Anthrax Vaccination, Gulf War Illness, and Human Leukocyte Antigen (HLA).

We report on a highly significant, positive association between anthrax vaccination and occurrence of Gulf War Illness (GWI) in 111 Gulf War veterans (42 with GWI and 69 controls). GWI was diagnosed in 47.1% of vaccinated veterans but only in 17.2% of non-vaccinated veterans (Pearson χ2 = 7.08, p = 0.008; odds ratio = 3.947; relative risk = 2.617), with 1.6x higher GWI symptom severity in vaccinated veterans (p = 0.007, F-test in analysis of covariance). Next, we tested the hypothesis that the susceptibility to GWI following anthrax vaccination could be due to inability to make antibodies against the anthrax protective antigen (PA), the key protein contained in the vaccine. Since the first step in initiating antibody production would be the binding of PA peptide fragments (typically 15-amino acid long [15-mer]) to peptide-binding motifs of human leukocyte antigen (HLA) Class II molecules, we assessed the binding-motif affinities of such HLA specific molecules to all linear 15-mer peptide fragments of the anthrax PA. We identified a total of 58 HLA Class II alleles carried by the veterans in our sample and found that, of those, 18 (31%) were present in the vaccinated group that did not develop GWI but were absent from the vaccinated group who developed GWI. Remarkably, in silico analyses revealed very high binding affinities of peptide-binding motifs of those 18 HLA alleles with fragments of anthrax vaccine PA, leading to the successful production of anti-PA antibodies. Conversely, the absence of these protective HLA alleles points to a reduced ability to develop antibodies against PA, thus resulting in harmful PA persistence and development of GWI.

Deep Learning Based Superconducting Radio-Frequency Cavity Fault Classification at Jefferson Laboratory.

This work investigates the efficacy of deep learning (DL) for classifying C100 superconducting radio-frequency (SRF) cavity faults in the Continuous Electron Beam Accelerator Facility (CEBAF) at Jefferson Lab. CEBAF is a large, high-power continuous wave recirculating linac that utilizes 418 SRF cavities to accelerate electrons up to 12 GeV. Recent upgrades to CEBAF include installation of 11 new cryomodules (88 cavities) equipped with a low-level RF system that records RF time-series data from each cavity at the onset of an RF failure. Typically, subject matter experts (SME) analyze this data to determine the fault type and identify the cavity of origin. This information is subsequently utilized to identify failure trends and to implement corrective measures on the offending cavity. Manual inspection of large-scale, time-series data, generated by frequent system failures is tedious and time consuming, and thereby motivates the use of machine learning (ML) to automate the task. This study extends work on a previously developed system based on traditional ML methods (Tennant and Carpenter and Powers and Shabalina Solopova and Vidyaratne and Iftekharuddin, Phys. Rev. Accel. Beams, 2020, 23, 114601), and investigates the effectiveness of deep learning approaches. The transition to a DL model is driven by the goal of developing a system with sufficiently fast inference that it could be used to predict a fault event and take actionable information before the onset (on the order of a few hundred milliseconds). Because features are learned, rather than explicitly computed, DL offers a potential advantage over traditional ML. Specifically, two seminal DL architecture types are explored: deep recurrent neural networks (RNN) and deep convolutional neural networks (CNN). We provide a detailed analysis on the performance of individual models using an RF waveform dataset built from past operational runs of CEBAF. In particular, the performance of RNN models incorporating long short-term memory (LSTM) are analyzed along with the CNN performance. Furthermore, comparing these DL models with a state-of-the-art fault ML model shows that DL architectures obtain similar performance for cavity identification, do not perform quite as well for fault classification, but provide an advantage in inference speed.

Public priorities on locally-driven sea level rise planning on the East Coast of the United States.

Sea level rise poses a substantial concern to communities worldwide. Increased inundation, storm surge, saltwater intrusion, and other impacts create challenges which will require considerable planning to address. Recognizing the broad and differing scope of sea level rise issues and the variability of policy options to address them, local planning frameworks are necessary in addition to tools and resources available from state and federal governments. To help assess priorities and preferences on sea level rise planning, a survey of 503 persons affiliated with coastal communities on the East Coast of the United States was conducted in December 2017. This survey studied key aspects locally-driven sea level rise plans, including planning priorities, funding options, methods to resolve conflict, and potential responses. Six key findings address these and other concerns to provide the foundation of a locally driven framework for public officials.

Rotating frame MRI relaxations as markers of diffuse white matter abnormalities in multiple sclerosis.

Even though MRI visualization of white matter lesions is pivotal for the diagnosis and management of multiple sclerosis (MS), the issue of detecting diffuse brain tissue damage beyond the apparent T2-hyperintense lesions continues to spark considerable interest. Motivated by the notion that rotating frame MRI methods are sensitive to slow motional regimes critical for tissue characterization, here we utilized novel imaging protocols of rotating frame MRI on a clinical 3 Tesla platform, including adiabatic longitudinal, T1ρ, and transverse, T2ρ, relaxation methods, and Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank 4 (RAFF4), in 10 relapsing-remitting multiple sclerosis patients and 10 sex- and age-matched healthy controls. T1ρ, T2ρ and RAFF4 relaxograms extracted from the whole white matter exhibited a significant shift towards longer relaxation time constants in MS patients as compared to controls. T1ρ and RAFF4 detected alterations even when considering only regions of normally appearing white matter (NAWM), while other MRI metrics such as T1w/T2w ratio and diffusion tensor imaging measures failed to find group differences. In addition, RAFF4, T2ρ and, to a lesser extent, T1ρ showed differences in subcortical grey matter structures, mainly hippocampus, whereas no functional changes in this region were detected in resting-state functional MRI metrics. We conclude that rotating frame MRI techniques are exceptionally sensitive methods for the detection of subtle abnormalities not only in NAWM, but also in deep grey matter in MS, where they surpass even highly sensitive measures of functional changes, which are often suggested to precede detectable structural alterations. Such abnormalities are consistent with a wide spectrum of different, but interconnected pathological features of MS, including the loss of neuronal cells and their axons, decreased levels of myelin even in NAWM, and altered iron content.

Informing Medication Discontinuation Decisions among Older Adults with Relapsing-Onset Multiple Sclerosis.

BACKGROUND: For older adults with relapsing-onset multiple sclerosis (MS), limited information is available to inform if, or when, disease-modifying drugs (DMDs) may be safely discontinued. OBJECTIVE: The aim of this study was to project the outcomes of DMD discontinuation among older adults with relapsing-onset MS. METHODS: We projected the 10-year outcomes of discontinuation of a DMD (interferon-ß, fingolimod, or natalizumab) among older adults (aged 55 or 70 years) who were relapse-free for 5 or more years and had not reached an Expanded Disability Status Scale (EDSS) score of 6. Outcomes included the percentage of people who had at least one relapse or reached EDSS 6, and quality-adjusted life-years (QALYs), which incorporated both relapses and disability. We used a simulation modeling approach. With increased age, relapses decreased and the effectiveness of DMDs for disability outcomes also decreased. RESULTS: We found lower projected benefits for DMD continuation at 70 years of age than at 55 years of age. Compared with discontinuation, the projected benefit of DMD continuation ranged from 0.007 to 0.017 QALYs at 55 years of age and dropped to 0.002-0.006 at 70 years of age. The annual projected benefits of DMD continuation (0.1-3.0 quality-adjusted life-days) were very low compared with typical patient preferences regarding treatment burden. CONCLUSION: The benefits of DMDs may not be substantial among older adults with relapsing-onset MS. Direct clinical evidence remains limited and the decision of whether to discontinue a DMD should also take into account patient preferences. It is important to gain a better understanding of how age-related changes in the trajectory of relapsing-onset MS affect treatment effectiveness among older adults.

Age-related decreases in relapses among adults with relapsing-onset multiple sclerosis.

BACKGROUND: Relapsing-onset multiple sclerosis (MS) typically starts in early- to mid-adulthood, yet the trajectory of disease activity over the subsequent lifetime remains poorly defined. Previous studies have not quantified the age-specific portion of decreases in annualized relapse rates (ARR). OBJECTIVE: The aim of this article is to determine, under a range of disease-related assumptions, the age-specific component of decreases in ARR over time among adults with relapsing-onset MS. METHODS: We used a simulation modeling approach to examine a range of assumptions about changes in ARR due to age versus disability status. Scenarios included variations in initial ARR and rate of worsening on the Expanded Disability Status Scale. Model parameters were developed through analysis of MS patients in British Columbia, Canada, and literature review. RESULTS: We found a substantial age-specific decrease in ARR in all simulated scenarios, independent of disability worsening. Under a range of clinically plausible assumptions, 88%-97% of the decrease was attributed to age and 3%-13% to disability. The age-specific decrease ranged from 22% to 37% per 5 years for a wide range of initial ARR (0.33-1.0). CONCLUSION: Decreases in ARR were due mostly to age rather than disability status. To facilitate informed decision making in MS, it is important to quantify the dynamic relationship between relapses and age.

Encoding of Serial Order in Working Memory: Neuronal Activity in Motor, Premotor, and Prefrontal Cortex during a Memory Scanning Task.

We have adapted Sternberg's context-recall task to investigate the neural mechanisms of encoding serial order information in working memory, in 2 male rhesus monkeys. We recorded from primary motor, premotor, and dorsolateral prefrontal cortex while the monkeys performed the task. In each cortical area, most neurons displayed marked modulation of activity during the list presentation period of the task, whereas the serial order of the stimuli needed to be encoded in working memory. The activity of many neurons changed in a consistent manner over the course of the list presentation period, without regard to the location of the stimuli presented. Remarkably, these neurons encoded serial position information in a relative (rather than absolute) manner across different list lengths. In addition, many neurons showed activity related to both location and serial position, in the form of an interaction effect. Surprisingly, the activity of these neurons was often modulated by the location of stimuli presented before the epoch in which the activity changes occurred. In motor and premotor areas, a large proportion of neurons with list presentation activity also showed direction-related activity during the response phase, whereas in prefrontal cortex most cells showed only list presentation effects. These results show that many neurons had a heterogeneous functionality by representing distinct task variables at different periods of the task. Finally, potential confounds could not account for the effects observed. For these reasons, we conclude that these neurons were indeed participating in sequence encoding in working memory.SIGNIFICANCE STATEMENT Traditionally, primary motor, premotor, and prefrontal areas have been considered to be mainly engaged in motor output, visuomotor transformation, and higher cognitive functions, respectively. Here we show that neurons in all three cortical regions participate in the encoding of a sequence of spatial stimuli in working memory. Furthermore, a central question in cognitive neuroscience has been the manner in which the position of an item within a sequence is encoded in the brain. Our findings provide direct neurophysiological support for a specific hypothesis from cognitive psychology: that of relative coding of serial order.

Brain Function in Gulf War Illness (GWI) and Associated Mental Health Comorbidities.

GWI has affected a substantial number of Gulf War (GW) veterans. The disease involves several organ systems among which the brain is most prominent. Neurological, cognitive and mood-related (NCM) symptoms frequently dominate and are at the root of chronic ill-health and disability in veterans suffering from GWI. In addition, such symptoms frequently co-occur with diagnosable mental health disorders, predominantly posttraumatic stress disorder (PTSD). Here we investigated the possibility that increased GWI severity leads, above a threshold, to a diagnosable mental health disorder (excluding psychosis). For this purpose, we used, in separate analyses, symptom severity scores and resting-state brain functional connectivity patterns, as determined by magnetoencephalography (MEG). Two-hundred-thirty GW-era veterans participated in this study. They completed diagnostic interviews to establish the presence of GWI and assess mental health status. This distinguished 3 groups: healthy controls (N = 41), veterans with GWI and no mental illness (GWI group, N = 91), and veterans with both GWI and mental health disorder (GWI+MH, N = 98). For each veteran, symptom severity scores in the 6 GWI domains (fatigue, pain, NCM, skin, gastrointestinal, respiratory) were available as well as 9 summary measures of the distribution of Synchronous Neural Interactions (SNI) derived from the MEG recordings. We tested the hypothesis that, in the presence of GWI, the appearance of a diagnosable mental health disorder may depend on GWI symptom severity. For that purpose, we performed a logistic regression on the GWI population, where the presence (or absence) of the MH disorder was the dependent variable and the age- and gender-adjusted GWI severity in the 6-symptom domains were the predictors. The outcome was the probability that a participant will have MH disorder or not. Similarly, we tested the hypothesis that the presence of the MH disorder can be predicted by the SNI distribution patterns by performing a second logistic regression as above but with the 9 SNI measures as predictors. We found GWI symptom severity differed significantly across groups (GWI+MH > GWI > Control). SNI distributions of the GWI group also differed significantly from the other groups in a systematic hemispheric pattern, such that the presence of GWI involved predominantly the left hemisphere, and presence of mental health disorders involved, in addition, the right hemisphere. Both logistic regressions yielded highly significant outcomes, demonstrating that both GWI symptom severity and SNI distribution measures can predict the presence of MH disorder in GWI. Remarkably, the prediction probabilities for MH presence derived from the symptom-based and SNI-based logistic regressions were positively and highly statistically significantly correlated. Taken together, both objective (neural) and subjective (symptoms) indices suggest that GWI is distinct from healthy controls and varies in severity in a continuum that leads, at the higher end, to a diagnosable MH disorder. The positive correlation between the GWI symptom-based and brain-based predicted classifications provides a key link between GWI symptom severity and synchronous neural interactions in the context of mental illness.

Human Leukocyte Antigen (HLA) and Gulf War Illness (GWI): HLA-DRB1*13:02 Spares Subcortical Atrophy in Gulf War Veterans.

BACKGROUND: Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-91 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. We reported previously on the protective role of six Human Leukocyte Antigen (HLA) alleles in GWI (Georgopoulos et al., 2016) and their association with regional brain function (James et al., 2016). More recently, we reported on the presence of subcortical brain atrophy in GWI (Christova et al., 2017) and discussed its possible relation to immune mechanisms. Here we focused on one of the six HLA GWI-protective HLA alleles, DRB1*13:02, which has been found to have a protective role in a broad range of autoimmune diseases (Furukawa et al., 2017), and tested its effects on brain volumes. METHODS: Seventy-six Gulf War veterans (55 with GWI and 21 healthy controls) underwent a structural Magnetic Resonance Imaging (sMRI) scan to measure the volumes of 9 subcortical brain regions to assess differences between participants with (N=11) and without (N=65) HLA class II allele DRB1*13:02. FINDINGS: We found that DRB1*13:02 spared subcortical brain atrophy in Gulf War veterans; overall subcortical volume was 6.6% higher in carriers of DRB1*13:02 (P=0.007). The strongest effect was observed in the volume of cerebellar gray matter which was 9.6% higher (P=0.007) in carriers of DRB1*13:02 than in non-carriers. By contrast, DRB1*13:01 had no effect. INTERPRETATION: These findings document the protective effect of DRB1*13:02 on brain atrophy in Gulf War veterans and are in keeping with recent results documenting sharing of brain mechanisms between GWI and other immune-related diseases (Georgopoulos et al., 2017). We hypothesize that the protective role of DRB1*13:02 is due to its successful elimination of external antigens to which Gulf War veterans were exposed, antigens that otherwise would persist causing low-grade inflammation and possibly leading to autoimmunity. FUNDING SOURCE: U.S. Department of Defense (W81XWH-15-1-0520), Department of Veterans Affairs, American Legion Brain Sciences Chair, and University of Minnesota.

Gulf War illness (GWI) as a neuroimmune disease.

Gulf War illness (GWI) is a chronic disease characterized by the involvement of several organs, including the brain (Christova et al., Exp Brain Res doi: 10.1007/s00221-017-5010-8 , 2017). In a previous study (Georgopoulos et al., J Neural Eng 4:349-355, 2015), we identified six protective alleles from Class II human leukocyte antigen (HLA) genes, and more recently, we investigated the brain correlates of this protection (James et al., EBioMedicine 13:72-79, 2016). Those and other studies (Israeli, Lupus, 21:190-194, 2012) suggested an involvement of the immune system in GWI. In a recent study (Engdahl et al., EBioMedicine doi: 10.1016/j.ebiom.2016.08.030 , 2016), we showed that the brain pattern of synchronous neural interactions (SNI; Georgopoulos et al., J Neural Eng 4:349-355, 2007) in GWI is distinctly different from that in healthy controls. Here we focused on the SNI itself, as a basic measure of neural communication (irrespective of specific connections) and compared it between GWI and seven other diseases that cover a broad spectrum of etiology and pathophysiology. Specifically, we sought to determine which, if any, of those diseases might resemble GWI SNI, overall and within the HLA protective domain, and thus gain further knowledge regarding the nature of GWI brain abnormality. We studied a total of 962 participants from a healthy control population (N = 583) and eight different diseases, including GWI (N = 40), schizophrenia (SZ; N = 21), Alzheimer's disease (AD; N = 66), posttraumatic stress disorder (PTSD; N = 159), major depressive disorder (MDD; N = 10), relapsing-remitting multiple sclerosis (RRMS; N = 43), Sjögren's syndrome (SS; N = 32), and rheumatoid arthritis (RA; N = 8). They all underwent a resting-state magnetoencephalographic (MEG) scan to calculate SNIs. Data were analyzed using analysis of covariance (ANCOVA) with disease as fixed factor, and sex and age as covariates. We found that GWI SNIs differed significantly from control SZ, AD, PTSD and MDD but not from RRMS, SS and RA. In addition, we compared GWI to RRMS, SS and RA with respect to SNIs of MEG sensor pairs that were related to the HLA alleles protective for GWI (James et al., EBioMedicine 13:72-79, 2016). We found that GWI SNIs did not differ significantly from any of these three diseases but they did so from control SZ, AD, PTSD and MDD. These findings indicate that (a) GWI brain synchronicity does not differ significantly from that of known immune-related diseases (RRMS, SS, RA), and (b) that this SNI similarity is present within the HLA-related SNIs. In contrast, GWI SNIs differed significantly from those of the other diseases. We conclude that altered brain communication in GWI likely reflects immune-related processes, as postulated previously (James et al., EBioMedicine 13:72-79, 2016). By extension, these findings also indicate that functional brain abnormalities in RRMS, SS and RA might be, in part, due to lack of protective HLA alleles as documented for GWI (Georgopoulos et al., EBioMedicine 3:79-85, 2015).

Subcortical brain atrophy in Gulf War Illness.

Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-1991 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. Although brain dysfunction in GWI has been well documented (EBioMedicine 12:127-32, 2016), abnormalities in brain structure have been debated. Here we report a substantial (~10%) subcortical brain atrophy in GWI comprising mainly the brainstem, cerebellum and thalamus, and, to a lesser extent, basal ganglia, amygdala and diencephalon. The highest atrophy was observed in the brainstem, followed by left cerebellum and right thalamus, then by right cerebellum and left thalamus. These findings indicate graded atrophy of regions anatomically connected through the brainstem via the crossed superior cerebellar peduncle (left cerebellum â†’ right thalamus, right cerebellum â†’ left thalamus). This distribution of atrophy, together with the observed systematic reduction in volume of other subcortical areas (basal ganglia, amygdala and diencephalon), resemble the distribution of atrophy seen in toxic encephalopathy (Am J Neuroradiol 13:747-760, 1992) caused by a variety of substances, including organic solvents. Given the potential exposure of Gulf War veterans to "a wide range of biological and chemical agents including sand, smoke from oil-well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, pyridostigmine bromide, …" (Institute of Medicine National Research Council. Gulf War and Health: Volume 1. Depleted uranium, pyridostigmine bromide, sarin, and vaccines. National Academies Press, Washington DC, 2000), it is reasonable to suppose that such exposures, alone or in combination, could underlie the subcortical atrophy observed.

Cutaneous cryptococcosis in a patient taking fingolimod for multiple sclerosis: Here come the opportunistic infections?

BACKGROUND: Fingolimod is an oral disease-modifying therapy for relapsing forms of multiple sclerosis, which acts by sequestering lymphocytes within lymph nodes. OBJECTIVE: To describe a case of extrapulmonary cryptococcosis in a patient taking fingolimod. METHODS: Case report. RESULTS: A 47-year-old man developed a non-healing skin lesion approximately 16 months after starting treatment with fingolimod. Biopsy revealed cryptococcosis. Fingolimod was discontinued and the lesion resolved with antifungal therapy. CONCLUSION: Despite few reported opportunistic infections in the pivotal clinical trials and first few years post-marketing, there has been a recent increase in reported AIDS-defining illnesses in patients taking fingolimod. Neurologists should be alert for opportunistic infections in their patients using this medication.

Practice Patterns After Acute Embolic Retinal Artery Occlusion.

PURPOSE: To compare stroke evaluations recommended by retina special-ists and neurologists for retinal artery occlusion (RAO). DESIGN: A cross-sectional survey. METHODS: An anonymous survey was emailed to members of the American Academy of Neurology Stroke Section listserv and vitreoretinal specialists registered with the American Academy of Ophthalmology. The survey was divided based on duration of symptoms before encounter: less than 12 hours, 24-48 hours, and more than 1 week. Institutional review board approval was obtained before data collection. RESULTS: Four hundred forty-eight surveys were completed (281 retinologists and 167 neurologists). Within 12 hours of RAO, most neurologists (75%) pursue a hospital-based evaluation, whereas the majority of retinologists (82%) pursue outpatient workup (P < 0.0001). Most neurologists (92%) and retinologists (98%) pursue outpatient stroke workup if symptoms have been present for more than 7 days. CONCLUSIONS: Neurologists pursue higher acuity care after RAO, whereas most retinologists order outpatient evaluations. Retina specialists should consider urgent stroke evaluation to mitigate stroke risk factors.

Successful treatment of paroxysmal ataxia and dysarthria in multiple sclerosis with levetiracetam.

BACKGROUND: Paroxysmal ataxia and dysarthria (PAD) is a relatively rare symptom in Multiple Sclerosis patients. PAD involves transient dysfunction in control, coordination and initiation of speech and/or limb movements. OBJECTIVE: To describe the successful use of levetiracetam for the treatment of PAD. METHODS: Case report. RESULTS: A 37-year-old woman with MS developed PAD approximately 3 months after a multifocal MS relapse. Brain MRI showed a lesion in the posterior aspect of the midbrain as well as in the right posterior internal capsule, both of which were adjacent to the red nucleus. Attack frequency was reduced after starting levetiracetam at a dose of 500mg twice daily, and attacks stopped completely once the dose was increased to 750mg twice daily. CONCLUSIONS: Given its advantages (in terms of side effects, safety profile and ease of use compared to other anticonvulsants), we suggest that levetiracetam be considered for management of PAD, and perhaps for other paroxysmal MS symptoms as well.

A Magnetoencephalographic (MEG) Study of Gulf War Illness (GWI).

BACKGROUND: Gulf War Illness (GWI) has affected many Gulf War veterans. It involves several organs, most notably the brain. Neurological-cognitive-mood-related symptoms frequently dominate and are at the root of chronic ill-health and disability in GWI. Here we investigated the neural mechanisms underlying brain dysfunction in GWI in the absence of mental health disorders. METHODS: Eighty-six veterans completed diagnostic interviews to establish the presence of GWI and assess mental health status. Participants diagnosed with GWI met both Center for Disease Control and Kansas criteria. We studied 46 healthy controls and 40 veterans with GWI without mental illness. They all underwent a resting-state magnetoencephalographic (MEG) scan to assess brain communication based on synchronous neural interactions (SNI; Georgopoulos et al., 2007). FINDINGS: We found substantial differences in SNI between control and GWI groups centered on the cerebellum and frontal cortex. In addition, using the maxima and minima of SNI per sensor as predictors, we successfully classified 94.2% of the 86 participants (95% sensitivity, 93.5% specificity). INTERPRETATION: These findings document distinct differences in brain function between control and GWI in the absence of mental health comorbidities, differences that are excellent predictors of GWI. FUNDING: U.S. Department of Veterans Affairs and University of Minnesota.

Coding of movements in the motor cortex.

The issue of coding of movement in the motor cortex has recently acquired special significance due to its fundamental importance in neuroprosthetic applications. The challenge of controlling a prosthetic arm by processed motor cortical activity has opened a new era of research in applied medicine but has also provided an 'acid test' for hypotheses regarding coding of movement in the motor cortex. The successful decoding of movement information from the activity of motor cortical cells using their directional tuning and population coding has propelled successful neuroprosthetic applications and, at the same time, asserted the utility of those early discoveries, dating back to the early 1980s.

Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery.

If immunized with an antigen of interest, transgenic mice with large portions of unrearranged human immunoglobulin loci can produce fully human antigen-specific antibodies; several such antibodies are in clinical use. However, technical limitations inherent to conventional transgenic technology and sequence divergence between the human and mouse immunoglobulin constant regions limit the utility of these mice. Here, using repetitive cycles of genome engineering in embryonic stem cells, we have inserted the entire human immunoglobulin variable-gene repertoire (2.7 Mb) into the mouse genome, leaving the mouse constant regions intact. These transgenic mice are viable and fertile, with an immune system resembling that of wild-type mice. Antigen immunization results in production of high-affinity antibodies with long human-like complementarity-determining region 3 (CDR3H), broad epitope coverage and strong signatures of somatic hypermutation. These mice provide a robust system for the discovery of therapeutic human monoclonal antibodies; as a surrogate readout of the human antibody response, they may also aid vaccine design efforts.

Magnetization transfer and adiabatic T1ρ MRI reveal abnormalities in normal-appearing white matter of subjects with multiple sclerosis.

BACKGROUND: Diffuse abnormalities are known to occur within the brain tissue of multiple sclerosis (MS) patients that is "normal appearing" on T1-weighted and T2-weighted magnetic resonance images. OBJECTIVES: With the goal of exploring the sensitivity of novel MRI parameters to detect such abnormalities, we implemented an inversion-prepared magnetization transfer (MT) protocol and adiabatic T1ρ and T2ρ rotating frame relaxation methods. METHODS: Nine relapsing-remitting MS patients and seven healthy controls were recruited. Relaxation parameters were measured in a single slice just above the lateral ventricles and approximately parallel to the AC-PC line. RESULTS: The MT ratio of regions encompassing the normal-appearing white matter (NAWM) was different in MS patients as compared with controls (p = 0.043); however, the T1 measured during off-resonance irradiation (T1sat) was substantially more sensitive than the MT ratio for detecting differences between groups (p = 0.0006). Adiabatic T1ρ was significantly prolonged in the NAWM of MS patents as compared to controls (by 6%, p = 0.026), while no differences were found among groups for T2ρ. No differences among groups were observed in the cortical gray matter for any relaxation parameter. CONCLUSIONS: The results suggest degenerative processes occurring in the NAWM of MS, likely not accompanied by significant abnormalities in iron content.

Therapeutic plasma exchange in neuromyelitis optica: a case series.

Neuromyelitis optica (NMO) is a relapsing inflammatory disease of the central nervous system that predominantly affects the spinal cord and optic nerves. The clinical hallmark of the disease is a step-wise deterioration of visual and spinal cord function. This study reviews patients with steroid resistant relapsing NMO presenting for therapeutic plasma exchange (TPE) at our institution from December 2005 to December 2012. A total of five patients were treated with single volume TPE. Both subjective and objective clinical response to TPE was estimated by three different sources (the patient, a Transfusion Medicine physician, and the treating Neurologist) with the patient and Transfusion Medicine physician's final assessment of response made at the time of the last TPE in the series and the treating neurologist's assessment of response made at the time of the next neurological exam after the last TPE. A total of 17 TPE series were performed with the average course of therapy being three series (ranged 1-5) with five TPE (ranged 3-7) per series. All patients demonstrated improvement with each series of TPE and all procedures were well tolerated with only transient and well-described reactions all of which were successfully resolved with minor or no sequelae.

Late onset multiple sclerosis: Is it really late onset?

BACKGROUND: Multiple sclerosis (MS) is the most common demyelinating disease, and onset over the age of 50 years is referred to as late onset MS (LOMS). It has been thought that LOMS patients will be more likely to exhibit a primary progressive (PPMS) clinical course. OBJECTIVE: To identify the clinical characteristics of demyelinating disease in patients over the age of 50 years from four different MS centers in the Northern Midwest USA. METHODS: We reviewed medical records of all patients seen at the MS centers and identified those who were 50 years of age or more at the time of first spontaneously reported symptoms. We included those who were diagnosed with MS or clinically isolated syndrome (CIS) and excluded MS mimickers. Demographics, initial clinical course diagnosis, clinical characteristics, and any available five-year follow up data were collected. The clinical course was reevaluated in each patient with careful questioning regarding any prior focal neurological symptoms that had persisted for at least 48h, not otherwise explained. Those with a prior event who were initially diagnosed with PPMS or CIS were reclassified as secondary-progressive MS (SPMS) and relapsing-remitting MS (RRMS) respectively. RESULTS: We identified 124 patients from a total of 3700 patients, making LOMS 3.4% MS in our population. The initial clinical course was RRMS in 50 (40%), PPMS in 44 (36%), SPMS in 15 (12%), and CIS in 15 (12%) patients. After reclassification the clinical course was RRMS in 55 (44%), PPMS in 25 (20%), SPMS in 34 (28%), and CIS in 10 (8%) patients. The clinical syndrome was identified as acute for 77 patients (62%) with transverse myelitis (N=25, 32%) as the most common type. The clinical syndrome was chronic for 47 patients (37%) and again transverse myelitis (N=24, 51%) was the most common type. Five-year follow up data was available for 44% of these patients. DISCUSSION: LOMS is rare and RRMS is the most common clinical course. Reclassification of the clinical course, not done before in any other LOMS study, with careful questioning regarding a prior neurological event reveals that SPMS is the most common type of progressive MS and PPMS may be less common than previously thought. Transverse myelitis is the most common clinical presentation.