Late rapid deterioration is a rare but lethal complication of ETV. The mechanism is unclear, but deterioration can occur long after the ETV becomes occluded. Patients and caregivers should be counseled regarding this potential complication. An indwelling ventricular access device is an option for patients undergoing ETV.
Glutamate excitotoxicity is a putative mechanism of secondary damage after traumatic brain injury (TBI). No relationship between glutamate release and clinical status has been shown in humans, however. We hypothesize a dose-response relationship between CSF glutamate concentrations and severity of injury, electrophysiological deterioration as measured by somatosensory evoked potential amplitudes, and clinical outcome. From August 1991 to March 1996, intensive monitoring of 55 patients with severe TBI (GCS < or = 8 after resuscitation) included twice daily CSF glutamate levels and hourly somatosensory evoked potentials (SSEPs) for an average of 5 days. Clinical outcomes were survival/nonsurvival and Glasgow outcome score (GOS) at 3 months or more post-injury. Glutamate levels were not associated with severity of injury, electrophysiological deterioration, or clinical outcome. Neither peak nor mean glutamate levels significantly improved a simple logistic regression model which used only age and presence of bilaterally unreactive pupils to predict survival. Using this methodology CSF glutamate concentrations did not display a dose-response relationship to severity of injury, electrophysiological deterioration, or predict clinical outcomes following TBI in a group of 55 patients. An early effect of glutamate, an effect dependent on time of exposure to glutamate or other modulating effects cannot be ruled out.
Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.
This prospective review of adult patients with head injuries examines the incidence of head injuries due to falls caused by seizures, the incidence and severity of intracranial hematomas, and the morbidity and mortality rates in this patient population. A head injury was attributed to a fall caused by a seizure if the seizure was witnessed to have caused the fall, or the patient had a known seizure history, appeared postictal or was found convulsing after the fall, and no other cause for the fall was evident. A total of 1760 adult head-injured patients were consecutively admitted to the authors' service between 1986 and 1993. Five hundred eighty-two head injuries (33.1%) were due to falls and 22 (3.8%) of these were caused by seizures. Based on the prevalence rates for epilepsy in the general population of 0.5 to 2%, these results indicate that epileptics are several times more likely to suffer a head injury due to a fall. Mass lesions were found in 20 (90.9%) of these 22 patients and the remaining two patients suffered mild diffuse head injuries. There was a high incidence of extraaxial mass lesions: 17 (85%) of the 20 intracranial hematomas were either epidural (five cases) or acute subdural (12 cases) hematomas. Eighteen (81.8%) of the 22 patients required evacuation of a hematoma. Both the incidence of intracranial hematomas (90.9% vs. 39.8%, p < 0.001, chi-square analysis) and the rate of hematoma evacuation (81.8% vs. 32.3%; p < 0.001) was significantly greater in patients injured in falls due to seizures (22 cases) than in the group injured in falls from all other causes (560 cases). The higher incidence of hematomas and the need for evacuation were not explained by differences in age, seventy of head injury, or incidence of alcohol intoxication. Despite the greater incidence of mass lesions and the need for operative treatment in patients injured because of seizures, their mortality rate was similar to that of patients injured in falls from other causes. On the basis of their review of patients admitted to a neurosurgical center with complaints of head injury, the authors conclude that patients with head injuries due to a fall caused by a seizure should undergo computerized tomography scanning early in their management. Until a mass lesion has been excluded, any decrease in level of consciousness or focal neurological deficit should not be attributed to the seizure itself.
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