Vertebral Artery Anomaly Causing C2 Suboccipital Neuralgia,Relieved by Neurovascular Decompression

We report imaging and surgical findings of a symptomatic 40‐year‐old male with an anomalous left vertebral artery. MR, CT myelography, angiography, and intraoperative photos demonstrate the vertebral artery entering the thecal sac at the C1‐C2 intervertebral foramen and compressing the dorsal C2 nerve rootlets against the cord. Open microvascular decompression alleviated the patient's long‐standing suboccipital and posterior cervical neck pain. An embryologic review of the vertebral and lateral spinal artery systems reveals possible developmental explanations for this variant. Intradural course of the vertebral artery at C2 is one of the few symptomatic developmental vertebral artery anomalies. Recognition of this condition is important because surgical intervention can alleviate associated neck pain.     

Failure of explicit movement control in patients with functional motor symptoms

Functional neurological symptoms are one of the most common conditions observed in neurological practice, but understanding of their underlying neurobiology is poor. Historic psychological models, based on the concept of conversion of emotional trauma into physical symptoms, have not been implemented neurobiologically, and are not generally supported by epidemiological studies. In contrast, there are robust clinical procedures that positively distinguish between organic and functional motor signs that rely primarily on distracting attention away from movement or accessing it covertly. We aimed to investigate the neurobiological principles underpinning these techniques and implications for understanding functional symptoms. We assessed 11 patients with functional motor symptoms and 11 healthy controls in three experimental set‐ups, where voluntary movements were made either with full explicit control or could additionally be influenced automatically by factors of which participants were much less aware (one‐back reaching, visuomotor transformation, and precued reaction time with variable predictive value of the precue). Patients specifically failed in those tasks where preplanning of movement could occur and under conditions of increasing certainty regarding the movement to be performed. However, they implicitly learned to adapt to a visuomotor transformation as well as healthy controls. We propose that when the movement to be performed can be preplanned or is highly predicted, patients with functional motor symptoms shift to an explicit attentive mode of processing that impairs kinematics of movement control, but movement becomes normal when such processes cannot be employed (e.g., during unexpected movement or implicit motor adaptation). © 2013 Movement Disorder Society     

Synaptic competition in the lateral amygdala and the stimulus specificity of conditioned fear: a biophysical modeling study

Competitive synaptic interactions between principal neurons (PNs) with differing intrinsic excitability were recently shown to determine which dorsal lateral amygdala (LAd) neurons are recruited into a fear memory trace. Here, we explored the contribution of these competitive interactions in determining the stimulus specificity of conditioned fear associations. To this end, we used a realistic biophysical computational model of LAd that included multi-compartment conductance-based models of 800 PNs and 200 interneurons. To reproduce the continuum of spike frequency adaptation displayed by PNs, the model included three subtypes of PNs with high, intermediate, and low spike frequency adaptation. In addition, the model network integrated spatially differentiated patterns of excitatory and inhibitory connections within LA, dopaminergic and noradrenergic inputs, extrinsic thalamic and cortical tone afferents to simulate conditioned stimuli as well as shock inputs for the unconditioned stimulus. Last, glutamatergic synapses in the model could undergo activity-dependent plasticity. Our results suggest that plasticity at both excitatory (PN–PN) and di-synaptic inhibitory (PN–ITN and, particularly, ITN–PN) connections are major determinants of the synaptic competition governing the assignment of PNs to the memory trace. The model also revealed that training-induced potentiation of PN–PN synapses promotes, whereas that of ITN–PN synapses opposes, stimulus generalization. Indeed, suppressing plasticity of PN–PN synapses increased, whereas preventing plasticity of interneuronal synapses decreased the CS specificity of PN recruitment. Overall, our results indicate that the plasticity configuration imprinted in the network by synaptic competition ensures memory specificity. Given that anxiety disorders are characterized by tendency to generalize learned fear to safe stimuli or situations, understanding how plasticity of intrinsic LAd synapses regulates the specificity of learned fear is an important challenge for future experimental studies.     

Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia

Five patients with sickle cell anemia were treated with hydroxyurea (HU), in hopes of augmenting their production of fetal hemoglobin. Laboratory responses in two patients treated for more than 2 years were encouraging and there were suggestions of clinical improvement. Long- term HU therapy should be considered for severely affected adults with sickle cell anemia who are willing to accept what is probably a small risk of carcinogenesis. Preliminary chromosomal analysis and knowledge of the clastogenic properties of HU suggest that conception and pregnancy should be avoided. Pharmacokinetic studies will probably be necessary to adjust individual dosage schedules so that cytotoxicity is avoided. F cell responses can be seen in 2 to 3 weeks if the HU dose is optimal, but establishment of a large number of F cells in the circulation may take a month or longer.     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

Quality control of multidrug resistance assays in adult acute leukemia: correlation between assays for P-glycoprotein expression and activity

We have compared multiple assays for the P-glycoprotein (Pgp/MDR1) phenotype in fresh and thawed adult acute leukemia to validate and quantitate measures for the expression and function of Pgp. The results are related to the Pgp-expressing KB8 and KB8-5 call lines. The most sensitive assay was the measurement of modulation of the rhodamine 123 (R123) fluorescence by 2 micromol/L PSC833, followed by the modulation of the probe calcein-AM. We also found a good intralaboratory and interlaboratory correlation between the values of the R123/PSC833 assay for fresh as well as thawed samples. In addition, the affects of PSC833 on 3H-daunorubicin (DNR) accumulation, DNR fluorescence, and 3H- vincristine accumulation were very similar. The correlation between the DNR/PSC833 and R123/PSC833 test was r = .86 (N = 51). The modulation of drug accumulation by 8 micromol/L verapamil was the some as the PSC833 effect for DNR (117%, N = 21), but was higher for vincristine in every single case (161% v 121%, N = 22; P< .001), indicating additional verapamil effects, not related to Pgp. The correlation of the staining of viable cells for Pgp with the monoclonal antibody MRK16 was r = .77 (N = 52) for the R123/PSC833 functional test and r = .84 (N = 50) for the DNR/PSC833 test. From these results it could be calculated that a maximal increase of the mean DNR accumulation of about 50% can be achieved by blocking Pgp pump activity with PSC833 in leukemic blast samples with the highest mean Pgp expression. Subpopulations of blast calls with higher Pgp activity are likely to be present. Their relevance has to be studied further. The methods outlined here allow the reliable, quantitative monitoring of the Pgp/MDR1 phenotype in leukemias in multicentered, clinical Pgp modulation studies.     

Pharmacogenetics in Cardiovascular Disease: The Challenge of Moving From Promise to Realization

Pharmacogenetics in cardiovascular medicine brings the potential for personalized therapeutic strategies that improve efficacy and reduce harm. Studies evaluating the impact of genetic variation on pharmacologic effects have been undertaken for most major cardiovascular drugs, including antithrombotic agents, β‐adrenergic receptor blockers, statins, and angiotensin‐converting enzyme inhibitors. Across these drug classes, many polymorphisms associated with pharmacodynamic, pharmacokinetic, or surrogate outcomes have been identified. However, their impact on clinical outcomes and their ability to improve clinical practice remains unclear. This review will examine the current clinical evidence supporting pharmacogenetic testing in cardiovascular medicine, provide clinical guidance based on the current evidence, and identify further steps needed to determine the utility of pharmacogenetics in cardiovascular care.     

Assurance of neuroattenuation of a live vaccine against West Nile virus: A comprehensive study of neuropathogenesis after infection with chimeric WN/DEN4Δ30 vaccine in comparison to two parental viruses and a surrogate flavivirus reference vaccine

The upsurge of West Nile virus (WNV) human infections in 2012 suggests that the US can expect periodic WNV outbreaks in the future. Availability of safe and effective vaccines against WNV in endemic areas, particularly for aging populations that are at high risk of West Nile neuroinvasive disease (WNND), could be beneficial. WN/DEN4Δ30 is a live, attenuated chimeric vaccine against WNV produced by replacement of the genes encoding the pre-membrane and envelope protein genes of the vaccine virus against dengue virus type 4 (DEN4Δ30) with corresponding sequences derived from a wild type WNV. Following intrathalamic inoculation of nonhuman primates (NHPs), a comprehensive neuropathogenesis study was performed and neurovirulence of WN/DEN4Δ30 vaccine candidate was compared to that of two parental viruses (i.e., WNV and DEN4Δ30), as well as to that of an attenuated flavivirus surrogate reference (i.e., yellow fever YF 17D). Clinical and virological data, as well as results of a semi-quantitative histopathological analysis, demonstrated that WN/DEN4Δ30 vaccine is highly attenuated for the central nervous system (CNS) of NHPs in comparison to a wild type WNV. Importantly, based on the virus replicative ability in the CNS of NHPs and the degree of induced histopathological changes, the level of neuroattenuation of WN/DEN4Δ30 vaccine was similar to that of YF 17D, and therefore within an acceptable range. In addition, we show that the DEN4Δ30 vaccine tested in this study also has a low neurovirulence profile. In summary, our results demonstrate a high level of neuroattenuation of two vaccine candidates, WN/DEN4Δ30 and DEN4Δ30. We also show here a remarkable sensitivity of our WNV-NY99 NHP model, as well as striking resemblance of the observed neuropathology to that seen in human WNND. These results support the use of this NHP model for translational studies of WNV neuropathogenesis and/or testing the effectiveness of vaccines and therapeutic approaches.