Sympathetic nerve hyperactivity in non-diabetic offspring of patients with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus with hyperinsulinaemia is a state of sympathetic nerve hyperactivity, which can develop subsequently in non-diabetic first-degree offspring of patients with type 2 diabetes. Although both type 2 diabetes and sympathetic activation are major cardiovascular risk factors, the level of sympathetic nerve activity is as yet unknown in offspring of type 2 diabetic patients who are ostensibly normal. We therefore sought to quantify sympathetic nerve activity and its relationship to plasma insulin levels in ostensibly normal offspring of patients with type 2 diabetes, relative to a matched normal control group with no family history of type 2 diabetes. SUBJECTS AND METHODS: In two closely matched groups comprising 23 non-diabetic offspring of type 2 diabetic patients and 23 normal control individuals we measured resting muscle sympathetic nerve activity (MSNA) as the mean frequency of multi-unit bursts of MSNA and single units of MSNA (s-MSNA) with defined vasoconstrictor properties. RESULTS: In offspring of type 2 diabetic patients, the fasting plasma levels of insulin (7.4+/-0.80 microU/ml) and s-MSNA (45+/-3.2 impulses/100 beats) were greater (p<0.009 and p<0.003) than those in control persons (4.6+/-0.76 microU/ml and 32+/-3.1 impulses/100 beats, respectively). MSNA bursts and derived insulin resistance followed similar trends. Sympathetic nerve activity was significantly correlated to insulin levels (p<0.0002) and resistance (p<0.0001) in offspring of type 2 diabetic patients, but not in control subjects. CONCLUSIONS/INTERPRETATION: Sympathetic activation occurred in normal non-diabetic offspring of patients with type 2 diabetes in proportion to their plasma insulin levels. Our data indicate the presence of a mechanistic link between hyperinsulinaemia and sympathetic activation, both of which could play a role in the subsequent development of cardiovascular risk factors.

Disparity of autonomic control in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Acute insulinaemia activates the sympathetic drive in a nonuniform manner. The extent and nature of such activation in type 2 diabetic patients who do not have neuropathy have not yet been addressed despite evidence relating sympathetic activation to cardiovascular risk. We planned to determine the magnitude and extent of the sympathetic drive and its reflex responses in patients with type 2 diabetes and fasting hyperinsulinaemia. METHODS: We measured resting muscle sympathetic nerve activity (MSNA) as the mean frequency of multi-unit bursts and single unit muscle sympathetic nerve activity (s-MSNA) in 17 overweight patients with type 2 diabetes and two matched normal control groups comprising 17 overweight and 16 normal-weight subjects. We also tested the MSNA and s-MSNA responses to cold pressor and isometric hand-grip tests, along with the effect of sympatho-vagal balance on heart period variability. RESULTS: Both MSNA and s-MSNA in the group with type 2 diabetes (66+/-3.5 bursts/100 beats and 78+/-4.5 impulses/100 beats) were greater (at least p<0.0001) than in the overweight control group (42+/-2.6 bursts/100 beats and 48+/-3.4 impulses/100 beats) and normal-weight control group (43+/-6.2 bursts/100 beats and 51+/-7.1 impulses/100 beats), though the three groups had similar reflex responses, baroreflex sensitivity and sympatho-vagal balance controlling the heart period. CONCLUSIONS/INTERPRETATION: The patients with type 2 diabetes had no evidence of impaired reflex or autonomic control of heart period variability at a time when there was central sympathetic activation to the periphery. Furthermore, being overweight itself was not associated with sympathetic activation.

Polycyclic aromatic hydrocarbon metabolites in the bile of a territorial benthic fish, oyster toadfish (Opsanus tau) from the Elizabeth River, Virginia.

Reverse-phase high-performance liquid chromatographic analyses of bile of a territorial benthic fish, oyster toadfish (Opsanus tau), indicated that fish from reference stations in the York and Elizabeth Rivers, Virginia, contained lower concentrations of polycyclic aromatic hydrocarbon (PAH) metabolites than fish from polluted stations. PAH metabolite levels in the bile of fish from mildly polluted stations were 7 to 10 times greater than those from reference stations. PAH metabolite levels in fish from a moderately polluted station and a highly polluted station were, respectively, 20 and 50 times greater than those from reference stations. Differential patterns of five major PAH metabolites in fish from the same station suggested individual variability in metabolic pathways possibly further convoluted by the differential inductions or suppressions of hepatic mixed-function oxygenase isozyme systems under various natural or anthropogenic habitat parameters. PAH metabolite levels in the bile of oyster toadfish correlated well with the gradient of PAH contamination in the Elizabeth River sediments. High levels of biliary PAH metabolites were not detected in muskrats (Ondatra zibethicus) collected along the polluted sections of the Elizabeth River, probably due to their primarily herbivorous nature. Assuming that the hepatobiliary system and the gastrointestinal tract are the major routes of biotransformation and excretion of PAHs in the muskrats, the contaminated diet appears to be a more important routes of exposure of muskrats (and possibly oyster toadfish) to PAHs than the transdermal transfer. Occurrence permitting, we propose oyster toadfish as a useful biological sentinel for early detection of estuarine PAH pollution.

Evidence of aberration of the natural cytotoxic cell activity in Fundulus heteroclitus (Pisces: Cyprinodontidae) from the Elizabeth River, Virginia.

There is a general agreement that exposure to high concentrations of polynuclear aromatic hydrocarbons (PAH) in sediments is associated with high frequencies of neoplasms in feral fish species. Since PAH modulate the activity of murine and amphibian natural cytotoxic (killer) cells, a leukocyte subpopulation that is believed to play an important role in immunosurveillance, we wished to determine if fish exposed to PAH could have an altered natural cytotoxic cell (NCC) activity. In the present study, mummichog (Fundulus heteroclitus L.) were collected from two sites in the Elizabeth River, VA that are heavily contaminated with PAH, and from a relatively unpolluted reference site in the York River, VA. The cytotoxic activity of anterior kidney and splenic leukocytes was tested against the tumor cell line K562. The leukocytes from Elizabeth River fish displayed a significant depression of the in vitro tumorilytic activity as compared with leukocytes from the York River fish. Analysis of leukocyte-tumor cell conjugates indicated that Elizabeth River fish leukocytes were unable to recognize and subsequently bind to the tumor target cells. This suggests an aberration in the early events of the cytotoxic mechanism. By keeping the fish in cleaner York River water for up to 28 weeks the suppressed NCC activity was reversed totally in one site, which is slightly contaminated, and partially in the other site, which is heavily polluted with creosote from an operating wood treatment plant. This indicates that the decreased NCC activity was related, at least in part, to exposure to the chemical pollutants in the Elizabeth River sediments.

Mitogen induced proliferative responses of lymphocytes from spot (Leiostomus xanthurus) exposed to polycyclic aromatic hydrocarbon contaminated environments.

The marine fish spot, Leiostomus xanthurus, was collected from five sites in the lower Chesapeake Bay system representing a gradient of sediment polycyclic aromatic hydrocarbon (PAH) concentrations. The proliferative responses to mitogens by anterior kidney lymphocytes were assessed using [3H]-thymidine uptake by replicating DNA. The data shows two different mitogen-dependent lymphocytic responses as the sediment PAH levels increase at the sampling sites; a suppression of the response to the T cell mitogens, concanavalin A (Con A) and phytohemagglutinin, and a sharp augmentation of the response to B cell mitogen, lipopolysaccharide (LPS), as well as to poke weed mitogen and peanut agglutinin. The magnitude of the lymphoproliferative responses correlated strongly with the total sediment PAH concentrations (r2 greater than 0.8). A similar correlation was also observed with 15 selected individual PAH compounds regardless of their molecular weights. By maintaining the fish in clean York River water for up to 24 weeks, it was possible to reverse the augmented proliferative responses to LPS of fish from all sampling sites and to increase the reduced responses to Con A, in fish from three sites, and partially in two sites where sediments were highly contaminated with PAH. These results suggest that the proliferative responses of fish lymphocytes to mitogens may be a potentially sensitive biomarker of exposure to, and effects of xenobiotics.

Hepatic neoplasms in the mummichog Fundulus heteroclitus from a creosote-contaminated site.

High prevalences of idiopathic hepatic lesions were found in mummichog, Fundulus heteroclitus, from a site in the southern branch of the Elizabeth River, VA, contaminated with polycyclic aromatic hydrocarbons. Grossly visible hepatic lesions occurred in a total of 93% of the individuals from this site and 33% of these fish had hepatocellular carcinomas. Hepatic lesions were not detected in fish from two less contaminated sites. Lesions included foci of cellular alteration, hepatocellular adenoma, early and advanced hepatocellular carcinomas, and cholangiocellular proliferative lesions. Advanced carcinomas exhibited several distinct cellular patterns and some livers contained multiple neoplasms occupying up to 80% of the hepatic parenchyma. Sediments from the contaminated site contained extremely high concentrations (2200 mg/kg dry sediment) of polycyclic aromatic hydrocarbons, which are believed to originate from an adjacent wood treatment facility that has used creosote. Concentrations were 730- and 35-fold higher than those at the two other sites. These findings indicate a strong positive association between exposure to creosote-contaminated sediments and the high prevalence of hepatic neoplasms in a feral population of mummichog and support the putative role of polycyclic aromatic hydrocarbons in fish hepatocarcinogenesis. Additionally, they suggest that the mummichog may be a useful indicator of exposure to carcinogens in aquatic environments.

The importance of natural variabilities in the total analytical scheme.

Concentrations of synthetic organics and trace metals in tissues or sediment may vary by hundreds of percents even when replicate samples are collected from the same biological population, i.e. school of fish, or the same location on the bottom of the stream. Without a knowledge of these variations, decisions based on analytical data interpretations are difficult and often in error. Some reasons for these variations will be discussed, with examples presented from field data which include: trace metals and pesticides in bottom sediments, pesticides in suspended sediments and plankton, pesticides in fish populations and trace metals in mollusks.

Pesticdies: transatlantic movements in the northeast trades.

Concentrations of chlorinated hydrocarbons in airborne dust carried by the trade winds from the European-African land areas to Barbados range from less than 1 to 164 parts per billion. The lower limit of the average content of 1 cubic meter of air is 7.8 x 10-(14) gram. The contributions of river-borne and atmospherically transported pesticides to parts of the marine environment are calculated approximately and comtpared. The amnounts of pesticides contributed to the tropical Atlantic by the trade winds appear to be comparable to those carried to the sea by major river systems.