Intestinal hemorrhage from exposure to pulsed ultrasound

Threshold exposures for producing intestinal hemorrhage in mice were determined using focused sources operating at 0.7, 1.1, 2.4 and 3.6 MHz. The choice of pulse length (10 microseconds) and pulse repetition frequency (100 Hz) made the exposures diagnostically relevant, while at the same time, minimized possible thermal contributions to the mechanism of action of the ultrasound. Each animal was irradiated at four to five abdominal sites for 5 min per site. Suprathreshold lesions ranged from small petechiae to hemorrhagic regions extending 4 mm or more along the intestine, depending upon the exposure levels. Higher frequencies were less effective in producing intestinal hemorrhage than lower frequencies. Thermocouple measurements of temperature rise in the intestine during ultrasound exposure revealed temperature increments between 1 degrees and 2 degrees C at the highest exposure levels. The frequency dependence of the production of intestinal hemorrhage together with the observed limited heating is consistent with a cavitation-related mechanism of action of pulsed ultrasound.     

Adeno-associated virus 2-mediated transduction and erythroid cell-specific expression of a human beta-globin gene

Two strategies for crossbreeding of indigenous and exotic cattle for milk production in the tropics, viz. rotational crossing and formation of a composite breed, have been compared. Genetic considerations suggest that rotational crossing would lead to somewhat better dairy performance, mainly because of more heterozygosity. Predictions based on the performance of adjacent genetic groups as obtained from a comprehensive literature review point in the same direction. Rotational crossbreeding depends on a continuous introduction of bulls of both parental breeds. The herd will consist of 2 (or more) genetic groups, which might be inconvenient for breeding arrangements, but provides more flexibility. The system requires good organisation and is most suitable in large farms. In small scale dairying the composite breed strategy is the most practical approach to dairy cattle breeding in the tropics.     

Estrogen modulation: tiered testing for human hazard evaluation. American Industrial Health Council, Reproductive and Developmental Effects Subcommittee

Recent concerns about the potential of certain chemicals to modulate estrogen-regulated processes have led to questions as to how chemicals should be tested for such effects. Therefore, AIHC has developed a comprehensive, resource-efficient, and flexible tiered strategy for estrogen modulation (EM) testing. Levels of evaluation include Tier 0, in which exposure, along with alerts based on structure-activity, persistence, bioaccumulation, and other data, are assessed to prioritize chemicals for preliminary testing. In Tier I, short term in vitro, ex vivo, and/or in vivo assays are used to obtain a preliminary indication of EM potential. Among these, an in vivo response assay is considered the most reliable at this time. However, none of these tests are intended for risk assessment, but rather to aid in choosing chemicals for further testing and in guiding the extent of that testing. Tier II is aimed at risk assessment and involves whole animal tests that contain EM-sensitive end points (e.g., two-generation reproduction study). Tier III consists of hypothesis-driven research reserved for situations where targeted research can reduce levels of uncertainty. This tiered approach provides a framework for the strategic and effective application of EM test methods to address specific information needs on a case by case basis.     

Application of rearrangements of T cell receptor gene in the diagnosis of mediastinal T-lymphoblastic lymphoma: a case report

Liver veno-occlusive disease is a severe toxic effect observed after bone marrow transplantation. Clinical manifestations are jaundice, painful liver enlargement, and fluid-sodium retention. Histologically there is non-thrombotic obliteration of the centro-lobular veins associated with centro-lobular necrosis. This severe complication of bone marrow transplantation occurs early and is caused by a toxic processing effect. Incidence is variable, 2 to 50% in reported series, depending on patients, type of marrow provessing and on diagnostic criteria (which hinders comparison between studies). According to most studies, veno-occlusive disease regresses spontaneously. Mortality, depending on the severity of the symptoms, varies from 20 to 50%. Pathogenesis remains under debate: the initial event would occur in the sinusoid endothelium creating a state of local hypercoagulability by release of tissue factors favoring deposit of coagulation factors, especially factor VIII, in the subendothelial region of the veinules. There is also a direct toxic effect on centro-lobular hepatocytes which is further aggravated by ischemia and venous stasis. use of heparin to prevent veno-occlusive disease was proposed by the Besan?on group in 1985 after they observed a low incidence (1 case in 65) in patients who were given low doses of heparin to maintain patent central catheters. The same team confirmed in 1992 the low incidence in a large retrospective series of 444 patients given either an autograft (3 cases in 253 patients, i.e. 1.2%), or an allograft (5 cases in 191 patients, i.e. 2.6%). Two single-center studies, one in Seattle and the other at the Saint-Antoine hospital in Paris, published in 1990 and 1991, did not show any difference in patients given heparin or not. Inversely, a randomized study published by Attal in 1992 including 161 patients showed a significant difference in the incidence of veno-occlusive disease between patients given heparin (2.5%) and those who were not given heparin (13.7%; p < 0.01). All these studies show that with low doses (100-150 U/kg) the risk is very very low. The mechanism of action of heparin would appear to be related to its protective effect on the endothelium rather than its hemostasis effect. The vascular protective effect of prostaglandin E1 suggests it might also be useful in preventing veno-occlusive disease.     

Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity

Excessive activation of NMDA receptors is thought to mediate the calcium-dependent neurotoxicity associated with hypoxic-ischemic brain injury, trauma, epilepsy, and several neurodegenerative diseases. For this reason, various NMDA antagonists have been investigated for their therapeutic potential in these diseases, but heretofore none have proven to be both effective and safe. In the present study, memantine, an adamantane derivative similar to the antiviral drug amantadine, is shown to block the channels activated by NMDA receptor stimulation. From whole-cell and single-channel recording experiments, the mechanism of action of memantine is deduced to be open-channel block, similar to MK-801; however, unlike MK-801, memantine is well tolerated clinically. Compared to MK-801, memantine's safety may be related to its faster kinetics of action with rapid blocking and unblocking rates at low micromolar concentrations. Furthermore, at these levels memantine is an uncompetitive antagonist and should theoretically allow near-normal physiological NMDA activity throughout the brain even in the face of pathologically high focal concentrations of glutamate. These pharmacological properties confer upon memantine a therapeutic advantage against NMDA receptor-mediated neurotoxicity with few side effects compared with other organic NMDA open-channel blockers. Moreover, memantine is increasingly effective against escalating levels of glutamate, such as those observed during a stroke. Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model. These results suggest that memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMDA receptor-mediated neurotoxicity.     

Purification of enolase and phosphoglycerate mutase from human brain and formation of a bienzymatic complex from them

Neuron-specific enolase and phosphoglycerate mutase with specific activities of 106 and 215 U/mg, respectively, have been purified from human brain. Hydrophobic chromatography for enolase and blue Sepharose affinity chromatography for phosphoglycerate mutase were used as the last steps of purification. A heterobifunctional complex with fully preserved enolase and phosphoglycerate mutase activities was synthesized with the use of a bifunctional reagent, N-succinimidyl 3-(2-pyridyldithio)propionate. Autoantibodies to the conjugate will be used for identifying the bienzymatic complex in vivo.