Use of calcitonin for the treatment of an odontoid fracture. Case report.

The authors report on the efficacy of nonsurgical treatment of an older patient with a fractured odontoid process. The patient, an 85-year-old woman, had multiple medical problems that put her at an increased surgery-related risk. Therefore, an alternative approach was elected, including immobilization with a Philadelphia collar and the provision of calcitonin nasal spray. Bone union and clinical recovery were achieved within 8 weeks of initiating the nasal calcitonin therapy (12 weeks postinjury). Considering the patient's age, comorbidities, and the severity of the fracture, the recovery period was unusually short. The authors believe that calcitonin played a pivotal role in the healing process of the fractured odontoid bone. There is no question that the fusion in this patient could be unrelated to the medical therapy. This description of one patient, as well as the lack of a large randomized study, precludes any scientific conclusions. Nevertheless, the authors believe that the development of a successful fusion in this high-risk patient should be reported as an observation that merits confirmation and study. The authors also discuss the physiological effects of calcitonin and the research and clinical experience with this hormone in different conditions affecting bone.

Prospects for gene therapy in pediatric neurosurgery.

Gene therapy represents a powerful tool for both the study and potential treatment of pediatric neurological diseases. The majority of strategies for brain gene therapy have focused upon the use of modified viruses as vehicles for efficient delivery of genes into cells of the central nervous system. Retroviruses were originally the most popular vehicles for gene transfer outside the brain; however, these only function in actively dividing cells and have thus been limited to developmental neurobiology and treatment of brain tumors. Viruses with DNA-based genomes can transfer genes to both dividing and nondividing cells such as neurons, and these include adenovirus, adeno-associated virus and herpes simplex virus. Each system has special features, and the choice of vehicle may be based upon a variety of factors including toxicity or immunogenicity of the vector in vivo, size of the gene which can be inserted, titer of virus which can be obtained and technical difficulty in generating reagent grade viruses. Pediatric patients present unique opportunities for gene therapy, and inherited genetic defects and brain tumors are among the pediatric disorders which would most benefit from this new field. Preclinical studies using each of these systems in a variety of models of pediatric CNS disease have proven promising. Several ongoing studies have been initiated for treatment of pediatric brain tumors, and a protocol for treatment of an inherited neurological defect has recently achieved approval for initial clinical trials. Continued advances in gene therapy technology and delivery systems combined with the explosion of available genetic information should make gene therapy an increasingly important tool for the future of pediatric neurosurgery.

Attenuation of acute lung injury caused by hind-limb ischemia-reperfusion injury by butyrolactone anti-inflammatory agent FL1003.

OBJECTIVE: Activation of systemic inflammation after reperfusion of ischemic tissue results in severe acute lung injury. Neutrophil activation and oxygen radical generation have been implicated in the pathogenesis. This study tested the hypothesis that treatment with FL1003, a butyrolactone with in vitro antioxidant properties, will down-regulate this response and abrogate acute lung injury. METHODS: Male Sprague-Dawley rats (n = 16) were divided into a surgical sham group (n = 4), a group that received 2 hours of ischemia by infrarenal aortic clip followed by 1 hour of reperfusion (n = 7), and an ischemia-reperfusion (I/R) group that received FL1003 100 mg/kg intravenously before ischemia (n = 5). After reperfusion, the heart and lungs were excised en bloc in an isolated lung perfusion apparatus for 1.5 hours of perfusion, while pulmonary artery pressures were held between 5 and 12 mm Hg and venous effluent was collected. Bronchoalveolar lavage fluid and both lungs were harvested at death for determination of tissue water content, pulmonary microvascular permeability, and indicators of neutrophil activation and tissue oxidation. RESULTS: After I/R, there were significant (p < 0.05) increases in intravenous fluid (IVF) requirements (18 +/- 1.2 mL) to maintain hemodynamic stability, wet weight/dry weight ratio of lung tissue, and isolated-lung lavage Ficoll concentrations (0.58 +/- 0.02 microg/mL) compared with sham animals (IVF, 0 mL; Ficoll concentration, 0.08 +/- 0.03 microg/mL). In addition, lung myeloperoxidase activity (0.60 +/- 0.03 vs. 0.12 +/- 0.02 units/g of tissue) and levels of lipid-conjugated dienes (0.042 +/- 0.012 vs. 0.018 +/- 0.006 optical density of 233 nm (OD233)/mL) were significantly higher (p < 0.05) compared with the sham group. In I/R animals treated with FL1003, the IVF requirement (8.5 +/- 1.0 mL), wet weight/dry weight ratio, lung tissue Ficoll concentration (0.21 +/- 0.02 microg/mL), myeloperoxidase concentration (0.217 +/- 0.02 units/g), and lipid-conjugated diene levels (0.012 +/- 0.005 OD233/ mL) were all significantly lower (p < 0.05) than after untreated I/R. CONCLUSION: A pulmonary microvascular permeability defect with pulmonary edema, neutrophil aggregation, and cell membrane damage resulted from ischemia and reperfusion. Treatment of animals with FL1003 significantly attenuated the inflammatory response associated with acute lung injury.

Mechanisms of cerebrovascular dysfunction.

Cerebrovascular dysfunction characterized by the loss of endothelial integrity has been observed following ischemic and traumatic insults to the brain, resulting in the net movement of fluid and solute out of the intravascular space and into the interstitium. Following traumatic brain injury, the development of intracranial hypertension secondary to cerebral edema plays a major role in the high morbidity and mortality in these patients. Although the precise mechanisms responsible for the disruption of the normally tightly regulated cerebrovascular tissue interface remain unclear, there is increasing evidence implicating inflammatory events in this process through the transient opening of tight junctional complexes. This article will examine the interaction of astrocytes, activated neutrophils, and inflammatory mediators in inducing endothelial contraction, thereby physically opening the permeability barrier and allowing the net movement of fluid out of the intravascular space.

Changes of MPO activity and brain water accumulation in traumatic brain injury experiments.

Comparison of brain tissue water content (BWC) data with myeloperoxidase activity assay (MPO) allows for analysis of the complex pathophysiological mechanisms of cerebral edema following catastrophic brain injuries. The neuroprotective effect of an experimental anti inflammatory drug (FL1003, butyrolactone) was tested in a traumatic brain injury (TBI) model using BWC and MPO analysis. We conducted these studies on a mini-pig model of severe TBI that is well characterized in our laboratory. The animals were divided into three animal groups: no injury, no treatment (control), injured and treated with FL1003, and injured, untreated with FL1003. They were maintained with fluids for 24 hours under general anesthesia. We employed the MPO assay to identify the degree of inflammatory cellular response (polymorphonuclear leukocytes, PMNLs) 24 hours following TBI and calculated brain density from the data of the gravimetric (Percoll) column method for BWC on brain samples. Our results demonstrated increased infiltration of PMNLs and a shift of water into the extravascular space in the injured animals. These changes were significantly (P < 0.05) attenuated in the animal group treated with FL1003.