John L. Moriarity

Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection.

In the penis, nitric oxide (NO) can be formed by both neuronal NO synthase and endothelial NOS (eNOS). eNOS is activated by viscous drag/shear stress in blood vessels to produce NO continuously, a process mediated by the phosphatidylinositol 3-kinase (PI3kinase)/Akt pathway. Here we show that PI3-kinase/Akt physiologically mediates erection. Both electrical stimulation of the cavernous nerve and direct intracavernosal injection of the vasorelaxant drug papaverine cause rapid increases in phosphorylated (activated) Akt and eNOS. Phosphorylation is diminished by wortmannin and LY294002, inhibitors of PI3-kinase, the upstream activator of Akt. The two drugs also reduce erection. Penile erection elicited by papaverine is reduced profoundly in mice with targeted deletion of eNOS. Our findings support a model in which rapid, brief activation of neuronal NOS initiates the erectile process, whereas PI3-kinase/Akt-dependent phosphorylation and activation of eNOS leads to sustained NO production and maximal erection.

The natural history of cavernous malformations: a prospective study of 68 patients

OBJECTIVE: Cavernous malformations are angiographically occult cerebrovascular malformations found in approximately 0.5% of the population. To help further understand the natural history of these lesions, we prospectively followed 68 patients harboring cavernous malformations. METHODS: The 68 patients in this study were all diagnosed radiographically (67 patients) or surgically (1 patient) and were entered into a patient database. Age, sex, clinical symptoms, seizure frequency, focal neurological deficits, and presence or absence of extralesional hemorrhage were all recorded at presentation. Patients were then followed prospectively to determine the rate of hemorrhage and new-onset seizures. RESULTS: The mean follow-up per patient was 5.2 years, and the total follow-up was 352.9 patient-years. There was an average of 3.4 lesions per patient. Thirteen of the patients (19%) had familial cavernous malformations. Patients with familial disease were more likely to have multiple lesions than patients with sporadic disease (85% versus 25%, respectively [P = 0.001]). Initial presentation included headache (65%), seizures (49%), and focal neurological deficit (46%). Eleven symptomatic, radiologically proven, extralesional hemorrhages occurred during the 352.9 patient-years of follow-up for an overall hemorrhage rate of 3.1% per patient-year. Female patients had a significantly higher prospective hemorrhage rate (4.2% per patient-year versus 0.9% per patient-year [P = 0.04]). A history of hemorrhage at presentation was not a risk factor for subsequent hemorrhage during follow-up. The rate of new-onset seizures was 2.4% per patient-year. CONCLUSION: The clinical presentation and prospective hemorrhage rate reported here agree well with findings of other prospective studies. This information, combined with our new-onset seizure rate, should aid clinicians caring for patients with cavernous malformations.

Phospholipase Cγ1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE

Phospholipase Cγ1 (PLC-γ1) hydrolyses phosphatidylinositol-4,5-bisphosphate to the second messengers inositol-1,4,5-trisphosphate and diacylglycerol. PLC-γ1 also has mitogenic activity upon growth-factor-dependent tyrosine phophorylation; however, this activity is not dependent on the phospholipase activity of PLC-γ1, but requires an SH3 domain. Here, we demonstrate that PLC-γ1 acts as a guanine nucleotide exchange factor (GEF) for PIKE (phosphatidylinositol-3-OH kinase (PI(3)K) enhancer). PIKE is a nuclear GTPase that activates nuclear PI(3)K activity, and mediates the physiological activation by nerve growth factor (NGF) of nuclear PI(3)K activity. This enzymatic activity accounts for the mitogenic properties of PLC-γ1.

Polymer Delivery of Camptothecin against 9L Gliosarcoma: Release, Distribution, and Efficacy

Camptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro; unfortunately, systemic toxicity has limited its in vivo efficacy. This is the first study to investigate the release, biodistribution, and efficacy of camptothecin from a biodegradable polyanhydride polymer. Tritiated camptothecin was incorporated into biodegradable polymers that were implanted intracranially in 16 male Fischer 344 rats and the animals were followed up to 21 days post-implant. A concentration of 11–45 μg of camptothecin-sodium/mg brain tissue was within a 3 mm radius of the polymer disc, with levels of 0.1 μg at the outermost margin of the rat brain, 7 mm from the site of implantation. These tissue concentrations are within the therapeutic ranges for human and rat glioma lines tested against camptothecin-sodium in vitro. The in vivo efficacy of camptothecin-sodium was evaluated with male Fischer 344 rats implanted intracranially with 9L gliosarcoma and compared with the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The animals were divided into four groups. Group 1 (control) had a median survival of 17 days. Group 2 (3.8% BCNU polymer) had a median survival of 23 days (P=0.006). Group 3 (20% camptothecin polymer) had a median survival of 25 days (P=0.023). Group 4 (50% camptothecin polymer) had a median survival of 69 days (P<0.001). Drug loadings of 20% and 50% camptothecin released intact camptothecin for up to 1000 h in vitro. We conclude that the biodegradable polymer p(CPP : SA) releases camptothecin-sodium, produces tumoricidal tissue levels, results in little or no systemic toxicity, and prolongs survival in a rat glioma model.

UDP-glucuronate Decarboxylase, a Key Enzyme in Proteoglycan Synthesis CLONING, CHARACTERIZATION, AND LOCALIZATION

UDP-glucuronate decarboxylase (UGD) catalyzes the formation of UDP-xylose from UDP-glucuronate. UDP-xylose is then used to initiate glycosaminoglycan biosynthesis on the core protein of proteoglycans. In a yeast two-hybrid screen with the protein kinase Akt (protein kinase B), we detected interactions with a novel sequence, which we cloned and expressed. The expressed protein displayed UGD activity but did not display the activities of homologous nucleotide sugar epimerases or dehydratases. We did not detect phosphorylation of UGD by Akt nor did we detect any influence of Akt on UGD activity. Effects of UGD on Akt kinase activity were also absent. Northern blot and Western blot analyses revealed the presence of UGD in multiple tissues and brain regions. Subcellular studies and histochemistry localized UGD protein to the perinuclear Golgi where xylosylation of proteoglycan core proteins is known to occur.

Reversible Posterior Leukoencephalopathy Occurring during Resection of a Posterior Fossa Tumor: Case Report and Review of the Literature

OBJECTIVE AND IMPORTANCE Our goal was to present a clinically and radiographically documented case of reversible posterior leukoencephalopathy (RPL) that occurred during resection of a posterior fossa tumor. Although RPL has been previously described in multiple nonsurgical settings, we hope that this case description makes RPL more clinically and radiographically recognizable to neurosurgeons. CLINICAL PRESENTATION RPL is the clinical syndrome of headaches, altered mental status, seizures, and visual loss, with radiographic findings of reversible parieto-occipital changes on cerebral computed tomographic and magnetic resonance imaging scans. It has been previously reported in the settings of malignant hypertension, renal disease, eclampsia, and immunosuppression. To our knowledge, the patient presented represents the first clinically and radiographically documented case of RPL occurring during resection of a posterior fossa tumor. The patient intraoperatively exhibited wide fluctuations in blood pressure and awoke with clinical and radiographic findings consistent with RPL. INTERVENTIONAggressive intraoperative and postoperative management of the patient’s blood pressure, supportive intensive care, rehabilitation, and close radiographic follow-up were performed. CONCLUSIONRPL can occur as a result of intraoperative variations in blood pressure, even among young, previously healthy individuals. With the aforementioned interventions, the patient experienced significant clinical and radiographic recovery.

Skull base chondrosarcoma presenting with hemorrhage.

A 34-year-old white man with a six month history of a feeling of deja vu presented with an acute onset of headache and blurred vision associated with nausea and vomiting. Neurological examination was significant for a right third cranial nerve palsy. Computerized tomography (CT) demonstrated a 2.0 cm rim calcified right paracavernous mass with intratumoral hemorrhage and an adjacent 2.6 cm by 2.0 cm right temporal lobe hematoma. Intraventricular hemorrhage (IVH) was present in both lateral ventricles, right more than left (Figure 1). Diagnostic cerebral angiography demonstrated no evidence of aneurysm. Brain magnetic resonance (MR) imaging revealed a 2 cm mass in the right paracavernous region extending into the suprasellar region with heterogeneous signal intensity on T1- and T2-weighted images and heterogeneous enhancement after gadolinium administration. Adjacent to the lesion was a right temporal lobe hematoma; intraventricular hemorrhage was also observed in the right lateral ventricle (Figure 2). The patient underwent a right pterional craniotomy for gross total resection of the tumour. Histopathological examination of the tumour demonstrated a low grade hyaline chondrosarcoma. The patient subsequently underwent proton beam radiotherapy and is currently 82 months out from surgery with no evidence of recurrence.

Surgical repair of brachial plexus injury: a multinational survey of experienced peripheral nerve surgeons

OBJECT Brachial plexus injuries (BPIs) are often devastating events that lead to upper-extremity paralysis, rendering the limb a painful extraneous appendage. Fortunately, there are several nerve repair techniques that provide restoration of some function. Although there is general agreement in the medical community concerning which patients may benefit from surgical intervention, the actual repair technique for a given lesion is less clear. The authors sought to identify and better define areas of agreement and disagreement among experienced peripheral nerve surgeons as to the management of BPIs. METHODS The authors developed a detailed survey in two parts: one part addressing general issues related to BPI and the other presenting four clinical cases. The survey was mailed to 126 experienced peripheral nerve physicians and 49 (39%) participated in the study. The respondents represent 22 different countries and multiple surgical subspecialties. They performed a mean of 33 brachial plexus reconstructions annually. Areas of significant disagreement included the timing and indications for surgical intervention in birth-related palsy, treatment of neuroma-in-continuity, the best transfers to achieve elbow flexion and shoulder abduction, the use of intra- or extraplexal donors for motor neurotization, and the use of distal or proximal coaptation during nerve transfer. CONCLUSIONS Experienced peripheral nerve surgeons disagree in important ways as to the management of BPI. The decisions made by the various treating physicians underscore the many areas of disagreement regarding the treatment of BPI, including the diagnostic approach to defining the injury, timing of and indications for surgical intervention in birth-related palsy, the treatment of neuroma-in-continuity, the choice of nerve transfers to achieve elbow flexion and shoulder abduction, the use of intra- or extraplexal donors for neurotization, and the use of distal or proximal coaptation during nerve transfer.