Spatial and temporal variation in biting rates and parasite transmission potentials of onchocerciasis vectors in Ecuador.

The influence of spatial and temporal factors on onchocerciasis transmission by Simulium exiguum s.l. and S. quadrivittatum in Ecuador was investigated to help develop sampling protocols for entomological surveillance of ivermectin programmes. Flies were collected in alternate months (November 1995-November 1996) at four sites each in the hyperendemic communities of San Miguel and El Tigre. A fixed-effects analysis of variance was used to explore the influence on vector abundance of locality, site, month and hour. Infectivity rates detected by dissection and PCR assays were compared. Simulium exiguum s.l. predominated at El Tigre (75%) whereas S. quadrivittatum prevailed at San Miguel (62%). Vector abundance was highest on river banks and outside houses. Biting and infection rates peaked from March to July. Hourly activity patterns were bimodal in S. exiguum but unimodal in S. quadrivittatum. Annual transmission potentials (ATP) for both species combined were 385 and 733 third stage larvae/person in San Miguel and El Tigre respectively, with S. exiguum accounting for 80% of the combined ATP at both localities. We recommend protocols that may maximize detection of parasite transmission. Infection rates thus obtained must be linked with vector density estimates to assess meaningfully host exposure as treatment progresses.

Determination of sample sizes for the estimation of Onchocerca volvulus (Filarioidea: Onchocercidae) infection rates in biting populations of Simulium ochraceum s.l. (Diptera: Simuliidae) and its application to ivermectin control programs.

Monthly samples of biting Simulium ochraceum s.l. Walker were collected before and after ivermectin treatment in southern Mexico and analyzed for Onchocerca volvulus Leuckart infection rates, infection intensity, and the characteristics of larval distribution among parous flies. The variance over mean ratio (VMR) indicated that in all cases this distribution departed from Poisson and was strongly aggregated (VMR > 1). The negative binomial was found to be an adequate model with a small value of the aggregation parameter k, but the degree of larval overdispersion increased as the mean larval load decreased, invalidating the use of a common kc value. A linear relationship between k and the mean (mu) was established, k(mu) = k1 mu, which permitted exploration of the relationship between the observed proportion of infected flies, p, and the estimated mean larval burden per fly, m (all larval stages in parous flies). This would allow mean numbers of larvae per parous fly to be predicted from presence-absence data (e.g., from infection rates provided by polymerase chain reaction methods applied to pools of flies), assuming that k1 is a known parameter. Given that both p and m are naturally low in S. ochraceum, their relationship was practically linear within the range of observed values. Predictions were tested with the Mexican data from which the clumping parameter was estimated as well as for Guatemalan data for which this information was not available. Results showed a highly satisfactory degree of agreement between predictions and observations. The sample sizes required to estimate mean larval loads from prevalence data for fixed levels of precision (defined as the ratio between SE[m] and m) were calculated for realistic S. ochraceum infection rates (those found in published pre- and postcontrol field surveys as well as in this work). For the special case in which the relationship between k and the mean is linear and goes through the origin, k(mu) = k1 mu, the number of flies to be examined for O. volvulus infections does not explicitly depend on the aggregation parameter, but rather on the unknown proportion of infected flies. Practical recommendations for the calculation of sample sizes are discussed. For infection levels < 0.2%, a minimum number between 6,000 and 13,000 parous flies would have to be examined to estimate the mean larval load with a precision between 0.20 and 0.30. The linearity between onchocercal infection rate and infection intensity in the fly population indicates that relationships between the former and onchocerciasis patterns in the human population should be further explored for the purposes of monitoring the impact of ivermectin control programs through entomological evaluations.

Interleukin-1 receptor antagonist inhibits proteoglycan breakdown in antigen induced but not polycation induced arthritis in the rabbit.

OBJECTIVE: To compare the alterations in proteoglycan metabolism in antigen induced arthritis and polycation induced arthritis and to determine the involvement of interleukin-1 (IL-1) in the cartilage degradation that occurs in these models of rheumatoid arthritis (RA). METHODS: The time course for loss of proteoglycan into the synovial fluid (SF) and inhibition of proteoglycan synthesis, as well as depletion of articular cartilage proteoglycan content, was compared in rabbit antigen arthritis and polycation arthritis. The ability of recombinant IL-1 receptor antagonist IL-1ra to block the acute cartilage loss at 24 h in these models was investigated, compared to its ability to block the cartilage breakdown induced by direct administration of IL-1 in rabbits. RESULTS: Initial loss of cartilage proteoglycan was accompanied by release of high levels of glycosaminoglycan (GAG) into the SF and decrease in proteoglycan synthetic rates in both antigen and polycation induced arthritis SF GAG rapidly returned to control levels, while proteoglycan synthesis and cartilage proteoglycan content remained depressed, suggesting that the inhibition in proteoglycan synthesis prevented recovery to normal levels. GAG loss from the cartilage into the SF in response to IL-1 injection, as well as other effects of IL-1 challenge, was blocked in a dose dependent manner by IL-1ra administered either intraarticularly (ED50 = 160 ng) or intravenously (iv) (ED50 = 0.09mg/kg). In the antigen induced arthritis model, IL-1ra (20 mg/kg, iv -2h) inhibited GAG release by 40%, whereas in polycation induced arthritis no inhibition was observed even with repeated administration of high doses of inhibitor. CONCLUSION: These studies suggest that sustained depression of proteoglycan synthesis may be responsible for the chronic depletion of articular cartilage proteoglycan in the antigen and the polycation model of RA. However, while IL-1 may play a role in the initial breakdown of articular cartilage in antigen induced arthritis, it does not appear to be involved in polycation induced arthritis in the rabbit.

Vector competence of Simulium exiguum for Onchocerca volvulus: implications for the epidemiology of onchocerciasis.

In the transmission of human onchocerciasis, competence of the black fly vector influences intensity of transmission by regulating how many infective-stage larvae are produced. The disease is intensifying in Ecuador where Simulium exiguum is a highly efficient limitation-type vector comparable with African forest species in terms of the percentage of flies developing infective-stage larvae and the numbers of larvae per infected fly. In contrast, the endemic foci in Guatemala and southern Mexico have remained stable and closely circumscribed around larval development sites for S. ochraceum, a vector that exhibits a facilitation type of competence and must feed on people with comparatively high microfiladeremia to develop significant numbers of infective-stage larvae. This comparison indicates that assessments of vector competence should be included when planning regional control programs for onchocerciasis.

New challenges and opportunities in child welfare outcomes and information technologies.

In spite of longstanding concern on the part of child welfare policymakers, researchers, and practitioners, we still lack basic information about the outcomes of child welfare services. This article describes the limitations of current efforts to generate data on child welfare outcomes, presents certain principles for the development of child welfare management information systems for the 21st century, and suggests steps to be taken to get from here to there. Particular attention is given to recent federal initiatives that provide an immediate opportunity to make a fundamental leap in our ability to understand the outcomes of child welfare services.

Strengthening mental health services in Head Start. A challenge for the 1990s.

Steps must be taken to strengthen mental health services by building on Head Start's philosophy and by translating innovations in mental health services for older children and adolescents into improved services for young children and their families. Recommendations for strengthening Head Start's mental health program include creating a unified vision that reaffirms a holistic, family-focused, and comprehensive services approach; ensuring that mental health services are responsive to the diversity in families served; increasing coordination of mental health services and linkages with new initiatives; increasing resources and providing assistance in gaining access to new sources of funding; supporting innovation; and integrating the new paradigm for children's mental health services into more traditional approaches to intervention within Head Start.

Adverse reactions after community treatment of onchocerciasis with ivermectin in Guatemala.

Male and female residents on a Guatemalan coffee plantation where Onchocerca volvulus infections were hyperendemic were offered oral ivermectin (100-200 micrograms/kg) as part of a community-wide treatment programme for onchocerciasis. Forty-five persons were treated and then questioned daily for 28 d about changes in their health. Those with complaints were monitored until all signs and symptoms had resolved. Sixty-seven percent complained of some adverse event after treatment; 60% developed observable adverse reactions attributed clinically to ivermectin. No reaction was life-threatening; the most common were oedema (53%) and fever (47%). Expulsion of intestinal helminths was reported by 38%. Almost all reactions began 24-48 h after treatment; their mean duration was 5 d, despite treatment with acetaminophen and antihistamines. Three patients had oedematous changes lasting over 2 weeks. Incidence, but not severity, of reactions was related to the pretreatment density of microfilariae in skin.

Glomerular hemodynamic alterations during acute hyperinsulinemia in normal and diabetic rats.

Treatment of insulin dependent diabetes invariably requires exogenous insulin to control blood glucose. Insulin treatment, independent of other factors associated with insulin dependent diabetes, may induce changes that affect glomerular function. Due to exogenous delivery of insulin in insulin dependent diabetes entering systemic circulation prior to the portal vein, plasma levels of insulin are often in excess of that observed in non-diabetics. The specific effects of hyperinsulinemia on glomerular hemodynamics have not been previously examined. Micropuncture studies were performed in control (non-diabetic), untreated diabetic and insulin-treated diabetic rats 7 to 10 days after administration of 65 mg/kg body weight streptozotocin. After the first period micropuncture measurements were obtained, 5 U of regular insulin (Humulin-R) was infused i.v., and glucose clamped at euglycemic values (80 to 120 mg/dl). Blood glucose concentration in non-diabetic controls was 99 +/- 6 mg/dl. In control rats, insulin infusion and glucose clamp increased nephron filtration rate due to decreases in both afferent and efferent arteriolar resistance (afferent greater than efferent) resulting in increased plasma flow and increased glomerular hydrostatic pressure gradient. However, insulin infusion and glucose clamp produced the opposite effect in both untreated and insulin-treated diabetic rats with afferent arteriolar vasoconstriction resulting in decreases in plasma flow, glomerular hydrostatic pressure gradient and nephron filtration rate. Thromboxane A2 (TX) synthetase inhibition partially decreased the vasoconstrictive response due to acute insulin infusion in diabetic rats preventing the decrease in nephron filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Microepidemiology of onchocerciasis in Guatemala: dispersal and survival of Simulium ochraceum.

Wild Simulium ochraceum females, both blood engorged and non-blood engorged, were collected from human volunteers infected with Onchocerca volvulus, marked with fluorescent dyes, and released from the same locality as they were collected during February and March 1989. A small hyperendemic village located within 0.5 km of streams supporting large populations of S. ochraceum larvae served as the site for both collection and release of adult females. Fifteen sites for the recapture of flies were located within this same village, within two other villages located 1.0 and 3.7 km from it, and at other places spaced approximately 0.25-3.5 km within a coffee agroecosystem. Flies from both groups were recaptured at distances ranging to 3.5 km from the point of release. Non-blood-engorged flies, however, exhibited a greater tendency to disperse away from the release site. Of the total number of blood-engorged flies recaptured, 51.9% were collected at the release point, 25.7% at 1.0 km, and 1.6% at 3.3-3.5 km. The corresponding percentages for non-blood-engorged flies were 26.9%, 40.4%, and 4.4%, respectively. No flies from either group were recaptured at the most distant site, a large village that was 3.7 km away. Marked flies from both groups were recaptured 12-14 days after release, which was sufficient time for the development of infective O. volvulus larvae. A survival rate (4.7%) of marked, blood-engorged flies over the second and third gonotrophic cycles was estimated from the slope of the regression line of the log number of flies recaptured.(ABSTRACT TRUNCATED AT 250 WORDS)

Ivermectin: reduction in prevalence and infection intensity of Onchocerca volvulus following biannual treatments in five Guatemalan communities.

Residents of five hyperendemic communities located in the central focus of onchocerciasis in Guatemala were treated with ivermectin (Mectizan) or placebo every six months for 30 months. The effects of treatment on prevalence and the intensity of skin infection (microfilarial skin density [MFD]) were evaluated. Significant and persistent reductions in both of these indices were achieved by coverage of 80.7% of the eligible populations. The highest proportionate reductions in both indicators of infection occurred after the first treatment, followed by more gradual decreases through the fourth treatment. In one community in which the mean coverage was 92.7%, prevalence decreased from 74.0% at pretreatment to 34.9% after four treatments, while the MFD decreased from 7.8 to 2.0; reductions of 52.8% and 74.3% from pretreatment values, respectively. In every ivermectin-treated community except one, in which drug acceptance was low, the mean community MFD values were reduced to the level associated with low infectiousness for the vector, Simulium ochraceum. Moreover, the category of MFD associated with high vector infectiousness was reduced at least ten-fold over the pretreatment level. One community had low participation during the first two treatments (32.8% and 22.7% of those eligible). This increased to 55.2% at the third treatment because of implementation of an educational program describing both the disease and the beneficial effects of ivermectin and because skin biopsies and nodulectomies were not performed. Secondary reaction rates for all communities were 29.5%, 9.9%, 10.3%, 8.2%, and 7.1% for the first through fifth treatments, respectively. Pruritus was the most common (34.0%) secondary reaction, followed by facial edema (31.8%). All reactions were classified as mild to moderate. Recommendations for mass distribution of ivermectin in Guatemala are given.

The effects of repetitive community-wide ivermectin treatment on transmission of Onchocerca volvulus in Guatemala.

The effects of biannual ivermectin treatment at the community level on transmission of Onchocerca volvulus during the dry season were measured over a 30-month period in Guatemala. In the Los Tarrales Transmission Zone, an area encompassing three villages, significant changes occurred in both the prevalence and quantity of infection in the Simulium ochraceum vector population. These included a 76% reduction in females with infective stage larvae (L3S) and an 80% reduction in number of L3S per 1,000 parous flies. Significant reductions in both the mean infective biting density (IBD) and mean transmission potential (TP) also occurred. In Santa Emilia, the prevalence of infection with L3S in S. ochraceum was significantly reduced by 77% from the baseline value. The number of O. volvulus L3S per 1,000 parous flies was also reduced by 92%. Changes in both the IBD and TP were substantial but not significant due to the high degree of variance in the occurrence of O. volvulus L3S in the vector population. This was due, in part, to the movement of infected migrant workers into the finca (coffee farm). In Los Andes, four recurrent treatments successfully blocked transmission of infective stage larvae. Prevalence (flies with all stages of developing larvae) in the vector population was reduced by 89% over the two-year period; yearly reductions in both the IBD and TP were also highly significant, ultimately ending in zero values. This finding is particularly striking since prior to treatment, Los Andes exhibited the highest IBD of the three study locations and the second highest TP.

Disassociation between glomerular hyperfiltration and extracellular volume in diabetic rats.

The relationship of the development of glomerular hyperfiltration in diabetes to changes in extracellular fluid volume has not been previously examined. To accomplish this task, male Wistar rats were chronically cannulated in the bladder, femoral artery and vein. Control measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), extracellular fluid volume (ECF), and urinary sodium excretion were performed on two separate days prior to infusion of streptozotocin (65 mg/kg body wt i.v.). After infusion of streptozotocin, the IDDM rats were separated into two groups: untreated IDDM group of rats and IDDM rats treated with insulin at doses sufficient to normalize blood glucose (Ultralente, 2 to 8 IU/day). A third group of normal non-diabetic rats served as time controls. Measurements of renal function occurred at 1, 4, 7, 11, and 15 days after infusion of streptozotocin. Blood glucose in the non-diabetic measurement period averaged 137 +/- 30 mg/dl and increased from 412 +/- 55 after 24 hours in the untreated diabetic rats to 533 +/- 33 mg/dl after 15 days of IDDM. The time controls and the insulin-treated diabetic rats did not differ in blood glucose values at the time measurements were performed. Glomerular filtration rate increased from 1.0 +/- 0.1 to 1.7 +/- 0.1 ml/min/100 g body wt by day 15 in the untreated diabetic rats with significant increases in GFR within 24 hours. GFR of both time controls and the insulin-treated IDDM rats did not significantly vary during the time of the study. The increase in GFR in the untreated IDDM group was associated with a concomitant increase in RPF.(ABSTRACT TRUNCATED AT 250 WORDS)

Basic aspects of functional brain metabolism.

Brain energy metabolism and blood flow are greatest in neuropil where there is a high density of oxidative enzymes and capillaries. Here fluctuations in synaptic potentials cause the greatest demand on metabolism through the continuous need to pump ions to maintain membrane charge. A transient increase in functional activity within a pathway causes an increase in energy metabolism followed by an increase in blood flow. The vascular response is biphasic, with an initial increase followed by a plateau phase. The site and magnitude of the response reflect the quality and intensity of the stimulus. Prolonged changes in functional activity within a pathway cause a reorganization of energy metabolizing enzymes and vascular architecture.

Metabolic anatomy of brain: a comparison of regional capillary density, glucose metabolism, and enzyme activities.

Regional variations in capillary density, glucose utilization rate, and activities of the glycolytic enzyme lactate dehydrogenase and the mitochondrial enzyme cytochrome oxidase were compared in the rat brain. The distributions of capillaries and enzymes were studied by means of histochemical staining techniques, and glucose metabolism was measured by means of [14C]2-deoxyglucose autoradiography. Analysis of 18 gray and five white matter regions revealed a positive correlation between capillary density and glucose utilization rate. A negative correlation was found between capillary density and lactate dehydrogenase among gray matter structures. Analysis of capillaries and enzymes was also performed within laminated histological fields: hippocampus, olfactory bulb, and olfactory cortex. In general, this revealed reciprocal patterns of staining for lactate dehydrogenase and cytochrome oxidase. Capillary density paralleled cytochrome oxidase activity. The zones of intense staining for lactate dehydrogenase and cytochrome oxidase corresponded to the synaptic terminal fields of different input pathways. These findings demonstrate distinct distributions of a glycolytic and an oxidative enzyme within the brain which are at least partly associated with pathway specificity.

Selective vulnerability of the brain: new insights into the pathophysiology of stroke.

Stroke is a major cause of morbidity and mortality in the United States with 250,000 cases per year. Cerebral ischemia is the largest category of stroke with cardiac arrest, profound hypotension, and vascular occlusion the principal causes. Traditional approaches to the treatment of ischemic stroke focus on maintaining cardiac output, blood pressure, cerebral blood flow, and on preventing thrombosis. Recently, attention has been focused on developing new therapies that are directed toward abnormal biochemical events at excitatory synapses. Ischemia causes impairment of brain energy metabolism and the release of excessive amounts of glutamate into the extracellular space. This process secondarily excites neurons and further depletes energy stores. The excitotoxic hypothesis of brain injury proposes that glutamate is a principal cause of damage in ischemia. Three components of this hypothesis have been tested and largely proved in experimental studies in tissue culture and in animal models of stroke. First, elevated concentrations of glutamate cause excessive excitation at a subset of glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor. Second, excitation at this receptor leads to excessive influx of sodium chloride and water which causes acute neuronal damage, and calcium which causes delayed and more permanent damage. Third, pharmacologic blockade at the NMDA receptor-ion channel complex prevents ischemic neuronal damage. Studies using specific pharmacologic compounds that block glutamate's action hold particular promise for treating stroke in humans, including competitive antagonists at the NMDA glutamate binding site (for example, 2-amino-5-phosphonovalerate, AP5), noncompetitive antagonists at the calcium channel (for example, MK-801, dextromethorphan, ketamine), and agents that might be directed at the glycine, zinc, and magnesium sites.

The effect of multiple ivermectin treatments on infection of Simulium ochraceum with Onchocerca volvulus.

Ivermectin, a broad spectrum antiparasitic agent, interrupted the uptake of Onchocerca volvulus microfilariae by Simulium ochraceum from a group of human volunteers given multiple oral treatments of 200 micrograms/kg body weight. Two treatments, given at 7 month intervals, resulted in almost complete suppression of developing or infective larvae in the vector population for a 6 month period. The overall decline following 2 treatments was an order of magnitude lower than the pretreatment level. Ivermectin administration, in addition to the beneficial clinical effects, also could be useful for the control of human onchocerciasis as an independent measure or in conjunction with vector control.

Histochemical changes in enzymes of energy metabolism in the dentate gyrus accompany deafferentation and synaptic reorganization.

The dentate gyrus of adult rats was examined histochemically for cytochrome oxidase and lactate dehydrogenase activity after unilateral lesions of the entorhinal cortex. In normal animals, synaptic terminal fields of the perforant pathway from the entorhinal cortex show high levels of cytochrome oxidase activity (the other two-thirds dentate molecular layer), whereas terminal zones of the commissural and associational fibers show high levels of lactate dehydrogenase activity (the inner one-third dentate molecular layer). Lesions of the entorhinal cortex result in a significant reduction in staining for cytochrome oxidase in the deafferented outer molecular layer of the dentate gyrus. The changes become prominent at 16-24 h after the lesion and persist until 90 days, the longest post-lesion survival time studied. In the non-deafferented inner zones ipsilateral to the lesion, there is an increase in staining for cytochrome oxidase and lactate dehydrogenase at 24 h post-lesion that disappears by days 2-4. From 8 to 90 days post-lesion, the band of high reactivity for lactate dehydrogenase in the inner molecular layer spreads approximately 40 microns into the overlying deafferented zone. This expansion parallels the expansion of the commissural and associational terminal fields into the adjacent deafferented molecular layer. Thus, lesion-induced synaptogenesis in the dentate gyrus is accompanied by a corresponding change in enzyme activity. The results indicate that the pattern of activity of enzymes involved in energy metabolism in the dentate gyrus depends on the distribution of pathway-specific synaptic input.

Transmission of Onchocerca volvulus by secondary vectors in Guatemala.

A comprehensive study of the transmission of Onchocerca volvulus at 4 locations in Guatemala with different prevalence rates of onchocerciasis included observations on potential secondary vectors, the most prevalent of which were Simulium metallicum, S. callidum, and S. gonzalezi. Filariae encountered in S. metallicum were primarily of a Dipetalonema-like species, but third-stage larvae indistinguishable from O. volvulus were found in 4 flies of this species. Our findings suggest that O. volvulus may occasionally be transmitted by S. metallicum, but such transmission is likely limited to areas having both a high parasite prevalence maintained by S. ochraceum and a relatively high host-seeking density of S. metallicum. Two third-stage larvae that could not be differentiated from O. volvulus were found once in S. gonzalezi; however, transmission by this species appears to be inconsequential.