Blocking brain‐derived neurotrophic factor inhibits injury‐induced hyperexcitability of hippocampal CA3 neurons

Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin‐related kinase B (TrkB), a receptor for brain‐derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF‐mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury‐induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB‐Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB‐Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two‐fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB‐Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB‐Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury‐induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post‐traumatic epilepsy. Therefore, our data suggest that blocking the BDNF–TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post‐traumatic epilepsy.     

Neurotransmitter receptors mediate cyclic GMP formation by involvement of arachidonic acid and lipoxygenase.

Evidence is presented that has led us to abandon the hypothesis that receptor-mediated cyclic GMP formation in cultured nerve cells occurs via the influx of extracellular calcium ions and an increase in the cytosolic free calcium ion concentration. While the cyclic GMP response is absolutely dependent on the presence of Ca2+, there is no increase in free intracellular Ca2+ subsequent to agonist stimulation. Instead, we have found that muscarinic or histamine H1 receptor stimulation elicits the release of arachidonic acid through a quinacrine-sensitive mechanism, possibly phospholipase A2. Inhibition of the release or metabolism of arachidonate by the lipoxygenase pathway prevents receptor-mediated cyclic GMP formation. We hypothesize that neurotransmitter receptors that mediate cyclic GMP synthesis function by releasing arachidonic acid and that an oxidative metabolite of arachidonic acid then stimulates soluble guanylate cyclase.     

The cytoskeleton in Chediak-Higashi syndrome fibroblasts

The Chediak-Higashi syndrome (CHS) trait is expressed in cultured human skin fibroblasts as an abnormal perinuclear concentration of moderately enlarged lysosomes. The cytoskeleton of CHS fibroblasts appears intact. Microtubules are normal in number and morphology, as assessed by colchicine binding studies, antitubulin immunofluorescence, and electron microscopy. Deformability by shear force is unaltered and microfilaments are abundant. However, CHS lysosomes appear to interact abnormally with the cytoskeleton, since the perinculear aggregation partially disperses after depolymerization of cell microtubules with colchicine. These results suggest that CHS is associated with a defect of either the lysosomal membrane itself or of lysosomal membrane- microtubule interaction.     

A laboratory model for studying blast overpressure injury

Blast injury remains an important source of trauma in both civilian and military settings. We have studied a recently developed blast wave generator to evaluate its effectiveness for laboratory study of blast injury. In order to determine the reliability of the device and the pathology of the lesions caused by the short duration (0.5-1.0 msec), and high intensity (60-375 psi) pressure wave, laboratory rats were exposed to the pressure waves generated by the machine. The animals were divided into three groups: the first exposed to midthoracic blasts, the second to abdominal blasts, and a group of controls exposed to a gentle stream of gas. Group I showed gross and microscopic evidence of lung blast injury of "rib imprint" hemorrhages, intra-alveolar hemorrhage, marked increase in lung weight, prolonged apnea, and bradycardia. Group II showed typical blunt abdominal trauma at the closest ranges, but characteristic submucosal hemorrhages up to 4.0 cm from the blast nozzle. In both groups, a protective effect was seen in heavier animals. The blast wave generator permits reproducible blast injury in the laboratory that is safer and faster than current methods. The lung and bowel lesions induced are grossly and microscopically similar to injuries of blast exposure seen in clinical patients.     

Management of a large intraoperative type IIIb endoleak in a bifurcated endograft-a case report

The purpose of this paper is to describe the intraoperative management of a type IIIb endoleak after deployment of a bifurcated endograft in a patient with narrow iliac access vessels. A 62-year-old man underwent elective endovascular repair (EVAR) of a 53 mm abdominal aortic aneurysm. After device deployment, a large IIIb endoleak, arising from the main body of the device, was visualized. Narrow iliac vessels precluded deployment of a second bifurcated graft, and the endoleak was successfully excluded with an aortomonoiliac device, followed by contralateral iliac occlusion and subsequent creation of a femorofemoral bypass. At 1-year follow-up, the aneurysm remains excluded and is decreasing in size. Type III endoleaks are a known complication of EVAR, requiring immediate treatment through their association with aneurysm enlargement and rupture. If an additional bifurcated graft cannot be used, aortomonoiliac conversion represents a feasible endovascular alternative treatment for type III endoleaks, other than conversion to open surgical repair. Therefore, aortomonoiliac converters with appropriate occluder devices should be readily available during deployment of bifurcated devices.