Continuous Tunneled Infraclavicular Nerve Catheter for Palliative Management of Critical Limb Ischemia: A Case Report.

Critical limb ischemia (CLI) is limb pain occurring at rest or impending limb loss as a result of lack of blood flow to the affected extremity. CLI pain is challenging to control despite multimodal pharmacologic analgesia and surgical intervention. We describe the successful use of a continuous local anesthetic infusion via an infraclavicular nerve catheter to control severe refractory ischemic upper limb pain in a patient with metastatic lung cancer for whom surgical and pharmacological intervention was unsuccessful. As her opioid requirements increased due to worsening ischemic pain, she subsequently developed opioid toxicity, hence prompting the palliative use of a tunneled infraclavicular nerve catheter under ultrasound guidance to minimize opioid requirements. Her opioid requirements tailed down subsequently with the successful insertion of the infraclavicular nerve catheter and she remained pain free till her death. Palliative use of nerve catheters is a safe and an effective alternative in patients with refractory cancer pain, and we describe our methods to prolong its use and minimizing its associated long-term complications.

A Proteome-Wide Effect of PHF8 Knockdown on Cortical Neurons Shows Downregulation of Parkinson's Disease-Associated Protein Alpha-Synuclein and Its Interactors.

Synaptic dysfunction may underlie the pathophysiology of Parkinson's disease (PD), a presently incurable condition characterized by motor and cognitive symptoms. Here, we used quantitative proteomics to study the role of PHD Finger Protein 8 (PHF8), a histone demethylating enzyme found to be mutated in X-linked intellectual disability and identified as a genetic marker of PD, in regulating the expression of PD-related synaptic plasticity proteins. Amongst the list of proteins found to be affected by PHF8 knockdown were Parkinson's-disease-associated SNCA (alpha synuclein) and PD-linked genes DNAJC6 (auxilin), SYNJ1 (synaptojanin 1), and the PD risk gene SH3GL2 (endophilin A1). Findings in this study show that depletion of PHF8 in cortical neurons affects the activity-induced expression of proteins involved in synaptic plasticity, synaptic structure, vesicular release and membrane trafficking, spanning the spectrum of pre-synaptic and post-synaptic transmission. Given that the depletion of even a single chromatin-modifying enzyme can affect synaptic protein expression in such a concerted manner, more in-depth studies will be needed to show whether such a mechanism can be exploited as a potential disease-modifying therapeutic drug target in PD.

Young Age, Liver Dysfunction, and Neurostimulant Use as Independent Risk Factors for Post-Traumatic Seizures: A Multiracial Single-Center Experience.

We aimed to determine the potentially modifiable risk factors that are predictive of post-traumatic brain injury seizures in relation to the severity of initial injury, neurosurgical interventions, neurostimulant use, and comorbidities. This retrospective study was conducted on traumatic brain injury (TBI) patients admitted to a single center from March 2008 to October 2017. We recruited 151 patients from a multiracial background with TBI, of which the data from 141 patients were analyzed, as 10 were excluded due to incomplete follow-up records or a past history of seizures. Of the remaining 141 patients, 33 (24.4%) patients developed seizures during long-term follow up post-TBI. Young age, presence of cerebral contusion, Indian race, low Glasgow Coma Scale (GCS) scores on admission, and use of neurostimulant medications were associated with increased risk of seizures. In conclusion, due to increased risk of seizures, younger TBI patients, as well as patients with low GCS on admission, cerebral contusions on brain imaging, and those who received neurostimulants or neurosurgical interventions should be monitored for post-TBI seizures. While it is possible that these findings may be explained by the differing mechanisms of injury in younger vs. older patients, the finding that patients on neurostimulants had an increased risk of seizures will need to be investigated in future studies.

Medical management of coral reef aorta through optimised diuretic use and angiotensin receptor blockade.

Coral reef aorta (CRA) is a rare condition with potentially devastating complications. It is characterised by atherosclerotic calcification and stenosis of the visceral part of the aorta, usually occurring at the juxtarenal or suprarenal locations, and causing refractory hypertension and renal dysfunction. Surgical intervention, which is the recommended definitive treatment, is associated with significant morbidity and mortality. Endovascular stenting has been reported to be an alternative management option. To the best of our knowledge, this is the first case report to describe medical management of a patient with CRA with diuretics and angiotensin receptor blockade without surgical treatment.

Whole Brain White Matter Microstructure and Upper Limb Function: Longitudinal Changes in Fractional Anisotropy and Axial Diffusivity in Post-Stroke Patients.

BACKGROUND: Diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) measuring fractional anisotropy (FA) and axial diffusivity (AD) may be a useful biomarker for monitoring changes in white matter after stroke, but its associations with upper-limb motor recovery have not been well studied. We aim to describe changes in the whole-brain FA and AD in five post-stroke patients in relation to kinematic measures of elbow flexion to better understand the relationship between FA and AD changes and clinico-kinematic measures of upper limb motor recovery. METHODS: We performed DTI MRI at two timepoints during the acute phase of stroke, measuring FA and AD across 48 different white matter tract regions in the brains of five hemiparetic patients with infarcts in the cortex, pons, basal ganglia, thalamus, and corona radiata. We tracked the progress of these patients using clinical Fugl-Meyer Assessments and kinematic measures of elbow flexion at the acute phase within 14 (mean: 9.4 ± 2.49) days of stroke symptom onset and at a follow-up appointment 2 weeks later (mean: 16 ± 1.54) days. RESULTS: Changes in FA and AD in 48 brain regions occurring during stroke rehabilitation are described in relation to motor recovery. In this case series, one patient with a hemipontine infarct showed an increase in FA of the ipsilateral and contralateral corticospinal tract, whereas other patients with lesions involving the corona radiata and middle cerebral artery showed widespread decreases in perilesional FA. On the whole, FA and AD seemed to behave inversely to each other. CONCLUSIONS: This case series describes longitudinal changes in perilesional and remote FA and AD in relation to kinematic parameters of elbow flexion at the subacute post-stroke period. Although studies with larger sample sizes are needed, our findings indicate that longitudinally measured changes in DTI-based measurements of white matter microstructural integrity may aid in the prognostication of patients affected by motor stroke.

Combining levodopa and virtual reality-based therapy for rehabilitation of the upper limb after acute stroke: pilot study Part II.

INTRODUCTION: This study aimed to evaluate the safety and efficacy of a combination of levodopa and virtual reality (VR)-based therapy for the enhancement of upper limb recovery following acute stroke. METHODS: This was a pilot single-blinded case series of acute stroke patients with upper extremity hemiparesis. Patients were randomised to standard care with concomitant administration of either levodopa alone (control group) or combination therapy consisting of VR-based motivational visuomotor feedback training with levodopa neuromodulation (VR group). Main clinical outcome measures were the Fugl-Meyer Upper Extremity (FM-UE) assessment and Action Research Arm Test (ARAT). Kinematic measurements of affected upper limb movement were evaluated as a secondary measure of improvement. RESULTS: Of 42 patients screened, four patients were enrolled in each of the two groups. Two patients dropped out from the control group during the trial. Patients receiving combination therapy had clinically significant improvements in FM-UE assessment scores of 16.5 points compared to a 3.0-point improvement among control patients. Similarly, ARAT scores of VR group patients improved by 15.3 points compared to a 10.0-point improvement in the control group. Corresponding improvements were noted in kinematic measures, including hand-path ratio, demonstrating that the quality of upper limb movement improved in the VR group. CONCLUSION: Our results suggest that VR-based therapy and pharmacotherapy may be combined for acute stroke rehabilitation. Bedside acquisition of kinematic measurements allows accurate assessment of the quality of limb movement, offering a sensitive clinical tool for quantifying motor recovery during the rehabilitation process after acute stroke.

Migraine with Multiple Sensory Auras.

Migraine auras are typically visual in nature but can manifest as disturbances in somatosensory, auditory, and olfactory senses. Reports of multiple sensory auras are rare in the literature, but their existence may offer novel insights into the pathogenesis of this highly common yet complex neurological condition. Here we report a case of multiple sensory auras involving somatosensory, auditory, and olfactory disturbances in a patient with migraine without visual manifestations. A 45-year-old woman with a 20-year history of migrainous headaches presented with complaints of rightsided facial and hand numbness and paraesthesia. In addition to somatosensory symptoms, she eventually presented with tinnitus, cutaneous allodynia, and phantosmia, each of which was temporally associated with episodes of headache. No abnormalities were detected on NCS, EEG, MRI, and laboratory investigations. Her symptoms were managed by prophylactic medications and acupuncture. The theories of cortical spreading depression, cortical sensitization, and thalamocortical network involvement were discussed as possible explanations for sensory auras in migraine. This case report of migraine with multiple sensory auras spanning somatosensory, auditory, and olfactory modalities offers novel insights into the pathophysiology of migrainous auras.

A Neuronal Activity-Dependent Dual Function Chromatin-Modifying Complex Regulates Arc Expression

Chromatin modification is an important epigenetic mechanism underlying neuroplasticity. Histone methylation and acetylation have both been shown to modulate gene expression, but the machinery responsible for mediating these changes in neurons has remained elusive. Here we identify a chromatin-modifying complex containing the histone demethylase PHF8 and the acetyltransferase TIP60 as a key regulator of the activity-induced expression of Arc, an important mediator of synaptic plasticity. Clinically, mutations in PHF8 cause X-linked mental retardation while TIP60 has been implicated in the pathogenesis of Alzheimer's disease. Within minutes of increased synaptic activity, this dual function complex is rapidly recruited to the Arc promoter, where it specifically counteracts the transcriptionally repressive histone mark H3K9me2 to facilitate the formation of the transcriptionally permissive H3K9acS10P, thereby favoring transcriptional activation. Consequently, gain-of-function of the PHF8-TIP60 complex in primary rat hippocampal neurons has a positive effect on early activity-induced Arc gene expression, whereas interfering with the function of this complex abrogates it. A global proteomics screen revealed that the majority of common interactors of PHF8 and TIP60 were involved in mRNA processing, including PSF, an important molecule involved in neuronal gene regulation. Finally, we proceeded to show, using super-resolution microscopy, that PHF8 and TIP60 interact at the single molecule level with PSF, thereby situating this chromatin modifying complex at the crossroads of transcriptional activation. These findings point toward a mechanism by which an epigenetic pathway can regulate neuronal activity-dependent gene transcription, which has implications in the development of novel therapeutics for disorders of learning and memory.

Neuromodulation for mood and memory: from the engineering bench to the patient bedside.

Brain stimulation, in the form of electroconvulsive therapy (ECT), has long been a gold standard treatment for depression, but today, the field of neuromodulation is rapidly changing with the advent of newer and more precise tools to alter neuroplasticity and to treat brain-based disorders. Now there are new means to induce focal seizures, as with magnetic seizure therapy (MST), or modifications to ECT. There are also surgical approaches to target brain circuits via implanted stimulators placed in the brain or on cranial nerves. Finally, there are noninvasive subconvulsive approaches for the transcranial application of either electric or magnetic fields. Collectively, these tools have transformed the face of neurotherapeutics and informed our understanding of the brain basis of complex neurobehavioral conditions.

Nuclear Arc Interacts with the Histone Acetyltransferase Tip60 to Modify H4K12 Acetylation(1,2,3).

Arc is an immediate-early gene whose genetic ablation selectively abrogates long-term memory, indicating a critical role in memory consolidation. Although Arc protein is found at synapses, it also localizes to the neuronal nucleus, where its function is less understood. Nuclear Arc forms a complex with the ß-spectrin isoform ßSpIVΣ5 and associates with PML bodies, sites of epigenetic regulation of gene expression. We report here a novel interaction between Arc and Tip60, a histone-acetyltransferase and subunit of a chromatin-remodelling complex, using biochemistry and super-resolution microscopy in primary rat hippocampal neurons. Arc and ßSpIVΣ5 are recruited to nuclear Tip60 speckles, and the three proteins form a tight complex that localizes to nuclear perichromatin regions, sites of transcriptional activity. Neuronal activity-induced expression of Arc (1) increases endogenous nuclear Tip60 puncta, (2) recruits Tip60 to PML bodies, and (3) increases histone acetylation of Tip60 substrate H4K12, a learning-induced chromatin modification. These mechanisms point to an epigenetic role for Arc in regulating memory consolidation.

Global quantitative proteomic profiling through 18O-labeling in combination with MS/MS spectra analysis.

Several stable-isotope-based peptide labeling methods have been developed to support large-scale relative quantitation, through mass spectrometry, of proteins present in two different biological samples. In one of these, trypsin-catalyzed 18O-based labeling, quantitation is typically performed at the full scan (MS) level by comparing the peak intensities of sister precursor ions corresponding to the labeled and unlabeled forms of an intact peptide as they co-elute during liquid chromatography (LC) separations. We show here that measuring relative abundance at the product ion (MS/MS) level after fragmentation provides excellent accuracy, sensitivity and signal-to-noise, while combining quantitation with global shotgun protein identification. To facilitate routine data analysis using this approach, we have developed two specialized software programs, ySelect and yRatios, which draw upon database search results for 18O-based data sets and combine fragmentation spectra peak lists to (1) accurately determine protein ratios between two samples while applying a correction for incomplete labeling and (2) tabulate these results in both intuitive summary reports and in formats amenable to systematic pathway level analysis. To validate our process, we subjected simple and complex test protein mixtures to single-step and multistep LC-MS/MS profiling experiments. Ratio distributions approached the expected means, allowing empirical derivation of confidence level cutoffs for determining statistically significant fold-changes in protein abundance. A set of stringent criteria for detecting spurious ratios based on consistency checking between unlabeled and labeled y-ion pairs was found to highlight putative false positive identifications. In summary, this toolkit facilitates comparative proteomic quantitation under conditions that are optimized for making reliable protein inferences.