Chemoprevention of spontaneous tumorigenesis in nullizygous p53- deficient mice by dehydroepiandrosterone and its analog 16alpha-fluoro- 5-androsten-17-one

Transgenic mice with both alleles of the p53 tumor suppressor gene product 'knocked out' by gene targeting are susceptible to early development of tumors, chiefly lymphomas and sarcomas. Compared with the control group, administration of dehydroepiandrosterone (DHEA) at 0.3% of the diet to male p53-deficient mice extended their lifespan by delaying death due to neoplasms (from 105 to 166 days on study, P = 0.002), primarily by suppressing lymphoblastic lymphoma (from 45 to 6% of neoplastic deaths, P = 0.010). Treatment with a synthetic DHEA analog, 16alpha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the diet also increased lifespan, to 140 days for mice that developed tumors (P = 0.037). The effects of these steroids on lifespan and tumor development did not appear to be strongly related to inhibition of food consumption and weight gain, in that a group pair-fed with control diet to the reduced food consumption of the DHEA-treated group developed and died of the same types of neoplasms at the same rate as the controls fed ad libitum. The chemopreventive effect of these steroids has been proposed to be due to suppression of DNA synthesis by inhibition of glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway. Although DHEA and its analog are strong non- competitive inhibitors of this enzyme in vitro, treatment with DHEA did not deplete cellular nucleotide pools in the liver, as would have been predicted. The chemopreventive effect of DHEA in this model may be due to steroid-induced thymic atrophy and suppression of T cell lymphoma, permitting these mice to survive long enough to develop tumors with longer latency.      

Failure of ablation of a mediastinal parathyroid adenoma by repeated contrast staining

In a patient with primary hyperparathyroidism an attempt was made to ablate a middle mediastinal parathyroid gland by forceful staining with radiographic contrast material. The gland was stained on two separate occasions, two weeks apart. Both times the serum calcium level temporarily fell to the normal range but reverted to abnormal levels. The patient ultimately required surgery for correction of hypercalcemia. The mechanism of staining and possible reasons for failure as well as potential complications are discussed.     

Gallium-67 lung uptake: conjugate-view technique

A conjugate-view technique is derived for calculation of absolute gallium-67 (Ga-67) uptake from scintillation-camera images. The technique combines counts of posterior and anterior images of the lung with an attenuation correction obtained from cobalt-57 (Co-57) transmission imaging. The formulation is such that the effects of Compton scatter build-up are accounted for. Studies utilizing a canine model indicated that, normally, more activity is located in the chest wall than in the lungs. The quantitative technique must therefore accurately account for a variety of Ga-67 distributions, including that in the chest wall. Calculations were performed using a three-component model comparing results obtained with the conjugate-view approach to the actual uptake. These calculations suggest that an assumption of uniform activity distribution allows an accuracy of approximately +/- 10% over a broad range of body-part thicknesses and uptake by the lungs. It was concluded that the conjugate-view technique is necessarily approximate but can provide clinically useful results.     

Occlusion of dentinal tubules and selective block of pulp innervation prevent the nociceptive behaviour induced in rats by intradental application of irritants

Objectives: Application of irritants on the exposed dentine of the incisors has been shown to produce aversive behaviour in awake rats. This study aims to demonstrate that the observed aversion is due to the infiltration of irritants through the dentinal tubules and the activation of capsaicin sensitive fibres in the tooth pulp. Methods: Different groups of rats were subjected, under anaesthesia, to cutting of the distal 2 mm of their lower incisors and the fixation of an artificial crown that allows the application of 10-15 μl of solution. Several procedures were followed to prevent the action of the irritants including occlusion of the dentinal tubules, local application of lidocaine, selective ablation of the capsaicin sensitive primary afferents (CSPA) or incisor pulpectomy; the reactions to intradental application of either capsaicin (1%) or formalin (2.5%) were tested using a newly designed behavioural score. Results: Occlusion of dentinal tubules produced significant attenuation of the nociceptive behaviour induced by dentinal application of either capsaicin or formalin. Similar results were observed following either local block with lidocaine (2%), selective ablation of capsaicin sensitive afferents or total denervation by pulpectomy. Conclusions: The present results confirm the hypothesis of infiltration of irritants to the incisor pulp through the dentinal tubules and suggest that the reported inflammatory reaction and hyperalgesia are mediated, to a large extent, by capsaicin sensitive primary afferents.     

Continuous perfusion with morphine of the orbitofrontal cortex reduces allodynia and hyperalgesia in a rat model for mononeuropathy

Recent imaging reports demonstrate the activation of the orbitofrontal cortical (OFC) area during acute and chronic pain. The aim of this study was to compare the effects of chronic perfusion of this area with morphine on nociception in control rats and in rats subjected to mononeuropathy. Chronic perfusion of morphine, using miniosmotic pumps, produced significant and naloxone-reversible depression of tactile and cold allodynias and thermal hyperalgesia, observed in neuropathic rats, while it produced significant elevation and naloxone insensitive increase of acute nociceptive thresholds in control rats. The observed results support the idea that this area is a component of a flexible cerebral network involved in pain processing and perception.     

Chronic thalamotomy increases pain-related behavior in rats

The thalamus has been traditionally considered as the 'chief organ' by which pain is perceived (Head H, Holmes G. Sensory disturbances from cerebral lesions. Brain 1911;34:102-254). However, several clinical and experimental observations led to a challenge of this traditional view. In this report, we demonstrate that chronic thalamic lesions, instead of producing hypoalgesia, increased pain reactivity in rats. Different groups of rats were subjected to either subtotal, lateral or medial thalamic lesions. Their reactions to nociceptive stimuli were then assessed for a period of 1-2 months. Rats in the different groups showed an increased reactivity to acute mechanical and thermal nociceptive stimuli and an increase in the pain scores of the formalin test. These results suggest an important role of the thalamus in pain modulation in addition to that of nociceptive transmission.