Tropomyosin Receptor Kinase B Expressed in Oligodendrocyte Lineage Cells Functions to Promote Myelin Following a Demyelinating Lesion.

The levels of brain-derived neurotrophic factor (BDNF) in the corpus callosum have previously been shown to have a critical impact on oligodendrocyte (OLG) lineage cells during cuprizone-elicited demyelination. In particular, BDNF+/- mice exhibit greater losses in myelin protein levels compared to wild-type mice after cuprizone. To investigate whether OLGs may directly mediate these effects of BDNF during a lesion in vivo, we used the cuprizone model of demyelination with inducible conditional male knockout mice to specifically delete the high-affinity tropomyosin receptor kinase B (TrkB) receptor from proteolipid protein + OLGs during cuprizone-elicited demyelination and subsequent remyelination. The loss of TrkB during cuprizone-elicited demyelination results in an increased sensitivity to demyelination as demonstrated by greater deficits in myelin protein levels, greater decreases in numbers of mature OLGs, increased numbers of demyelinated axons, and decreased myelin thickness. When mice are removed from cuprizone, they exhibit a delayed recovery in myelin proteins and myelin. Our data indicate that following a demyelinating lesion, TrkB in OLGs positively regulates myelin protein expression, myelin itself, and remyelination.

Glasgow Coma Scale on Presentation Predicts Outcome in Endovascular Treatment for Acute Posterior Large-Vessel Occlusion.

Use of mechanical thrombectomy for stroke has increased since the publication of trials describing outcome improvement when used in the anterior circulation. These results, however, cannot be directly translated to the posterior circulation. While a high NIHSS score has demonstrated an association with poor outcomes in posterior stroke, the NIHSS is weighted toward hemispheric disease, and complex scores potentially delay definitive imaging diagnosis. We performed a retrospective analysis to ascertain whether any rapidly obtainable demographic or clinical and imaging data have a correlation with patient outcome postthrombectomy. Seventy-three cases were audited between September 2010 and October 2017. Presenting with a Glasgow Coma Scale score of >13 meant that the odds of reaching the primary end point of functional independence (defined as a 90-day modified Rankin Scale score of 0-2) were 5.70 times greater; similarly, presenting with a posterior circulation ASPECTS of >9 resulted in the odds of reaching the primary end point being 4.03 times greater. Older age correlated to a lower odds of independence (0.97, p = .04).

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice.

Treatment with the antileukemic agent asparaginase can induce acute pancreatitis, but the pathophysiology remains obscure. In the liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2) is essential for mitigating metabolic stress caused by asparaginase. We determined the consequences of asparaginase treatment on the pancreata of wild-type (WT, GCN2-intact) and GCN2-deleted (ΔGcn2) mice. Mean pancreas weights in ΔGcn2 mice treated with asparaginase for 8 days were increased (P < 0.05) above all other groups. Histological examination revealed acinar cell swelling and altered staining of zymogen granules in ΔGcn2, but not WT, mice. Oil Red O staining and measurement of pancreas triglycerides excluded lipid accumulation as a contributor to acini appearance. Instead, transmission electron microscopy revealed dilatation of the endoplasmic reticulum (ER) and accumulation of autophagic vacuoles in the pancreas of ΔGcn2 mice treated with asparaginase. Consistent with the idea that loss of GCN2 in a pancreas exposed to asparaginase induced ER stress, phosphorylation of protein kinase R-like ER kinase (PERK) and its substrate eIF2 was increased in the pancreas of asparaginase-treated ΔGcn2 mice. In addition, mRNA expression of PERK target genes, activating transcription factors 4, 3, and 6 (Atf4, Atf3, and Atf6), fibroblast growth factor 21 (Fgf21), heat shock 70-kDa protein 5 (Hspa5), and spliced Xbp1 (sXbp1), as well as pancreas mass, was elevated in the pancreas of asparaginase-treated ΔGcn2 mice. Furthermore, genetic markers of oxidative stress [sirtuin (Sirt1)], inflammation [tumor necrosis factor-α (Tnfα)], and pancreatic injury [pancreatitis-associated protein (Pap)] were elevated in asparaginase-treated ΔGcn2, but not WT, mice. These data indicate that loss of GCN2 predisposes the exocrine pancreas to a maladaptive ER stress response and autophagy during asparaginase treatment and represent a genetic basis for development of asparaginase-associated pancreatitis.

Long-Term Follow-Up Results following Elective Treatment of Unruptured Intracranial Aneurysms with the Pipeline Embolization Device.

BACKGROUND AND PURPOSE: Numerous reports of treatment of wide-neck aneurysms by flow diverters have been published; however, long-term outcomes remain uncertain. This article reports the imaging results of unruptured aneurysms treated electively with the Pipeline Embolization Device for up to 56 months and clinical results for up to 61 months. MATERIALS AND METHODS: One hundred nineteen aneurysms in 98 patients from 3 centers admitted between August 2009 and June 2011 were followed at 6-month, 1-year, and 2+-year postprocedural timeframes. Analyses on the effects of incorporated vessels, previous stent placement, aneurysm size, and morphology on aneurysm occlusion were performed. RESULTS: The 1- and 2+-year imaging follow-ups were performed, on average, 13 and 28 months postprocedure. At 2+-year follow-up, clinical data were 100% complete and imaging data were complete for 103/116 aneurysms (88.8%) with a 93.2% occlusion rate. From 0 to 6 months, TIA, minor stroke, and major stroke rates were 4.2%, 3.4%, and 0.8% respectively. After 6 months, 1 patient had a TIA of uncertain cause, with an overall Pipeline Embolization Device-related mortality rate of 0.8%. An incorporated vessel was significant for a delay in occlusion (P = .009) and nonocclusion at 6 months and 1 year, with a delayed mean time of occlusion from 9.1 months (95% CI, 7.1-11.1 months) to 16.7 months (95% CI, 11.4-22.0 months). Other factors were nonsignificant. CONCLUSIONS: The Pipeline Embolization Device demonstrates continued very high closure rates at 2+ years, with few delayed clinical adverse sequelae. The presence of an incorporated vessel in the wall of the aneurysm causes a delay in occlusion that approaches sidewall closure rates by 2 years.

Routine histology techniques for the developing and adult central nervous system.

The preparation of tissue for histological study is a multi-step process in which potential loss of quality and the introduction of artifacts can occur during each step. Knowledge of the process and the potential pitfalls at each step will serve the investigator well. Here I describe the most basic histologic techniques, worked out so long ago they are often absent from current literature.

Mystery of chronic cerebrospinal venous insufficiency: identical venographic and ultrasound findings in patients with MS and controls.

BACKGROUND AND PURPOSE: Stenosis of the internal jugular, azygos, and other veins detected by using intracranial and neck Doppler and B-mode sonography and confirmed by venography has been reported in MS with a high degree of sensitivity. This article reports the results of sonographic findings in patients with MS and controls, looking for evidence of the controversial entity chronic cerebrospinal venous insufficiency. Furthermore, the venographic appearance in controls is documented. MATERIALS AND METHODS: Thirty consecutive patients with definite MS and 10 controls had TCD and high-resolution Doppler sonography of the neck vessels by using the published sonography criteria of Zamboni et al. Those with 2 positive findings consented to undergo contrast digital subtraction venography for delineation of possible venous stenosis. Nine consecutive patients undergoing digital subtraction venography for petrosal venous sampling or parathormone sampling had images of their internal jugular veins obtained as part of their procedure, and they were assessed for stenosis. RESULTS: No patient with MS or control had 2 positive sonographic findings; therefore, none were subjected to venography. Of the 9 controls undergoing venography for other reasons, 6 had bilateral IJV narrowing of ≥50%, and 2 others had unilateral narrowing. CONCLUSIONS: No difference was detected between patients with MS and controls by using the objective sonographic criteria of Zamboni et al. Furthermore, normal physiologic narrowing is found very commonly in the internal jugular veins in healthy individuals. Nonblinded subjective sonographic assessment of the IJV may erroneously lead to venography, the findings of which may be misinterpreted due to the lack of widespread knowledge about the appearance of these veins in healthy individuals.

Safety of the pipeline embolization device in treatment of posterior circulation aneurysms.

BACKGROUND AND PURPOSE: The published results of treating internal carotid artery aneurysms with the PED do not necessarily apply to its use in the posterior circulation because disabling brain stem infarcts can be caused by occlusion of a single perforator. In this multicenter study, we assessed the safety of PED placement in the posterior circulation. MATERIALS AND METHODS: A prospective case registry was maintained of all posterior circulation aneurysms treated with PEDs at 3 Australian neurointerventional centers during a 27-month period. The objective was to assess the complications and aneurysm occlusion rates associated with posterior circulation PEDs. RESULTS: Thirty-two posterior circulation aneurysms were treated in 32 patients. No deaths or poor neurologic outcomes occurred. Perforator territory infarctions occurred in 3 (14%) of the 21 patients with basilar artery aneurysms, and in all 3, a single PED was used. Two asymptomatic intracranial hematomas were recorded. No aneurysm rupture or PED thrombosis was encountered. The overall rate of permanent neurologic complications was 9.4% (3/32); all 3 patients had very mild residual symptoms and a good clinical outcome. Aneurysm occlusion was demonstrated in 85% of patients with >6 months of follow-up and 96% of patients with >1 year of follow-up. CONCLUSIONS: The PED is effective in the treatment of posterior circulation aneurysms that are otherwise difficult or impossible to treat with standard endovascular or surgical techniques, and its safety is similar to that of stent-assisted coiling techniques. A higher clinical perforator infarction rate may be associated with basilar artery PEDs relative to the internal carotid artery.

Immediate and midterm results following treatment of recently ruptured intracranial aneurysms with the Pipeline embolization device.

BACKGROUND AND PURPOSE: A number of flow-diverting devices have become available for endovascular occlusion of cerebral aneurysms. This article reports immediate and midterm results in recently ruptured aneurysms treated with the PED. MATERIALS AND METHODS: A prospective registry was established at 3 Australian neurointerventional sites to collect data on ruptured and unruptured aneurysms treated with PED during a 12-month period from August 2009. From this data base of 65 patients, 11 cases of recent aneurysmal SAH were examined. Relevant data including antiplatelet therapy, technical issues, complications, and imaging findings during at least a 6-month period of follow-up were collected and analyzed. RESULTS: Eleven patients had acutely ruptured aneurysms with SAH. Clinical follow-up was available on all cases with imaging follow-up at 6 months in 9 patients. Two patients died from rebleeding during the acute illness. There was no other procedural or delayed significant symptomatic morbidity. Eight aneurysms were occluded with a single case of residual body filling. CONCLUSIONS: PED should be used in SAH with caution, reserved for suitable patients concomitantly treated with endosaccular coiling if possible.

Immediate and midterm results following treatment of unruptured intracranial aneurysms with the pipeline embolization device.

BACKGROUND AND PURPOSE: A number of flow-diverting devices have become available for endovascular occlusion of cerebral aneurysms. This article reports immediate and midterm results in treating unruptured aneurysms with the PED. MATERIALS AND METHODS: A prospective registry was established at 3 Australian neurointerventional units. Aneurysms were treated on the basis of unfavorable anatomy or recurrence following previous treatment. Aneurysms were treated with PED or PED and coils. Data including antiplatelet therapy, technical issues, complications, and imaging findings were recorded during at least a 6-month period. RESULTS: A total of 57 aneurysms in 54 patients were treated by 5 neurointerventional radiologists. Forty-one aneurysms were asymptomatic, and 16 patients had mass-induced neurological deficit. Clinical follow-up was available in 57 aneurysms with imaging follow-up at 6 months in 56. Permanent morbidity and mortality in the series was 0% at 6 months. Four TIAs and 1 small retinal branch occlusion occurred, but no stroke. The demonstrated aneurysm occlusion rate at 1 month was 61.9%, and the overall occlusion rate at 6 months was 85.7%. In cases previously untreated, the 6-month occlusion was 92.5%. Three of 6 aneurysms with a previous stent in situ were occluded. Two patients (3.5%) had asymptomatic in-construct stenosis of >50%. Acute aneurysm-provoked mass effect resolved or improved significantly in all cases. CONCLUSIONS: Use of the PED is safe and efficacious in difficult aneurysms with a high occlusion rate at 6 months, but lower occlusion rates were seen in a small population with previous stents in situ.

Endovascular treatment using predominantly stent-assisted coil embolization and antiplatelet and anticoagulation management of ruptured blood blister-like aneurysms.

BACKGROUND AND PURPOSE: BBA is a rare type of intracranial aneurysm that is difficult to treat both surgically and endovascularly and is often associated with a high degree of morbidity/mortality. The aim of this study was to present clinical and angiographic results, as well as antiplatelet/anticoagulation regimens, of endovascular BBA treatment by using predominantly stent-assisted coil embolization. MATERIALS AND METHODS: Thirteen patients (men/women, 6/7; mean age, 49.3 years) with ruptured BBAs were included from 2 different institutions. Angiographic findings, treatment strategies, anticoagulation/antiplatelet protocols, and clinical (mRS) and angiographic outcome were retrospectively analyzed. RESULTS: Eleven BBAs were located in the supraclinoid ICA, and 2 on the basilar artery trunk. Nine of 13 were ≤3 mm in the largest diameter, and 8/13 showed early growth before treatment. Primary stent-assisted coiling was performed in 11/13 patients, double stents and PAO in 1 patient, each. Early complementary treatment was required in 3 patients, including PAO in 2. In stent-placement procedures, altered periprocedural antiplatelet (11/12) and postprocedural heparin (6/12) protocols were used without evidence of thromboembolic events. Two patients had early rehemorrhage, including 1 major fatal SAH. Twelve of 13 BBAs showed complete or progressive occlusion at late angiographic follow-up. Clinical midterm outcome was good (mRS scores, 0-2) in 12/13 patients. CONCLUSIONS: Stent-assisted coiling of ruptured BBAs is technically challenging but can be done with good midterm results. Reduced periprocedural and postprocedural antiplatelet/anticoagulation protocols may be used with a low reasonable risk of thromboembolic complications. However, regrowth/rerupture remains a problem underlining the importance of early angiographic follow-up and re-treatment, including PAO if necessary.

A 42-year-old man with "pseudo-coprolalia".

A 42-year-old right-handed man presented with one week's history of uncharacteristic use of coarse language with associated anomia, inappropriate word usage and slowness of thoughts. Imaging demonstrated a solitary infarct involving the anterior left thalamus. Clinical and imaging findings and the current literature on anterior thalamic insult are discussed.

Pulsatile tinnitus from reversal of flow in an aberrant occipital artery: resolved after carotid artery stenting.

Carotid artery stent placement, performed for correction of an asymptomatic severe stenosis, leads to the resolution of persistent and troublesome pulsatile tinnitus. Tinnitus has been reported as a consequence of severe carotid stenoses on previous occasions. This case highlights how an aberrant occipital artery originating above a carotid artery stenosis can result in flow reversal and be a mechanism by which tinnitus may develop.

Efficient method for generating nuclear fractions from marrow stromal cells.

Stem cells have received significant attention for their envisioned potential to treat currently unapproachable diseases. No less important is the utility of stem cells to serve as model systems of differentiation. Analyses at the transcriptome, miRNA and proteome levels have yielded valuable insights into events underlying stem cell differentiation. Proteomic analysis is often cumbersome, detecting changes in hundreds of proteins that require subsequent identification and validation. Targeted analysis of nuclear constituents would simplify proteomic studies, focusing efforts on transcription factor abundance and modification. To facilitate such studies, a simple and efficient methodology to isolate pure nuclear fractions from Marrow Stromal Cells (MSCs), a clinically relevant stem cell population, has been developed. The modified protocol greatly enhances cell disruption, yielding free nuclei without attached cell body remnants. Light and electron microscopic analysis of purified nuclei demonstrated that preparations contained predominantly intact nuclei with minimal cytoplasmic contamination. Western analysis revealed an approximately eightfold enrichment of the transcription factor CREB in the isolated nuclei over that in the starting homogenates. This simple method for isolation of highly purified nuclear fractions from stem cell populations will allow rigorous examination of nuclear proteins critical for differentiation.

Endovascular treatment of intracranial aneurysms with Guglielmi detachable coils: analysis of midterm angiographic and clinical outcomes.

BACKGROUND AND PURPOSE: The previous decade has witnessed increasing application of Guglielmi detachable coils (GDCs) for the treatment of intracranial aneurysms. However, the midterm angiographic and clinical outcomes are not well documented. We report here the angiographic and clinical outcomes of patients treated with GDCs over an 8-year period. METHODS: Between 1992 and 1998, 144 patients with 160 intracranial aneurysms were treated with GDCs. Clinical follow-up data were obtained from medical records, questionnaires, and telephone interviews. Angiographic studies were reviewed by 2 neuroradiologists to obtain consensus regarding the degree of aneurysm occlusion. RESULTS: Eighty-one patients had ruptured aneurysms; 63 had unruptured aneurysms. Technical success was achieved in 91% of patients, with complete aneurysm occlusion in 46%, neck remnants in 16%, and residual body filling in 38%. Angiographic follow-up revealed that residual body filling in some aneurysms was resolved, small neck remnants were stable, and the recanalization rate decreased with time. All 63 patients with unruptured aneurysms were discharged from hospital with independent clinical status (Glasgow Outcome Score, 1 or 2). For patients with ruptured aneurysms, discharge clinical status correlated with the Hunt & Hess clinical grade at the time of treatment. Clinical follow-up for a minimum of 2 years was available in 98.5% of patients. Ninety-four percent of patients treated for unruptured aneurysms were independent at 2 years, and 82% of Hunt & Hess grade I to II patients were independent. CONCLUSIONS: Coil embolization is a safe and effective treatment for both ruptured and unruptured aneurysms. Increasing angiographic stability is demonstrated in treated aneurysms up to 3 years from coil embolization. Therefore, follow-up angiography until this time is advisable.

Lhermitte-Duclos disease associated with Cowden's syndrome: case report and literature review.

Lhermitte-Duclos disease (LDD) is a rare entity that may occur in the setting of Cowden's syndrome (CS). Accurate preoperative diagnosis can be made on the characteristic CT and MR appearances, thereby obviating the need for biopsy. It is important to be aware of the link between LDD and CS so that appropriate genetic counselling and tumour surveillance can be undertaken.

Carotid arterial stent placement: results and follow-up in 53 patients.

PURPOSE: To describe the results, complications, and follow-up data after stent placement for occlusive internal carotid arterial disease and to compare the results with those in the literature. MATERIALS AND METHODS: Carotid arterial stent placement was attempted in 57 arteries in 53 patients. Thirty-six (68%) of 53 patients were symptomatic. Forty-two (79%) of 53 patients had one to three clinically important comorbidities and were considered at high risk. All patients underwent pre- and postprocedural independent neurologic examinations. Follow-up consisted of serial duplex ultrasonography and clinical assessment. RESULTS: The immediate technical success rate of stent deployment was 97%. Periprocedurally, three (three [5%] of 57 interventions) transient ischemic attacks and three (three [5%] of 57 interventions) minor strokes occurred. Two deaths occurred in the first 30 days (one myocardial infarction, one renal failure). One ipsilateral major stroke occurred 3 weeks after the procedure. The 30-day ipsilateral major stroke and death rate was 5% (three of 57 interventions). At 30 days, one of three patients with minor stroke had mild residual dysphasia. Treatment remained clinically successful in 48 (96%) of 50 patients. The restenosis rate was 4% (two patients). CONCLUSION: Carotid arterial stent placement in a high-risk population has morbidity and mortality rates comparable to those of carotid endarterectomy in a lower risk population. Carotid arterial stent placement can be performed with a low restenosis rate.

Delayed aneurysm rerupture following total endovascular occlusion.

Endovascular coiling is a well established technique for the treatment of selected intracranial aneurysms, but its long-term efficacy, including the rate of rehaemorrhage from treated lesions, remains to be clearly determined. We report a case in which the rerupture of a small aneurysm occurred 12 months after embolization, despite angiographic occlusion on immediate post-procedural and 6-month check angiography.

Endovascular management of acute subarachnoid haemorrhage in the elderly.

The objective of this study was to analyse the technical and clinical outcome in elderly patients receiving endovascular treatment for acutely ruptured intracranial aneurysms. The case notes and angiograms of 14 patients over the age of 69 years undergoing endovascular treatment for subarachnoid haemorrhage within the Interventional Neuroradiology Unit, Royal Perth Hospital over a period of 6 years were retrospectively reviewed. The degree of angiographic occlusion achieved, and periprocedural, short-term and long-term clinical outcome were retrospectively assessed. Greater than 90% occlusion was obtained in 92% of cases. 82% of patients with Hunt and Hess grade I and II had an excellent clinical outcome. We conclude that endovascular coiling is an effective means of treating acute subarachnoid haemorrhage in grade I and II elderly patients.