A Feasibility Study Exploring Measures of Autonomic Function in Patients With Failed Back Surgery Syndrome Undergoing Spinal Cord Stimulation.

OBJECTIVES: Failed back surgery syndrome (FBSS) is associated with impaired autonomic tone, characterized by sympathetic prevalence and vagal withdrawal. Although spinal cord stimulation (SCS) alleviates pain in FBSS, there is limited research investigating how SCS affects measures of autonomic function. This was a prospective, open-label, feasibility study exploring measures of autonomic function in patients with FBSS receiving SCS therapy. MATERIALS AND METHODS: A total of 14 patients with FBSS were recruited for baseline measurements and underwent a trial of 10-kHz SCS. There were three failed trials, resulting in the remaining 11 participants receiving a fully implanted 10-kHz SCS system. One participant requested an explant, resulting in ten participants completing both baseline and follow-up (three to six months after SCS implant) measurements. Autonomic function was assessed using time- and frequency-domain heart rate variability (HRV), baroreceptor reflex sensitivity (BRS), and muscle sympathetic nerve activity (MSNA) using microneurography. Because this was a feasibility study, most of the analysis was descriptive. However, paired t-tests and Wilcoxon signed-rank tests tested for differences between baseline and follow-up. RESULTS: In the whole (N = 14) and final (N = 10) samples, there was between-participant variation in baseline and follow-up measures. This, combined with a small sample, likely contributed to finding no statistically significant differences in any of the measures between baseline and follow-up. However, plotting baseline and follow-up scores for individual participants revealed that those who showed increases in MSNA frequency, square root of the mean of the squared differences between adjacent RR intervals (RMSSD), percentage of the number of RR intervals >50 ms (pRR50), total power, and up BRS between baseline and follow-up had distinct clustering of baseline values compared with those who showed decreases in these measures. CONCLUSIONS: Findings from this feasibility study will aid with informing hypotheses for future research. A key aspect that should be considered in future research concerns exploring the role of baseline measures of autonomic function in influencing change in autonomic function with SCS therapy.

Mechanisms underpinning sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation.

NEW FINDINGS: What is the topic of this review? This review briefly considers what modulates sympathetic nerve activity and how it may change as we age or in pathological conditions. It then focuses on transcutaneous vagus nerve stimulation, a method of neuromodulation in autonomic cardiovascular control. What advances does it highlight? The review considers the pathways involved in eliciting the changes in autonomic balance seen with transcutaneous vagus nerve stimulation in relationship to other neuromodulatory techniques. The autonomic nervous system, consisting of the sympathetic and parasympathetic branches, is a major contributor to the maintenance of cardiovascular variables within homeostatic limits. As we age or in certain pathological conditions, the balance between the two branches changes such that sympathetic activity is more dominant, and this change in dominance is negatively correlated with prognosis in conditions such as heart failure. We have shown that non-invasive stimulation of the tragus of the ear increases parasympathetic activity and reduces sympathetic activity and that the extent of this effect is correlated with the baseline cardiovascular parameters of different subjects. The effects could be attributable to activation of the afferent branch of the vagus and, potentially, other sensory nerves in that region. This indicates that tragus stimulation may be a viable treatment in disorders where autonomic activity to the heart is compromised.

Implementation of Certified EHR, Patient Portal, and "Direct" Messaging Technology in a Radiology Environment Enhances Communication of Radiology Results to Both Referring Physicians and Patients.

Since 2009, the Federal government distributed over $29 billion to providers who were adopting compliant electronic health record (EHR) technology. With a focus on radiology, we explore how EHR technology impacts interoperability with referring clinicians' EHRs and patient engagement. We also discuss the high-level details of contributing supporting frameworks, specifically Direct messaging and health information service provider (HISP) technology. We characterized Direct messaging, a secure e-mail-like protocol built to allow exchange of encrypted health information online, and the new supporting HISP infrastructure. Statistics related to both the testing and active use of this framework were obtained from DirectTrust.org, an organization whose framework supports Direct messaging use by healthcare organizations. To evaluate patient engagement, we obtained usage data from a radiology-centric patient portal between 2014 and 2015, which in some cases included access to radiology reports. Statistics from 2013 to 2015 showed a rise in issued secure Direct addresses from 8724 to 752,496; a rise in the number of participating healthcare organizations from 667 to 39,751; and a rise in the secure messages sent from 122,842 to 27,316,438. Regarding patient engagement, an average of 234,679 patients per month were provided portal access, with 86,400 patients per month given access to radiology reports. Availability of radiology reports online was strongly associated with increased system usage, with a likelihood ratio of 2.63. The use of certified EHR technology and Direct messaging in the practice of radiology allows for the communication of patient information and radiology results with referring clinicians and increases patient use of patient portal technology, supporting bidirectional radiologist-patient communication.

Effects of transcutaneous vagus nerve stimulation in individuals aged 55 years or above: potential benefits of daily stimulation.

Ageing is associated with attenuated autonomic function. Transcutaneous vagal nerve stimulation (tVNS) improved autonomic function in healthy young participants. We therefore investigated the effects of a single session of tVNS (studies 1 and 2) and tVNS administered daily for two weeks (study 3) in volunteers aged ≥ 55 years. tVNS was performed using modified surface electrodes on the tragus and connected to a transcutaneous electrical nerve stimulation (TENS) machine. Study 1: participants (n=14) received a single session of tVNS and sham. Study 2: all participants (n=51) underwent a single session of tVNS. Study 3: participants (n=29) received daily tVNS for two weeks. Heart rate variability and baroreflex sensitivity were derived. Quality of life (QoL), mood and sleep were assessed in study 3. tVNS promoted increases in measures of vagal tone and was associated with greater increases in baroreflex sensitivity than sham. Two weeks of daily tVNS improved measures of autonomic function, and some aspects of QoL, mood and sleep. Importantly, findings showed that improvements in measures of autonomic balance were more pronounced in participants with greater baseline sympathetic prevalence. This suggests it may be possible to identify individuals who are likely to encounter significant benefits from tVNS.

Non-invasive vagus nerve stimulation acutely improves spontaneous cardiac baroreflex sensitivity in healthy young men: A randomized placebo-controlled trial.

BACKGROUND: Despite positive outcomes of transcutaneous vagus nerve stimulation (tVNS) via the auricular branch of the vagus nerve (ABVN), the mechanisms underlying these outcomes remain unclear. Additionally, previous studies have not been controlled the possible placebo effects of tVNS. OBJECTIVE: To test the hypothesis that tVNS acutely improves spontaneous cardiac baroreflex sensitivity (cBRS) and autonomic modulation, and that these effects are specific to stimulation of ABVN. METHODS: Thirteen healthy men (23±1yrs) were randomized across three experimental visits. In active tVNS, electrodes were placed on the tragus of the ear and electrical current was applied by using a Transcutaneous Electrical Nerve Stimulation device. A time-control visit was performed with the electrodes placed on tragus, but no current was applied (sham-T). Additionally, to avoid a placebo effect, another sham protocol was performed with same electrical current of the active visit, but the electrodes were placed on the ear lobe (an area without cutaneous nerve endings from the vagus - tLS). Beat-to-beat heart rate (HR) and blood pressure (BP) were monitored at rest, during stimulation (active, sham-T and tLS) and recovery. cBRS was measured via sequence technique. Both HR (HRV) and BP variability (BPV) were also measured. RESULTS: Arterial BP and BPV were not affected by any active or sham protocols (P > 0.05). Resting HR and LF/HF ratio of HRV decreased (Δ-3.4 ± 1% and Δ-15 ± 12%, P < 0.05, respectively) and cBRS increased (Δ24 ± 8%, P < 0.05) during active tVNS, but were unchanged during both sham protocols. CONCLUSION: tVNS acutely improves cBRS and autonomic modulation in healthy young men.

The strange case of the ear and the heart: The auricular vagus nerve and its influence on cardiac control.

The human ear seems an unlikely candidate for therapies aimed at improving cardiac function, but the ear and the heart share a common connection: the vagus nerve. In recent years there has been increasing interest in the auricular branch of the vagus nerve (ABVN), a unique cutaneous subdivision of the vagus distributed to the external ear. Non-invasive electrical stimulation of this nerve through the skin may offer a simple, cost-effective alternative to the established method of vagus nerve stimulation (VNS), which requires a surgical procedure and has generated mixed results in a number of clinical trials for heart failure. This review discusses the available evidence in support of modulating cardiac activity using this strange auricular nerve.

Thalamic and prefrontal FDG uptake in never medicated patients with schizophrenia.

OBJECTIVE: Because neuroleptic treatment may cause long-lasting changes in brain structure and function, a group of patients with schizophrenia who had never been medicated was recruited to examine regional glucose metabolic rates in the frontal-striato-thalamic circuit. METHOD: Twelve never medicated patients with schizophrenia (seven men, five women; mean age=29 years) and 13 normal volunteers (eight men and five women; mean age=28.5 years) underwent (18)F-fluorodeoxyglucose (FDG) positron emission tomography, and coregistered anatomical magnetic resonance imaging scans were also obtained. During FDG uptake, subjects performed a spatial attention task previously shown to activate the pulvinar region of the thalamus. RESULTS: Diminished regional glucose metabolism was found in the medial dorsal nucleus, posterior thalamus, and prefrontal cortex of patients with schizophrenia relative to normal volunteers, extending earlier results from studies of medicated and previously medicated patients. CONCLUSIONS: The finding of lower relative metabolic rates in the frontothalamic circuits of patients with schizophrenia is consistent with extended circuit deficits involving interactions of frontal executive areas with thalamic sensory and association processes.

Intraoperative thrombosis of right coronary artery drug-eluting stent after 2 years of dual antiplatelet therapy.

This study presents the case of intraoperative thrombosis of a right coronary drug-eluting stent and subsequent right heart ischemia more than 2 years poststent placement and after recent withdrawal of clopidogrel therapy. Dual antiplatelet therapy had been continued uninterrupted since placement until 7 days prior to surgery when clopidogrel was stopped. This case highlights the emerging evidence that drug-eluting stents are susceptible to late occlusive thrombosis on acute withdrawal of antiplatelet therapy. Right heart ischemia resolved with rapid intraoperative management and emergent cardiac catheterization. This emphasizes the necessity of immediate availability to cardiac interventional facilities, which can influence outcomes.

Desketoneoenactin-siderophore conjugates for Candida: evidence of iron transport-dependent species selectivity.

We investigated the inhibitory activity of synthetic isocyanurate-based as well as linear mono- and trihydroxamate siderophore-drug conjugates against Candida spp. The conjugated drug was 13C-desketoneoenactin (DE). The MICs of siderophore-drug conjugates were determined in the absence and presence of 2,2'-dipyridyl to restrict iron availability. The ability of various siderophore types to promote growth in an iron-restricted medium was also assayed. Addition of a siderophore portion to the drug strongly impaired the inhibitory activity of DE. However, the activity of the drug conjugates was increased by up to 16-fold in iron-depleted medium for species having their growth strongly promoted by most hydroxamate-type siderophores (C. albicans, C. stellatoidea, and C. pseudotropicalis). The uptake of (55)Fe from ferrichrome and from two siderophore-drug conjugates was improved when C. albicans cells were grown in a low-iron medium. In the same assay, unlabeled ferrichrome was able to compete with the uptake of (55)Fe from both conjugates, indicating a common mechanism of uptake. A C. albicans strain lacking the siderophore transporter CaSit1/CaArn1 was not able to use ferrichrome or the synthetic ornithine-based trihydroxamate siderophore for growth promotion and was much less susceptible to the siderophore-drug conjugates than its isogenic parent strain. In summary, the ability of some Candida spp. to use ferrichrome-like siderophores for growth promotion explains the selective activity of hydroxamate-drug conjugates, and this activity seems to be related to the presence, in C. albicans, of the siderophore transporter CaSit1/CaArn1. New conjugate designs are necessary to fully restore or improve the initial DE activity.

Differential agonist-mediated internalization of the human 5-hydroxytryptamine 7 receptor isoforms.

The human 5-hydroxytryptamine 7 (5-HT(7)) serotonin receptor is a class A G-protein coupled receptor that has three isoforms, 5-HT(7(a)), 5-HT(7(b)), and 5-HT(7(d)), which are produced by alternative splicing. The 5-HT(7) receptors are expressed in discrete areas of the brain and in both vascular and gastrointestinal smooth muscle. Central nervous system 5-HT(7) receptors may play a role in mood and sleep disorders. 5-HT(7) receptors show high affinity for a number of antidepressants and typical and atypical antipsychotics. We report here that the human 5-HT(7(d)) isoform expressed in human embryonic kidney (HEK) 293 cells exhibits a pattern of receptor trafficking in response to agonist that differ from 5-HT(7(a)) or 5-HT(7(b)) isoforms. We employed a modification of a live cell-labeling technique to demonstrate that surface 5-HT(7(d)) receptors are constitutively internalized in the absence of agonist. This is in contrast to 5-HT(7(a)) and 5-HT(7(b)) isoforms, which do not show this profound agonist-independent internalization. Indeed, the 5-HT(7(d)) isoform displays this internalization in the presence of a 5-HT(7) -specific antagonist. In addition, the human 5-HT(7) isoform shows a diminished efficacy in stimulation of cAMP-responsive reporter gene activity in transfected cells compared with 5-HT(7(a)) or 5-HT(7(b)) receptors expressed at comparable levels. Thus, the carboxy-terminal tail of 5-HT(7(d)), which is the longest among known human 5-HT(7) isoforms, may contain a motif that interacts with cellular transport mechanisms that is distinct from 5-HT(7(a)) and 5-HT(7(b)).

The preparation of a fully differentiated "multiwarhead" siderophore precursor.

A protected, fully differentiated siderophore analogue has been prepared so that "Trojan Horse"-like siderophore drug conjugates with different drugs can be synthesized. The key steps in the synthesis include controlled preparation of an unsymmetrical urea and its conversion to a fully differentiated isocyanurate by reaction with chloro(carbonyl) isocyanate.