Faculty Bibliography

Illicit drug abuse is a common differential diagnosis of acquired central nervous system vasculitis even though there are only a handful of histopathologically confirmed patients in the literature from among the many potential classes of abused drugs traditionally implicated in this disease. This article considers the major classes of illicit drugs in those with and without human immunodeficiency virus type-1 infection and acquired immune deficiency syndrome.

Vasculitis is defined as inflammation of blood vessel walls for at least some time during the course of the disease, and affects arteries and veins of varying caliber. Two Chapel Hill Consensus Conferences, in 1994 and 2012, provide consensus on nosology and definitions for the commonest forms of vasculitis. The category of single-organ vasculitis, suggesting the limited expression of a systemic vasculitis, includes primary central nervous system vasculitis and nonsystemic peripheral nervous system vasculitis. The historical aspects of systemic and limited forms of vasculitis are reviewed in 11 relevant themes.

BACKGROUND AND PURPOSE/OBJECTIVE:Patients with ischemic stroke of cardioembolic origin are at risk of visceral (renal or splenic) infarction. We hypothesized that serum troponin level at time of ischemic stroke would be associated with presence of visceral infarction. METHODS:Data were abstracted from a single center prospective stroke database over 18 months and included all patients with ischemic stroke who underwent contrast-enhanced computerized tomography (CT) of the abdomen and pelvis for clinical purposes within 1 year of stroke. The primary predictor was troponin concentration ≥.1 ng/mL. The primary outcome was visceral infarct (renal and/or splenic) on CT abdomen and pelvis. Univariate and multivariable logistic regression models were used to estimate the odds ratio and 95% confidence intervals (OR, 95% CI) for the association of troponin with visceral infarction. RESULTS:Of 1233 patients with ischemic stroke, 259 patients had a qualifying visceral CT. Serum troponin level on admission was measured in 237 of 259 patients (93.3%) and 41 of 237 (17.3%) had positive troponin. There were 25 patients with visceral infarcts: 16 renal, 7 splenic, and 2 both. In univariate models, patients with a positive troponin level (versus negative) were more likely to have visceral infarcts (39.1% [9/23] versus 15.0% [32/214], P = .008) and this association persisted in multivariable models (adjusted OR 3.83; 95% CI 1.42-10.31, P = .006). CONCLUSIONS:In ischemic stroke patients, elevated serum troponin levels may help identify patients with visceral infarcts. This suggests that troponin in the acute stroke setting is a biomarker of embolic risk. Larger studies with systematic visceral imaging are needed to confirm our findings.

BACKGROUND AND PURPOSE/OBJECTIVE:-THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling. EXPERIMENTAL APPROACH/METHODS:Cannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography-telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract-treated rats, and treatment-naïve rat, mouse, chicken, dog and human tissue. KEY RESULTS/RESULTS:-THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract-induced seizures (rat) than a species that did not (dog). CONCLUSION AND IMPLICATIONS/CONCLUSIONS:Sustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis-induced convulsions from animal models.

There has been extraordinary research in the blood-brain barrier. Once considered a static anatomic barrier to the traffic of molecules in and out of the central nervous system when fully developed in adults, the blood-brain barrier is now known to be not only fully functional in development but also vital in cerebrovascular angiogenesis. Blood-brain barrier breakdown has been recognized as an important factor in a variety of primary neurologic diseases; however, such disturbances have yet to be critically analyzed. This article reviews the history, neurodevelopment, ultrastructure, function, and clinicopathologic correlation and relevance to central nervous system vasculitis.

Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.

Background: Research based Developmental Theory of Somatoform/Centralized Pain (S/CP) (Landa et al., 2012) suggests that early interpersonal adversity(EIA) interacts with multigenerational factors leading to neural predisposition to S/CP. Interpersonal affect regulation between infant and caregiver is crucial for optimal maturation of nervous system; EIA may impede development of capacities for emotion-somatic sensation differentiation, awareness, expression and regulation of emotions, leading to experiencing distress in somaticaly. These mechanisms of symptom formation suggest that psychotherapies targeting development of these capacities can help treat S/CP; studies show that psychotherapies that focus on emotion expression and working through interpersonal traumas can alleviate S/CP. However, the exact neurophysiologic mechanisms underlying these effects are not yet fully understood. In our previous study, 90% of S/CP patients (vs 10% of controls) presented with the Unmet Need for Closeness with Others (UNCO) as main representation of relationships. We now present the data on autonomic regulation (HRV) and verbally expressed emotions/alexithymia during patient's interviews on interpersonal relationships.
Method(s): Twenty patients with S/CP from Pain, Neurology, and Primary Care clinics, and 20 age-, sex-, ethnicity-, and level of education-matched healthy controls completed the Relationship Anecdotes Paradigm (RAP)-a semi-structured interview coded for representations of relationships (Core Conflictual Relationship Theme method). HRV was measured continuously during RAP. RAP narratives were coded for Verbally Expressed Emotion using coding method adapted from Levels of Emotional Awareness Scale.
Result(s): S/CP patients had higher levels of UNCO and RAP alexithymia, and significant increase in HRV during RAP vs controls. Relationship between these dimensions and history of interpersonal traumas will be explored.
Discussion(s): Talking about interpersonal relationships and expressing UNCO to others was associated with HRV increase among S/CP patients, which has direct implications for psychophysiologic mechanisms underlying change in psychotherapeutic interventions for S/CP, therefore helping reverse effects of EIA suggested by the Developmental Theory of S/CP. Implications for diagnosis and treatment of S/CP will be discussed

Interactions between axons and Schwann cells are essential for the acquisition of Schwann cell radial and longitudinal polarity and myelin sheath assembly. In the internode, the largest of these longitudinal domains, axon-Schwann cell interactions are mediated by the Nectin-like (Necl) cell adhesion proteins, also known as SynCAMs or Cadms. In particular, Necl-1/Cadm3 expressed on the axon surface binds to Necl-4/Cadm4 expressed along the adaxonal membrane of myelinating Schwann cells. Necl-4 promotes myelination in vitro and is required for the timely onset of myelination and the fidelity of the organization of the myelin sheath and the internode in vivo. A key question is the identity of the downstream effectors of Necl-4 that mediate its effects. The cytoplasmic terminal region (CTR) of Necl-4 contains a PDZ-domain binding motif. Accordingly, we used the CTR of Necl-4 in an unbiased proteomic screen of PDZ-domain proteins. We identify Par-3, a multi-PDZ domain containing protein of the Par-aPKC polarity complex previously implicated in myelination, as an interacting protein. Necl-4 and Par-3 are colocalized along the inner Schwann cell membrane and coprecipitate from Schwann cell lysates. The CTR of Necl-4 binds to the first PDZ domain of Par-3 thereby recruiting Par-3 to sites of Necl-4/Necl-1 interaction. Knockdown of Necl-4 perturbs Par-3 localization to the inner membrane of Schwann cells in myelinating co-cultures. These findings implicate interactions of Necl-1/Necl-4 in the recruitment of Par-3 to the Schwann cell adaxonal membrane and the establishment of Schwann cell radial polarity.