Treatment with transducible phosphopeptide analogues of the small heat shock-related protein, HSP20, after experimental subarachnoid hemorrhage: prevention and reversal of delayed decreases in cerebral perfusion.

OBJECT: Delayed vasospasm is a significant cause of morbidity and mortality after subarachnoid hemorrhage (SAH). Proteomic therapeutics offers a new modality in which biologically active proteins or peptides are transduced into cells via covalent linkage to cell permeant peptides (CPPs). The hypothesis of this study was that either intrathecal or intravenous delivery of a phosphopeptide mimetic of the small heat shock-related protein, HSP20, linked to a CPP, would inhibit delayed decreases in cerebral perfusion after experimental SAH in a rat model. METHODS: This study was conducted in 3 parts: 1) prevention and 2) reversal of delayed decreases in cerebral perfusion via either intrathecal or intravenous administration of a CPP linked to phosphopeptide mimetics of HSP20 (AZX100) and 3) determining the effect of intravenous administration of AZX100 on blood pressure and heart rate. Subarachnoid hemorrhage was induced in rats by endovascular perforation. Subsequently, AZX100 was administered intrathecally via a cisternal catheter or intravenously. Cerebral perfusion was determined by laser Doppler monitoring. Blood pressure was monitored by telemetry in a separate group of naïve animals treated with AZX100 for 24 hours. RESULTS: The maximal decrease in cerebral perfusion occurred 3 days after SAH. Cisternal administration of AZX100 (0.14-0.57 mg/kg) 24 hours after hemorrhage prevented decreases in cerebral perfusion after SAH. Animals receiving lower doses of AZX100 (0.068 mg/kg) or a scrambled sequence of the active HSP20 peptide linked to CPP developed decreases in cerebral perfusion similar to those seen in control animals. Intravenous administration of AZX100 (1.22 mg/kg) 24 hours after hemorrhage prevented the decreases in cerebral perfusion seen in the controls. Intravenous administration (0.175 mg/kg and 1.22 mg/kg) of AZX100 on Days 2 and 3 after SAH reversed decreases in cerebral perfusion as early as Day 3. There was no impact of AZX100 on blood pressure or heart rate at doses up to 2.73 mg/kg. CONCLUSIONS: Cisternal administration of AZX100 24 hours after hemorrhage prevented decreases in cerebral perfusion. Intravenous administration of AZX100 also prevented and reversed decreases in cerebral perfusion at doses that did not induce hypotension. Transduction of biologically active motifs of downstream regulators like HSP20 represents a potential novel treatment for SAH.

Golf-associated head injury in the pediatric population: a common sports injury.

OBJECT: Golf-related injuries constitute a common type of sports injury in the pediatric population. The increase in the frequency of these injuries is largely attributed to the increase in the popularity of golf and greater use of golf carts by children. METHODS: The purpose of this study was to investigate the mechanisms and complications associated with golf-related injuries in the pediatric population and, by doing so, assist in the prevention of such injuries. We reviewed the charts of 2546 pediatric patients evaluated by the neurosurgery service at the authors' institution over a 6-year period. There were 64 cases of sports-related injuries. Of these, 15 (23%) were golf-related, making these injuries the second-largest group of sports-related injuries. Depressed skull fracture was the most common injury observed. Neurosurgical intervention was required in 33% of the cases. With rare exceptions, patients made good recoveries during a mean follow-up period of 22.2 months. One death occurred due to uncontrollable cerebral edema following a golf cart accident. One child required shunt placement and several revisions following an injury sustained from a golf ball. CONCLUSIONS: Children should be advised on the proper use of golf equipment as a preventive measure to avoid these injuries. Precautionary guidelines and safety training guidelines should be established. The institution of a legal minimum age required to operate a golf cart should be considered.

Distal anterior inferior cerebellar artery aneurysms. Report of four cases.

Aneurysms of the distal anterior inferior cerebellar artery (AICA) are rare; fewer than 100 cases have been reported. The authors detail their experience with four cases and present endovascular as well as microsurgical management options. The medical records and neuroimaging studies obtained in four patients who were treated at a single institution were reviewed. Clinical presentations, neuroimaging and intraoperative findings, and clinical outcomes were analyzed. There were three men and one woman; their mean age was 43 years. Two patients presented with acute subarachnoid hemorrhage (SAH), and two presented with ataxia and vertigo (one with tinnitus, the other with hearing loss). Angiographic studies demonstrated aneurysms of the distal segment of the AICA. In one patient with von Hippel-Lindau syndrome and multiple cerebellar hemangioblastomas, a feeding artery aneurysm was found on a distal branch of the AICA. Three of the patients underwent successful surgical obliteration of their aneurysms, one by clipping, one by trapping, and one by resection along with the tumor. The fourth patient underwent coil embolization of the distal AICA and the aneurysm. All patients made an excellent neurological recovery. Patients with aneurysms in this location may present with typical features of an acute SAH or with symptoms referable to the cerebellopontine angle. Evaluation with computerized tomography, magnetic resonance (MR) imaging, MR angiography, and digital subtraction angiography should be performed. For lesions distal to branches coursing to the brainstem, trapping and aneurysm resection are viable options that do not require bypass. Endovascular obliteration is also a reasonable option, although the possibility of retrograde thrombosis of the AICA is a concern.

Heat shock protein expression in cerebral vessels after subarachnoid hemorrhage.

OBJECTIVE: The mechanisms of cerebral vasospasm after subarachnoid hemorrhage (SAH) remain controversial. Recent data have implicated two small heat shock proteins (HSPs), namely HSP20 and HSP27, in the regulation of vascular tone. Increases in the phosphorylation of HSP20 are associated with vasorelaxation, and increases in the phosphorylation of HSP27 are associated with impaired vasorelaxation. Therefore, we hypothesized that alterations in the expression and/or phosphorylation of these two small HSPs might play a role in cerebral vasospasm after SAH. METHODS: A rat model of endovascular perforation was used to induce SAH. Middle cerebral arteries were harvested from control animals, sham-treated animals, and animals with SAH, 48 hours after SAH induction. Dose-response curves for endothelium-independent (sodium nitroprusside, 10(-8) to 10(-4) mol/L) and endothelium-dependent (bradykinin, 10(-10) to 10(-5) mol/L) relaxing agents were recorded ex vivo. Physiological responses were correlated with the expression and phosphorylation of HSP20 and HSP27 by using one- and two-dimensional immunoblots. RESULTS: There was impaired endothelium-independent and endothelium-dependent relaxation in cerebral vessels after SAH. These changes were associated with decreased expression of both total and phosphorylated HSP20 and increases in the amount of phosphorylated HSP27. CONCLUSION: In this model, impaired relaxation of cerebral vessels after SAH was associated with increases in the amount of phosphorylated HSP27 and decreases in the expression and phosphorylation of HSP20. These data are consistent with alterations in the expression and phosphorylation of these small HSPs in other models of vasospasm.