Distribution of the [3H]-label from low doses of radioactive ochratoxin a ingested by rats,and evidence for DNA single-strand breaks caused in liver and kidneys

The distribution of a single low dose of [³H]ochratoxin A (OTA) in different tissues of male Wistar rats, after administration by intubation, was investigated after 5 h, 24 h and 48 h. This dose corresponds to concentrations encountered in naturally contaminated feed (4 ppm). The distribution of [³H]-label varied with the time elapsed after administration; at 5 h the highest specific label was found in the stomach contents and in decreasing order in: intestinal contents, lung, liver, kidney, heart, fat, intestine, testes, and the lowest in muscles, spleen and brain. With exception of brain, fat, stomach and lung, all tissues showed maximum levels at 24 h, after which time the label decreased steadily, whereas in fat it increased.After a 12-week feeding experiment, with doses of 288.8 g/kg corresponding to an intake of 4 ppm in feed each 48 h, the DNA in liver and kidneys was investigated for damage. By the alkaline elution method combined with micro-spectrofluorimetric determinations of DNA, evidence for DNA single-strand breaks was obtained. These findings support reports on the carcinogenic action of OTA.     

Transferrin gene frequencies in Cádiz (southern Spain)

Summary The genetic polymorphism of transferrin (Tf) was studied in a sample of 385 healthy unrelated subjects of both sexes resident in the province of Cádiz (southern Spain). Isoelectric focusing was carried out in polyacrylamide gels, followed by staining with Coomassie Blue R250. The gene frequencies obtained were as follows: Tf C1, 0.7922; Tf C2, 0.1883; Tf C3, 0.0195.     

Obesity and subcutaneous fat patterning in relation to survival of postmenopausal breast cancer patients participating in the DOM-project

Summary The effect of obesity and fat distribution on survival of breast cancer patients was studied prospectively in 241 women with a natural menopause who participated in a breast cancer screening project, the DOM-project in Utrecht, The Netherlands. Mean follow-up time was 9.1 years and endpoint of interest was death from breast cancer. Fat distribution was assessed by contrasting groups of subscapular and triceps skinfold thickness.No significant differences in survival time between more obese (Quetelet's index 26 kg/m²) and leaner (Quetelet's index < 26 kg/m²) patients or between patients with central fat distribution and patients with peripheral fat distribution were observed. Analyses were stratified by axillary node status, estrogen receptor status, and way of detection (by first screening or afterwards). Results of the stratified analyses were suggestive of a modifying effect of these factors.The absence of an association between obesity and survival time might be explained by two counteracting mechanisms. On the one hand obesity might be related to impaired survival, due to a tumor growth promoting effect of extra-ovarian estrogens. On the other hand obesity might be related to improved survival in a screened population, because obese patients profit more from screening by earlier detection of tumors than leaner counterparts.     

Extracellular fluid and its proteins: dehydration, shock, and recovery

This review highlights characteristics of extracellular fluid (ECF) that are often overlooked. ECF has, in addition to plasma and interstitial fluid (ISF) surrounding cells, a third large compartment, the ISF of skin and connective tissue. This acts as a reservoir that gives up ECF to plasma volume (PV) in order to sustain circulation in the event of either shock or dehydration. While Starling forces drive filtration, ECF is returned to PV more by lymph and less by Starling forces than previously appreciated. Lymph return to PV is dependent on physical activity and muscle contraction to overcome gravity. Regional change in metabolic rate alters the need for oxygen and nutrients that is met by a regional increase in capillary blood flow. Blood flow is controlled by vasoactive compounds released in response to a drop in PO₂; these relax capillary smooth muscle to increase blood flow and delivery of oxygen and nutrients. Plasma proteins, including albumin, are filtered into the interstitium through larger pores than those filtering ECF. The rate of protein filtration is set by size and charge of these larger endothelial pores and by size and charge of proteins. Charge of these pores, hence albumin permeability, is regulated by many of the same vasoactive compounds that control capillary flow. As a consequence, in response to gravitational stress and other forms of shock that reduce effective circulation, albumin as well as ECF is rapidly shifted from plasma and sequestered in ISF. When this has occurred, as in burn shock, restoration is better effected by generous expansion of ECF with Ringer’s solution alone, rather than with Ringer’s solution supplemented with human serum albumin or other colloid. Restoring both PV and ISF volume restores lymph circulation and returns sequestered albumin to PV. Received: 12 November 1998 / Revised: 30 March 1999 / Accepted: 2 April 1999     

Relations of hippocampal volume and dentate gyrus width to gonadal hormone levels in male and female meadow voles

The present study examined hippocampal volume and dentate gyrus width and their relations to gonadal hormone levels in adult male and female meadow voles, Microtus pennsylvanicus. Females were split into High and Low Estradiol groups based on the median estradiol level. Males were similarly split into High and Low Testosterone groups. Contrary to previous reports in wild meadow voles, there was no evidence of an overall sex difference in hippocampal volume. However, when male-female comparisons were limited to High Testosterone males and Low Estradiol females a significant sex difference in hippocampal volume favouring males did emerge. Hippocampal volume in males was related to testosterone level, with High Testosterone males having significantly larger hippocampi than Low Testosterone males. Similarly, there was a significant influence of plasma estradiol level on hippocampal volume and left dentate gyrus width, with High Estradiol females having larger hippocampi and dentate gyrus width than Low Estradiol females. In addition, consistent with previous findings in the laboratory rat, there were sex differences favouring males in right dentate gyrus width. These findings show that there is a complex relationship between hippocampal volume, dentate gyrus width and gonadal hormone levels in male and female meadow voles.     

Morphine antinociception elicited from the ventrolateral periaqueductal gray is sensitive to sex and gonadectomy differences in rats

Sex differences have been observed in antinociception following central administration of morphine into either the lateral ventricles or rostral ventromedial medulla (RVM) such that male rats exhibit significantly greater antinociception than female rats. The present study examined whether sex and adult gonadectomy differences were observed in morphine-induced (1-10 micrograms) antinociception elicited from the ventrolateral periaqueductal gray (vlPAG) on two nociceptive measures. Both sham-operated (ED50=1.20-1.60 microgram) and castrated (ED50=1.08-1.09 micrograms) male rats displayed significantly greater magnitudes and potencies of morphine-induced antinociception on both tests than female rats. Sham-operated female rats tested during the estrous phase (ED50=>50 micrograms) were significantly less sensitive to morphine than ovariectomized female rats (ED50=1.98-2. 51 micrograms). Thus, the vlPAG, a site sensitive to interactions between estradiol-containing hypothalamic loci and opioid peptides, elicits morphine-induced antinociception which is sensitive to sex differences and adult gonadectomy.     

Drug Distribution in Obesity and following Bariatric Surgery: A Literature Review

Background: The pharmacokinetic variables of drug clearance and volume of distribution are usually corrected for body weight or surface area. Only recently have the relationships which exist between body size, physiologic function and pharmacokinetic variables been evaluated in the obese population. These effects are not widely known, and data on this and the effects of bariatric surgical procedures are scantily documented in the surgical literature. Methods: Literature review. Results: Drugs with a low or moderate affinity for adipose tissue have a moderate increase in the volume of distribution (Vd), and this correlates with the increase in lean body mass (LBM). Highly lipophilic drugs, with some exceptions, show the expected increase in Vd and prolongation of elimination half-life, indicating a marked distribution into adipose tissue. Drug absorption, in general, is slowed by delayed gastric emptying and is normal when gastric emptying is normal or increased. Most drug absorption occurs in the small intestine where duration of drug/mucosal contact is the most important factor. Conclusions: Drugs whose distribution is restricted to LBM should utilize a loading dose based on ideal body weight (IBW). For those drugs which distribute freely into adipose tissue, the loading dose should be based on total body weight (TBW). Adjustment of the maintenance dose depends on clearance rates. In a few cases dosage adjustment depends on pharmacodynamic data, since drug clearance does not conform to these recommendations, for reasons which remain to be defined. Following bariatric surgery, in the absence of delayed gastric emptying or uncontrolled diarrhea, drug absorption rates are usually comparable to the non-operated patient.     

A blood cyanide distribution study in the rabbits intoxicated by oral route and by inhalation

Summary Blood cyanide concentration was determined in rabbits intoxicated orally or by inhalation. Experiments were carried out under urethane anaesthesia. In the inhalation experiments, rabbits inhaled a combustion product containing HCN via the tracheal cannula and in the oral studies animals were administered NaCN solution into the stomach. In addition to the carotid artery and jugular vein blood samples, postmortem samples were obtained from both sides of the heart and the descending vena cava.The arterial cyanide concentration in the inhalation group showed a close relationship with ventilation. After an initial rise, blood levels decreased a little, in some cases with transient apnea. At the last stage it again increased with gasping, reaching its maximal value. After ultimate apnea, the blood cyanide concentration declined. The blood cyanide values were higher in the oral group than in the inhalation group. The difference between the two groups became larger in the inferior order, the left heart blood-the right heart blood-blood in the descending vena cava. The left heart/right heart ratio of the inhalation group was significantly higher than that of the oral group (1.28 ±0.28 vs. 0.95 ±0.09). The coefficient of variation (c.v.) of the inhalation group was larger than that of the other group. Within the inhalation group, the left heart blood showed the largest c.v. values and this was probably due to redistribution of the cyanide by bloodstream after attainment of the maximal concentration.

---

Bestimmung der Blutzyanidkonzentration in oral oder inhalatorisch vergifteten Kaninchen

Zusammenfassung Die Blutzyanidkonzentrationen wurden an Zyanid-vergifteten Kaninchen in Urethannarkose bestimmt. Die Kaninchen inhalierten HCN-haltige Verbrennungsgase durch die Trachealkanüle. Eine andere Gruppe von Tieren erhielt NaCN-Lösung per os. Während der Versuche wurden Blutproben aus einer katheterisierten Halsarterie gewonnen. Postmortale Blutproben wurden aus beiden Ventrikeln des Herzens und der kaudalen Hohlvene entnommen.Der arterielle Blutzyanidspiegel der ersten Gruppe zeigte eine enge Beziehung mit der Ventilation auf. Nach einer Konzentrationszunahme im Anfangsstadium nahm der Blutspiegel mit einer vorübergehenden Apnoe ab. Mit der terminalen Atembewegung stiegen die Blutspiegel und erreichten ihre maximalen Werte. Die Blutzyanidwerte verminderten sich nach endgültiger Apnoe. Der Blutspiegel der per-os-Gruppe nahm stetig unabhängig von der Ventilationsgröße zu. Die inhalatorische Gruppe hatte niedrigere Zyanidwerte als die orale Gruppe.