Suppression of N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis by dietary feeding of auraptene

The modifying effects of auraptene on N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis were investigated in male F344 rats. At 5 weeks of age, all animals, except those with the test chemical alone and control rats, received s.c. injections of NMBA (0.5 mg/kg body weight/injection, three times per week) for 5 weeks. At the end of the study (20 weeks), 75% of the rats treated with NMBA alone had esophageal neoplasms (papillomas). However, the groups who received a dose of 500 ppm auraptene during the initiation phase developed significantly reduced incidence of tumors (39%; P<0.05). Exposure to auraptene (500 ppm) during the post-initiation phase also decreased the frequency of the tumors (29%; P<0.01). The reduction of the incidence of severe dysplasia was obtained when auraptene was administered in the post-initiation phase (P<0.05). Cell proliferation in the esophageal epithelium determined by proliferating cell nuclear antigen (PCNA) was lowered by auraptene (P<0.01). Blood polyamine contents in rats who received NMBA and the test compound were also smaller than those of rats that received the carcinogen (P<0.05). These findings suggest that dietary auraptene is effective in inhibiting the development of esophageal tumors by NMBA when given during the initiation as well as post-initiation phases, and such inhibition is related to suppression of cell proliferation in the esophageal epithelium.     

Neural pathways mediating the inhibition of shivering by nonthermal afferent impulses from ischemic limbs

Hind-limb tourniquet ischemia in the rat inhibits thermoregulatory shivering, lowering the ambient temperature at which it commences. This effect was prevented by the injection of 0.5% bupivacaine into the nerve trunks of the hind limbs and around the base of the thighs before the application of the tourniquets and also by lesions in the ventrolateral part of the spinal cord. The effect was also prevented by infiltrating the tissues distal to the tourniquets with 0.5% bupivacaine 15 min after their application. This was not effective if delayed until 105 min after application. We conclude that the afferent impulses that produce this effect ascend in the same part of the spinal cord as those concerned in neuroendocrine responses to trauma. Other effects of tourniquets on the responses to lowering the ambient temperature, i.e., the reduction in slope of the regression line realting the intensity of shivering to ambient temperature and the reduction in the increase in colon temperature, were not corrected by any of these procedures.     

Effects of bradykinin and indomethacin on cyclic GMP and cyclic AMP in lung slices

Bradykinin, 1-100 mug/ml, produced a rapid rise in the concentration of 3':5'-guanosine monophosphate (cyclic GMP) and 3':5'-adenosine monophosphate (cyclic AMP) in slices of guinea pig lung. Concentrations of both nucleotides reached a maximum in about 2 min, then declined to a basal levels in 6-12 min. The transient nature of the effect was presumbaly due to the rapid destruction of bradykinin as evidenced by (1) reaccumulation of nucleotides when bradykinin was added a second time, and (2) potentiation of the bradykinin effects by pyroGlu-Lys-Trp-Ala-Pro, a peptide that inhibits inactivation of bradykinin by kininase. It has been reported elsewhere that histamine, prostaglandins E(1) and E(2), and beta-adrenergic stimulation can cause accumulation of cyclic AMP in lung slices without affecting cyclic GMP concentration, whereas acetylcholine increases the concentrations of both cyclic GMP and cyclic AMP. Thus it was possible that the effects of bradykinin were indirect, i.e., secondary to release of one or more of these compounds. Promethazine (an antihistamine), propranolol (a beta-adrenergic blocking agent) and atropine (an anticholinergic agent) did not alter basal cyclic nucleotide concentrations or the effects of bradykinin. Two inhibitors of prostaglandin synthesis, indomethacin and aspirin, which alone were without effect, in the presence of bradykinin completely prevented the rise in cyclic AMP but did not interfere with cyclic GMP accumulation. Similarly, the effect of acetylcholine on cyclic AMP was abolished by indomethacin while that on cyclic GMP was unaltered. We suggest that in lung and probably in other tissues, bradykinin, acetylcholine, and perhaps other stimuli enhance the synthesis and release of prostaglandins as one of the consequences of their effects on cyclic GMP metabolism.     

Suppression of premature ventricular contractions by acebutolol.

The antiarrhythmic action of the beta-blocking drug, acebutolol, was evaluated in patients with frequent premature ventricular contractions (PVCs). In the 12 hours following administration of a single 300 mg oral dose, 8 of 10 patients showed a greater than 50% reduction in PVC frequency, and statistical analysis indicated that PVC reduction persisted for 10 hours after the single dose. Analysis of plasma concentrations of acebutolol and an acetyl metabolite indicated that after single oral doses of plasma concentrations of the metabolite exceed those of unchanged acebutolol. When patients were studied during periods of 300 mg doses every 8 hours, eight of 11 showed a 70% reduction in PVC frequency, and analysis showed that the therapeutic effect was present throughout the 24-hour monitoring period. Acebutolol slowed the heart rate and prolonged the PR interval without affecting the QT interval. Significant clinical or laboratory toxicity was not encountered. In the small group studied, acebutolol was found to be safe and effective for short-term administration to patients with frequent PVCs and possessed a relatively long duration of antiarrhythmic action.     

Changes in cyclic adenosine 3':5'-monophosphate-dependent protein kinases during the progression of urethan-induced mouse lung tumors

The cyclic adenosine 3':5'-monophosphate (cAMP)-dependent protein kinases in lung adenomas are functionally different from those of normal lung. The relevance of this change to neoplastic conversion was examined by comparing tumor kinases with those obtained from the normal cell of origin and by studying the kinases at different stages of tumor growth. Lung tumors were collected from A strain mice at different times after a single injection of urethan. These tumors are predominantly of alveolar type two cell origin, and cAMP-binding proteins in extracts from isolated type two cells and from lung adenomas at various stages of tumor progression were compared. Both the incorporation of the cAMP photoaffinity analogue, cyclic 8-azidoadenosine 3':5'-[32P]monophosphate (8-N3-[32P]cAMP), into the regulatory subunits of the type I (RI) and type II (RII) cAMP-dependent protein kinases and the autophosphorylation of RII were similar in extracts from whole normal lung and from type two cells. Altered protein kinases are thus not characteristic of normal type two cells. Lung tumors showed a decrease in photodetectable RII which correlated in degree with tumor size and extent of anaplasticity. This decreased RII photolabeling during tumor growth was associated with increased RII autophosphorylation. In contrast, decreased RII photolabeling in extracts from neonatal lung is accompanied by a substantial decrease in RII autophosphorylation. The characteristics of RII during normal development thus clearly differ from those during neoplastic development. An increase in the amount of an Mr 37,000 proteolytic fragment derived from R-subunits was also noted as a function of tumor progression. DEAE-cellulose chromatography of tumor cytosol showed that the increase in the amount of Mr 37,000 protein was accompanied by increased subunit dissociation of the type I isozyme. The dissociated RI subunit has been shown to be more sensitive to cleavage by a Ca2+-dependent neutral protease than when RI was in the holoenzyme form. This protease is present in both normal lung and lung adenomas, and its activity increases during the later stages of tumor progression. A comparison of cAMP binding and the light-induced covalent incorporation of 8-N3-[32P]cAMP showed that, for both RI and RII, photoincorporation was about 75% as efficient as noncovalent binding. In contrast, although the Mr 37,000 fragment can be photolabeled with low concentrations of 8-N3-[32P]cAMP, noncovalent cAMP binding to the endogenous Mr 37,000 fragment could not be demonstrated with a standard filtration assay. Such altered cAMP binding characteristics following Ca2+-dependent proteolysis of R-subunits would all     

Pharmacokinetics of anthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 days

Eleven subjects completed a clinical trial to determine the safety/tolerability of freeze-dried black raspberries (BRB) and to measure, in plasma and urine, specific anthocyanins-cyanidin-3-glucoside, cyanidin-3-sambubioside, cyanidin-3-rutinoside, and cyanidin-3-xylosylrutinoside, as well as ellagic acid. Subjects were fed 45 g of freeze-dried BRB daily for 7 days. Blood samples were collected predose on days 1 and 7 and at 10 time points postdose. Urine was collected for 12 hours predose on days 1 and 7 and at three 4-hour intervals postdose. Maximum concentrations of anthocyanins and ellagic acid in plasma occurred at 1 to 2 hours, and maximum quantities in urine appeared from 0 to 4 hours. Overall, less than 1% of these compounds were absorbed and excreted in urine. None of the pharmacokinetic parameters changed significantly between days 1 and 7. In conclusion, 45 g of freeze-dried BRB daily are well tolerated and result in quantifiable anthocyanins and ellagic acid in plasma and urine.     

Safety and efficacy of reoperative carotid endarterectomy: a 14-year experience

BACKGROUND: Reoperative carotid endarterectomy (CEA) is an accepted treatment for recurrent carotid stenosis. With reports of a higher operative morbidity than primary CEA and the advent of carotid stenting, catheter-based therapy has been advocated as the primary treatment for this reportedly "high-risk" subgroup. This study reviews a contemporary experience with reoperative CEA to validate the high-risk categorization of these patients. METHODS: From 1989 to 2002, 153 consecutive, isolated (excluding CEA/coronary artery bypass graft and carotid bypass operations) reoperative CEA procedures were reviewed. Clinical and demographic variables potentially associated with the end points of perioperative morbidity, long-term durability, and late survival were assessed with multivariate analysis. RESULTS: There were 153 reoperative CEA procedures in 145 patients (56% men, 36% symptomatic) with an average age of 69 +/- 1.3 years. The average time from primary CEA (68% primary closure, 23% prosthetic, 9% vein patch) to reoperative CEA was 6.1 +/- 0.4 years (range, 0.3 to 20.4 years). At reoperation, patch reconstruction was undertaken in 93% of cases. The perioperative stroke rate was 1.9%, with no deaths or cardiac complications. Other complications included cranial nerve injury (1.3%) and hematoma (3.2%). Average follow-up after reoperative CEA was 4.4 +/- 0.3 years (range, 0.1 to 12.7 years), with an overall total stroke-free rate of 96% and a restenosis rate (>50%) by carotid duplex of 9.2%. Among variables assessed for association with restenosis after reoperative CEA, only younger age was found to be significant (66 +/- 2.5 years vs 70 +/- 0.7 years, P < .05). The all-cause long-term mortality rate was 29%. Multivariate analysis of long-term survival identified diabetes mellitus as having a negative impact (hazard ratio, 3.4 +/- 0.3, P < .05) and lipid-lowering agents as having a protective effect (hazard ratio, 0.42 +/- 0.4, P < .05) on survival. CONCLUSION: Reoperative CEA is a safe and durable procedure, comparable to reported standards for primary CEA, for long-term protection from stroke. These data do not support the contention that patients who require reoperative CEA constitute a "high-risk" subgroup in whom reoperative therapy should be avoided.