Non-endemic Population Research Articles

Inbreeding and Extinction in Island Populations: Reply to Elgar and Clode

Elgar and Clode (2001 [this issue]) present a misleading view of the content of my paper (Frankham 1998), criticize me for deficiencies that were addressed in a previous paper, ignore much of the evidence on inbreeding depression, misquote me in several places, and make several other misleading statements. My paper was not concerned solely with differences between nonendemic and endemic island populations, as Elgar and Clode imply. I made four main points in my paper:

Inbreeding and Extinction in Island Populations: a Cautionary Note

Extinction rates may appear generally higher on island than mainland populations, but the reason for this difference is controversial (e.g., Pimm 1991). Characteristically, small island populations are susceptible to demographic and environmental stochasticity (e.g., Pimm 1991), but genetic factors such as inbreeding and lack of genetic variation may also decrease their viability (e.g., Frankham 1995). For example, there is compelling evidence that inbreeding depresses individual reproductive success in typically out-breeding domestic plants and animals (e.g., Wright 1977; Falconer 1989; Frankham 1999) and captive populations of vertebrate wildlife (e.g., Ralls et al. 1988). But drawing general conclusions from individual species requires quantitative comparative analyses, rather than appeals to particular studies. Frankham (1998) addresses this issue by using interspecific comparative data to test several hypotheses derived from theoretical population genetics. In particular, Frankham (1998) claims that inbreeding coefficients are significantly higher in endemic than nonendemic island populations and that many island populations show levels of inbreeding associated with elevated extinction rates in domestic and laboratory species. Such interspecific comparative studies and meta-analyses of different populations are useful techniques to address apparently inconsistent empirical evidence (e.g., Harvey 1996; Frankham 1999). However, phylogenetic information should be taken into account in such analyses (Harvey & Pagel 1991), because closely related species share many traits as a result of common ancestory (Harvey 1996). Unfortunately, Frankham (1998) did not incorporate phylogenetic data into his analyses; hence, his conclusions may be misleading. We reanalyzed the data presented by Frankham (1998), correcting for taxonomic relationships. In particular, we explored the relationship between inbreeding and population viability and compared the inbreeding coeffi-

Onchocerciasis in a nonendemic population: clinical and immunologic assessment before treatment and at the time of presumed cure.

Although suppressive therapy for onchocerciasis with intermittent ivermectin prevents the development of pathology in endemic populations, the clinical and immunologic effects of therapy in the absence of continued exposure are unknown. To address this question, 14 patients treated with ivermectin for onchocerciasis acquired >10 years ago during temporary residence in Africa were reevaluated. None had evidence of continued infection or pathology at follow-up. Although eosinophilia, serum IgE, and antifilarial antibody levels decreased after ivermectin therapy, none of these parameters was useful in predicting the resolution of symptoms in infected patients. Peripheral blood mononuclear cells isolated from patients at follow-up were more responsive to parasite antigen in vitro, which is as assessed by proliferation and production of interferon-gamma and interleukin (IL)-5. In contrast, antigen-induced levels of IL-10 were significantly decreased at follow-up, consistent with diminished down-regulatory factors rather than a switch from type 2 to type 1 immune responses.

Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection

A third of the world's population has latent infection with Mycobacterium tuberculosis, and in areas of low endemicity, most cases of active tuberculosis arise as a result of reactivation of latent bacilli. We sought to establish the cellular location of these latent organisms to facilitate their elimination. We applied in-situ PCR to sections of macroscopically normal lung tissue from 13 individuals from Ethiopia and 34 from Mexico who had died from causes other than tuberculosis. Sections of lung tissue from six Norwegian individuals (ie, individuals from a non-endemic population) acted as negative controls, and six Ethiopian tuberculosis cases acted as positive controls. Control necropsy samples from the Norwegian individuals were all negative by in-situ PCR and conventional PCR, whereas all samples from known Ethiopian tuberculosis cases were positive by both methods. However, in macroscopically normal lung tissue from Ethiopian and Mexican individuals without tuberculous lesions, the in-situ PCR revealed five of 13 and ten of 34 positive individuals, respectively. These results were confirmed by conventional PCR with extracted DNA. Positive cells included alveolar and interstitial macrophages, type II pneumocytes, endothelial cells, and fibroblasts. M. tuberculosis can persist intracellularly in lung tissue without histological evidence of tuberculous lesions. M. tuberculosis DNA is situated not only in macrophages but also in other non-professional phagocytic cells. These findings contradict the dominant view that latent organisms exist in old classic tuberculous lesions, and have important implications for strategies aimed at the elimination of latent and persistent bacilli.

Predisposition to urinary tract epithelial metaplasia in Schistosoma haematobium infection.

Although there is strong epidemiologic evidence linking Schistosoma haematobium infection with carcinoma of the bladder, the utility of cytologic screening for urinary tract cancer has not been critically evaluated in S. haematobium-endemic populations. The present cross-sectional study examined urine cytology findings among 1,014 residents (ages 1 to 91) of the S. haematobium-endemic Msambweni area of Coast Province, Kenya. Among 705 evaluable cytology specimens, prevalence of inflammation (39%), hyperkeratosis (30%), metaplasia (33%), and frank atypia (0.4%) was notably higher than in previously studied, non-endemic populations. Overall, S. haematobium infection was strongly associated with increased risk for cytologic abnormality (> 2.8-fold relative risk of metaplasia or hyperkeratosis; P < 0.001). Age-group analysis confirmed parallel increases in metaplasia and S. haematobium infection prevalence early in life (from age I to 15 for both boys and girls). However, above age 20, metaplasia prevalence persisted at 33-45% prevalence despite a decline in infection prevalence and intensity. Prevalence of advanced (moderate or severe) metaplasia showed two age-related peaks: the first at 10-14 years of age (at the time of peak infection), and the second among subjects > or = 60 years old. No cancers were detected in the study population either on cytology or on follow-up ultrasound examination. These data suggest an age-dependent progression of cellular abnormalities in the urinary epithelium that is associated with chronic S. haematobium infection, which becomes independent of concurrent infection intensity as subjects grow older. Implications for cancer screening are discussed.

Natural history of infection with Bartonella bacilliformis in a nonendemic population.

An investigation was performed after an outbreak of bartonellosis in a region of Peru nonendemic for this disorder. Symptoms of acute and chronic bartonellosis were recorded. Serological analysis was performed on 55% of the affected population (554 individuals), 77.5% of whom demonstrated previous infection with Bartonella bacilliformis. The attack rate of Oroya fever was 13.8% (123 cases); the case-fatality rate was 0.7%. The attack rate of verruga peruana was 17.6%. A new specific immunostain was developed and used to confirm the presence of B. bacilliformis in the biopsied skin lesions. Most seropositive individuals (56%) were asymptomatic. The symptoms that were associated with prior infection, as determined by Western blot, included fever (37.2% of the seropositive vs. 17.2% of the seronegative population; P<.001), bone and joint pain (27% vs. 9%; P<.001), headache (27% vs. 12.3%; P <.001), and skin lesions described as verruga peruana (26.8% vs. 4.9%; P<.001). Our findings suggest that infection with B. bacilliformis causes a broad spectrum of disease that is significantly milder in severity than that frequently reported.

Is T-cell priming required for initiation of pathology in malaria infections?

The pathology of malaria infection is mediated in part by components of the innate immune system, particularly tumour necrosis factor α, but the relationship between malaria infection and disease is not straightforward. Here, Eleanor Riley proposes that T-cell priming is required for amplification of the inflammatory response to malaria and that this explains patterns of clinical malaria in both endemic and non-endemic populations.

Inbreeding and Extinction: Island Populations

Island populations are more prone to extinction than mainland populations, with island endemic species having higher extinction rates than nonendemic species. Inbreeding depression is one possible explanation for this. Insular populations are expected to suffer increased inbreeding relative to mainland populations due to bottlenecks at foundation and to lower subsequent population sizes. Inbreeding coefficients for 182 nonendemic and 28 endemic island populations were estimated from allozyme and microsatellite heterozygosities in island and related mainland populations. Island populations were significantly inbred, with inbreeding coefficients significantly higher in endemic than nonendemic island populations. Many island populations showed levels of inbreeding associated with elevated extinction rates in domestic and laboratory species. Inbreeding depression cannot be excluded as a factor in the extinction proneness of island populations.Intracruza y Extinción: Poblaciones IsleñasPoblaciones Isleñas presentan una mayor tendencia a la extinció que las poblaciones continentales, teniendo las especies endémicas una mayor tasa de extinción que las especies no endémicas. La depresión por intracruza es una explicación posible a esto. Es de esperarse que poblaciones insulares sufran una intracruza relativemente mas alta que las poblaciones continentales debido a cuellos de botella a nivel de tamaño poblacional de fundación y subsecuentes tamaños poblacionales menores. Los coeficientes de intracruza para 182 poblaciones no endémicas y 28 poblaciones endémicas se estimaron mediante heterozigocidades de alozimas y microsatélites de poblaciones de islas y especies continentales relacionadas. Las poblaciones isleñas estuvieron significativamente intracruzadas, con coeficientes de intracruza signifiativamente mayores en poblaciones endémicas que en las poblaciones no endémicas. Muchas poblaciones isleñas mostraron niveles de intracruza asocidos con elevadas tasas de extinción en especies domesticas y de laboratorio. La depresión por intracruza no puede ser excluída como un factor en la tendencia a la extinción de especies isleñas.

Polymerase chain reaction assay for the detection and identification of Mycobacterium leprae in patients in the United States.

The differentiation of leprosy from other cutaneous granulomatous diseases is routinely based on characteristic histopathologic features and the demonstration of Mycobacterium leprae by acid-fast staining. Increased ascertainment of other mycobacterial infections in the skin has made this task more difficult, but the distinction remains fundamental for the selection of appropriate treatment. Experience with formalin-fixed, paraffin-embedded tissues, frozen tissues, and tissue lysates referred for detection of M. leprae DNA by a polymerase chain reaction (PCR) assay during the past 4 years was reviewed. This assay was done by using primers and probes previously developed in our laboratory to amplify a 360-base-pair fragment of the gene for an 18-kD protein of M. leprae. Among biopsy samples obtained from 37 patients, PCR results were positive for 10 of 20 samples diagnosed as leprosy by histopathologic criteria and in 0 of 17 not diagnosed as leprosy. The specificity of the assay was 100% in this clinical referral material; sensitivity ranged from 50% to 83%. The PCR assay also identified M. leprae in one third of samples in which acid-fast organisms were seen and the histopathologic features were consistent with but not definitive of leprosy. In a nonendemic population, the sensitivity and specificity of PCR assay recommend its use primarily to identify M. leprae when acid-fast organisms are discernible but atypical clinical or histopathologic features obscure the diagnosis. The assay is not highly informative when acid-fast bacilli are not detectable by light microscopy.

Do island populations have less genetic variation than mainland populations?

Island populations are much more prone to extinction than mainland populations. The reasons for this remain controversial. If inbreeding and loss of genetic variation are involved, then genetic variation must be lower on average in island than mainland populations. Published data on levels of genetic variation for allozymes, nuclear DNA markers, mitochondrial DNA, inversions and quantitative characters in island and mainland populations were analysed. A large and highly significant majority of island populations have less allozyme genetic variation than their mainland counterparts (165 of 202 comparisons), the average reduction being 29 per cent. The magnitude of differences was related to dispersal ability. There were related differences for all the other measures. Island endemic species showed lower genetic variation than related mainland species in 34 of 38 cases. The proportionate reduction in genetic variation was significantly greater in island endemic than in nonendemic island populations in mammals and birds, but not in insects. Genetic factors cannot be discounted as a cause of higher extinction rates of island than mainland populations.

Do island populations have less genetic variation than mainland populations?

Island populations are much more prone to extinction than mainland populations. The reasons for this remain controversial. If inbreeding and loss of genetic variation are involved, then genetic variation must be lower on average in island than mainland populations. Published data on levels of genetic variation for allozymes, nuclear DNA markers, mitochondrial DNA, inversions and quantitative characters in island and mainland populations were analysed. A large and highly significant majority of island populations have less allozyme genetic variation than their mainland counterparts (165 of 202 comparisons), the average reduction being 29 per cent. The magnitude of differences was related to dispersal ability. There were related differences for all the other measures. Island endemic species showed lower genetic variation than related mainland species in 34 of 38 cases. The proportionate reduction in genetic variation was significantly greater in island endemic than in nonendemic island populations in mammals and birds, but not in insects. Genetic factors cannot be discounted as a cause of higher extinction rates of island than mainland populations.

Dengue fever among travelers

The present paper describes the epidemiology and clinical manifestations of dengue fever in a nonendemic population of travelers. Clinical manifestations, epidemiologic information, and laboratory findings are described for a series of 18 Israeli travelers who tested serologically positive for dengue. All the patients in the series contracted the disease in Southeast Asia, mostly in Thailand; 30% had to be evacuated due to severe morbidity. The clinical symptoms in travelers somewhat differ from the classical description among endogenous populations. High fever, chills, extreme fatigue, and severe headaches were prevalent. Other symptoms considered to be typical of dengue fever, such as myalgia, arthralgia, rash, biphasic fever, were uncommon. Laboratory findings were marked leukopenia, usually accompanied by lymphopenia, thrombocytopenia, liver function impairment, and hyponatremia. Some hemorrhagic phenomena were manifest despite it being the first exposure, without mortality. Dengue fever among the nonimmune has a somewhat different manifestation from that reported for the Southeast Asian population. Although it is a significant cause for morbidity and hospitalization, it is underestimated as a factor affecting traveler's health. More efforts should be expended in developing an effective vaccine.

A comparative study on specific antibodies and circulating antigen (CAA) in serum and parasitological findings for diagnosis of schistosomiasis mansoni in an endemic area in Tanzania

A baseline study to evaluate the prevalence of Schistosoma mansoni infection as well as the diagnostic efficacy of serodiagnostic tests was performed in Kabaganga village, Kome island, Lake Victoria, Tanzania. A total of 1108 individuals were examined parasitologically and clinically. Egg excretion was demonstrated by one-sample Kato-Katz test. Specific IgG1 and IgG4 antibodies against S. mansoni adult worm (SAWA) and egg (SEA) antigens as well as circulating anodic antigen (CAA) were determined in serum samples from 250 of these subjects. As a control population 41 individuals from a non-endemic area were examined parasitologically, clinically and serologically. In the parasitologically examined Kabaganga population 45% were excreting eggs. The pattern of egg excretion was typical for an endemic area with a peak in the age group 10–14 years. Sixty-five percent of the serologically tested villagers were positive in the CAA test. A total of 80% were positive in either of the two tests, indicating an active infection. In 67–95% of these individuals the levels of isotype specific antibodies were increased. The prevalence of CAA positivity corresponded fairly well with that of Kato-Katz results in the age groups 10–29 years, but in the younger age groups a considerably greater number of individuals were positive in the CAA test than in the Kato-Katz test. The results obtained indicate that virtually all of the Kabaganga villagers, regardless of age, had an ongoing, active infection or had previously been infected with S. mansoni. This population, therefore, may be useful for evaluation of the diagnostic efficacy of various antibody tests. The highest degree of discrimination between the endemic and the non-endemic village populations was noted for anti-egg IgG4 antibodies. It is concluded that the combined determination of parasite eggs in faeces and CAA in serum provides high sensitivity as regards active infection. Increased levels of isotype-specific antibodies, particularly of the IgG4 subclass, is a sensitive indicator of past or present infection, and the prevalence of individuals with such increased levels may be a simple and reliable indicator of the frequency of schistosomiasis in a community.

The phylogeny and molecular epidemiology of human T-cell lymphotropic virus type II.

Phylogenetic analysis of long terminal repeat (LTR) sequences from 29 human T-cell lymphotropic virus type II (HTLV-II) strains from endemic and nonendemic populations led to the proposition of three HTLV-IIa phylogroups (A-I, A-II, and A-III) and four HTLV-IIb phylogroups (B-I, B-II, B-III, B-IV). B-I and B-II represented sequences from U.S. and European intravenous drug users, and B-IV included Amerindian sequences from the Guaymi and Wayuu. Interestingly, sequences from an African Pygmy and Seminole and Pueblo Indians and other non-India U.S. samples clustered together in B-III. Similarly, sequences from the Kayapo Indians from Brazil, a Brazilian blood donor, a Cameroonian, and a Ghanaian prostitute clustered together in A-II. Sequences from non-Indian U.S./European samples and a Pueblo Indian formed A-III. A restriction fragment length polymorphism (RFLP) assay was developed to identify rapidly the prevalence of the A and B phylogroups in 246 HTLV-II samples. The RFLP results suggest that A-III and B-II may represent cosmopolitan subtypes because of global distribution in urban areas. In contrast, B-IV and A-II infections were restricted primarily to Central and South America. The phylogenetic data suggest a possible Amerindian origin for B-III, A-II, and A-III infections in non-Indians and an evolution into A and B subtypes that preceded population migrations to the Americas.

Onchocerciasis In Endemic And Nonendemic Populations: Differences In Clinical Presentation And Immunologic Findings

To characterize the clinical and laboratory features of onchocerciasis in visitors to endemic areas and to compare them with those seen in endemic subjects, 20 returned visitors and 21 endemic subjects with onchocerciasis were evaluated. Dermatitis was the most frequent clinical finding among the returned visitors. None had nodules or eye disease and, in contrast to the endemic subjects, microfiladermia was often absent or of low density. All persons studied had antibody responses measurable by ELISA to both soluble Onchocerca volvulus antigen and a panel of diagnostic recombinant antigens. Eosinophil and IgE levels were significantly higher in the endemic group, as was the capacity of peripheral blood mononuclear cells from this group to produce the T helper cell-like cytokines interleukin-4 and -5. It is likely that the chronicity and intensity of infection in endemic subjects account for the clinical and immunologic differences observed between the 2 groups.

Age-specific sero-prevalence of amoebiasis and giardiasis in southern Indian infants and children.

The age-specific sero-prevalence of amoebiasis and giardiasis was estimated in 91 pediatric diarrhoea and in 70 non-diarrhoeal cases from Southern India. Anti-amoeba/giardia IgG assays on 20 children with inflammatory bowel disease from the UK yielded base-line levels in a non-endemic symptomatic population. IgG, IgM, and IgA levels were estimated to E. histolytica and G. lamblia using an ELISA. Concomittant faecal examinations were done for the Indian children. There was a significant correlation between acquisition of sero-positivity and age. A rise in the IgG response to both organisms was evident between 38 and 47 and 13-24 months, respectively, in diarrhoeal and non-diarrhoeal cases. An appreciable IgM response occurred predominantly in diarrhoea cases and at a younger age (less than 24 months). IgA responses were low. Anti-protozoal IgG levels in the UK children were negligible. There was no relationship between faecal excretion and sero-positivity. The study shows an age-related antibody response to E. histolytica and G. lamblia.

Bancroftian Lymphadenopathy: a Histopathologic Study of Fifty-Eight Cases from Northeastern Brazil

Histologic study of Bancroftian lymphadenopathy in 58 patients originating from an endemic area revealed a wide range of tissue reactions to the filarial worms. In seven patients (12.0%), no attendant inflammation or parasite damage was observed. A mild-to-intense nongranulomatous chronic lymphangitis was found in 12 patients (20.7%). Granulomatous reactions with variable composition were the most common pattern observed (37 patients, 63.8%); fibrotic lesions containing calcified worms were present in 13 of these patients. Epithelioid granulomas without worms, associated either with granulomatous reactions to the worms (seven patients) or nongranulomatous lymphangitis (two patients), were also detected. Lymphoid hyperplasia and lymphatic dilation were constant, and eosinophil infiltration was usually remarkable. These findings were compared with those reported from nonendemic populations and emphasize the parallelism between the pathologic findings and the immune responsiveness reported in such patients.

Loiasis in Endemic and Nonendemic Populations: Immunologically Mediated Differences in Clinical Presentation

To define the clinical spectrum of loiasis more precisely and to begin to assess the immunologic basis for the difference in clinical manifestations between visitors to endemic areas and natives of these areas, 51 West African patients with loiasis were evaluated and compared with 42 infected expatriates. Microfilaremia was present in 90% and Calabar swellings in only 16% of the endemic patients. Conversely, only 10% of the expatriates were microfilaremic while 95% complained of Calabar swellings. The endemic population showed significantly decreased levels of peripheral blood eosinophils, parasite-specific IgG, and lymphocyte proliferation to parasite antigens compared with the nonendemic population. These findings support the hypothesis that differences in the modulation of the immune response to parasite antigen are responsible for the observed differences in clinical presentation between expatriate and endemic populations with loiasis.

Examination of HTLV-I ELISA-Positive Leukemia/Lymphoma Patients by Western Blotting Gave Mostly Negative or Indeterminate Reaction

We used enzyme-linked immunosorbant assay (ELISA) and Western blotting, with "purified" human T-cell leukemia virus I (HTLV-I), to test for HTLV-I antibodies in 2583 plasma samples from 1053 leukemia/lymphoma patients treated at Roswell Park Memorial Institute, mostly between 1972 and 1984, and in 110 sera samples from normal healthy persons. The results demonstrate that ELISA and Western blot assay have limitations for HTLV-I antibody detection in an adult T-cell leukemia/lymphoma (ATL) nonendemic population. This conclusion is based on the many false reactives obtained by ELISA, and weak and indeterminate reaction (mostly p19 band) on Western blotting. All moderate to strongly HTLV-I ELISA-positive samples tested were negative for human immunodeficiency virus (HIV) antibodies. Although 6/27 mycosis fungoides (MF) patients tested gave mostly a weak reaction on HTLV-I ELISA, 3/6 MF patients gave multiple bands (p19, p31, p36, gp46) on Western blotting and three samples from one patient gave the same p31, p36, and gp46 bands. This may suggest involvement of some HTLV-I-related virus in MF. These results also indicate that prevalence of HTLV-I infection in leukemia/lymphoma patients was rare, if it exists at all, since, despite the reactivity of some sera with HTLV-I-suspected antigens, none of the samples satisfy the USPHS criteria for positivity which is based on the detection of antibodies to gag protein p24 and to an env gene product gp46 or gp61/68.

Genetic differentiation among natural populations of the vector of onchocerciasis, Simulium ochraceum in Guatemala

Electrophoretic studies of Guatemalan blackflies, Simulium ochraceum , the main vector of Central American onchocerciasis, were performed using isozyme patterns. A total of six larval and adult populations originating from four localities (a non-endemic area, Finca La Ruda, a low-endemic area, Finca Rincon, and two high-endemic areas, Finca Brote and Finca Recreo) were analyzed. The enzymes examined were adenylate kinase (AK), alkaline phosphatase (ALP), glucose phosphate isomerase (GPI), hexokinase (HK), isocitrate dehydrogenase (IDH), leucine aminopeptidase (LAP), malic enzyme (ME), and phosphoglucomutase (PGM). Of these, six enzymes, AK, ALP, HK, IDH, LAP, and ME showed no variation either within or among populations. GPI and PGM were found to be highly polymorphic in all of the six populations. χ 2 -test for fit to Hardy-Weinberg equilibrium (HWE) revealed that the distribution of the phenotypes of the two polymorphic enzymes was not significantly out of the HWE. A verages of values of proportion of polymorphic loci ( P ) and heterozygosity per individual ( H ) of the six populations were 0.234 and 0.084, respectively, each of which was similar to the values reported for different groups of organisms (Nei, 1975). Genetic diversity among populations was measured by F ST and G ST and both parameters showed that the non-endemic population from the Finca La Ruda (Dl) was greatly differentiated genetically from the other five populations. Estimates of genetic distance (Nei, 1975) showed that the Dl population was furthest from the other populations.