Diesel Exhaust Is Not a Pulmonary Carcinogen in CD-1 Mice Exposed under Conditions Carcinogenic to F344 Rats

Differences among laboratory animal species in the pulmonarycarcinogenicity of chronic inhalation exposure to diesel exhausthave raised several important interpretive issues. Under similarheavy exposure conditions, it is clear that diesel exhaust isa pulmonary carcinogen in rats, but not in Syrian hamsters.Previous reports give conflicting views of the response of mice,which is presently considered equivocal. This report describescarcinogenicity results from a bioassay of CD-1 mice conductedin parallel with a previously reported bioassay of F344 rats(Mauderly et al. (1987) Fundam. Appl. Toxicol. 9, 208–221).Exposure to whole diesel exhaust 7 hr/day, 5 days/week for 24months at soot concen trations of 0.35, 3.5, or 7.1 mg/m³ causedaccumulations of soot in mouse lungs similar to those in lungsof rats and, like the results from rats, did not significantlyaffect survival or body weight. In contrast to the dose-relatedneoplastic response of rats, however, the exposures of micedid not increase the incidence of lung neoplasms. This findingis consistent with other data showing that mice, as well asSyrian hamsters, differ from rats in their lung neoplastic andnonneoplastic responses to heavy, chronic inhalation exposureto diesel exhaust soot and several other particles. Althoughrodents serve as useful indicators of potential human carcinogenichazards, it is not yet clear which, if any, rodent species havelung neoplastic responses that are useful for quantitative predictionsof human lung cancer risk from chronic inhalation of poorlysoluble, respirable particles.     

Diesel Exhaust Is a Pulmonary Carcinogen in Rats Exposed Chronically by Inhalation

Diesel Exhaust Is a Pulmonary Carcinogen in Rats Exposed Chronicallyby Inhalation. MAUDERLY, J. L., JONES, R. K., GRIFFITH, W. C.,HENDERSON, R. F., AND MCCLELLAN, R. O. (1987). Fundam. Appl.Toxicol 9, 208–221. Male and female F344 rats were exposed7 hr/day, 5 day/week for up to 30 months to automotive dieselengine exhaust at soot concentrations of 0.35, 3.5, or 7.0 mg/m³or were sham-exposed to clean air. Rats were terminated at 6-monthintervals to measure lung burdens of diesel soot and for histopathology.Other rats either died or were terminated after 30 months ofexposure. Lungs were fixed, sectioned into 3-mm slices, andexamined by a dissecting microscope to detect tumors. Lesionswere stained and examined by light microscopy. Survival andbody weight were unaffected by exposure. Focal fibrotic andproliferative lung disease accompanied a progressive accumulationof soot in the lung. The prevalence of lung tumors was significantlyincreased at the high (13%) and medium (4%) dose levels abovethe control prevalence (1%). Four tumor types, all of epithelialorigin, were observed: adenoma. adenocarcinoma, squamous cyst,and squamous cell carcinoma. Logistic regression modeling demonstrateda significant relationship between tumor prevalence and bothexposure concentration and soot lung burden. These results demonstratethat diesel exhaust, inhaled chronically at a high concentration,is a pulmonary carcinogen in the rat.     

His Bundle Ablation with the Laser Thermal Probe ("Hot Tip"): A Feasibility Study

Successful percutaneous ablation of the bundle of His requires accurate localization together with delivery of the minimum effective energy to avoid unwanted effects. The energy output from laser sources can be controlled very precisely but is not easily directed to the bundle of His using conventional fiber optics. The laser thermal probe ("hot tip") consists of an optical fiber and a terminal metal cap that is rapidly heated during energy delivery. When applied to cadaver hearts at energies of 100-150 joules (10 watts for 10-15 seconds) the 2.0-mm diameter peripheral artery probe was able to damage the bundle of His without extensive surrounding damage. The right ventricular free wall and interventricular septum were perforated during some applications at these energies leaving a tract with a diameter of less than 2.0 mm. The atrioventricular (AV) membranous septum, Foramen Ovale, right atrial appendage, and septal leaflet of the tricuspid valve were more resistant at these energy levels and perforations were always less than 1.0 mm in diameter. The probe was modified for use during electrophysiological studies and good quality unipolar electrograms were recorded from the metal cap confirming that the probe could be accurately positioned adjacent to the bundle of His. The laser thermal probe deserves further study as a "self directing" ablation tool.     

Twister

A 75-year-old male presented with an extensive anterior myocardial infarction. He underwent primary coronary angioplasty to the proximal left anterior coronary artery, which was successful and uncomplicated. Several days later he sustained a cardiac arrest and was successfully resuscitated. An electrophysiological study revealed inducible ventricular tachycardia. An automatic implantable cardioverter defibrillator (ICD) was placed in a subcutaneous abdominal position. After the device was implanted, the patient developed pneumonia and a hematoma in the generator pocket.     

Pharmacokinetics:Pharmacokinetics and Hypotensive Effect of Diltiazem in Rabbits: Comparison of Diltiazem with its Major Metabolites*

To assess the contribution of its metabolites to the antihypertensive effects of diltiazem, a previously established rabbit model has been used to compare the pharmacokinetics and haemodynamic effects of the drug with those of its major metabolites deacetyldiltiazem (M₁) and deacetyl-N-monodemethyldiltiazem (M₂). Diltiazem, M₁ and M₂ were administered separately to each animal (n = 5 or 6 per study group) as a single 5 mg kg^?1 intravenous dose. Blood samples, systolic and diastolic blood pressure (SBP and DBP) and heart rate were recorded for each rabbit up to 8 h, and urine samples were collected for 48 h post-dose. Plasma concentrations of diltiazem and its major metabolites were determined by HPLC. The results showed that systemic clearance (CL) and volume of distribution at steady state (Vd_ss) were smaller for diltiazem than for the metabolites. Diltiazem and the metabolites reduced both SBP and DBP, the effects of diltiazem being most potent. Their effects on heart rate were highly variable and not statistically different between treatment groups (P > 0.05). These results indicate that diltiazem is a more potent hypotensive agent than M₁ or M₂, possibly because of the higher plasma concentrations secondary to the smaller CL and Vd_ss of diltiazem compared with the metabolites. The effects of the metabolites might, however, be more sustained.     

脑内注射脂多糖后常驻小胶质细胞死亡而中性粒细胞和单核细胞浸润成为主要炎症细胞

为了研究小胶质细胞和血中炎症细胞对脑炎症的影响,在正常和白细胞减少大鼠的黑质致密部(SNpc)、皮层和海马注射脂多糖(LPS),用特异标记来研究中性粒细胞、小胶质细胞和单核细胞的行为学。CD11b+和Iba-1+阳性细胞在正常脑和LPS注射后6h反应相似。注射后12hIba-1+细胞消失而CD11b+变成圆形。CD11b/Iba-1双阳性网状小胶质细胞在LPS注射后6h死亡。注射后12h检测到的CD11b+细胞是MPO+细胞。这些CD11b+/MPO+细胞在白细胞减少的大鼠脑内不出现,提示中性粒细胞浸润。MPO+中性粒细胞表达一氧化氮合酶(iNOS)、IL-1β、环氧合酶-2(COX-2)和单核细胞趋化蛋白-1(MCP-1),但在注射后18h死亡。在24h检测到的CD11b+细胞是浸润的单核细胞,因为这些细胞曾经是Iba-1+而且在白细胞减少的大鼠脑内不出现。而且,在LPS注射的脑内可以检测到移植的单核细胞。这些结果提示,在发生炎症的脑内,至少有一部分中性粒细胞和单核细胞被认为是活化的小胶质细胞。