No abstract

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.

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.

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.

We report the presence of quadrigeminal cistern arachnoid cysts in siblings.

We report on our experience with long-term monitoring of the EEG power spectrum and somatosensory evoked potentials (SSEPs) in 103 patients with severe closed head injury (Glasgow Coma Scale -GCS < 8). Patients were monitored for an average of 5 days post injury and monitoring was terminated when they died, regained consciousness or their intracranial physiologic parameters (primarily intracranial pressure -ICP) were stable for 2-3 days. Patients were treated according to a standard protocol that included mechanical ventilation, sedation, and neuromuscular blockade. At 7 of 9 twelve hour time intervals post injury, SSEPs were significantly (p < .05) different between outcome groups using the Glasgow Outcome Score collapsed to 3 categories. The percent slow (delta) activity in the EEG was not significantly different between outcome groups at any time point, post injury. The total power in the EEG power spectrum differed only at the last time epoch post injury (108 hr.). Based on the superior prognostic capabilities of the SSEP, we routinely base critical management decisions on SSEP values. We have not been able to rely on EEG parameters for these same decisions due to the lack of clear distinction between good and poor prognosis groups based on common EEG parameters. RESUME: Surveillance des trauniatismes craniens severes: comparaison de I'EEG et des potentiels evoques somesthesiques. Nous rapportons notre experience de surveillance a long terme du spectre de puissance EEG et des potentiels eVoques somethesiques (PESs) chez 103 patients ayant subi un traumatisme cranien ferine (echelle de coma de Glasgow < 8). Nous avons surveillS les patients pendant en moyenne 5 jours apres la lesion et la surveillance 6tait interrompue au d£ces, si le patient reprenait conscience ou si leurs parametres physiologiques intracranients (principalement la pression intracranienne -PIC) 6taient stables dupuis 2 ou 3 jours. Les patients Staient trails selon un protocole standard qui incluait la ventilation mecanique, , la sedation et le blocage neuromusculaire. Au septieme du neuf intervalles de 12 heures apres la lesion, les PESs dtatent significativemenl difKrents (p < 0.05) entre les groupes selon leur Evolution eValuee au moyen de l'6chelle de Glasgow reduite a trois categories. Le pourcentage d'activit6 lente (delta) n'etait pas significativement different entre les groupes selon leur evolution, quelque soit le dernier intervalle de temps apres le lesion (108 hrs). Comme la valeur pronostique des PESs est superieure, nos decisions critiques de traitement sont habituellement basees sur les valeurs de PESs. Nous n'avons pas pu nous fier sur les parametres EEG pour prendre ces decisions a cause de l'absence de distinction claire entre le groupe avec un bon pronostic et celui avec un mauvais pronostic sur la base de parametres EEG communs.Can. J. Neurol. Sci. 1998; 25: S7-S11 Given the limitations of the clinical neurological examination in comatose head injury patients, an objective, reliable measure of neurologic functio...

Arginine methylation is a prevalent post‐translational modification in eukaryotic cells. Two significant debates exist within the field: do these enzymes dimethylate their substrates in a processive or distributive manner, and do these enzymes operate using a random or sequential method of bisubstrate binding? We revealed that human protein arginine N‐methyltransferase 1 (PRMT1) enzyme kinetics are dependent on substrate sequence. Further, peptides containing an Nη‐hydroxyarginine generally demonstrated substrate inhibition and had improved KM values, which evoked a possible role in inhibitor design. We also revealed that the perceived degree of enzyme processivity is a function of both cofactor and enzyme concentration, suggesting that previous conclusions about PRMT sequential methyl transfer mechanisms require reassessment. Finally, we demonstrated a sequential ordered Bi–Bi kinetic mechanism for PRMT1, based on steady‐state kinetic analysis. Together, our data indicate a PRMT1 mechanism of action and processivity that might also extend to other functionally and structurally conserved PRMTs.