Aortic wall injury following intraoperative irradiation

The type, extent, and probability of vasculopathy in canine abdominal aortas were determined 5 years after large single radiation doses given intraoperatively (IORT) either alone or with fractionated doses of external beam irradiation (EBRT) to compare with the response following EBRT only. Young adult beagle dogs were used. For IORT, a 5 x 8 cm electron applicator was used to deliver 6 MeV electrons to the paraaortic region. For EBRT of the paraaortic region, 6 MV photons were given in variable total doses in 30 fractions in 6 weeks. For the combination, variable IORT doses were given following an EBRT dose of 50 Gy given in 2 Gy fractions in 5 weeks. Necropsies were performed 4 to 5 years after irradiation. Transverse sections of the aorta were examined for lesions. Probit analyses were done to determine the dose with a 50% probability to cause severe lesions of the aorta 5 years after treatment. The most severe lesions were variably organized thrombi which occupied at least a third of the luminal area or intimal surface of the aorta. Six dogs with thrombi had dissecting aneurysms. That occurred at doses as low as 25 Gy IORT plus 50 Gy EBRT (1 of 4 dogs). The doses with a 50% probability for causing aneurysms and/or severe thromboses of the aorta were 35 Gy IORT (95% C.I., 29 to 46 Gy) and 27 Gy IORT plus 50 Gy EBRT (95% C.I., 20-40 Gy). No large thrombi or aneurysms were observed 5 years after EBRT to doses as high as 80 Gy. Comparison of the ED50s for IORT alone to that of IORT combined with EBRT indicated that 50 Gy given in 25 fractions had the impact of about 8 Gy IORT. Based on the response of younger adult dogs it appears that IORT doses greater than 30 Gy alone or 20 Gy IORT combined with 50 Gy EBRT would be accompanied by a significant risk of life threatening lesions of the aorta. This is in contrast with several earlier reports indicating that the tolerance dose of canine aorta was 50 Gy IORT.     

Carbon monoxide and nitric oxide: interacting messengers in muscarinic signaling to the brain's circadian clock

Within the central nervous system, acetylcholine (ACh) functions as a state-dependent modulator at a range of sites, but its signaling mechanisms are yet unclear. Cholinergic projections from the brain stem and basal forebrain innervate the suprachiasmatic nucleus (SCN), the master circadian clock in mammals, and cholinergic stimuli adjust clock timing. Cholinergic effects on clock state require muscarinic receptor-mediated activation of guanylyl cyclase and cGMP synthesis, although the effect is indirect. Here we evaluate the roles of carbon monoxide (CO) and nitric oxide (NO), major activators of cGMP synthesis. Both heme oxygenase 2 (HO-2) and neuronal nitric oxide synthase (nNOS), enzymes that synthesize CO and NO, respectively, are expressed in rat SCN, with HO-2 localized to the central core of the SCN, whereas nNOS is a punctate plexus. Hemin, an activator of HO-2, but not the NO donor, SNAP, mimicked cholinergic effects on circadian timing. Selective inhibitors of HO fully blocked cholinergic clock resetting, whereas NOS inhibition partially attenuated this effect. Hemoglobin, an extracellular scavenger of both NO and CO, blocked cholinergic stimulation of cGMP synthesis, whereas l-NAME, a specific inhibitor of NOS, had no effect on cholinergic stimulation of cGMP, but decreased the cGMP basal level. We conclude that basal NO production generates cGMP tone that primes the clock for cholinergic signaling, whereas HO/CO transmit muscarinic receptor activation to the cGMP-signaling pathway that modulates clock state. In light of the recently reported inhibitory interaction between HO-2/CO and amyloid-beta, a marker of Alzheimer's disease (AD), we speculate that HO-2/CO signaling may be a defective component of cholinergic neurotransmission in the pathophysiology of AD, whose manifestations include disintegration of circadian timing.     

The effects of alpha-thalassaemia in HbSC disease

In HbSC disease, as in sickle cell anaemia, there is a spectrum of clinical severity. A reduced mean corpuscular volume and haemoglobin concentration, traits typical of thalassaemia, might retard sickling. We therefore ascertained the prevalence of alpha-thalassaemia in 53 adults with HbSC disease and related alpha-globin gene deletion to the haematologic and clinical findings. Alpha-globin genotype was identified by restriction endonuclease gene mapping. Indirect ophthalmoscopy and fluorescein angiography were used to document the presence of proliferative retinopathy. Bone necrosis and infarction were determined roentgenographically or by radionuclide scanning. Either heterozygous or homozygous alpha-thalassaemia-2 was present in 26% of patients. There was no relationship between alpha-globin genotype and haematocrit, pain crises, bone lesions, proliferation retinopathy or clinical severity score.     

A theoretical examination of the effects of gut wall metabolism,hepatic elimination,and enterohepatic recycling on estimates of bioavailability and of hepatic blood flow

A model including two eliminating compartments (the liver and the gastrointestinal mucosa) and a noneliminating compartment (the blood or central compartment) was developed to predict the effects of hepatic elimination, gastrointestinal mucosal metabolism, and the occurrence of enterohepatic recycling of a drug and its metabolites on the area under the blood concentrationtime curve (AUC). Several limiting cases where complete absorption or complete or nonexistent enterohepatic recycling of a drug and its metabolite occurred were only considered. Under linear kinetic conditions, the occurrence of hepatic elimination and enterohepatic recycling of a drug and its metabolite in the absence of intestinal mucosal metabolism should affect only the area under the curve and not the availability for both the intraperitoneal and the oral dose. In the presence of intestinal mucosal metabolism, the area under the curve should change with different routes of administration; a larger area, hence a higher availability, should occur after intraperitoneal administration than after oral administration of the drug. For a drug which is eliminated solely by the liver, apparent hepatic flow can be estimated by the dose divided by the difference in the area under the curve for an intravenous dose and the area under the curve for the same intraperitoneal or oral dose. In the absence of gastrointestinal mucosal metabolism, the presence of enterohepatic recycling of a drug and its metabolite should not affect the estimation of apparent hepatic blood flow. However, when gastrointestinal mucosal metabolism is present, there should be an overestimation of hepatic flow when AUC_i.p. and AUC_i.v. are used and a slight underestimation of hepatic flow when AUC_i.v. and AUC_p.o. are used.