ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout.

Many patients fail to achieve the recommended serum urate (SU) target (<6 mgdl-1) with allopurinol. The aim of our study was to examine the association of ABCG2 with SU target in response to standard doses of allopurinol using a cohort with confirmed adherence. Good response was defined as SU<6 mgdl-1 on allopurinol ⩽300 mgd-1 and poor response as SU⩾6 mgdl-1 despite allopurinol >300 mgd-1. Adherence was confirmed by oxypurinol concentrations. ABCG2 genotyping was performed using pre-designed single nucleotide polymorphism (SNP) TaqMan assays. Of 264 patients, 120 were good responders, 68 were poor responders and 76 were either non-adherent or could not be classified. The minor allele of ABCG2 SNP rs2231142 conferred a significantly increased risk of poor response to allopurinol (odds ratio=2.71 (1.70-4.48), P=6.0 × 10-5). This association remained significant after adjustment for age, sex, body mass index, ethnicity, estimated glomerular filtration rate, diuretic use and SU off urate-lowering therapy. ABCG2 rs2231142 predicts poor response to allopurinol, as defined by SU⩾6 mgdl-1 despite allopurinol >300 mgd-1.

Standard operating procedures in experimental liver research: thioacetamide model in mice and rats.

In addition to carbon tetrachloride (CCl4), thioacetamide (TAA) represents a second widely used model for the induction of experimental liver fibrosis, but can also be employed for the development of acute liver failure and liver tumours. While TAA itself is not hepatotoxic, its reactive metabolites covalently bind to proteins and lipids thereby causing oxidative stress and centrilobular necrosis. Compared with CCl4, TAA leads to more periportal infiltrates and more pronounced ductal proliferation. While TAA has been shown to induce liver fibrosis development in several different mouse strains, wide variations in the administration routes, doses and treatment durations have been reported. Therefore, an adoption of a universal standard operating procedure for the administration of TAA is urgently needed. For that purpose, we are presenting here two TAA models (intraperitoneal administration of 150 mg/kg of TAA three times per week for 11 weeks in rats, and TAA administration in drinking water at 300 mg/L for 2-4 months in mice) with which we have had success in reliably and reproducibly developing chronic liver injury and fibrosis.

Hydrocephalus secondary to hydrodynamic disequilibrium in an adult patient with a choroidal-type arteriovenous malformation.

We describe an adult patient with an unruptured choroidal-type arteriovenous malformation (AVM) associated with progressive hydrocephalus. There was no evidence of mechanical obstruction of the ventricular system by the AVM nidus itself or a draining vein. However significant reflux into periventricular and transmedullary veins was demonstrated. Following partial targeted embolization of the AVM, no further reflux was observed, the patient's clinical deficits resolved, and the hydrocephalus improved. We suggest a hydrodynamic disorder as a potential pathomechanism of hydrocephalus in this adult patient with an unruptured AVM.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Management and clinical outcome of posterior fossa arteriovenous malformations: report on a single-centre 15-year experience.

OBJECTIVES: Posterior fossa brain arteriovenous malformations (PFbAVMs) are rare lesions. Management is complicated by eloquence of adjacent neurological structures, multimodality treatment is often necessary, and obliteration is not always possible. We describe a 15-year experience in the management of posterior fossa brain AVMs with a focus on clinical outcome. METHODS: From 1989 to 2004, prospectively collected information on 106 patients with diagnosis of a PFbAVMs was obtained. Clinical and angioarchitectural characteristics, management options and complications are described and reviewed to evaluate their impact on final outcome as measured by the Modified Rankin Score (mRS). RESULTS: Ninety-eight patients were followed for an average of 3.3 years (1-14.6). The male-to-female ratio was 1:1. Ninety-five out of 98 patients (96.9%) were symptomatic at presentation, with 61 (62.2%) intracranial haemorrhages. Sixty-two patients were treated (46 cerebellar, 16 brainstem). Ten haemorrhages occurred in follow-up (4.1%/year). The mRS was obtained in 62 patients and was classified as low (good, mRSor=3). Haemorrhage was the only predictor of poor mRS at presentation (p = 0.0229). A poor clinical outcome was correlated with the presence of AA (p = 0.0276), a poor initial mRS (p<0.0001) and the number of treatments needed (p = 0.0434). Patients were significantly more likely to improve than to deteriorate over time (p = 0.0201). CONCLUSION: The final clinical outcome in PFbAVMs relates directly with the presence of associated aneurysms, number of treatments needed to obliterate the AVM and mRS at presentation. Despite the fact that patients tend to improve after brain AVM haemorrhage, the relationship of MRS at presentation and final outcome suggests that an expedited, more definitive treatment is probably a better choice, especially in patients with good grades after the initial bleeding.

Surgical disconnection of cortical venous reflux as a treatment for Borden type II dural arteriovenous fistulae.

OBJECTIVE: The presence of cortical venous reflux is recognized as an indicator of increased risk of intracranial hemorrhage and neurological deficits in cranial dural arteriovenous fistulas. Its disconnection is well accepted as a treatment for fistulas with direct cortical reflux (Borden type III), but the role of disconnection of the cortical venous reflux in the management of fistulas that involve the venous sinus and cortical venous reflux (Borden type II) is still a matter of debate. We analyze the experience of the Toronto Brain Vascular Malformation Study Group in the management of these lesions by simple cortical venous reflux disconnection and its impact in the future risk of bleeding. METHODS: From June 1984 to August 2004, 347 patients with dural arteriovenous fistulas, either cranial or spinal, were evaluated by the group. Fifty-three patients had a Borden type II dural arteriovenous fistulas. Twenty-five patients were submitted to simple surgical disconnection of the dural arteriovenous fistulas, two were lost for follow-up. There were 15 females and 8 males, with mean age at diagnosis of 53.9 years. Follow-up time was 112.6 patient-years, from 2 months to 11 years, mean 4.9 years. Endovascular treatment was attempted in all patients, but no disconnection was possible. Twelve patients had their fistulas completely occluded by endovascular means, but are not analyzed here. There were four complications from the 93 endovascular procedures, and 3 from the 27 surgical procedures. Two patients required a repeated surgical procedure. No episode of intracranial hemorrhage or worsening neurological deficit was seen after disconnection of the cortical venous reflux in 4.9 years of follow-up. CONCLUSION: Simple surgical disconnection of the cortical venous reflux maybe an option in the management of patients with Borden type II dural arteriovenous fistulas. This procedure is a much smaller surgical undertaking and is associated with fewer complications than attempts to resect or pack the whole fistula, especially if located in the skull base.

A new locus for autosomal dominant intracranial aneurysm, ANIB4, maps to chromosome 5p15.2-14.3.

BACKGROUND: Intracranial aneurysms (IA) are dilatations of intracranial arteries that occur most commonly at arterial bifurcations. Unruptured IA are present in approximately 1-2% of the population aged over 30 years of age. Aneurysms are only rarely symptomatic unless they rupture, which typically results in a subarachnoid haemorrhage associated with high morbidity and mortality. METHODS: A large French Canadian (FC) family (Aneu60) was identified which contained 12 affected individuals with intracranial aneurysms. Nine of the affected patients and three unaffected individuals were sent for an 8 cM genome-wide scan. Multipoint and two-point methods were used to analyse the scan data by using a dominant parametric model. RESULTS: We identified an IA susceptibility locus (ANIB4) located on chromosome 5p15.2-14.3. The locus was found by genome-wide linkage analysis and follow up analyses provided a maximum multipoint LOD score of 3.57 over the region. An identical haplotype segment of 7.2 Mb was found in a second FC pedigree and contributes to the refinement of the candidate gene interval. CONCLUSIONS: Our results indicate that there is a major gene locus on chromosome 5p.

Unemployment in an underserviced specialty?: The need for co-ordinated workforce planning in Canadian neurosurgery.

BACKGROUND: A recent report suggested that newly trained Canadian neurosurgeons are experiencing difficulty finding employment in Canada. Such occurrences, in combination with recent certification restrictions imposed in the US, have resulted in increasing concern that we will shortly be seeing a surplus of graduating neurosurgeons in Canada. The purpose of this study was to develop a better understanding of training and employment patterns in the Canadian neurosurgical workforce. METHODS: Using a database provided by the Royal College of Physicians and Surgeons of Canada, the current practice location of recent (1990-2002) neurosurgical certificants and a list of all neurosurgeons practicing in Canada were generated. From these data the number of surgeons per 100,000 patient population, and the number of residents required to maintain this workforce were determined. RESULTS: Practice location could be identified for 183/189 individuals who passed their qualifying examination in neurosurgery during this time. Only 45% of them are currently practicing in Canada. The current service ratio for this specialty is 0.65 per 100,000 population overall. Although 14.6 residents/year are being trained, only 6.5/year are required to maintain the existing neurosurgical workforce. CONCLUSIONS: Our data supports the concern about an imminent employment crisis for young neurosurgeons in Canada with more than twice the required number of residents being trained. However, this shortfall of staff positions is at a time when the specialty may be underservicing the country's population. These results highlight the necessity for more cohesive workforce planning in Canada, and in particular, ensuring the appropriate balance between training and need.

Shotgun pellet embolization to the posterior cerebral circulation.

The embolization of missiles to the intracranial circulation is a rare event. We describe here a case of a man shot by a shotgun, presenting with a posterior fossa stroke and occlusion of the superior cerebellar artery by a metallic pellet. To our knowledge, this is the third case of posterior fossa circulation pellet emboli.

The accuracy of transcranial Doppler to detect vasospasm in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVES: To examine the accuracy of transcranial Doppler to detect cerebral vasospasm in a patient population with aneurysmal subarachnoid hemorrhage. DESIGN: Prospective blind comparison of transcranial Doppler with cerebral angiography. Diagnostic accuracy of transcranial Doppler was assessed using receiver operating characteristic (ROC) analysis and likelihood ratios. Sensitivity and specificity were calculated using directly measured middle cerebral artery diameter as reference standard. SETTING: Intensive Care Unit of a large university teaching hospital. PATIENTS AND PARTICIPANTS: Twenty-two patients with subarachnoid hemorrhage were included. Patients underwent angiography on admission and after 8 days to diagnose vasospasm and were defined as having clinical vasospasm, angiographic vasospasm, or no vasospasm. MEASUREMENTS AND RESULTS: Sensitivity and specificity were 1.00 and 0.75 for angiographic vasospasm and both equal to 1.00 for clinical vasospasm diagnosis. A transcranial Doppler mean velocity threshold value of 100 cm/s for angiographic vasospasm and 160 cm/s for clinical vasospasm detection were chosen by ROC analysis. CONCLUSIONS: A Transcranial Doppler mean velocity threshold of 160 cm/s, calculated by the ROC analysis, accurately detects clinical vasospasm. A daily transcranial Doppler examination performed by a trained operator should be routinely used to provide early identification of patients at high risk and to orient therapeutic decisions.

Acute alcohol administration inhibits the refeeding response after starvation in rat skeletal muscle.

This study determined whether an acute alcohol dose could inhibit the refeeding response in starved muscle. Rats starved for 24 h were pretreated with alcohol or saline before refeeding by intragastric or intravenous infusion of enteral diet (ENT), total parenteral nutrition (TPN), or saline. Refeeding by TPN or ENT stimulated increases in the fractional rate of protein synthesis (k(s)) in skeletal muscle. Alcohol prevented the increase in k(s) when refeeding occurred intragastrically (TPN or ENT) (P < 0.001) but not intravenously (TPN). Upon intragastric refeeding, alcohol inhibited the increase in both eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) and p70 S6 kinase (p70(S6K)) phosphorylation in plantaris but caused only partial inhibition in soleus muscle (ENT only). When rats were refed intravenously, alcohol had no effect on the increased 4E-BP1 or p70(S6K) phosphorylation in either muscle. Plasma insulin levels were augmented by alcohol. Alcohol-related changes in plasma amino acid concentrations were similar irrespective of the route of feeding, whereas IGF-I levels showed differential changes. This is the first study to demonstrate that acute alcohol ingestion impedes the starved-to-fed response in skeletal muscle.

Temporal relationship between endothelin-1 concentrations and cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Endothelin 1 (ET-1) is a potent vasoconstrictor that may play a role in cerebral vasospasm following subarachnoid hemorrhage (SAH). However, data regarding its pathogenic role in the development of vasospasm are controversial. We planned a prospective, observational clinical study to investigate the temporal relationship between increased ET-1 production and cerebral vasospasm or other neurological sequelae after SAH. METHODS: ET-1 levels in cerebrospinal fluid (CSF) were measured in 20 SAH patients from admission (within 24 hours from the bleeding) until day 7. Patients received a daily transcranial Doppler study and a neurological evaluation. On day 7, angiography was performed to verify the degree and extent of vasospasm. Patients were then classified as having (1) clinical vasospasm, (2) angiographic vasospasm, (3) no vasospasm, or (4) poor neurological condition without significant vasospasm (low Glasgow Coma Scale score [GCS]). RESULTS: On admission, ET-1 levels were increased in the low-GCS group compared with the other groups (P=0.04). On day 4 ET-1 levels were not significantly different among groups, whereas on day 7 ET-1 levels were significantly increased in both the clinical vasospasm and low-GCS groups compared with the angiographic vasospasm and no vasospasm groups (P<0.005). Moreover, when the low-GCS group was excluded, there was a significant relationship between vasospasm grade and CSF ET-1 levels (R(2)=0.73). CONCLUSIONS: CSF ET-1 levels were markedly elevated in patients with clinical manifestations of vasospasm (day 7) and with a poor neurological condition not related to vasospasm. However, ET-1 levels were low in clinical vasospasm patients before clinical symptoms were evident (day 4) and remained low in angiographic vasospasm patients throughout the study period. Thus, our data suggest that CSF ET-1 levels are increased in conditions of severe neuronal damage regardless whether this was due to vasospasm or to the primary hemorrhagic event. In addition, CSF ET-1 levels paralleled the neurological deterioration but were not predictive of vasospasm.

Increased phosphorylation of the NR1 subunit of the NMDA receptor following cerebral ischemia.

The effects of transient cerebral ischemia on phosphorylation of the NR1 subunit of the NMDA receptor by protein kinase C (PKC) and protein kinase A (PKA) were investigated. Adult rats received 15 min of cerebral ischemia followed by various times of recovery. Phosphorylation was examined by immunoblotting hippocampal homogenates with antibodies that recognized NR1 phosphorylated on the PKC phosphorylation sites Ser890 and Ser896, the PKA phosphorylation site Ser897, or dually phosphorylated on Ser896 and Ser897. The phosphorylation of all sites examined increased following ischemia. The increase in phosphorylation by PKC was greater than by PKA. The ischemia-induced increase in phosphorylation was predominantly associated with the population of NR1 that was insoluble in 1% deoxycholate. Enhanced phosphorylation of NR1 by PKC and PKA may contribute to alterations in NMDA receptor function in the postischemic brain.

Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP.

Cerebral ischemia results in activation of the mitogen-activated protein kinase pathway and increased tyrosine phosphorylation of proteins associated with postsynaptic densities (PSDs). The authors investigated the possible relation between these events by determining the effect of ischemia on tyrosine phosphorylation of the brain-specific, PSD-enriched, Ras-GTPase activating protein, SynGAP. Transient (15 minutes) global ischemia was produced in rats by 4-vessel occlusion and PSDs prepared from forebrains immediately after ischemia or at 20 minutes, 1 hour, or 24 hours of reperfusion. Tyrosine phosphorylation of SynGAP was elevated relative to sham-operated controls by 20 minutes of reperfusion and remained elevated for at least 24 hours. Tyrosine phosphorylation of SynGAP also increased in CA1 and CA3/DG subfields of the hippocampus. Enhanced tyrosine phosphorylation of SynGAP was not accompanied by a change in PSD RasGAP activity. SynGAP bound to the SH2 domains of Src and Fyn in a tyrosine phosphorylation-dependent fashion, and this interaction increased after ischemia. SynGAP binds to the PDZ domains of PSD-95/SAP90 and coimmunoprecipitated with PSD-95. The coimmunoprecipitation of SynGAP with PSD-95 decreased after ischemia. The results indicate that changes in the properties and interactions of SynGAP may be involved in the neuropathology of ischemia.

Developing information literacy: a key to evidence-based nursing.

This report describes the evaluation of a curriculum-integrated programme designed to help students develop an awareness of the nursing literature, the skills to locate and retrieve it, and skills required in its evaluation; in other words'information literacy'. Positive changes in student performance on objective measures of information-literacy skills were revealed as well as a significant increase in the levels of confidence of the student in performing those skills. Students who had undertaken the information-literacy programme ('programme' students) performed better on a range of objective measures of information literacy, as well as reporting higher levels of confidence in these skills, than students who had not participated in the programme ('non-programme' students). Evaluation of this programme provides evidence of the potential usefulness of a curriculum-integrated approach for the development of information-literacy skills within nursing education. With these underlying skills, students will be better equipped to consolidate and extend their key information-literacy skills to include research appreciation and application. These are vital for effective lifelong learning and a prerequisite to evidence-based practice.

Partial labyrinthectomy approach for brainstem vascular lesions.

Conventional wisdom has typically dictated that the bony labyrinth is an inviolate structure. This notion, however, was successfully challenged following the introduction of the partial labyrinthectomy approach, which was primarily used for the surgical management of cerebellopontine and petrous apex meningiomas. In this article, we discuss an extension of the technique of partial labyrinthectomy in a series of patients that has been used for the treatment of brainstem vascular lesions. We believe that this technique provides superior exposure to the brain stem when compared with conventional retrosigmoid and retrolabyrinthine approaches while reducing the inherent morbidity seen in transotic or petrosectomy approaches.

Embolisation of Small (< 3 cm) Brain Arteriovenous Malformations. Correlation of Angiographic Results to a Proposed Angioarchitecture Grading System.

SUMMARY: The role of embolisation in the treatment of small < 3cm) brain arteriovenous malformations (AVMs) has not been elucidated. We reviewed our experience using embolisation in the treatment of small AVMs and correlated a proposed grading system based on the angioarchitecture to the percentage obliteration achieved by embolisation. Eighty-one small AVMs in 80 patients were embolised from 1984 to 1999. The age range was from 3 to 72 years. The AVMs were given a score from 0 to 6 based on the angioarchitecture. The assigned scores were as follows: nidus (fistula = 0, < 1 cm = 1, 1-3 cm = 2), type offeeding arteries (cortical = 0, perforator or choroidal = 1), number of feeding arteries (single = 0, multiple = 2) and number of draining veins (single = 0, multiple = 1). Angiographic results based on percentage obliteration were grouped into three categories: complete, 66-99%, and 0-65%. The goal of embolisation was cure in 27 AVMs, pre-surgical in 23, pre-radiosurgery in 26, and elimination of an aneurysm in five. Embolisation achieved complete obliteration in 22 (27%) of the 81 AVMs. In the AVMs where the goal was cure, 19 (70%) of 27 were completely obliterated. In the AVMs with angioarchitecture scores of 0-2, 12 (86%) of 14 were cured, with scores of 3-4, 8 (34%) of 24 were cured and with scores of 5-6, 2 (4%) of 44 were cured. Embolisation resulted in transient morbidity of 5.0%, permanent morbidity of 2.5%, and mortality of 1.2%. There were no complications in AVMs with scores of 0-2. Embolisation is an effective treatment of small AVMs when the angioarchitecture is favourable (scores 0-2). This includes pure fistulas and AVMs with a single, pial, feeding artery.

Teaching information literacy skills: an evaluation.

This paper describes an evaluation of a curriculum-integrated information literacy programme in an undergraduate nursing course. The aim of the programme was to provide students with an awareness of the discipline's literature and the skills to locate and retrieve the literature. A multidimensional process for determining nursing students' development was utilised in the evaluation of the programme. Pre- and post-programme questionnaires were distributed to a cohort of students who undertook the programme. A cohort of more senior students who had not undertaken the information literacy programme was utilised as a comparison group. Questionnaire results were analysed using a range of inferential statistics. This paper will focus on two main findings related to objective measures of information literacy skills. These include pre-programme/post-programme change in student performance and differences in student performance between those who undertook the programme and those who did not. The programme demonstrated its effectiveness in developing information literacy skills, however the challenge remains for both academics and students to ensure that these skills are consolidated and extended for effective life-long learning.

The transmastoid partial labyrinthectomy approach to medial skull base lesions.

INTRODUCTION: It has long been thought that surgical disruption of the membranous labyrinth invariably results in sensorineural hearing loss and balance dysfunction. Recent evidence suggests that the inner ear can withstand such manipulation without loss of function. The technique of transmastoid partial labyrinthectomy has recently been described as a means of providing access to lesions of the medial skull base by removing part of the labyrinth and at the same time attempting to preserve hearing and vestibular function of the lateral semicircular canal (LSCC) and otolithic organs. PROCEDURE: An extended cortical mastoidectomy is performed and the posterior and middle cranial fossa dura are exposed widely. The posterior and superior semicircular canals are occluded at their ampullated ends and at the crus commune, and then resected. The LSCC and vestibule are left undisturbed. The petrous apex is removed and the medial end of the internal auditory canal is exposed. Posterior cranial fossa dural flaps are raised allowing access to the brainstem, petro-clival area and cerebellopontine angle. Temporal and suboccipital craniotomies can be performed, as required. RESULTS: Four patients underwent this procedure by a joint Otolaryngological-Neurosurgical team for access to the following lesions: three intra-axial pontine cavernomas and a basilar artery aneurysm. The preliminary hearing and balance results are discussed. CONCLUSIONS: The partial labyrinthectomy approach provides improved access to certain lesions of the medial skull base and requires less brain retraction compared with the retrolabyrinthine approach. It also has the potential to preserve serviceable hearing.

Anatomic variations of anterior cerebral artery cortical branches.

The anterior cerebral artery (ACA) is a major vessel responsible for the blood supply to the interhemispheric region. The ACA segment after the anterior communicating artery (AComA) origin is called the distal ACA and has central and cortical branches. The cortical branches are distributed in the different regions of the orbital and medial part of the brain. The objects of this study are the anatomical variations found in the distal ACA. In 76 hemispheres the ACA distal branches were injected with latex and dissected under microscope magnification. Vessel diameters and distances between vessel origins and anterior communicating artery were recorded and analyzed. Microsurgical dissection was carried out to demonstrate anatomic variations of these vessels. Average diameter of ACA at origin was 2.61 +/- 0.34 mm and average diameter of cortical branches diameter ranged from 0.79 +/- 0.27 mm to 1.84 +/- 0.3 mm. Distances between vessel origin and AComA ranged from 7.68 +/- 3.91 mm (orbitofrontal) to 112.6 +/- 11.63 mm (inferior internal parietal). This study found anatomical variations: a single (azygos) ACA was present in one case and three in three cases. Crossing branches of the distal ACA to the contralateral hemisphere were present in 26% of the cases. In some cases a single ACA may supply the posterior hemispheric region through crossing branches. This calls attention to potential bilateral brain infarcts due to a single unilateral ACA occlusion.