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SummaryThe roles of Aβ low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions ofSplitCrelabeled Aβ-LTMRs in this regard. Genetic ablation of SplitCre-Aβ-LTMRs increased mechanical pain but not thermosensation in both acute and chronic inflammatory pain conditions, indicating their modality-specific role in gating mechanical pain transmission. Local optogenetic activation of SplitCre-Aβ-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a new model, in which Aβ-LTMRs play distinctive local and global roles in transmitting and alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a new strategy of global activation plus local inhibition of Aβ-LTMRs for treating mechanical hyperalgesia.

Background/AimsOptic neuritis (ON) is the primary ophthalmic manifestation of myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD), but numerous reports have expanded the visual manifestations of this condition. The goal of this study was to synthesise the extensive literature on this topic to help ophthalmologists understand when testing for MOG-IgG should be considered.MethodA systematic review of the English-language literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searches were conducted using Ovid MEDLINE (from January 1, 1948 to April 1, 2020) and Ovid EMBASE (from January 1, 1947 to April 1, 2020). Inclusion criteria included studies describing non-isolated ON ophthalmic manifestations where cell-based assays were used for the detection of MOG antibodies.ResultsFifty-one articles representing 62 patients with a median age of 32.0 (range 2–65), female gender (51%) and follow-up of 20.0 months (range: 1–240) were included. Twenty-nine patients had non-isolated ON afferent visual manifestations: uveitis, peripheral ulcerative keratitis, acute macular neuroretinopathy, neuroretinitis, venous stasis retinopathy, large preretinal macular haemorrhage, orbital inflammatory syndrome, orbital apex syndrome, optic perineuritis, papilloedema and homonymous visual field defects. Incomplete recovery of ON was associated with a case of Leber’s hereditary optic neuropathy. Efferent ophthalmic manifestations included cranial neuropathies, internuclear ophthalmoplegia, central nystagmus, saccadic intrusions and ocular flutter. Cranial nerve involvement was secondary to enhancement of the cisternal portion or brainstem involvement. All included cases were treated with corticosteroids with 31% of cases requiring additional immunosuppressive therapy.ConclusionsMOGAD has been associated with various afferent and efferent ophthalmic manifestations apart from isolated ON. Awareness of these findings may result in earlier diagnosis and treatment.

Purpose To examine the epidemiological characteristics, trends, risk factors, management strategies, and clinical outcomes of Candida albicans and non-albicans keratitis over a 15-year period in a tertiary Canadian eye center. Methods In a retrospective observational case series of Candida keratitis from 2003 to 2017, demographics, risk factors, corrected distance visual acuity (CDVA) at initial and final consultations, medical and surgical management, and follow-up duration were recorded. Results Twenty-one cases of Candida keratitis were identified (62.5% of total fungal keratitis; 10 C. albicans and 11 non-albicans). The most commonly associated risk factors were topical steroid use (16 patients, 76%), ocular surface disease (15 patients, 71%), contact lens use (11 patients, 52%), and previous corneal surgery (8 patients, 38%); all patients had 2 or more combined risk factors. The number of patients with a visual acuity of 20/200 or better remained the same before and after the treatment (5/21, 24%). The mean duration of the antifungal treatment was 98 ± 126 days. Sixteen patients ultimately required surgical management (76%; 12 therapeutic keratoplasties, 3 enucleation, and 1 optical keratoplasty). When comparing C. albicans with non-albicans keratitis, we found no difference in presenting visual acuity, final visual acuity, or requirement for surgical management. Conclusions Candida keratitis accounts for the most identified fungal keratitis cases in this temperate climate area. An exposure to multiple risk factors appears necessary. A surgical intervention is required for the resolution of most cases. Different subspecies of Candida ultimately resulted in similar clinical outcomes.

Orofacial muscle pain is a significant clinical problem because it affects eating, speaking, and other orofacial functions in patients. However, mechanisms underlying orofacial muscle pain are not fully understood. In the present study we induced orofacial muscle pain by injecting Complete Freund's Adjuvant (CFA) into masseter muscle of rats and assessed pain by the orofacial operant test. In comparison with the control group, CFA-injected animals (CFA group) showed decreases in operant behaviors, suggesting the presence of orofacial pain. Trigeminal ganglion (TG) neurons innervating masseter muscles were retrograde-labeled with DiI and their electrophysiological properties studied using patch-clamp recordings. About 20% of DiI-labeled TG neurons showed spontaneous action potentials (APs) in the CFA group but none in the control group. AP rheobase levels were significantly lower in DiI-labeled TG neurons of the CFA group than in the control group. Membrane input resistance of DiI-labeled TG neurons was significantly higher in the CFA group than in the control group. Several other membrane parameters were also different between DiI-labeled TG neurons of the CFA and control groups. Voltage-dependent currents were examined and the most significant changes following CFA were background K+ currents, which showed significantly smaller in DiI-labeled TG neurons of CFA group compared to the control group. Collectively, orofacial muscle pain in CFA model is accompanied with changes of electrophysiological properties and background K+ currents in TG neurons that innervate masseter muscles.

Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective. A common symptom of trigeminal neuropathic pain is cold allodynia/hyperalgesia or cold hypersensitivity in orofacial area, a region where exposure to cooling temperatures are inevitable in daily life. Mechanisms underlying trigeminal neuropathic pain manifested with cold hypersensitivity are not fully understood. In this study, we investigated trigeminal neuropathic pain in male rats following infraorbital nerve chronic constrictive injury (ION-CCI). Assessed by the orofacial operant behavioral test, ION-CCI animals displayed orofacial cold hypersensitivity. The cold hypersensitivity was associated with the hyperexcitability of small-sized trigeminal ganglion (TG) neurons that innervated orofacial regions. Furthermore, ION-CCI resulted in a reduction of A-type voltage-gated K+currents (IA currents) in these TG neurons. We further showed that these small-sized TG neurons expressed Kv4.3 voltage-gated K+channels, and Kv4.3 expression in these cells was significantly downregulated following ION-CCI. Pharmacological inhibition of Kv4.3 channels with phrixotoxin-2 inhibited IA-currents in these TG neurons and induced orofacial cold hypersensitivity. On the other hand, pharmacological potentiation of Kv4.3 channels amplified IA currents in these TG neurons and alleviated orofacial cold hypersensitivity in ION-CCI rats. Collectively, Kv4.3 downregulation in nociceptive trigeminal afferent fibers may contribute to peripheral cold hypersensitivity following trigeminal nerve injury, and Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain.SIGNIFICANCE STATEMENTTrigeminal neuropathic pain, the most debilitating pain disorder, is often triggered and exacerbated by cooling temperatures. Here, we created infraorbital nerve chronic constrictive injury (ION-CCI) in rats, an animal model of trigeminal neuropathic pain to show that dysfunction of Kv4.3 voltage-gated K+channels in nociceptive-like trigeminal ganglion (TG) neurons underlies the trigeminal neuropathic pain manifested with cold hypersensitivity in orofacial regions. Furthermore, we demonstrate that pharmacological potentiation of Kv4.3 channels can alleviate orofacial cold hypersensitivity in ION-CCI rats. Our results may have clinical implications in trigeminal neuropathic pain in human patients, and Kv4.3 channels may be an effective therapeutic target for this devastating pain disorder.

A 37-year-old woman presented with a 1-week history of painful vision loss in both eyes from optic neuritis. She was treated with intravenous, followed by oral corticosteroids. After she completed intravenous corticosteroids, she developed a new area of blurred vision inferiorly (right eye) and centrally (left eye) secondary to central serous chorioretinopathy (CSCR), which resolved after oral prednisone taper (figure). CSCR is characterized by well-circumscribed serous detachments of the retina and is typically seen after exogenous corticosteroid use. CSCR can be misdiagnosed as optic neuritis1 or develop in patients with optic neuritis after corticosteroid treatment2 and should be kept in the differential diagnosis for worsening vision after corticosteroids.

Sensitivity to cooling temperatures often becomes heightened in orofacial regions leading to orofacial cold allodynia/hyperalgesia after chronic trigeminal nerve injury. KCNQ2 channels are involved in controlling excitability of primary afferent neurons and thereby regulate sensory functions under both physiological and pathological conditions. In the present study, we sought to determine whether KCNQ2 channels in trigeminal nerves are involved in regulating orofacial operant behavioral responses to cooling stimulation. We also sought to examine whether chronic trigeminal nerve injury may alter KCNQ2 channel expression in trigeminal ganglions. Using the orofacial operant tests, animals show cold allodynia/hyperalgesia in orofacial regions following infraorbital nerve chronic constrictive injury (ION-CCI), which could be alleviated by subcutaneous administration of retigabine, a KCNQ2 activator. In contrast, subcutaneous administration of the KCNQ2 inhibitor XE991 directly elicits cold allodynia/hyperalgesia in sham animals. Using immunostaining, we show that KCNQ2 channels are primarily expressed in small-sized TG neurons. Interestingly, KCNQ2 channel expression becomes significantly upregulated in TG neurons following the ION-CCI. Our results suggest that KCNQ2 channels are involved in regulating orofacial cold sensitivity. Upregulation of KCNQ2 channels may be a compensatory change in attempting to limit injury-induced trigeminal hyperexcitability.

The Merkel disc is a main type of tactile end organ consisting of Merkel cells and Aβ-afferent endings that responds to tactile stimulation with slowly adapting type 1 (SA1) afferent impulses. Our recent study has shown that Merkel discs in whisker hair follicles are serotonergic synapses using endogenous serotonin to transmit tactile signals from Merkel cells to Aβ-afferent endings. In the present study, we hypothesize that tactile sensitivity of Merkel discs can be modulated by chemical messengers. We tested this hypothesis by determining whether and how SA1 responses of mouse whisker hair follicles may be affected by exogenously applied chemical messengers. We found that SA1 responses were potentiated by serotonin at low concentration (10 μM) but almost completely occluded by serotonin at high concentration (2 mM). In contrast, SA1 responses were not significantly affected by ATP and its metabolically stable analog α,β-methylene-ATP, glutamate, GABA, and histamine. SA1 responses were also not affected by antagonists for P2X receptors, ionotropic glutamate receptors, and ionotropic GABA and glycine receptors. Whole-cell patch-clamp recordings reconfirm the presence of both ionotropic and metabotropic 5-HT receptors on afferent neurons and their terminals innervating whisker hair follicles. All whisker afferent neurons expressed hyperpolarization-activated inward currents (Ih), which are potentiated by serotonin through the activation of metabotropic 5-HT receptors. Taken together, the findings substantiate the serotonergic mechanism of tactile transmission at Merkel discs and identify the involvement of Ih currents in postsynaptic excitatory actions of serotonin. In addition, the findings do not favor any significant involvement of ATP, glutamate, histamine, GABA, or glycine in tactile transmission at the Merkel discs of whisker hair follicles. This article is protected by copyright. All rights reserved.

Rapid conduction of nerve impulses is critical in life and relies on action potential (AP) leaps through the nodes of Ranvier (NRs) along myelinated nerves. While NRs are the only sites where APs can be regenerated during nerve conduction on myelinated nerves, ion channel mechanisms underlying the regeneration and conduction of APs at mammalian NRs remain incompletely understood. Here, we show that TREK-1 and TRAAK, the thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels, are clustered at NRs of rat trigeminal Aβ-afferent nerves with a density over 3,000-fold higher than that on their somas. These K2P channels, but not voltage-gated K

The Piezo2 channel is a newly identified mammalian mechanical transducer that confers rapidly adapting mechanically activated (RA-MA) currents in primary afferent neurons. The Piezo2 channels sense rapid membrane displacement, but it is not clear whether they are sensitive to osmotic swelling, which slowly increases static plasma membrane tension (SPMT). Here, we show that SPMT exerts a profound impact on the mechanical sensitivity of RA-MA channels in primary afferent neurons. RA-MA currents are greatly enhanced, and the mechanical threshold was reduced in both primary afferent neurons of rat dorsal root ganglia (DRG) and HEK293 cells heterologously expressing Piezo2 when these cells undergo osmotic swelling to increase SPMT. Osmotic swelling switches the kinetics of RA-MA currents to the slowly adapting type in both cultured DRG neurons and HEK293 cells heterologously expressing Piezo2. The potentiation of RA-MA currents is abolished when cultured DRG neurons are treated with cytochalasin D, an actin filament disruptor that prevents SPMT of cultured DRG neurons from an increase by osmotic swelling. Osmotic swelling significantly increases DRG neuron mechano-excitability such that a subthreshold mechanical stimulus can result in action potential firing. Behaviorally, the mechanical hind paw withdrawal threshold in rats is reduced following the injection of a hypotonic solution, but this osmotic effect is abolished when cytochalasin D or Gd(3+) is co-administered with the hypo-osmotic solution. Taken together, our findings suggest that Piezo2-mediated mechanotransduction is regulated by SPMT in primary afferent neurons. Because SPMT can be changed by multiple biological factors, our findings may have broad implications in mechanical sensitivity under physiological and pathological conditions.

We studied the discursive processes through which core stigmatized organizations attempt to reduce their stigma by analyzing the websites of addiction treatment organizations. While it is well acce...

Chemotherapy drugs such as oxaliplatin can increase nociceptive neuron excitability to result in neuropathic pain in orofacial and other regions in patients following chemotherapy. However, mechanisms underlying chemotherapy-induced increases of nociceptive neuron excitability are not fully understood. Kv4.3 channels are voltage-gated K+ channels mediating A-type K+ (IA) currents to control neuronal excitability. In the present study, we examined Kv4.3 channel expression on trigeminal neurons that innervate orofacial regions (V2 TG neurons) of rats using immunostaining method. We showed that strong Kv4.3 immunoreactivity (Kv4.3-ir) was present mainly in small-sized V2 TG neurons. The numbers of Kv4.3-ir positive V2 TG neurons were significantly reduced in oxaliplatin-treated rats, suggesting down-regulation of Kv4.3 channel expression on V2 TG neurons by the chemotherapy drug. Patch-clamp recordings from acutely dissociated rat V2 TG neurons showed that almost all nociceptive-like V2 TG neurons displayed IA currents with slow inactivation kinetics. The amplitudes of IA currents were significantly reduced in these nociceptive-like V2 TG neurons of oxaliplatin-treated group. Furthermore, we found that the excitability of nociceptive-like V2 TG neurons was significantly higher in the oxaliplatin-treated group than in the control group. These findings raise a possibility that down-regulation of Kv4.3 channels and IA currents in nociceptive V2 TG neurons is an underlying mechanism of oxaliplatin-induced orofacial neuropathic pain.

Long-term atherosclerotic adverse events are anticipated in patients undergoing carotid endarterectomy (CEA); however, their incidence and risk predictors remain unknown.A consecutive cohort of CEAs between 1/1/2000-12/31/2007 was analyzed. End points were any stroke, coronary event (myocardial infarction, coronary bypass, or stenting), vascular interventions for critical limb ischemia, aortic aneurysm or carotid disease, and death. Survival analysis and Cox regression models were used to identify clinical predictors.A total of 1,136 CEAs (bilateral, 89; mean age, 71.2 ± 9.2 years; 56.5% male; 36.3% symptomatic, and 3.9% combined with coronary bypass) were performed during the study period with a mean clinical follow-up of 60 months (0-155 months). The postoperative combined stroke and/or death rate was 2.7% and 1.9% for asymptomatic and 4.1% for symptomatic patients. Five and 10-year risks of the end points were 7.2% and 16.1% for stroke, 18.4% and 31.5% for coronary interventions, 20.6% and 28.5% for major vascular interventions, and 25.8% and 50.1% for death. Statins conferred a significant protective effect for stroke (hazard ratio [HR], 0.53; P = 0.016) and death (HR, 0.66; P0.0001). Baseline vascular disease predicted future vascular interventions: aortic aneurysm (HR, 1.90; P = 0.003), peripheral arterial disease (HR, 2.03; P0.0001), and contralateral internal carotid artery (ICA) stenosis ≥50% (HR, 4.61; P0.0001). Renal insufficiency predicted worse outcomes for all other end points (HR, 2.21; P = 0.023 for stroke; HR, 1.62; P = 0.008 for coronary events; HR, 2.38; P0.0001 for death).Patients undergoing CEA continue to derive long-term low stroke rate benefit but still sustain major coronary events and require vascular interventions, indicating a need for more intensive medical treatment and rigorous follow-up.

Multiple studies have evaluated the perioperative outcomes of patients with chronic renal insufficiency (CRI) undergoing carotid endarterectomy (CEA), generally indicating worse survival and cardiovascular (CV) outcomes, although not consistently and with a paucity of long-term data. The present study addresses the perioperative and long-term impact of CRI on CV events and survival after CEA.A cohort of consecutive patients treated with CEA between January 1, 2000, and December 31, 2008, was analyzed based on medical records and Social Security Death Index. Estimated glomerular filtration rate (GFR) was assessed at baseline. Renal function was used to divide patients into 3 groups: normal (GFR ≥ 60 mL/min/1.73 m(2)), moderate CRI (GFR, 30-59), and severe CRI (GFR30). The end points were major coronary events, major cerebrovascular events (any stroke), noncardiac vascular interventions (aortic disease, carotid disease, and critical limb ischemia), and mortality. Subgroup analysis based on the presence of preoperative neurologic symptoms was also performed. Survival analysis and Cox regression models were used to assess the effect of baseline predictors.A total of 1,342 CEAs (mean age, 71.2 ± 9.2 years; 55.6% male; 35.3% symptomatic) were performed during the study period with a mean clinical follow-up of 57 months (median, 55; range, 0-155 months). Eight hundred sixty-eight (65%) patients had normal renal function, 414 (31%) had moderate CRI, and 60 (4%) had severe CRI (24 on dialysis). The combined 30-day stroke/death rates for the symptomatic and asymptomatic groups were 3.2% and 1.4% (normal renal function), 5.7% and 2.6% (moderate CRI), and 14.3% and 10.3% (severe CRI), respectively, with the differences being significant only for the severe-CRI group. At 5 years, the severe-CRI group experienced significantly more coronary events (36.9% vs. 16.3%, P0.001), more cerebrovascular events (21.6% vs. 6.3%, P0.001), and deaths (70.0% vs. 20.3%, P0.001), whereas the moderate-CRI group had no significantly different outcomes compared with the normal group, except for mortality (29.8% vs. 20.3%, P0.001). After adjusting for all risk factors, severe CRI remained predictive of coronary events (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.25-3.90; P = 0.007), cerebrovascular events (HR, 3.11; 95% CI, 1.44-6.74; P = 0.004), and mortality (HR, 4.36; 95% CI, 3.00-6.34; P0.001). Symptomatology at baseline was predictive of 5-year mortality (HR, 1.43; 95% CI, 1.14-1.81; P = 0.002). The need for noncardiac vascular interventions was equally distributed among all the groups.Severe but not moderate CRI is associated with poor perioperative outcomes and is an independent predictor of CV events and death at 5 years after CEA. The decision to perform CEA in symptomatic and asymptomatic patients with severe CRI should be individualized given the poor reported outcomes.

SummarySensory systems for detecting tactile stimuli have evolved from touch-sensing nerves in invertebrates to complicated tactile end organs in mammals. Merkel discs are tactile end organs consisting of Merkel cells and Aβ-afferent nerve endings and are localized in fingertips, whisker hair follicles, and other touch-sensitive spots. Merkel discs transduce touch into slowly adapting impulses to enable tactile discrimination, but their transduction and encoding mechanisms remain unknown. Using rat whisker hair follicles, we show that Merkel cells rather than Aβ-afferent nerve endings are primary sites of tactile transduction and identify the Piezo2 ion channel as the Merkel cell mechanical transducer. Piezo2 transduces tactile stimuli into Ca2+-action potentials in Merkel cells, which drive Aβ-afferent nerve endings to fire slowly adapting impulses. We further demonstrate that Piezo2 and Ca2+-action potentials in Merkel cells are required for behavioral tactile responses. Our findings provide insights into how tactile end-organs function and have clinical implications for tactile dysfunctions.

Systemic inflammation at the development of an acute coronary syndrome (ACS) might alter the high-density lipoprotein (HDL) components and function. One of the major functions of HDL particles is their ability to remove cellular cholesterol from macrophages. The aim of the present study was to characterize the HDL efflux capacity in patients with ACS. We analyzed the cholesterol efflux in those ACS (within 72 hours of symptoms [ACS1]) and, again, 3 months later (ACS2). As controls, we used normal subjects without coronary artery disease (CAD) and patients with chronic, stable CAD. The 4 groups were matched for age and HDL cholesterol levels. We used a cell-based efflux system in (3)[H]-cholesterol-labeled J774 macrophages to measure cholesterol efflux from apolipoprotein B-depleted plasma. The present study included 20 patients with ACS. Their mean age was 58 ± 9 years, and the mean HDL cholesterol level was 1.06 ± 0.22 mmol/L (41 ± 9 mg/dl). The ACS1 group showed a marked increase in high-sensitivity C-reactive protein and serum amyloid A, reflecting systemic inflammation. The HDL cholesterol efflux capacity was reduced in ACS1 subjects and remained reduced 12 weeks later and in those with stable CAD. These results suggest that the acute presence of serum amyloid A does not account for the impairment of HDL-mediated cholesterol efflux capacity in the ACS1 group. Little correlation was found between HDL cholesterol and HDL efflux capacity (r = 0.233; p = 0.049), suggesting that HDL cholesterol is a poor marker of HDL function in inflammatory states and CAD. In conclusion, our data support the concept that atherogenic HDL dysfunction and impaired efflux occur in ACS, independent of changes in plasma HDL cholesterol and apolipoprotein A-I levels.

Rapid conduction of nerve impulses is critical in life and relies on action potential (AP) leaps through the nodes of Ranvier (NRs) along myelinated nerves. While NRs are the only sites where APs can be regenerated during nerve conduction on myelinated nerves, ion channel mechanisms underlying the regeneration and conduction of APs at mammalian NRs remain incompletely understood. Here, we show that TREK-1 and TRAAK, the thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels, are clustered at NRs of rat trigeminal Aβ-afferent nerves with a density over 3,000-fold higher than that on their somas. These K2P channels, but not voltage-gated K+ channels as in other parts of nerves, are required for rapid AP repolarization at the NRs. Furthermore, these channels permit high-speed and high-frequency AP conduction along the myelinated afferent nerves, and loss of function of these channels at NRs retards nerve conduction and impairs sensory behavioral responses in animals.

Purpose: To identify the characteristics predictive of unfavorable outcomes for pneumatic retinopexy (PR) in the repair of pseudophakic rhegmatogenous retinal detachments (RD). Methods: A retrospective chart review was performed at a single institution to identify patients who underwent PR in pseudophakic eyes. Pre- and postoperative data were reviewed and analyzed to evaluate predictive factors of failure. Results: Forty-four patients met the study criteria. PR was successful in 23 (52.3%) patients. The failed cases underwent scleral buckles, vitrectomies, or both. A retinal tear located outside the superior four clock hours was a significant predictor of PR failure. At six months post-intervention, the failure and success groups were statistically similar for vision and rate of reattachment. Conclusions: Modified criteria for PR in pseudophakia may include cases with retinal breaks within the superior four clock hours. If further surgery is required, the final vision and anatomic reattachment ar...

The evolution of sensory systems has let mammals develop complicated tactile end organs to enable sophisticated sensory tasks, including social interaction, environmental exploration, and tactile discrimination. The Merkel disc, a main type of tactile end organ consisting of Merkel cells (MCs) and Aβ-afferent endings, are highly abundant in fingertips, touch domes, and whisker hair follicles of mammals. The Merkel disc has high tactile acuity for an object's physical features, such as texture, shape, and edges. Mechanisms underlying the tactile function of Merkel discs are obscured as to how MCs transmit tactile signals to Aβ-afferent endings leading to tactile sensations. Using mouse whisker hair follicles, we show herein that tactile stimuli are transduced by MCs into excitatory signals that trigger vesicular serotonin release from MCs. We identify that both ionotropic and metabotropic 5-hydroxytryptamine (5-HT) receptors are expressed on whisker Aβ-afferent endings and that their activation by serotonin released from MCs initiates Aβ-afferent impulses. Moreover, we demonstrate that these ionotropic and metabotropic 5-HT receptors have a synergistic effect that is critical to both electrophysiological and behavioral tactile responses. These findings elucidate that the Merkel disc is a unique serotonergic synapse located in the epidermis and plays a key role in tactile transmission. The epidermal serotonergic synapse may have important clinical implications in sensory dysfunctions, such as the loss of tactile sensitivity and tactile allodynia seen in patients who have diabetes, inflammatory diseases, and undergo chemotherapy. It may also have implications in the exaggerated tactile sensations induced by recreational drugs that act on serotoninergic synapses.

A variety of classification approaches for the detection of ironic or sarcastic messages has been proposed in the last decade to improve sentiment classification. However, despite the availability of psychologically and linguistically motivated theories regarding the difference between irony and sarcasm, these typically do not carry over to a use in predictive models; one reason might be that these concepts are often considered very similar. In this paper, we contribute an empirical analysis of Tweets and how authors label them as irony or sarcasm. We use this distantly labeled corpus to estimate a model to distinguish between39 both classes of figurative language with the aim to, ultimately, improve the semantically correct interpretation of opinionated statements. Our model separates irony from sarcasm with 79 % accuracy on a balanced set. This result suggests that the task is harder than separating irony or sarcasm from regular texts with 89 % and 90 % accuracy, respectively. A feature analysis shows that ironic Tweets have on average a lower number of sentences than sarcastic Tweets. Sarcastic Tweets contain more positive words than ironic Tweets. Sarcastic Tweets are more often messages to a specific recipient than ironic Tweets. The analysis of bag-of-words features suggests that the comparably high classification performance to distinguish irony from sarcasm is supported by specific, reoccurring topics.

Rapidly adapting mechanically activated channels (RA) are expressed on somatosensory neurons and thought to play a role in mechanical transduction. Because mechanical sensations can be significantly affected by temperatures, we examined thermal sensitivity of RA currents in cultured dorsal root ganglion (DRG) neurons to see if RA channel activity is highly temperature-dependent. RA currents were evoked from DRG neurons by membrane displacements and recorded by the whole-cell patch-clamp recording technique. We found that RA currents were significantly enhanced by warming temperatures from 22 to 32 °C and reduced by cooling temperatures from 24 to 14 °C. RA channel activation exhibited steep temperature-dependence with a large temperature coefficient (Q10 > 5) and a high activation energy (Ea > 30 kcal/mol). We further showed that RA channel activation by mechanical stimulation led to membrane depolarization, which could result in action potential firing at 22 °C or 32 °C but not at 14 °C. Taken together, our results provide the measurements of thermal dynamics and activation energy of RA channels, and suggest that a high energy barrier is present for RA channels to open. These findings are in agreement with temperature sensitivity of mechanical sensations in mammals.

Cooling temperatures may modify action potential firing properties to alter sensory modalities. Herein, we investigated how cooling temperatures modify action potential firing properties in two groups of rat dorsal root ganglion (DRG) neurons, tetrodotoxin-sensitive (TTXs) Na(+) channel-expressing neurons and tetrodotoxin-resistant (TTXr) Na(+) channel-expressing neurons. We found that multiple action potential firing in response to membrane depolarization was suppressed in TTXs neurons but maintained or facilitated in TTXr neurons at cooling temperatures. We showed that cooling temperatures strongly inhibited A-type K(+) currents (IA) and TTXs Na(+) channels but had fewer inhibitory effects on TTXr Na(+) channels and non-inactivating K(+) currents (IK). We demonstrated that the sensitivity of A-type K(+) channels and voltage-gated Na(+) channels to cooling temperatures and their interplay determine somatosensory neuron excitability at cooling temperatures. Our results provide a putative mechanism by which cooling temperatures modify different sensory modalities including pain.

The purpose of this article is to study the role of uncertainty and crisis in a field on institutional entrepreneurship and the role of the institutional entrepreneur’s experiences on this relation...

Chemotherapy drugs such as oxaliplatin can increase nociceptive neuron excitability to result in neuropathic pain in orofacial and other regions in patients following chemotherapy. However, mechanisms underlying chemotherapy-induced increases of nociceptive neuron excitability are not fully understood. Kv4.3 channels are voltage-gated K+ channels mediating A-type K+ (IA) currents to control neuronal excitability. In the present study, we examined Kv4.3 channel expression on trigeminal neurons that innervate orofacial regions (V2 TG neurons) of rats using immunostaining method. We showed that strong Kv4.3 immunoreactivity (Kv4.3-ir) was present mainly in small-sized V2 TG neurons. The numbers of Kv4.3-ir positive V2 TG neurons were significantly reduced in oxaliplatin-treated rats, suggesting down-regulation of Kv4.3 channel expression on V2 TG neurons by the chemotherapy drug. Patch-clamp recordings from acutely dissociated rat V2 TG neurons showed that almost all nociceptive-like V2 TG neurons displayed IA currents with slow inactivation kinetics. The amplitudes of IA currents were significantly reduced in these nociceptive-like V2 TG neurons of oxaliplatin-treated group. Furthermore, we found that the excitability of nociceptive-like V2 TG neurons was significantly higher in the oxaliplatin-treated group than in the control group. These findings raise a possibility that down-regulation of Kv4.3 channels and IA currents in nociceptive V2 TG neurons is an underlying mechanism of oxaliplatin-induced orofacial neuropathic pain.

Parent education programs may be offered or mandated at various stages of the child welfare services continuum. However, little is known regarding their efficacy in addressing the parenting problems that bring families to the attention of child welfare services. This article synthesizes outcome data generated from 58 parenting programs with families determined to be at-risk of child maltreatment and/or abusive or neglectful. It places parent education programs within the broader context of research on effective parenting as well as the leading etiological models of child maltreatment to assess the evaluations of these programs with regard to methodological rigor as well as theoretical salience. Practical and theoretical implications are presented along with recommendations for future research.