Computed Tomography Perfusion for the Diagnosis of Brain Death: A Technical Review.

Timely diagnosis of brain death (BD) is critical as it prevents unethical and futile continuation of support of vital organ functions when the patient has passed. Furthermore, it helps with avoiding the unnecessary use of resources and provides early opportunity for precious organ donation. The diagnosis of BD is mainly based on careful neurological assessment of patients with an established underlying diagnosis of neurological catastrophe capable of causing BD.Ancillary testing, however, is tremendously helpful in situations when the presence of confounders prevents or delays comprehensive neurological assessment. Traditionally, four-vessel digital subtraction angiography and computed tomography angiography have been used for blood flow (BF) examinations of the brain. The lack of BF in the intracranial arteries constitutes conclusive evidence that the brain is dead. However, there is an apparent discrepancy between the BF and sufficient cerebral perfusion; several studies have shown that in 15% of patients with confirmed clinical diagnosis of BD, BF is still preserved. In these patients, cerebral perfusion is significantly impaired. Hence, measurement of cerebral perfusion rather than BF will provide a more precise assessment of the brain function.In this review article, we discuss a brief history of BD, our understanding of its complex pathophysiology, current Canadian guidelines for the clinical diagnosis of BD, and the ancillary tests-specifically CT perfusion of the brain that help us with the prompt and timely diagnosis of BD.

Cholesterol synthesis inhibition promotes axonal regeneration in the injured central nervous system.

Neuronal regeneration in the injured central nervous system is hampered by multiple extracellular proteins. These proteins exert their inhibitory action through interactions with receptors that are located in cholesterol rich compartments of the membrane termed lipid rafts. Here we show that cholesterol-synthesis inhibition prevents the association of the Neogenin receptor with lipid rafts. Furthermore, we show that cholesterol-synthesis inhibition enhances axonal growth both on inhibitory -myelin and -RGMa substrates. Following optic nerve injury, lowering cholesterol synthesis with both drugs and siRNA-strategies allows for robust axonal regeneration and promotes neuronal survival. Cholesterol inhibition also enhanced photoreceptor survival in a model of Retinitis Pigmentosa. Our data reveal that Lovastatin leads to several opposing effects on regenerating axons: cholesterol synthesis inhibition promotes regeneration whereas altered prenylation impairs regeneration. We also show that the lactone prodrug form of lovastatin has differing effects on regeneration when compared to the ring-open hydroxy-acid form. Thus the association of cell surface receptors with lipid rafts contributes to axonal regeneration inhibition, and blocking cholesterol synthesis provides a potential therapeutic approach to promote neuronal regeneration and survival in the diseased Central Nervous System. SIGNIFICANCE STATEMENT: Statins have been intensively used to treat high levels of cholesterol in humans. However, the effect of cholesterol inhibition in both the healthy and the diseased brain remains controversial. In particular, it is unclear whether cholesterol inhibition with statins can promote regeneration and survival following injuries. Here we show that late stage cholesterol inhibition promotes robust axonal regeneration following optic nerve injury. We identified distinct mechanisms of action for activated vs non-activated Lovastatin that may account for discrepancies found in the literature. We show that late stage cholesterol synthesis inhibition alters Neogenin association with lipid rafts, thereby i) neutralizing the inhibitory function of its ligand and ii) offering a novel opportunity to promote CNS regeneration and survival following injuries.

Extracellular phosphorylation drives the formation of neuronal circuitry.

Until recently, the existence of extracellular kinase activity was questioned. Many proteins of the central nervous system are targeted, but it remains unknown whether, or how, extracellular phosphorylation influences brain development. Here we show that the tyrosine kinase vertebrate lonesome kinase (VLK), which is secreted by projecting retinal ganglion cells, phosphorylates the extracellular protein repulsive guidance molecule b (RGMb) in a dorsal-ventral descending gradient. Silencing of VLK or RGMb causes aberrant axonal branching and severe axon misguidance in the chick optic tectum. Mice harboring RGMb with a point mutation in the phosphorylation site also display aberrant axonal pathfinding. Mechanistic analyses show that VLK-mediated RGMb phosphorylation modulates Wnt3a activity by regulating LRP5 protein gradients. Thus, the secretion of VLK by projecting neurons provides crucial signals for the accurate formation of nervous system circuitry. The dramatic effect of VLK on RGMb and Wnt3a signaling implies that extracellular phosphorylation likely has broad and profound effects on brain development, function and disease.

Exosomes Mediate Mobilization of Autocrine Wnt10b to Promote Axonal Regeneration in the Injured CNS.

Developing strategies that promote axonal regeneration within the injured CNS is a major therapeutic challenge, as axonal outgrowth is potently inhibited by myelin and the glial scar. Although regeneration can be achieved using the genetic deletion of PTEN, a negative regulator of the mTOR pathway, this requires inactivation prior to nerve injury, thus precluding therapeutic application. Here, we show that, remarkably, fibroblast-derived exosomes (FD exosomes) enable neurite growth on CNS inhibitory proteins. Moreover, we demonstrate that, upon treatment with FD exosomes, Wnt10b is recruited toward lipid rafts and activates mTOR via GSK3ß and TSC2. Application of FD exosomes shortly after optic nerve injury promoted robust axonal regeneration, which was strongly reduced in Wnt10b-deleted animals. This work uncovers an intercellular signaling pathway whereby FD exosomes mobilize an autocrine Wnt10b-mTOR pathway, thereby awakening the intrinsic capacity of neurons for regeneration, an important step toward healing the injured CNS.

Effect of birth asphyxia on p wave dispersion.

OBJECTIVES: To evaluate the cardiac conduction system using P wave dispersion on electrocardiogram and its relationship with the short term mortality and development of arrhythmia in asphyxiated neonates. METHODS: Thirty term babies with evidence of asphyxia and without any congenital abnormalities were consecutively evaluated as cases. They were compared with thirty healthy term babies without asphyxia. Twelve-lead surface electrocardiography was obtained from all the patients and the controls, and P wave dispersion was calculated according to its definition as the difference between P maximum duration and P minimum duration in 12-lead electrocardiogram. RESULTS: A statically significant difference of P wave dispersion was observed between the patients and the control group (0.027 ± 0.011 mm/s and 0.016 ± 0.006 mm/s, respectively; P value = 0.0001). The P wave dispersion had a statistically significant correlation with the grade of asphyxia (P = 0.004, r = 0.62), the P wave dispersion had no statistically significant correlation with Apgar scores, short term arrhythmia, and troponin I level in asphyxiated neonates (P < 0.05). CONCLUSIONS: The P wave dispersion increased in asphyxiated neonates and correlated with grade of asphyxia; however, the increased P wave dispersion was not correlated with the short term mortality, arrhythmia and troponin I level of the asphyxiated neonates.

Cardiac repolarization changes in the children with breath-holding spells.

OBJECTIVE: Breath-holding spells are known as benign attacks, frequencies of which decrease by the development of the autonomic nervous system. The present study aims to compare the electrocardiographic repolarization in children with breath-holding spells. METHODS: In this study, QT dispersion, QTc dispersion, T peak to T end dispersion, and P wave dispersion of the twelve-lead surface electrocardiography of fifty children who had breath-holding spells were measured and compared with normal children from April 2011 to August 2012. FINDINGS: Forty-four (88%) patients had cyanotic spells, while 6 (12%) had pallid spells. QTc dispersion was increased in the patients with breath-holding spells (148.2±33.1) compared to the healthy children (132±27.3) and the difference was statically significant (P = 0.01). Meanwhile, no statistically significant differences were observed between the patients and the control subjects regarding the other parameters (P > 0.05). CONCLUSION: QTc dispersion was significantly increased in the patients with breath-holding spells compared to normal children and this is a sign of cardiac repolarization abnormality as well as the increased risk of cardiac arrhythmia in patients with breath-holding spells.

Comparative study of pulmonary circulation and myocardial function in patients with ß-thalassemia intermedia with and without hydroxyurea, a case-control study.

OBJECTIVES: To compare myocardial systolic and diastolic functions and pulmonary circulation by two-dimensional, M-mode, Doppler, and pulsed tissue Doppler imaging in patients with ß-thalassemia intermedia who received hydroxyurea at least for 1 yr, patients who did not receive hydroxyurea, and a healthy control group. METHODS: We assigned 84 patients with thalassemia intermedia into two groups: one of two was treated with hydroxyurea for at least 1 yr and no hydroxyurea. M-mode echocardiographic, Doppler, and pulsed Doppler tissue images were compared in these two groups and in 20 control participants who did not have thalassemia. For the estimation of pulmonary hypertension, pulmonary acceleration time below 100 ms was considered as an index of pulmonary hypertension. RESULTS: There were no significant differences in M-mode echocardiographic findings between three groups. Doppler echocardiography detected no significant differences between the treated and untreated groups. In treated hydroxyurea group, 11.7% patients had pulmonary acceleration time below 100 ms and in untreated group 21% (LR = 1.45, P = 0.22). Pulsed Doppler tissue imaging parameters did not differ significantly between treated and untreated patients (P > 0.05). Pulsed Doppler tissue images showed significant changes between patients and controls in peak systolic velocity of the septum, peak atrial velocity of the septum (Aas), the peak systolic velocity of the tricuspid valve (St), the peak early diastolic velocity of the tricuspid valve (Eat), and the peak late diastolic velocity of the tricuspid valve (Aat). CONCLUSION: This study revealed that in spite of decrease in estimated pulmonary hypertension in treated group, HU has no statistically significant effect on pulmonary acceleration time and M-mode, Doppler, and tissue Doppler changes of patients with TI.

Early echocardiographic findings in ß-thalassemia intermedia patients using standard and tissue Doppler methods.

Heart complications are among the serious problems of patients with ß-thalassemia intermedia. This study aimed to evaluate myocardial function in these patients. Clinical parameters and both standard Doppler and pulsed Doppler tissue imaging parameters were compared in 51 ß-thalassemia intermedia patients (mean age, 17.05 ± 5.8 years) and 20 normal subjects (mean age, 17.81 ± 7.35 years, p = 0.98). In 11 patients (21.5%), pulmonary artery hypertension was detected. M-mode echocardiographic findings such as ejection fraction and fractional shortening did not show statistically significant changes (p > 0.005). Pulsed Doppler showed a significant difference in the early (E) to late diastolic (A) velocity ratio of the tricuspid and mitral valve between the patients and the control subjects (p < 0.05). In the pulsed tissue Doppler study, the peak systolic velocity of the septum (Ss), the peak atrial velocity of the septum (Aas), the peak systolic velocity of the tricuspid annulus (St), the peak early diastolic velocity of the tricuspid annulus (Eat), and the peak late diastolic velocity of the tricuspid annulus (Aat) were increased significantly (p < 0.05). The pulse tissue Doppler of the lateral mitral annulus did not change significantly (p > 0.005). The peak systolic velocity of the posterior wall and the peak late diastolic velocity of the anterior wall changed significantly (p < 0.05). This study showed that ß-thalassemia intermedia patients with normal M-mode and two-dimensional echocardiography had statistically significant changes in pulsed Doppler and pulsed tissue Doppler imaging.