Recombinant human alpha lymphotoxin (tumor necrosis factor-beta) induces peripheral neutrophilia and lymphopenia in the rat.

Recombinant human alpha lymphotoxin (rLT) administered intravenously to Lewis rats induces peripheral neutrophilia and lymphopenia in a dose-response dependent fashion. A dose of 30,000 units of rLT induced a neutrophilia (1589 +/- 326 to 5554 +/- 1050 neutrophils/cu mm) and lymphopenia (10,368 +/- 992 to 4636 +/- 878 lymphocytes/cu mm) at 2 hours after injection that was highly significant (P less than 0.001 and P less than 0.001, respectively) in comparison with vehicle controls. The kinetics of the neutrophilia that peaked at 2 hours as well as of the lymphopenia were highly reminiscent of the neutrophilia and lymphopenia following intravenous administration of either recombinant human interleukin-1 (IL-1) alpha or beta to rats. The peripheral neutrophilia was accompanied by a significant depletion of bone marrow neutrophils (P less than 0.001), as is also known to occur after administration of IL-1. Systemic blood pressure was not affected by rLT, which suggested that the changes in circulating leukocyte subsets were not attributable to hemodynamic changes nor to the hemodynamic-change-related release of adrenal hormones. Adrenalectomy did not alter the rLT-induced neutrophilia or lymphopenia, which suggested that rLT does not mediate its hematologic effects on peripheral blood leukocytes via the release of adrenal hormones. Pretreatment of rats with dexamethasone, indomethacin, or aspirin also did not alter rLT-induced neutrophilia or lymphopenia, which suggested that rLT-induced hematologic effects were not mediated via arachidonic acid metabolites, in stark contrast to IL-1 induced neutrophilia, which is inhibited by both dexamethasone and indomethacin.     

Endobronchial HIV associated lymphoma.

A 27 year old HIV infected man presented with two days of haemoptysis. Flexible bronchoscopy revealed a large carinal mass partially obstructing the left and right main stem bronchi. Rigid bronchoscopy was required to make the diagnosis of large cell immunoblastic lymphoma.     

Inter-cohort differences in coronary heart disease mortality in the 25-year follow-up of the seven countries study

Sixteen cohorts of men aged 40–59 years at entry were examined with the measurement of some risk factors and then followed-up for mortality and causes of death for 25 years. These cohorts were located in the USA (1 cohort), Finland (2), the Netherlands (1), Italy (3), the former Yugoslavia (5), Greece (2), and Japan (2), and included a total of 12,763 subjects.Large differences in age-adjusted coronary heart disease (CHD) death rates were found, with extremes of 45 per 1000 in 25 years in Tanushimaru, Japan, to 288 per 1000 in 25 years in East Finland. In general, higher rates were found in the US and Northern European cohorts as compared to the Southern European and Japanese cohorts. However, during the last 10 years of follow-up large increases of CHD death rates were found in some Yugoslavian areas. Out of 5 measured entry characteristics treated as age-adjusted levels (serum cholesterol, systolic blood pressure, cigarette smoking, body mass index and physical activity at work), only serum cholesterol was significant in explaining cohort differences in CHD death rates.Over 50% of the variance in CHD death rates in 25 years was accounted for by the difference in mean serum cholesterol. This association tended to decline with increasing length of follow-up, but this was due to the great changes in mean serum cholesterol in the two Jugoslavian cohorts of Velika Krsna and Zrenjanin. When these two cohorts were excluded the association increased with time.Changes in mean serum cholesterol between year 0 and 10 helped in explaining differences in CHD death rates from year 10 onward.It can be concluded that this study suggests that mean serum cholesterol is the major risk factor in explaining cross-cultural differences in CHD.     

Longevity of man: relative weight and fatness in middle age

By February, 1948, examinations in the Twin Cities Prospective Study were completed on 284 executive men, then aged 45-55 and "healthy". In 35 years 183 died, 110 were alive, one was lost. Entry body fatness, indicated by body mass index, skinfold thickness at three sites, relative girth, and body density, did not significantly discriminate the 35-year dead from survivors. Age at death was not related to any fatness measure. The multiple logistic equation in five solutions using age, blood pressure and smoking plus each fatness item separately, found no discrimination of dead from survivors by any fatness measure. In other long time prospective studies, two suggested excess mortality at far extremes of over- and under-weight, several found survivors significantly fatter than the dead, others found no relation between fatness and longevity. Framingham reported fatness a risk factor for death when allowance is made for smoking but that singular claim has been criticized.     

Pulvinar nuclei of the behaving rhesus monkey: visual responses and their modulation

We have examined the properties of neurons in three subdivisions of the pulvinar of alert, trained rhesus monkeys 1) an inferior, retinotopically mapped area (PI), 2) a lateral, retinotopically organized region (PL), and 3) a dorsomedial visual portion of the lateral pulvinar (Pdm), which has a crude retinotopic organization. We tested the neurons for visual responses to stationary and moving stimuli and for changes in these responses produced by behavioral manipulations. All areas contain cells sensitive to stimulus orientation as well as neurons selective for the direction of stimulus movement; however, the majority of cells in all three regions are either broadly tuned or nonselective for these attributes. Nearly all cells respond to stimulus onset, a significant number also give a response to stimulus termination, and rarely a cell gives only off responses. Nearly all cells increase their discharge rate to visual stimuli. Receptive fields in the two retinotopically mapped regions, PI and PL, have well-defined borders. The sizes of these receptive fields show a positive correlation with the eccentricity of the receptive fields. The receptive fields in the remaining region, Pdm, are frequently very large, but with these large fields excluded, show a similar correlation with eccentricity. All pulvinar cells tested (n = 20) were mapped in retinal coordinates; the receptive fields are positioned in relation to the retina. We found no cells with gaze-gated characteristics (2), nor cells mapped in a spatial coordinate system. The response latencies in PI and PL are shorter and less variable than the latencies in Pdm. Active use of a stimulus can produce an enhancement or attenuation of the visual response. Eye-movement modulation was found in all three subdivisions in about equal frequencies. Attentional modulation was common in Pdm and was rare in PI and PL. The modulation is spatially selective in Pdm and nonselective in PI for a small number of tested cells. These data demonstrate functional differences between Pdm and the other two areas and suggest that Pdm plays a role in selective visual attention, whereas PI and PL probably contribute to other aspects of visual perception.     

Self-administration of cocaine increases the release of acetylcholine to a greater extent than response-independent cocaine in the nucleus accumbens of rats

  Rationale: The neurochemical effects of psychostimulant exposure may depend on how these drugs are encountered. A useful method for examining this issue is to compare neurotransmitter release following response-dependent, or self-administered, drug exposure and response-independent exposure. Objectives: This experiment examined the effect of active and passive cocaine administration on acetylcholine (ACh) efflux in the shell region of the nucleus accumbens (NAc) in rats. Methods: One group of rats (CSA: cocaine self-administration) was trained to lever-press for intravenous infusions of cocaine (0.42 mg/kg per infusion) on a fixed-ratio-1 schedule of reinforcement. Cocaine infusions were accompanied by the onset of a stimulus light that signaled a 20-s time-out period. Control rats received intravenous cocaine (cocaine non-contingent: CNC) or saline (SAL) in a manner that was not contingent upon their behavior. Drug infusions in these groups were determined by the lever-press behavior of the animals in the CSA group, i.e. they were yoked to rats in the self-administration group such that CNC animals received equal amounts of cocaine as CSA rats. Animals received cocaine or saline in 3-h sessions for 13 consecutive days before testing. On day 14, extracellular ACh was measured in 15-min intervals before, during and after a 3-h session of cocaine exposure using unilateral microdialysis probes located in the NAc shell coupled with HPLC. Results: ACh efflux was significantly increased above baseline in both groups of rats that received cocaine but CSA rats had significantly higher ACh levels during the self-administration period compared to their yoked counterparts. In addition, ACh efflux remained elevated longer in CSA animals relative to CNC rats following cessation of cocaine exposure. Conclusions: These results demonstrate that ACh interneurons in the NAc shell are responsive to cocaine exposure. In addition, these findings suggest that the manner in which the drug is administered (i.e. either by active self-administration or passive exposure) may be relevant to the magnitude of the neural response. Received: 28 April 1998 / Final version: 4 November 1998     

Tissue dosimetry expansion and cross-validation of rat and mouse physiologically based pharmacokinetic models for trichloroethylene.

Trichloroethylene (TCE), a volatile liquid used as a degreasing agent, is a common environmental pollutant. In 2001, the EPA published a draft risk assessment for TCE that incorporates dosimetry predictions of physiologically based pharmacokinetic (PBPK) models. The current modeling effort represents an expansion and extensive tissue dosimetry validation of rodent PBPK models for TCE. The pharmacokinetics of TCE in male Sprague-Dawley (S-D) rats were characterized (1) during and after inhalation exposure to 50 or 500 ppm TCE, (2) following administration of 8 mg/kg TCE PO, and (3) following intra-arterial injection of 8 mg/kg TCE. Blood and tissues (including liver, kidney, fat, skeletal muscle, heart, spleen, gastrointestinal tract, and brain) were collected at selected time-points from 5 min up to 24 h post initial exposure. The fat compartment was modified to be diffusion-limited to predict the observed slow release of TCE from the fat. The addition of a deep liver compartment was necessary to accurately predict the slower hepatic clearance of TCE for all three exposure routes. Simulations of liver concentrations following gavage of male B6C3F1 mice with 300-2000 mg/kg TCE were also improved with the addition of a deep liver compartment. Liver predictions were calibrated and validated using a cross-validation technique novel to PBPK modeling. Splitting of compartments did not significantly affect predictions of TCE concentrations in the liver, fat, or venous blood. This model expansion and validation increases both the utility and our confidence in the current use of rodent TCE PBPK models in human health risk assessment.