A decade's experience at Tufts with a four-year combined curriculum in medicine and public health.

The absence of a good working relationship between medicine and public health is a cardinal feature of the health care system in the United States. Nowhere has the "uneasy alliance" between proponents of care for the individual versus those who advocate greater attention to the health needs of the population been more apparent than within medical schools. This article chronicles ten years of experience at the Tufts University School of Medicine where, for a limited number of students, the Combined MD-MPH (Master of Public Health) Program has been created and sustained and continues to produce professionals trained and credentialed in both public health and medicine. The four-year program has graduated over 75 students and provides a medical-school-based model that combines education in medicine with a comprehensive, prevention-oriented, population-based approach to health. The Program is described, and experience-based suggestions are offered for medical schools interested in developing training opportunities that address both the care of the individual patient and the care of populations. The Tufts experience shows that a four-year program that combines rigorous education in medicine and public health does not require drastic changes in medical school admission policy or major revisions in curricula. The introduction of combined MD-MPH programs can better serve the changing needs of medical practitioners and their patients while also fostering the health of the public.

Isolation and functional characterization of murine T cell lines and clones specific for the protozoan parasite Trypanosoma cruzi.

Murine T cell lines responsive to the protozoan parasite Trypanosoma cruzi were generated in vitro by stimulating hyperimmune C57BL/6 lymphoid cells with trypomastigote stage antigen. A spleen-derived line designated ST1 and eight clones derived from ST1 were characterized. All lines bear the surface phenotype Thy-1.2+, Ly-1.2+, 2.2- and respond to T. cruzi antigen only in the presence of antigen-presenting cells matched at the I-A subregion of the H2 locus. Clonal specificity analyses indicated that these T. cruzi-selected T cells are species specific and recognize antigenic determinants that are expressed predominantly in the trypomastigote stage. On the basis of their distinct patterns of response to a panel of different T. cruzi strains, clones recognizing strain-specific, shared, or common determinants were identified. Functional studies indicated that ST1 and some but not all of the clones are capable of expressing antigen-specific T helper function in vitro and in vivo. In addition, co-incubation of T. cruzi-specific T cells with cultured T. cruzi-infected syngeneic macrophages led to the dose-dependent destruction of intracellular parasites. Most notably, ST1 and several of the cloned T. cruzi-specific T cell lines were able to passively protect syngeneic recipients from lethal T. cruzi challenge infection. Efforts to identify the parasite antigens recognized by these T cell lines, particularly the protective clones, are currently in progress.

Characterization of a new endoglucanase from Erwinia chrysanthemi.

The structural gene coding for a new endo-beta-1,4-glucanase of Erwinia chrysanthemi strain 3665, previously identified in a cosmid library, was subcloned into pUC18. The gene is expressed from a 1.9 X 10(3)-base-pair insert and its direction of transcription was determined. The properties of the gene product purified from cell-free extracts of Escherichia coli have been studied. The purified protein has an endoglucanase activity but is significantly different from the major endoglucanase Z secreted by E. chrysanthemi strain 3665. The new enzyme was designated as endoglucanase Y and the related gene celY. In E. coli, most of the endoglucanase activity was found in the periplasmic space.

Susceptibility to acute Trypanosoma cruzi infection in autoimmune strains of mice.

We previously observed that mice bearing the autoimmune associated lpr gene exhibit increased susceptibility to challenge with Trypanosoma cruzi, the causative agent of Chagas' disease. We have now tested two other autoimmune prone strains of mice, BXSB and NZB, and found that these animals also show increased sensitivity to acute T. cruzi infection. When challenged with a standard dose (10(2)) of Y strain trypomastigotes, BXSB males (BXSB-YSB), which develop early onset autoimmune disease, suffered high mortality, while late onset autoimmune BXSB females and minimally autoimmune male BXSB mice whose Y chromosome was derived from C57BL/6J mice (BXSB-YB/6) also recover. NZB mice were found to be highly susceptible to challenge while NZW and NZB/W were resistant. A finding common to all groups of susceptible autoimmune mice was increased plasma levels of T. cruzi specific antibody, especially IgM. The data indicate that in two of the three autoimmune prone strains examined, increased T. cruzi susceptibility appears to be linked to restricted genetic elements (i.e. lpr gene and the YSB associated factor) which also influence the rapidity of onset of autoimmunity.

Trypanosoma cruzi: susceptibility in mice carrying mutant gene lpr (lymphoproliferation).

There is evidence that autoimmune aberrations may contribute to the immunopathological consequences of Chagas' disease and because of this we sought to determine whether four inbred strains of mice bearing the single autosomal recessive gene, lpr (lymphoproliferation), which controls certain autoimmune manifestations, are particularly susceptible to acute infection with the Y strain of Trypanosoma cruzi. MRL/MpJ-lpr/lpr, C57Bl/6J-lpr/lpr, AKR/J-lpr/lpr, C3H/HeJ-lpr/lpr showed parasitaemias 2-10 times higher when compared to their congenic partners. Mortality was significantly higher in three of the four lpr strains. The results indicate that a single autosomal recessive gene which is associated with autoimmunity can influence susceptibility to acute T. cruzi infection in mice.

Effect of transferred adult Schistosoma mansoni on resistance of mice to cercarial challenge.

Four or eight adult Schistosoma mansoni surgically transfered to the mesenteric veins of mice survive well and may play a role in resistance to later cercarial challenge. After receiving transfers of single sex or paired flukes, animals exposed to 50or 100 cercariae showed decreased numbers of parasites derived from the challenge infection when compared with control animals 30 days later. Although statistical analysis of the data indicated that the presence of transferred S. mansoni probably had an adverse effect on the survival of worms in a subsequent challenge, the results were interpreted as inconclusive.

The host antigen phenomenon in experimental murine schistosomiasis. III. Destruction of parasites transferred from mice to hamsters.

The surgical transfer of 23- to 28-day-old Schistosoma mansoni from donor mice to the mesenteric vessels of outbred hamsters is followed by recovery of 70% of the transferred trematodes 30 days later. Prior immunization of hamsters with mouse erythrocytes results in anti-mouse erythrocyte antibody titers of greater than 1:4,096 and death of 98% of the parasites. Destruction is correlated with evidence of the presence of mouse antigenic determinants on the surfaces of schistosomes from donor mice.

The host antigen phenomenon in experimental murine schistosomiasis. II. Failure to demonstrate destruction of parasites transferred from hamsters to mice.

Adult Schistosoma monsoni grown in hamsters and transferred directly to the mesenteric vessels of C57BL10J mice previously immunized with hamster cells survive normally despite evidence of cytoxic and hemagglutinating antibodies directed against hamster cells. This finding indicates that species differences may play an important part in the manifestions of the host antigen phenomenon in experimental schistosomiasis.

The intensity and effects of infection with Schistosoma mansoni in a rural community in northeast Brazil.

The intensity of infection with Schistosoma mansoni and its effects were investigated in a defined population living on three contiguous fazendas (subcounties) in a nonmalarious area of northeast Brazil near Salvador, Bahia. Quantitative stool egg counts (Bell technique) were performed on 363 of 417 individuals (90%) of all ages; physical examinations were done on 294 of 357 individuals (82%) 5 years of age and older. The maximum increase in prevalence was observed between the 1- to 4- and 5- to 9-year age groups, while the maximum increase in fecal egg count occurred between 5- to 9- and 10- to 14-year age groups. Highest egg counts were observed in the 10- to 14-year age group (geometric mean of 301 eggs per ml of stool) while the maximum prevalence (100%) was in the 20- to 24-year age group. In the fazenda with the lowest quantitative egg counts the age specific prevalence rates increased more slowly than in the fazendas with higher egg counts. In the study group nearly 50% of the total fecal egg output was accounted for by 22 individuals (6%) who had a mean age of 12.6 years. Egg counts for this selected group were all over 800 eggs per ml of stool with a mean of 1,514 eggs per ml of stool. In children under 15 years of age, the frequency of hepatomegaly and splenomegaly varied directly with the egg count; further, the degree of hepatomegaly was directly correlated with increasing egg counts. No splenic enlargement was noted in children not excreting eggs. In adults, on the other hand, neither splenomegaly nor hepatomegaly could be directly related to schistosomal infection per se. In children, neither the presence of infection with S. mansoni nor its intensity was reflected by altered anthropometric measurements. In the one fazenda tested the frequency of stools positive for occult blood correlated with increasing S. mansoni egg counts.

Mechanism of eosinophilia. I. Factors affecting the eosinophil response of rats to Trichinella spiralis.

The phenomenon of eosinophilia was studied in rats using inoculation with Trichinella larvae as the experimental stimulus. Comparisons were made between the eosinophil response accompanying active infestation via the gastrointestinal tract and that resulting from parenteral inoculation of larvae or their products. A vigorous eosinophilia could be provoked by a single intravenous injection of intact parasites. In this circumstance the larvae lodged in the lungs causing an acute inflammatory reaction which led to their disintegration within 24 hr. Intraaortic injection also produced a significant response, whereas inoculation of the same number of parasites by the intramuscular, intraperitoneal, or subcutaneous routes did not cause eosinophilia. Eosinophilia likewise failed to develop if parasites were homogenized before intravenous injection, so that they were not arrested in the lungs. Antibody levels, as measured by a hemagglutination technique, using whole larval extract as antigen, did not correlate closely with the eosinophil response. The findings are interpreted as suggesting that increased eosinophil production is induced under some circumstances as a consequence of interaction between intact parasites and certain host cells in blood and tissue. No evidence was found for the existence of a specific constituent of the parasite capable of stimulating eosinophil production. Attention is directed to features of eosinophilia which fit with the concept that this phenomenon belongs in the category of immunologic reactions.