to become a stable, continuous academic offering.

Curriculum↗
PubMed2001

TAPI polymorphisms in several human ethnic groups: characteristics, evolution, and genotyping strategies.

Genetic variations in the locus encoding the transporter associated with antigen processing, subunit 1 (TAP1), were systematically studied using samples from Caucasians, Africans, Brazilians, and compared with data from chimpanzees. PCR-amplified genomic sequences corresponding to the 11 exons were analyzed by single-strand conformation polymorphism (SSCP) and sequencing. Six nonsynonymous and 2 synonymous single nucleotide polymorphisms (SNPs) were found to be common in one ethnic group or another, and they involved codons 254 (Gly-GGC/Gly-GGT) in exon 3, 333 (Ile-ATC/Val-GTC) in exon 4, 370 (Ala-GCT/Val-GTT) in exon 5, 458 (Val-GTG/Leu-TTG) in exon 6, 518 (Val-GTC/Ile-ATC) in exon 7, 637 (Asp-GAC/Gly-GGC), 648 (Arg-CGA/Gln-CAA) and 661 (Pro-CCG/Pro-CCA) in exon 10. At each SNP site the sequence listed first was predominant in all ethnic groups. Several SNPs segregated on the same chromosome regardless of populations and species. Together, the SNPs produced 5 major human TAP1 alleles, 4 of which matched the officially recognized alleles *0101, *02011, *0301, and *0401; the 5th allele differed from each of those by at least 4 SNPs. Overall, TAP1*0101 was the predominant allele in all ethnic groups, with frequencies ranging from 0.667 in Zambians to 0.808 in US Caucasians. The TAP1*0401 frequency showed the greatest difference between Africans (0.221-0.254) and Caucasians (0.033), with Brazilians (0.058) fitting in the middle. Consistent with earlier work based on Caucasians and gorillas, *0101 appeared to be the newest human TAP1 allele, suggesting a dramatic spread of *0101 into all human populations examined. Characterization of TAP1 polymorphisms allowed the design of a PCR-based genotyping scheme that targeted 7 SNP sites and required 2 separate genotyping techniques.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Genotyping TAP2 variants in North American Caucasians, Brazilians, and Africans.

The protein forms of transporter associated with antigen processing, subunit 2 (TAP2), differ either by amino acid substitutions (Thr374Ala, Ile379Val, Ile467Val, Thr565Ala, Val577Met, Cys651Arg, and Ala665Thr) or by a truncation (Gln687Stop) of 17 amino acid residues at the C-terminus. Nonsynonymous single nucleotide polymorphisms (N-SNPs) causing these amino acid variations except 577Val were detected in genomic DNA samples from North American Caucasians (n = 76), Brazilians (n = 148), Rwandans (n = 285), and Zambians (n = 117). Exclusive (100%) and nearly exclusive (>95%) linkage disequilibrium was seen with a number of N-SNPs. The average heterozygosity at any given dimorphic site ranged from 7.3% to 44.6%, and at least four N-SNPs showed clear population specificity. N-SNP combinations alone led to the identification of 16 relatively common alleles, which appeared to form at least three lineages. Further analyses of 101 cDNA samples from Brazilians detected nine expressed TAP2 alleles, four of which matched the official assignments. Genetic complexity at the TAP2 locus was further enhanced by two out of five synonymous SNPs (S-SNPs), especially the GGT386GGG (Gly) that had similar heterozygosity rates in Caucasians (28.9%), Rwandans (33.3%), and Zambians (33.3%). Overall, distribution of both synonymous and nonsynonymous SNPs in the various ethnic groups examined here conformed well to the Hardy-Weinberg equilibrium, and between 57.9% and 77.0% of subjects in each ethnic group were heterozygous with two TAP2 alleles predicted to differ by at least one amino acid residue. Such complexity of TAP2 polymorphisms, in the form of SNPs as well as alleles, is likely to complicate the analyses of disease associations and haplotype structures in the HLA class II region.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Effect of aggressive prolonged diethylcarbamazine therapy on circulating antigen levels in bancroftian filariasis.

BACKGROUND: Single dose diethylcarbamazine (DEC) as used in control programmes is effectively microfilaricidal for periods of up to a year or more but has incomplete ability to kill Wuchereria bancrofti adult parasites. These regimens can be effective in breaking transmission by suppression of circulating microfilariae available to mosquito vectors. Whether prolonged or aggressive therapy with DEC has a significant effect on adult worms, which may live up to 12 years or more, and is important in the context of the treatment of individual patients, is still incompletely understood. METHODS: In order to investigate the adulticidal effect of aggressive therapy, DEC was given at 6 mg/kg/day for 12-day courses at 0, 6, 12, and 18 months and Og4C3 antigenaemia followed over two years in 38 CAg + Brazilians in a W. bancrofti endemic area. RESULTS: At two year follow-up, the median level of antigenaemia was 21% of the pre-treatment value. 92% of individuals had antigen levels < 50% of pretreatment values, but only 26% had completely cleared antigenaemia. The clearance rate at 24 months was only 12% (3/26) in the asymptomatic CAg + patients but 58% (7/12) in those with clinical manifestations of filariasis. The latter individuals cleared significantly more antigen (median of 0% pretreatment antigenaemia vs. 26%; P=0.02) than asymptomatic but infected individuals. CONCLUSION: Aggressive repeated therapy with DEC alone is ineffective in consistently eradicating adult W. bancrofti, especially in infected but asymptomatic individuals. Prolonged courses of combination therapy with other antifilarial drugs should be investigated for treatment of individual patients with the means to pursue aggressive personal medical care.

Adolescent↗
PubMed1999

Biased TCR repertoire in infiltrating lesional T cells in human Bancroftian filariasis.

To investigate the hypothesis that T cells recognizing specific Ags localize to the site of disease activity in human bancroftian filariasis, we have compared the repertoire of TCR Vbeta gene segments in lesions vs blood in individual patients by RT-PCR ELISA. Vbeta14 and Vbeta24 were overrepresented (5% greater in tissue compared with PBMCs and/or tissue/PBMC ratios in the highest 5% of all tissue/PBMC ratios for all Vbetas for all subjects) in 50% and 40% of study subjects, respectively. Overrepresentation of these two Vbetas did not occur in any control subject. In comparing three patient groups, the proportion of individuals meeting at least one criterion for Vbeta14 overrepresentation was shown to increase in tandem with our current concepts of disease progression (asymptomatic filariasis = 25%; clinical filariasis with active infection = 60%; clinical filariasis without active infection = 71%). In 6 of the 10 individuals with Vbeta14 overrepresentation, Vbeta14 represented >20% of the entire lesional Vbeta repertoire. All but one of the 20 study subjects had at least one Vbeta gene segment that was overrepresented in tissue compared with PBMCs. Only a small number of Vbetas, usually three or less, were overrepresented in any single filariasis patient. However, in the same tissue, no differences between patient groups were found when IFN-gamma, TNF-alpha, IL-4, IL-5, and IL-12 mRNA expression were examined. Taken together, these findings suggest that, in principle, in essentially all patients, whether with subclinical or with clinical filariasis, distinct and limited T cell populations are concentrated in affected tissue.

Animals↗
PubMed1999

Epidemiology and immunopathology of bancroftian filariasis.

Human lymphatic filariasis affects 120 million people worldwide. Although the disease is considered to be potentially erradicable by the World Health Organization, comprehensive studies on epidemiological aspects as well as mechanisms of pathology development are still premature. The following review summarizes currently available data on these topics and ends by discussing the latest control strategies.

Animals↗
PubMed1999

GeoSentinel: the global emerging infections sentinel network of the International Society of Travel Medicine.

GeoSentinel is a network of 22 member travel/tropical medicine clinics (14 in the United States and 8 in other countries) initiated in 1995 by the International Society of Travel Medicine (ISTM). GeoSentinel is based on the concept that these clinics are ideally situated to effectively detect geographic and temporal trends in morbidity among travelers. The core surveillance tool is a single-page faxable form submitted to a central data site for each post-travel patient, including immigrants, refugees, and foreign visitors. Diagnoses are entered either as specific etiologies or as syndromes and are then linked to geographic locations, reference dates, and clinical presentations. In addition, electronic communication with the larger body of worldwide ISTM member clinics is periodically done to obtain broader data collection in response to specific inquiries. The scope of GeoSentinel has broadened from the initial vision of a provider-based sentinel network tracking emerging infections at their point of entry into developed countries. Its present goals are (1) to monitor global trends in disease occurrence among travelers; (2) to ascertain risk factors and morbidity in groups of travelers categorized by travel purpose and type of traveler; (3) to respond to urgent public health queries; (4) to develop educational priorities for travelers' health; and (5) to effect a rapid response by electronically disseminating alerts to surveillance sites, to all ISTM members in 55 countries, and to public health authorities. In addition, a major byproduct of the network, and now one of its strongest assets, has been the growth of partnerships between ISTM, Centers for Disease Control and Prevention and health-care providers around the world, as well as other medical societies, government, and private organizations. The demographic data, travel patterns, and clinical presentations for the first 2813 patient records analyzed from the GeoSentinel sites are summarized in this paper.

Adolescent↗
PubMed1999

Strongyloides stercoralis hyperinfection associated with human T cell lymphotropic virus type-1 infection in Peru.

A study was conducted in Lima, Peru to determine if patients with Strongyloides hyperinfection had human T cell lymphotropic virus type-1 (HTLV-I) infection. The study included patients with Strongyloides hyperinfection and a control group consisted of sex- and age-matched asymptomatic healthy individuals whose stools were negative for Strongyloides. A third group included patients with intestinal strongyloidiasis. Sera from each study subject were tested for HTLV-1/2I by an ELISA and Western blot. The HLTV-1 infection rates (85.7%, 18 of 21) were significantly (P < 0.001) associated with Strongyloides hyperinfection compared with the control group (4.7%, 1 of 21). The HTLV-1 rate (10%, 6 of 62) for patients with intestinal strongyloidiasis was significantly (P < 0.001) lower than patients with Strongyloides hyperinfection, but did not differ significantly (P > 0.05) from the control group. The association of HTLV-1 infection was observed among 17 of 19 patients more than 20 years of age and one of two younger patients. None had HTLV-2 infection. In conclusion, Strongyloides hyperinfection among Peruvian patients was highly associated with HTLV-1 infection.

Adult↗
PubMed1999

Emerging infectious diseases and risk to the traveler.

This article examines the relationship between travel and emerging infections. The authors begin with an overview of disease emergence and follow with a brief infection-by-infection examination of selected emerging pathogens of particular relevance to travelers and the medical care providers who counsel them. Emphasis is given to those agents that clearly have emerged as significant new or increased risk to travelers; or are of sufficiently new interest, even in the face of inadequate data in travelers, to be of potential immediate concern. The authors also discuss several novel pathogens, such as Ebola virus, that are clearly of insignificant or minimal risk to travelers, but are the subject of frequent questions from patients requesting pre-travel advice from medical providers.

Humans↗
PubMed1998

Immune dynamics in the pathogenesis of human lymphatic filariasis.

Despite the longstanding recognition of the spectral nature of human disease due to lymphatic filariasis, immunologists interested in pathogenesis have mostly examined patients classified as being at either one extreme pole or the other. While the clinically asymptomatic individuals with microfilaremia who sit at one pole always have active infection, it has been difficult to define who else on the clinical spectrum is actively infected with living adult worms. In this review, David Freedman discusses how the ability to measure circulating filarial antigen in patient serum has advanced our ability to understand the immunopathogenesis of lymphatic filariasis by improving the precision of patient classification. Recent work suggests that the presence (or absence) of antigenemia, rather than overt clinical manifestations of disease, is closely associated with specific cytokine responses. A framework for patient classification based on these findings is proposed.

Journal Article↗
PubMed1998

Keeping current. Travel medicine resources available on the Internet.

As travel medicine practices expand and multiply, practitioners increasingly need to be familiar with constantly changing disease epidemiology and drug resistance patterns in over 220 different countries. Nowadays, keeping current means utilizing the wide array of resources available on the internet. This article contains background information on the most relevant travel medicine-oriented Internet sites and provides their universal resource locators in a convenient table.

Computer Communication Networks↗
PubMed1998

Differences in the frequency of cytokine-producing cells in antigenemic and nonantigenemic individuals with bancroftian filariasis.

Individuals with clinical manifestations of lymphatic filariasis may be currently infected or not. Twenty-five individuals from a Wuchereria bancrofti-endemic area of Brazil were classified as being asymptomatic microfilaremic individuals, antigenemic individuals with clinical filariasis, or nonantigenemic individuals with clinical filariasis. Intracellular cytokine staining of mitogen-stimulated peripheral blood mononuclear cells (PBMC) showed that the frequency of either gamma interferon (IFN-gamma)- or interleukin-4 (IL-4)-producing cells was higher in the nonantigenemic individuals with clinical filariasis than in the asymptomatic microfilaremic individuals (geometric means, 22.1 versus 10.7% [P = 0.02] and 2.9 versus 1.4% [P = 0.01], respectively). When the asymptomatic microfilaremic individuals and antigenemic individuals with clinical filariasis were grouped together to constitute all actively infected individuals, the frequency of IFN-gamma-producing cells was also lower than in the nonantigenemic individuals with clinical filariasis (P = 0.04). Likewise, the frequency of IL-4-producing cells in the actively infected individuals was also lower than in the nonantigenemic individuals with clinical filariasis (P = 0.02). No differences in the frequency of IFN-gamma-, IL-4-, or IL-5-producing cells in purified CD4 T lymphocytes were found among the groups. These findings suggest that the presence of antigenemia, which is an indicator of current active infection, is closely associated with the frequency of IFN-gamma- and IL-4-producing cells in lymphatic filariasis. The differences found in the frequency of cytokine-producing cells among the three groups appear to be due to a subset of cells other than CD4 T cells.

Adolescent↗
PubMed1997

T-lymphocytes from individuals with filarial inflammatory disease have increased transendothelial migration in vitro.

The in vitro transendothelial migration of circulating filarial antigen-specific T-cells was examined in Wuchereria banerofti infection. Circulating T-cells from individuals with filaria-induced lymphatic pathology (LP) had significantly greater migration through unstimulated HUVEC monolayers than did T-cells from asymptomatic infected (MF) individuals (P = 0.04). In contrast to the MF individuals where no effect was seen, transendothelial migration of 48-hr filarial antigen stimulated T-cells from LP individuals was significantly (P = 0.01) greater than migration of 48-hr media-stimulated T-cells. In six of seven patients examined, inhibition of the VLA-4/VCAM-1 pathway resulted in greater than 50% inhibition of transendothelial migration of T-cells.

Adult↗
PubMed1996

Very late antigen-4/vascular cell adhesion molecule-1 (VLA-4/VCAM-1) pathway is involved in the transendothelial migration of lymphocytes in bancroftian filariasis.

The role of endothelial vascular cell adhesion molecule-1 (VCAM-1) in the trafficking of lymphocytes from the vascular circulation through endothelium and into sites of filarial inflammation was investigated in asymptomatic microfilaremic (MF; n = 16) and in patients with filaria-associated lymphatic pathology (LP; n = 23). When compared, by human umbilical vein endothelial cell ELISA, with PBMC supernatants generated from MF patients, filarial Ag (Brugia malayi adult Ag (BmA))-stimulated supernatants from LP patients stimulated over 50% more VCAM-1 (lymphatic pathology (LP) = 0.377 relative ELISA units vs MF = 0.246; p = 0.02). No difference was seen between patient groups with nonfilarial Ag (streptolysin O)-stimulated supernatant (LP = 0.160 relative ELISA units vs MF = 0.166). BmA-stimulated supernatants from LP patients stimulated significantly more T cell migration (percentage of relative migration LP = 79.9% vs MF = 25.8%; p = 0.01) through tightly confluent human umbilical vein endothelial cell monolayers cultured on collagen gels. Anti-VCAM-1 inhibited the increased T cell migration induced by BmA-stimulated supernatants by 97.7%, anti-VLA-4 by 74.7%, and blockade of NF-kappa B-dependent VCAM-1 transcription with 50 microM pyrrolidine dithiocarbamate resulted in 87.7% inhibition. Biopsies from 87.5% of the LP patients, but only 38.5% of the MF patients, demonstrated VCAM-1 on vascular endothelium. BmA-stimulated supernatants pretreated with anti-IL-1 alone resulted in VCAM-1 expression that was 23.7% of that with untreated supernatants while anti-IL-4, anti-IFN-gamma, or anti-TNF alone had essentially no effect on VCAM-1 expression.

Adolescent↗
PubMed1996

The presence or absence of active infection, not clinical status, is most closely associated with cytokine responses in lymphatic filariasis.

Twenty-eight Brazilians from an area in which Wuchereria bancrofti is endemic were classified as asymptomatic microfilaremic or having clinical filariasis with active infection or without current active infection. Total accumulation of antigen-specific interleukin (IL)-4 and IL-5 in 48 h peripheral blood mononuclear cell supernatants was not significantly different between groups. However, when cytokine kinetics were examined, responses segregated according to infection status. Sustained production of IL-4 and IL-5 beyond the first 24 h of stimulation and production of interferon-gamma were seen only in the group with clinical filariasis without active infection. CD8 T cells were the major source of IL-5 production in this group, while CD8 production of IL-5 was undetectable in any subject with active infection (asymptomatic microfilaremic or with clinical filariasis and active infection). These findings indicate that active infection, rather than clinical status, is most closely associated with cytokine patterns in lymphatic filariasis.

Adult↗
PubMed1996

Immunoregulation in onchocerciasis: persons with ocular inflammatory disease produce a Th2-like response to Onchocerca volvulus antigen.

To examine the role of specific cytokines in mediating the clinical manifestations of human onchocercal disease, microfilariae-positive Ghanaian subjects with inflammatory ocular disease were compared with microfilariae-positive subjects without ocular disease. Onchocerca volvulus antigen (OvAg)-stimulated peripheral blood mononuclear cells (PBMC) from subjects with disease produced significantly more interleukin (IL)-10 (with disease = 447.34 vs. without disease = 292.22 pg/mL; P < .01) and IL-5 (with disease = 33.36 vs. without disease = 27.26 pg/mL; P = .02). OvAg-stimulated IL-4 and interferon (IFN)-gamma levels were essentially undetectable in either group. When cytokine mRNA levels were measured by reverse transcriptase-polymerase chain reaction ELISA, persons with disease produced significantly more OvAg-stimulated IL-4, IL-5, and IL-10 mRNA (P = .03, < .01, .05, respectively). No difference in IFN-gamma mRNA production by either group was seen. Addition of neutralizing alpha IL-10 antibody to OvAg-stimulated PBMC increased TFN-gamma production to detectable levels in 20 of 24 persons.

Adolescent↗