Evaluation of xanthotoxol for central nervous system activity.

Xanthotoxol (XT), 8-hydroxypsoralen, exhibited dose-graded sedative activity in dogs, cats, rats, mice and hamsters. At doses of 5-20 mg/kg intraperitoneally (i.p.) in cats and 3-100 mg/kg orally (p.o.) in dogs, XT blocked predatory mouse/rat killing behavior. In mice, XT (10-300 mg/kg i.p.) exhibited a dose-dependent reduction in locomotor activity but was less potent in this regard than reference diazepam (10-100 mg/kg i.p.). XT in mice (0.1-10.0 mg/kg i.p.) and in hamsters (0.1-10.0 mg/kg p.o.) antagonized amphetamine-induced hypermobility but was less potent than diazepam. XT elevated the electrical threshold in foot-shock-induced fighting behavior in rats. XT (0.1-30.0 mg/kg p.o.) potentiated pentobarbital-induced narcosis in hamsters at otherwise subeffective doses of pentobarbital. Conditioned avoidance responses in rats were not significantly altered with 1-3 mg/kg i.p. and 30-100 mg/kg p.o. doses of XT but 300 mg/kg p.o. blocked both conditioned and unconditioned response. Doses of 100-1000 mg/kg i.p. of XT in mice were used to study 48-h acute toxicity of XT and its LD50 was estimated to be 468 mg/kg. Doses of 10, 40 and 80 mg/kg p.o. were used to study the chronic toxicity of XT in rats for 6 months and no side effects or abnormalities in reproductive activity or endocrine integrity were noted. The F1 generation of rats from 6-month XT-treated parents were free of teratogenic effects.     

A cocaine analog and a GBR analog label the same protein in rat striatal membranes.

Because some evidence suggests that cocaine and GBR12935 bind to different sites, we utilized photoaffinity probes from both classes of compounds to see if they label the same protein. [125I]RTI-82 a cocaine analog, and [125I]DEEP, a GBR analog, labeled protein(s) showing the same molecular weight, a similar pharmacological profile and a similar sensitivity to neuraminidase.     

Comparison of the potential therapeutic effects of interleukin 2 or interleukin 4 secretion by a single tumour.

Engineering of a variety of rodent tumour cells to secrete either interleukin 2 (IL-2), or interleukin 4 (IL-4), has been demonstrated to reduce their tumorigenicity. However the mechanisms of action of secreted IL-2 and IL-4 have not been compared in a single rodent tumour. Here we demonstrate that the weakly immunogenic murine fibrosarcoma FS29 had reduced growth rate and in some cases was rejected by syngeneic animals, when modified to secrete either IL-2 or IL-4, but not IL-5. Immunohistochemical analysis of tumour nodules undergoing regression showed stimulation of a largely lymphocytic infiltrate by IL-2 and a macrophage and granulocyte infiltrate, with a small number of lymphocytes by IL-4. Indeed, secretion of low levels of IL-2 and IL-4 in combination resulted in optimal rejection, suggesting that the two cytokines might mobilise different and complementary effector cell mechanisms. Both IL-2 and IL-4-secreting cells failed to induce the rejection of admixed, unmodified FS29 cells. The loss of cytokine secreting cells from such admixtures occurred more rapidly for IL-2-secreting cells. Injection of IL-4-secreting, but not IL-2-secreting FS29 cells could protect mice from a delayed challenge with unmodified FS29 cells. These data suggest that IL-4 secretion stimulates the better long-term host anti-tumour response.     

Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgical blood loss.

The hemostatic dysfunction induced by cardiopulmonary bypass is due, in part, to a platelet dysfunction evidenced by a postoperative extension of the bleeding time; it leads to increased postoperative blood loss and morbidity. This study, which was conducted in 85 patients undergoing cardiopulmonary bypass, was designed to characterize the hematologic changes during and after cardiopulmonary bypass and to elucidate the relationships between these changes, the extension of the bleeding time, and the magnitude of the postoperative nonsurgical blood loss. Variables were measured before, during, and 2, 24, 48, and 72 hours after cardiopulmonary bypass. Univariate and multivariate analyses were performed with either the 2-hour postbypass bleeding time or the 4-hour postbypass blood loss as the dependent variables. The reversal of the extension of the bleeding time in the postoperative period was accompanied by a significant increase in the mean platelet volume and by a significant increase in the level of thromboxane B2 measured in the blood shed from the site of the bleeding time determination. The postoperative bleeding time correlated with the postoperative blood loss, and both parameters were dependent on the duration of cardiopulmonary bypass. In addition, the postoperative bleeding time correlated with the skin temperature and the plasma level of D-dimer, while the postoperative blood loss also correlated with temperature and the plasma levels of C3. These data establish a direct relationship between the postoperative bleeding time, the postoperative blood loss, and temperature. They indicate that the reversal of the postoperative extension of the bleeding time is due in part to rewarming and to the release of larger platelets into the circulation, and they suggest that hyperfibrinolysis and complement activation may play an important role in the cardiopulmonary bypass-induced platelet dysfunction.     

Fatal self-induced hyperinsulinaemia: a delayed post-mortem analytical detection.

The inconspicuous number of cases of self-induced hyperinsulinaemia reported in the literature may suggest that many are obscure enough to escape their detection. A case of fatal suicidal hyperinsulinaemia in a non-diabetic is reported here, and in whom only a retrospective biochemical analysis provided an explanatory cause of death. A quantitative radioimmuno assay (RIA) estimation of the refrigerated postmortem blood sample stored at 4 degrees C for three weeks gave a positive insulin yield. It reiterates the need, in forensic cases, for a very low threshold of suspicion and a good back-up for the appropriate body fluid analysis or tissue microexamination, especially when full details of the circumstances surrounding the death are not available at the autopsy. A brief résumé on insulin is presented as a background to the current forensic interest in the apparent increase in sudden deaths in young diabetics amidst the controversy about the bio-designed 'human' insulin and subjective unawareness of severe hypoglycaemia.     

Fournier''s gangrene of the scrotum following day case vasectomy.

A case of Fournier's gangrene of the scrotum is reported in a 31-year old man who had outpatient vasectomy during an intercurrent diarrheal illness. The surgery was done through a midline incision, under local anesthesia of plain 2% lignocaine, with a preoperative chlorhexidine scrub. Although his scrotum was red and swollen within 3 hours, he did not have medical care until admission to hospital 48 hours later. At admission he had Fournier's gangrene of the scrotum and penis, Gram-negative septic shock, and acute renal failure. In the intensive care unit he was treated with continuous dialysis, parenteral metronidazole, benzylpenicillin, Ceftazidime and inotropes. He had a cardiorespiratory arrest after emergency radical debridement. After resuscitation he developed adult respiratory distress syndrome and disseminated intravascular coagulation. Pathological exam showed necrosis of the dermis and subcutaneous layers, thrombosis and beta-hemolytic streptococci. After adding gentamicin and vancomycin, 2 weeks of ventilator care, 4 more surgical debridements, a left orchidectomy, and a despite a grossly abnormal EEG recording, the man regained consciousness and recovered. His scrotal and penile skin re-epithelialized over 3 months. Patients requesting vasectomy should be assessed for local and systemic illness before performing the procedure.     

Nasopharyngeal glioma: A unique presentation in infants

Despite the complex embryological development of the nose and surrounding structures, significant developmental nasal anomalies are rare. Of the various anomalies like-nasopharyngeal cysts, hairy polyps, dermoids, haemangiomata, fibromas, mucocoeles, lipoma, aplasias. We are presenting a rare case of Heterotopic Brain Tissue in the nasopharynx. This 1.5-month-old patient was operated through transpalatal route and mass excised. Histopathologicaly it consisted of various central nervous tissue elements. Seven months post surgery patient is thriving well.     

Trigger fingers and thumb: when to splint, inject, or operate.

Fifty trigger fingers were treated by splinting of the metacarpophalangeal joint at 10 to 15 degrees of flexion for an average of 6 weeks (range, 3 to 9 weeks). Another 50 trigger fingers were injected with 0.5 ml of betamethasone sodium phosphate and acetate suspension (Celestone) and 0.5 ml of lidocaine. All patients were followed up for a minimum of 1 year (range, 1 to 4 years). Treatment was successful in 33 (66%) of the splinted digits and 42 (84%) of the injected digits. Fifty percent of the 10 splinted thumbs and 70% of the 40 splinted fingers had a successful outcome. Of the 17 unsuccessfully treated digits in the splinted group, 15 were later cured with injections and 2 required surgery. All of the 7 unsuccessfully treated digits in the injected group were cured with surgery. Patients with marked triggering, symptoms of more than 6 months' duration, and multiple involved digits had a higher rate of failure in both groups. Splinting offers an alternative for patients who have a strong objection to cortisone injection.     

Human breast cancer cells contain a phosphoramidon-sensitive metalloproteinase which can process exogenous big endothelin-1 to endothelin-1: a proposed mitogen for human breast fibroblasts.

Endothelin-1 (ET-1) levels are elevated in human breast tumours compared with normal and benign tissues, and in the presence of insulin-like growth factor 1 (IGF-I) ET-1 is a potent mitogen for human breast fibroblasts. In this study we have examined the ability of intact human breast cancer cell lines to process exogenously added big ET-1 (1-38) to the active mature ET-1 peptide by using a specific radioimmunometric assay. In both hormome-dependent (MCF-7, T47-D) and hormone-independent (MDA-MB-231) breast cancer cell lines the putative endothelin-converting enzyme (ECE) exhibited apparent Michaelis-Menten kinetics when converting added big ET-1 to ET-1. Both basal ET-1 production and exogenously added big ET-1 to ET-1 conversion were greatly reduced in all three cell lines in response to the metalloproteinase inhibitor phosphoramidon but were insensitive to other classes of protease inhibitors. Inhibition was also observed when cells were incubated in the presence of the divalent cation chelators 1,10-phenanthroline and EDTA. In MCF-7 cells the optimal pH for the ECE activity using a saponin cell permeabilisation procedure was found to residue within a narrow range of 6.2-7.26. Our results indicate that human breast cancer cells contain a neutral phosphoramidon-sensitive metalloproteinase which can process big ET-1 to ET-1. In the breast this conversion could contribute substantially to the local extracellular levels of this proposed paracrine breast fibroblast mitogen.