Multidisciplinary amyotrophic lateral sclerosis telemedicine care: The store and forward method.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) patients benefit from multidisciplinary care in an ALS clinic. We studied whether multidisciplinary care of ALS patients using the store and forward method of telemedicine was feasible and acceptable to patients and providers. METHODS: ALS patients seen in the University of Florida (UF) Jacksonville ALS clinic were eligible for our study. A trained telemedicine nurse performed and recorded a multidisciplinary assessment of the patient in their home. Clinic team members reviewed the assessments and provided recommendations, and the clinic director discussed the plan with the patient via videoconference. Patient and provider satisfaction was evaluated using surveys. RESULTS: Eighteen patients completed a total of 27 telemedicine visits. Patient satisfaction was excellent and provider satisfaction was very good. DISCUSSION: The store and forward method of telemedicine is an acceptable alternative to live telemedicine for the multidisciplinary care of ALS patients. This method of care may improve access to multidisciplinary care for this patient population. Muscle Nerve 59:34-39, 2019.

Human Amygdala Tracks a Feature-Based Valence Signal Embedded within the Facial Expression of Surprise.

Human amygdala function has been traditionally associated with processing the affective valence (negative vs positive) of an emotionally charged event, especially those that signal fear or threat. However, this account of human amygdala function can be explained by alternative views, which posit that the amygdala might be tuned to either (1) general emotional arousal (activation vs deactivation) or (2) specific emotion categories (fear vs happy). Delineating the pure effects of valence independent of arousal or emotion category is a challenging task, given that these variables naturally covary under many circumstances. To circumvent this issue and test the sensitivity of the human amygdala to valence values specifically, we measured the dimension of valence within the single facial expression category of surprise. Given the inherent valence ambiguity of this category, we show that surprised expression exemplars are attributed valence and arousal values that are uniquely and naturally uncorrelated. We then present fMRI data from both sexes, showing that the amygdala tracks these consensus valence values. Finally, we provide evidence that these valence values are linked to specific visual features of the mouth region, isolating the signal by which the amygdala detects this valence information.SIGNIFICANCE STATEMENT There is an open question as to whether human amygdala function tracks the valence value of cues in the environment, as opposed to either a more general emotional arousal value or a more specific emotion category distinction. Here, we demonstrate the utility of surprised facial expressions because exemplars within this emotion category take on valence values spanning the dimension of bipolar valence (positive to negative) at a consistent level of emotional arousal. Functional neuroimaging data showed that amygdala responses tracked the valence of surprised facial expressions, unconfounded by arousal. Furthermore, a machine learning classifier identified particular visual features of the mouth region that predicted this valence effect, isolating the specific visual signal that might be driving this neural valence response.

Discovery of disubstituted cyclohexanes as a new class of CC chemokine receptor 2 antagonists.

We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC50 = 5.1 nM) and potent functional antagonism (calcium flux IC50 = 18 nM and chemotaxis IC 50 = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.

Synthesis and evaluation of cis-3,4-disubstituted piperidines as potent CC chemokine receptor 2 (CCR2) antagonists.

A series of cis-3,4-disubstituted piperidines was synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. Compound 24 emerged with an attractive profile, possessing excellent binding (CCR2 IC(50)=3.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.4 nM). Studies to explore the binding of these piperidine analogs utilized a key CCR2 receptor mutant (E291A) with compound 14 and revealed a significant reliance on Glu291 for binding.

From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis.

Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.

A face versus non-face context influences amygdala responses to masked fearful eye whites.

The structure of the mask stimulus is crucial in backward masking studies and we recently demonstrated such an effect when masking faces. Specifically, we showed that activity of the amygdala is increased to fearful facial expressions masked with neutral faces and decreased to fearful expressions masked with a pattern mask-but critically both masked conditions discriminated fearful expressions from happy expressions. Given this finding, we sought to test whether masked fearful eye whites would produce a similar profile of amygdala response in a face vs non-face context. During functional magnetic resonance imaging scanning sessions, 30 participants viewed fearful or happy eye whites masked with either neutral faces or pattern images. Results indicated amygdala activity was increased to fearful vs happy eye whites in the face mask condition, but decreased to fearful vs happy eye whites in the pattern mask condition-effectively replicating and expanding our previous report. Our data support the idea that the amygdala is responsive to fearful eye whites, but that the nature of this activity observed in a backward masking design depends on the mask stimulus.

Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency.

Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.

Discovery and structure-activity relationship of N-(ureidoalkyl)-benzyl-piperidines as potent small molecule CC chemokine receptor-3 (CCR3) antagonists.

Structure-activity relationship (SAR) studies of initial screening hits from our corporate library of compounds and a structurally related series of CCR1 receptor antagonists were used to determine that an N-(alkyl)benzylpiperidine is an essential pharmacophore for selective CCR3 antagonists. Further SAR studies that introduced N-(ureidoalkyl) substituents improved the binding potency of these compounds from the micromolar to the low nanomolar range. This new series of compounds also displays highly potent, in vitro functional CCR3-mediated antagonism of eotaxin-induced Ca(2+) mobilization and chemotaxis of human eosinophils.

BMP-2 tethered hydroxyapatite for bone tissue regeneration: coating chemistry and osteoblast attachment.

The goal of this study was to determine the effectiveness of using polyethyleneimine (PEI) and a polyethylene glycol (PEG) tether to bind human recombinant bone morphogenetic protein-2 (rhBMP-2) to hydroxyapatite (HAp) to enhance rhBMP-2 loading, alter its release properties, and enhance cellular interaction with the material. By using a branched PEI that was derived to express free thiols, rhBMP-2 was coated onto dense HAp surfaces at ~43 ng/cm(2). Using this novel attachment methodology, it was observed that the PEI-SH coating did not change the morphology of the HAp surfaces and that the amount of rhBMP-2 loaded was comparable to a direct adsorption method. In addition, it was also observed that the PEI and PEG tether significantly retained the rhBMP-2 to the HAp surface, inhibiting the burst release effect. Using human fetal osteoblast cells, the PEI- and PEG-tethered BMP-2 was also observed to increase cellular attachment by 10-fold when compared with uncoated HAp and adsorbed rhBMP-2. It was concluded from this study that PEI and PEG tether significantly reduce the initial burst release effect of rhBMP-2. It was also concluded that the rhBMP-2 conjugation to PEI and PEG tether promoted an increase in cellular attachment to the HAp surface.

The structural and functional connectivity of the amygdala: from normal emotion to pathological anxiety.

The dynamic interactions between the amygdala and the medial prefrontal cortex (mPFC) are usefully conceptualized as a circuit that both allows us to react automatically to biologically relevant predictive stimuli as well as regulate these reactions when the situation calls for it. In this review, we will begin by discussing the role of this amygdala-mPFC circuitry in the conditioning and extinction of aversive learning in animals. We will then relate these data to emotional regulation paradigms in humans. Finally, we will consider how these processes are compromised in normal and pathological anxiety. We conclude that the capacity for efficient crosstalk between the amygdala and the mPFC, which is represented as the strength of the amygdala-mPFC circuitry, is crucial to beneficial outcomes in terms of reported anxiety.

INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support.

Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways in tumor cells and promote tumor growth, survival, and drug resistance. INCB16562 was developed as a novel, selective, and orally bioavailable small-molecule inhibitor of JAK1 and JAK2 markedly selective over JAK3. The specific cellular activity of the inhibitor was demonstrated by its potent and dose-dependent inhibition of cytokine-dependent JAK/STAT signaling and cell proliferation in the absence of effects on Bcr-Abl-expressing cells. Treatment of myeloma cells with INCB16562 potently inhibited interleukin-6 (IL-6)-induced phosphorylation of STAT3. Moreover, the proliferation and survival of myeloma cells dependent on IL-6 for growth, as well as the IL-6-induced growth of primary bone marrow-derived plasma cells from a multiple myeloma patient, were inhibited by INCB16562. Induction of caspase activation and apoptosis was observed and attributed, at least in part, to the suppression of Mcl-1 expression. Importantly, INCB16562 abrogated the protective effects of recombinant cytokines or bone marrow stromal cells and sensitized myeloma cells to cell death by exposure to dexamethasone, melphalan, or bortezomib. Oral administration of INCB16562 antagonized the growth of myeloma xenografts in mice and enhanced the antitumor activity of relevant agents in combination studies. Taken together, these data suggest that INCB16562 is a potent JAK1/2 inhibitor and that mitigation of JAK/STAT signaling by targeting JAK1 and JAK2 will be beneficial in the treatment of myeloma patients, particularly in combination with other agents.

Accuracy of the BRCAPRO model among women with bilateral breast cancer.

BACKGROUND: The likelihood of identifying a BRCA mutation was often calculated using the BRCAPRO model. A previous study suggested that this model may overestimate the chance of detecting a BRCA mutation among women diagnosed with bilateral breast cancer. Studies also suggested that few patients with bilateral breast cancer whose age at first diagnosis is >40 years were mutation carriers. The objectives of this study were to determine the accuracy of the BRCAPRO model among women with bilateral breast cancer and to determine whether their mutation status was dependent on their age at first diagnosis. METHODS: A retrospective chart review was performed. Women who were diagnosed with bilateral or unilateral breast cancer and who had undergone comprehensive BRCA1 and BRCA2 genetic testing at M. D. Anderson Cancer Center between 1997 and 2006 were included in the study. RESULTS: For individuals with pre-test carrier probabilities >31%, the proportion of positive tests was significantly lower than predicted by the BRCAPRO model (P < .05). In addition, the carrier rate of BRCA mutations was significantly higher (P = .002, Fisher exact test) in women with bilateral breast cancer whose age at first diagnosis was 40 years. CONCLUSIONS: The BRCAPRO model was overestimating the relative contribution bilateral breast cancer had on the likelihood of detecting a BRCA1 or BRCA2 mutation. Bilateral breast cancer did not appear to be a good indicator of mutation status, particularly for women whose age at first diagnosis is >40 years.

Capped diaminopropionamide-glycine dipeptides are inhibitors of CC chemokine receptor 2 (CCR2).

A new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure-activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three different substituents (benzylamine, carboxamide, and benzamide). Several of the acyclic compounds display 10-30 nM binding affinity for CCR2. Moreover, these antagonists are able to block both MCP-1-induced Ca(2+) flux and monocyte chemotaxis, and are selective for binding to CCR2 over CCR1 and CCR3.

CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity.

DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.

2,4-Disubstituted piperidines as selective CC chemokine receptor 3 (CCR3) antagonists: synthesis and selectivity.

Linear unselective CCR3 antagonist leads with IC(50) values in the 200 nM range were converted into low nM binding compounds selective at CCR3 by moving the piperidine nitrogen substituent to the carbon at the 2-position of the ring. Substitution of the piperidine nitrogen with simple alkyl and acyl groups was found to improve the selectivity of this new compound class. In particular, N-{3-[(2S, 4R)-1-(propyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N'-(3-acetylphenyl)urea exhibited single digit nanomolar IC(50) values for CCR3 with >100-fold selectivity against an extensive counter screen panel.

Selective inhibition of eosinophil influx into the lung by small molecule CC chemokine receptor 3 antagonists in mouse models of allergic inflammation.

CC chemokine receptor (CCR) 3 is a chemokine receptor implicated in recruiting cells, particularly eosinophils (EPhi), to the lung in episodes of allergic asthma. To investigate the efficacy of selective, small molecule antagonists of CCR3, we developed a murine model of EPhi recruitment to the lung. Murine eotaxin was delivered intranasally to mice that had previously received i.p. injections of ovalbumin (OVA), and the effects were monitored by bronchoalveolar lavage. A selective eosinophilic influx was produced in animals receiving eotaxin but not saline. Furthermore, the number of EPhi was concentration- and time-dependent. Although anti-CCR3 antibody reduced the number of EPhi, the effect of eotaxin in OVA-sensitized mice was not a direct chemotactic stimulus because mast cell deficiency (in WBB6F1-Kitw/Kitw-v mice) significantly reduced the response. Two representative small molecule CCR3 antagonists from our program were characterized as being active at mouse CCR3. They were administered p.o. to wild-type mice and found to reduce eotaxin-elicited EPhi selectively in a dose-dependent manner. Pump infusion of one of the inhibitors to achieve steady-state levels showed that efficacy was not achieved at plasma concentrations equivalent to the in vitro chemotaxis IC90 but only at much higher concentrations. To extend the results from our recruitment model, we tested one of the inhibitors in an allergenic model of airway inflammation, generated by adoptive transfer of OVA-sensitive murine T helper 2 cells and aerosolized OVA challenge of recipient mice, and found that it inhibited EPhi recruitment. We conclude that small molecule CCR3 antagonists reduce pulmonary eosinophilic inflammation elicited by chemokine or allergenic challenge.

CCR3 antagonists: a potential new therapy for the treatment of asthma. Discovery and structure-activity relationships.

CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.