Oral treatment of rodents with fipronil for feed-through and systemic control of sand flies (Diptera: Psychodidae).

The sand fly Phlebotomus papatasi Scopoli is the vector of Leishmania major (Yakimoff & Schokhor), which is maintained in populations of burrowing rodents. The purpose of this study was to conduct a laboratory study to determine the efficacy of oral treatment of rodents with fipronil for control of sand flies that feed on rodent feces as larvae or on rodent blood as adults. We determined through larval bioassays that fipronil was eliminated in feces of orally-treated hamsters at a level that was significantly toxic to sand fly larvae for 21 d after the hamsters had been withdrawn from a fipronil-treated diet. Through bloodfeeding bioassays, we also found that fipronil was present in the peripheral blood of hamsters at a concentration that was significantly toxic to bloodfeeding adult female sand flies for 49 d after the hamsters had been withdrawn from their treated diet. The results of this study suggest that fipronil acts as well as or better than feed-through or systemic insecticides that previously have been measured against sand flies, and is particularly promising because this single compound acts against both larvae and bloodfeeding adults. An area-wide approach using rodent baits containing a fipronil could suppress vector populations that originate in the vicinity of rodent reservoirs, and could be used to eliminate the most epidemiologically important part of the vector population: female sand flies that take bloodmeals on rodent reservoirs.

Laboratory evaluation of rubidium as a long-lasting marker for bloodfeeding sand flies (Diptera: Psychodidae).

The objective of this study was to evaluate the use of the trace element rubidium (Rb) as a long-lasting systemic biomarker for bloodfeeding females of the sand fly Phlebotomus papatasi Scopoli. Baits containing Rb chloride were found to be palatable to hamsters in this study. We were able to detect Rb using a portable X-ray fluorescence analyzer in all sand flies that fed on Rb-treated hamsters for at least 14 d postbloodmeal. We also detected Rb in sand flies that took a bloodmeal from hamsters up to 10 d after the hamsters were withdrawn from a Rb-treated diet. Results of this study constitute proof of concept for the incorporation of Rb chloride into rodent baits for marking bloodfeeding sand flies, and suggest that Rb marking could be used as a technique for evaluating rodent-targeted sand fly control methods and in ecological studies on sand flies.

Evaluation of three feed-through insecticides using two rodent and two sand fly species as models.

The efficacy of 3 rodent feed-through insecticides (novaluron, pyriproxyfen, and ivermectin) was determined against larvae of the sand flies Phlebotomus duboscqi and P. papatasi using Syrian hamsters (Mesocricetus auratus) and Mongolian gerbils (Meriones unguiculatus) as laboratory models. For each insecticide, there were no significant differences between the longevity or percentage survival of sand fly larvae that had been fed feces of treated rodents for each sand fly or rodent species pairing. The results of this study suggest that larvae of P. duboscqi and P. papatasi are equally susceptible to the concentrations of the rodent feed-through insecticides tested in this study and that these insecticides are pharmacologically compatible with different rodent/sand fly interactions.

Hyperinsulinemia and atherosclerosis.

For more than 25 years, there has been an expansion in the clinical and experimental evidence linking hyperinsulinemia with cardiovascular disease and atherosclerosis. Assessment of the evidence under the headings of the strength of the association, dose response, temporality, consistency, specificity, and plausibility supports the concept that hyperinsulinemia has a causal role in atherogenesis. Evidence that reducing insulin levels prevents atherosclerosis is lacking. The evidence available is strong enough to support preventive measures to lower insulin levels such as regular physical exercise and avoidance of obesity.

The role of insulin in atherosclerosis in diabetics and nondiabetics: a review.

Disease of coronary, cerebral, and peripheral arteries is associated with exaggerated insulin responses to oral glucose. In three populations, high fasting or post-glucose insulin levels have a predictive value in the incidence of ischemic heart disease and in cardiac mortality. Diabetics who are obese or who have received treatment with insulin have elevated insulin levels and, as a group, have an increased incidence of cardiovascular disease. Insulin, in small concentrations, has effects on arterial tissue including stimulation of smooth muscle cell proliferation and of glucose incorporation into lipid. It is suggested that insulin has a role in the development of atherosclerosis.

Insulin and atheroma. 20-yr perspective.

Many clinical studies have shown an increased insulin response to oral glucose in patients with ischemia of the heart, lower limbs, or brain. Hyperinsulinemia also occurs in patients with angiographically proved atherosclerosis without ischemia and thus appears to be related to arterial disease and not to be a nonspecific response to tissue injury. Fasting insulin levels and insulin responses to intravenous stimuli, including glucose, tolbutamide, and arginine, are normal, suggesting a gastrointestinal factor may be involved in the increased insulin response to oral glucose. In patients with atherosclerosis, insulin sensitivity appears to be normal or enhanced with respect to both glucose and lipid metabolism. Five population studies have shown that insulin responses to glucose are higher in populations at greater risk of cardiovascular disease. Many of the hyperinsulinemic populations also had upper-body obesity, hypertriglyceridemia, lower high-density lipoprotein (HDL) levels, and hypertension. These prospective studies support an independent association between hyperinsulinemia and ischemic heart disease, although their results differ in detail. Hyperinsulinemia is associated with raised triglyceride and decreased HDL cholesterol levels. Total and low-density lipoprotein (LDL) cholesterol is less closely related to hyperinsulinemia. Upper-body adiposity is associated (in separate studies) with coronary heart disease, diabetes, hyperinsulinemia, and hypertriglyceridemia. Insulin and blood pressure are closely related in both normotensive and hypertensive people. Although obesity and diabetes are often found in hypertensive people, hyperinsulinemia also occurs in nonobese nondiabetic hypertensive people. Thus, hyperinsulinemia is closely associated with a cluster of cardiovascular risk factors, i.e., hypertriglyceridemia, low HDL levels, hypertension, hyperglycemia, and upper-body obesity. There is a possibility that insulin has a role in the sex differences in ischemic heart disease incidence and their absence in diabetes, but additional work is required for its clarification. Long-term treatment with insulin results in lipid-containing lesions and thickening of the arterial wall in experimental animals. Insulin also inhibits regression of diet-induced experimental atherosclerosis, and insulin deficiency inhibits the development of arterial lesions. Insulin stimulates lipid synthesis in arterial tissue; the effect of insulin is influenced by hemodynamic factors and may be localized to certain parts of the artery. In physiological concentrations, insulin stimulates proliferation and migration of cultured arterial smooth muscle cells but has no effort on endothelial cells cultured from large vessels. Insulin also stimulates cholesterol synthesis and LDL binding in both arterial smooth muscle cells and monocyte macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)

The relationship of abnormal circulating insulin levels to atherosclerosis.

The evidence linking insulin with atherosclerosis can be divided into two parts. First, there is evidence that a proportion of subjects who have atherosclerosis or who are at risk of developing atherosclerosis hav elevated circulating insulin levels. The high insulin levels may be associated with another metabolic abnormality such as obesity, hypertriglyceridaemia, uraemia or consumption of oral contraceptives, may be inappropriate to the blood sugar levels as in mild diabetes, or may be of exogenous origin as in insulin-treated diabetics. The tissues of these subjects are exposed to high concentrations of insulin, and it seems reasonable to suggest that elevated insulin levels may have pathological effects on these tissues. Secondly, there is increasing evidence that the arterial wall is an insulin sensitive tissue. Exposure of arterial tissue to insulin results in proliferation of smooth muscle cells, inhibition of lipolysis, and synthesis of cholesterol, phospholipid and triglyceride. Chronic exposure to high concentrations of insulin results in the development of lipid filled lesions similar to those of early atherosclerosis. Thus, insulin has the ability to promote changes in the artery which, in the long term, may progress to atherosclerosis. The two lines of evidence together suggest that high levels of circulating insulin may have a role in the development of atherosclerosis.

PIP: Lipid and carbohydrate metabolism abnormalities are reviewed with particular emphasis on the role of insulin and interrelationships between carbohydrate and lipid metabolism. The pathogenesis of atherosclerosis is discussed in terms of the association of abnormal circulating insulin levels. Some of the conditions associated with abnormal insulin levels and atherosclerosis are diabetes mellitis, hypertriglyceridemia, obesity, uremia, and oral contraceptive use. There is evidence that a proportion of subjects who have atherosclerosis or at risk have elevated circulating insulin levels. There is also increasing evidence that the arterial wall is an insulin-sensitive tissue. More women with myocardial infarction take oral contraceptives than controls do. Those who take the pill have 9 times the risk of others to develop cerebral ischemia or thrombosis. Many oral contraceptives cause abnormalities in glucose tolerance associated with elevated plasma insulin levels, and a degree of insulin resistance is induced. A number of the metabolic consequences of the pill may be caused by the elevated insulin levels.

The effect of insulin and glucose on sterol synthesis in cultured rat arterial smooth muscle cells.

The smooth muscle cell plays an important role in the process of atherogenesis, proliferating in the arterial intima and becoming filled with lipid during the course of the disease. In these experiments the effect of insulin and glucose on sterol synthesis in cultured rat arterial smooth muscle cells was studied. Arterial smooth muscle cells were cultured from pieces of intima and inner media of young rat aortas. The cells were grown in Petri dishes in culture medium with foetal calf serum and when confluent were exposed to insulin or glucose for 24 hours. Insulin in concentrations of 10 micromicron-100 millimicron per ml stimulated the incorporation of sodium [2-(14)C]acetate into non-saponifiable lipids and digitonin precipitable sterols. However, insulin had no effect on the incorporation of labelled mevalonate into cell sterols. Increasing concentrations of glucose in the medium up to 140 mM had had no effect on the incorporation of isotope into sterols, but higher concentrations of glucose caused cell damage and sterol synthesis was markedly depressed. These results may have relevance to the development of atherosclerosis in diabetes and obesity.

Dibutyryl cyclic AMP inhibits LDL binding in cultured fibroblasts and arterial smooth muscle cells.

The interaction of low density lipoproteins (LDL) with cell membrane receptors is regulated by certain hormones. To test whether LDL receptor activity is influenced by cyclic AMP, the effect of dibutyryl cyclic AMP on LDL binding uptake and degradation was studied in cultured human skin fibroblasts and in rat and human arterial smooth muscle cells. Dibutyryl cyclic AMP in concentrations of 10(-3) to 10(-7)M inhibited LDL binding and degradation in fibroblasts and rat arterial smooth muscle cells, and degradation in human arterial smooth muscle cells. Inhibition of LDL receptor activity by dibutyryl cyclic AMP did not appear to be due to a non-specific toxic effect of the nucleotide. It appeared to be mediated on the affinity of the receptor for LDL rather than receptor number.

Control of DNA synthesis in cultured vascular endothelial and smooth muscle cells--response to serum, platelet-deficient serum, lipid-free serum, insulin and oestrogens.

Endothelial and smooth muscle cell proliferation has an important role in the pathogenesis of atherosclerosis. To study the effect of serum and some of its putative growth factors on DNA synthesis, the incorporation of thymidine into DNA was studied in cultured human umbilical endothelial and rat aortic smooth muscle cells. DNA synthesis in endothelial cells was progressively stimulated by increasing concentrations of human serum, maximum stimulation occurring with 20% serum. Foetal calf serum had a much lesser effect on DNA synthesis in endothelial cells. Smooth muscle cells responded equally to human and foetal calf serum. Exposure to serum prepared to exclude the platelet-derived growth factor resulted in reduced DNA synthesis in smooth muscle cells. However, endothelial cells increased DNA synthesis in platelet-poor serum. Serum from which lipid had been extracted stimulated DNA synthesis less well than whole serum in both endothelial and smooth muscle cells. Insulin stimulated DNA synthesis in smooth muscle cells but not in endothelial cells, while ethinylestradiol, estrone and estriol had no effect on DNA synthesis in either type of cell. Thus cultured endothelial and smooth muscle cells differ in their requirements for human serum and in their response to platelet factor and to insulin.

Sex hormone levels in younger male stroke survivors.

Increased plasma oestrogen levels have been reported in men with myocardial infarction. To establish whether similar findings occur in stroke, plasma oestradiol and testosterone levels were measured in 26 male survivors of stroke and 27 healthy male controls. There was no difference in oestradiol or testosterone levels between the two groups and the oestradiol : testosterone ratio was also identical. The result of this study does not support the suggestion that hyperoestrogenaemia is a risk factor for atherosclerosis in general.

Insulin as a mitogenic factor: role in the pathogenesis of cardiovascular disease.

Evidence has been accumulating that insulin has actions that may promote the development of atherosclerosis. Research has involved three broad areas: actions of insulin on cultured arterial cells, the effect of insulin on isolated artery preparations, and the development of lipid-containing lesions in the arteries of experimental animals. Insulin, in concentrations similar to those found in physiologic conditions, stimulates proliferation of cultured arterial smooth muscle cells from a number of species, including humans. Insulin also stimulates migration of smooth muscle cells. Cholesterol synthesis and low-density lipoprotein interaction with its receptor in smooth muscle cells are stimulated by insulin. Insulin's mitogenic action appears to be mediated by the insulin-like growth factor receptor. Endothelial cells cultured from large vessels are resistant to the actions of insulin, but hyperglycemia inhibits their proliferation. Insulin deficiency protects animals from experimental atherosclerosis; this protection is lost with insulin treatment. Insulin administration results in lipid-containing lesions in chickens and rats fed a normal diet, and in increased lipid synthesis in the arteries of pigs and dogs. Isolated artery preparations from insulin-deficient or insulin-treated animals undergo lipid metabolism at a rate that correlates with the insulin concentrations in the donor animals. The biological actions of insulin (and glucose) on arterial tissue suggest that hyperglycemia and hyperinsulinemia may promote the development of atherosclerosis.

Overview of the association between insulin and atherosclerosis.

The suggestion that insulin is associated with atherosclerosis is based on clinical, epidemiologic, and experimental evidence. In general, atherosclerosis of the coronary, cerebral, and peripheral arteries is associated with abnormally high insulin responses to oral glucose. This hyperinsulinemia is not related to acute injury or to tissue necrosis, does not occur in response to intravenous glucose or tolbutamide, and is independent of other cardiovascular risk factors. Populations who are at high risk for cardiovascular disease have higher insulin responses to oral glucose than those at lower risk. Prospective studies carried out in Australia, Finland, and France have shown that elevated insulin levels, either fasting or in response to oral glucose, have a predictive role in the development of cardiovascular disease. This association is independent of the effects of other cardiovascular risk factors. In experimental animals, insulin deficiency retards the development of diet-induced arterial disease, whereas administration of insulin promotes lesion development and prevents lesion regression. Insulin stimulates lipid synthesis in isolated arteries and stimulates proliferation and lipid accumulation in cultured arterial smooth muscle cells. The evidence linking insulin with atherosclerosis has been gathered from nondiabetic subjects; this evidence is unavailable in diabetics. As it is clear that hyperinsulinemia is often present in diabetes, either in relation to mild glucose intolerance or obesity (in noninsulin-dependent diabetes mellitus) or because of insulin therapy (in insulin-dependent diabetes mellitus), it is essential that further consideration should be given to the possibility that hyperinsulinemia may have harmful effects on the arterial wall.

Changes in seasonal deaths from myocardial infarction.

BACKGROUND: Cardiovascular disease is the major contributor to excess morbidity and mortality in winter. With the rise in temperatures through global warming, and the use of central heating and air conditioning, this seasonal variation may be declining. AIM: To study possible changes in seasonal variation in case-fatality rates of myocardial infarction (MI), in men and women, over a 20-year period and compare this with possible environmental influences. DESIGN: Retrospective analysis of death certificate and climatological data. METHODS: We analysed all monthly death certificate data from Northern Ireland, for death caused by MI from 1979 through 1998 (n=68 683). Mortality data were standardized to a single reference group for the whole period. Seasonal variation in mortality and in environmental variables was described using the cosinor model. RESULTS: A total of 29 875 women and 38 808 men died from MI during the 20-year period. A significant decrease in mortality from MI was observed in both sexes, accompanied by a non-significant decline in the amplitude of the seasonal rhythm over the study period. Low temperature was associated with higher mortality rates from MI. DISCUSSION: We have documented an overall decline in cardiovascular mortality from 1979 to 1998, together with a small but non-significant decrease in seasonal variation. While improvements in medical care, lifestyle, housing and diet may have contributed to the observed decline in mortality rate, seasonal fluctuations remain a significant problem.

The relationship between elevated fibrinogen and markers of infection: a comparison of seasonal cycles.

To test the hypothesis that higher levels of fibrinogen in winter are related to infections via the acute phase response, we assessed seasonal variation in fibrinogen and C-reactive protein, together with three other responses to infection: white cell count, human herpesvirus-6 IgG antibody and interleukin-6. Monthly blood samples from 24 subjects aged 75+ years were assessed for fibrinogen, C-reactive protein, white cell count, and human herpesvirus-6 IgG antibody. Interleukin-6 was measured in seven. Seasonal variation of these measures was determined by the population-mean cosinor procedure. Fibrinogen had a significant seasonal variation with a winter peak (mid-February) 1.26 g/l above the corresponding summer trough. C-reactive protein had a late-February peak, 3.71 mg/l above the summer trough. No seasonal rhythm was found in any other response to infection investigated. This study provides no evidence that winter infections are responsible for the seasonal variation in fibrinogen or C-reactive protein. The explanation for the seasonal changes in these proteins remains unknown.

Alcohol-related mortality in the U.S. Air Force, 1990.

Alcohol-related morbidity and mortality represent a major public health problem in the United States, particularly among young men. Standardized comparisons of alcohol use have demonstrated that members of the military consume more alcohol than matched civilians. To quantify the impact of alcohol use by active duty members of the Air Force for calendar year 1990, we reviewed 283 death certificates and analyzed the cause of death using the Alcohol-Related Disease Impact (ARDI) computer program. Injuries accounted for 73% of all deaths among active duty Air Force personnel, with motor vehicle accidents (MVAs) accounting for 31% of total mortality. Sixty-six deaths (23%) were attributable to alcohol-related causes and accounted for 2,300 years of potential life lost before 65 years of age. Analysis of blood alcohol levels taken from a subset of active duty deaths resulting from MVAs and suicides yielded alcohol-attributable fractions similar to those obtained by the ARDI method. Periodic assessment and dissemination of alcohol-related mortality statistics in the military using the ARDI methodology represent an important public health education tool.

Measurement of fibrinogen in frozen plasma.

Several large studies have compared fibrinogen measurements determined over a particular time interval. These assays are subject to difficulties encountered by all laboratories on tests carried out over a period of time such as assay drift. To avoid this problem, plasma can be stored frozen and fibrinogen determined in a large number of samples simultaneously. However, a thorough comparison of measurements carried out in fresh and frozen plasma has not yet been performed. Fibrinogen concentration was therefore determined in fresh plasma samples and then at a later date in the same samples after storage at -70 degrees C. A good correlation was observed between the two measurements, however, bias increased at the higher fibrinogen levels which are most critical in the determination of thrombotic risk. An increase in measurement error as a result of freezing was also observed. These effects may, therefore, be important considerations in future studies of this nature.

The effects of acute moderate exercise on leukocyte and lymphocyte subpopulations.

The extent and duration of changes in circulating leukocyte and lymphocyte subpopulations, cortisol, and catecholamines were examined in 12 women who walked 45 min at 60% VO2max in a laboratory setting. A two-factor, 2 x 6 design with repeated measures on both factors was utilized. The first factor was condition (exercise and rest), and the second factor was time (six points of measurement over a 24-h period), with treatment order counterbalanced. The 45-min walk, in comparison with rest in a seated position, was associated with a significant but moderate leukocytosis and lymphocytosis immediately following the walk. The leukocytosis was still evident after 3 h of recovery and was primarily due to a neutrophilia. The change in lymphocyte count, relative to baseline levels and the control condition, lasted less than 1.5 h, with an increase in the natural killer (CD16 and/or CD56) and cytotoxic T cell component (CD3 and CD16 and/or CD56) (NKCT) representing approximately two-thirds of the lymphocytosis and T cells (CD5) the other third. A significant decrease in the CD4:CD8 ratio was seen, with cytotoxic/suppressor (CD8) cells increasing and helper/inducer (CD4) cells demonstrating little change in comparison with baseline. This seems to have been due to a subpopulation of CD8 (low density antigen) cells, probably natural killer cells. The 45-min walk had no effect on plasma cortisol and epinephrine levels relative to the rest condition but was associated with a moderate increase in norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes and atherosclerosis.

Atherosclerosis is the most important complication of diabetes and diabetes is an important risk factor for cardiovascular disease. Atherosclerosis develops more rapidly and at an earlier age in diabetic patients than in non-diabetic people. Although a number of cardiovascular risk factors are more common in diabetic than non diabetic people, these do not entirely account for the increased frequency of cardiovascular disease. The identity of the additional factor or factors which result in increased atheroslerosis in diabetes is unknown but attention should be paid to the role of glycated lipoproteins and of hyperinsulinaemia. In treating diabetic patients, attention should be paid to cardiovascular risk factors such as dyslipidaemia and hypertension as well as to the control of blood glucose.