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.     

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.     

Inhibition of autophagy increases apoptosis during re‐warming after cold storage in renal tubular epithelial cells

Prolonged cold storage and re‐warming (CS/REW) of kidneys are risk factors for delayed graft function (DGF). Studies in renal tubular epithelial cells (RTECs) have determined apoptosis and autophagy in models of either cold storage (CS) or re‐warming alone. The effect of both cold storage and re‐warming on apoptosis and autophagy, in RTECS is not known and is relevant to DGF as the kidney is subjected to both CS and re‐warming. We hypothesized that CS/REW of RTECs would induce autophagy that protects against apoptosis. In CS/REW, there was increased autophagic flux of RTECs. Autophagy inhibition using an Atg5 siRNA resulted in increased cleaved caspase‐3 and increased apoptotic cells (on both morphology and annexin V staining) during CS/REW. The effect of autophagy inhibition on necrosis in RTECs is unknown. There were increased necrosis and caspase‐1, a mediator of necrosis, during CS/REW, and the Atg5 siRNA had no effect on necrosis and caspase‐1. In a kidney transplant model, there was an increase in LC3 II, a marker of autophagy, in kidneys transplanted after cold storage. In summary, autophagic flux is increased during CS/REW. Autophagy inhibition resulted in increased cleaved caspase‐3 and increased apoptosis during CS/REW without an effect on necrosis or caspase‐1. In conclusion, autophagy inhibition in RTECs after CS/REW induces apoptotic cell death and may be deleterious as a therapy to decrease DGF.