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Moderate coolness is sensed by TRPM8 ion channels in peripheral sensory nerves, but the mechanism by which noxious cold is detected remains elusive. Here, we show that somatosensory and sympathetic neurons express two distinct mechanisms to detect noxious cold. In the first, inhibition by cold of a background outward current causes membrane depolarization that activates an inward current through voltage-dependent calcium (CaV ) channels. A second cold-activated mechanism is independent of membrane voltage, is inhibited by blockers of ORAI ion channels and by downregulation of STIM1, and is recapitulated in HEK293 cells by co-expression of ORAI1 and STIM1. Using total internal reflection fluorescence microscopy we found that cold causes STIM1 to aggregate with and activate ORAI1 ion channels, in a mechanism similar to that underlying store-operated calcium entry (SOCE), but directly activated by cold and not by emptying of calcium stores. This novel mechanism may explain the phenomenon of cold-induced vasodilation (CIVD), in which extreme cold increases blood flow in order to preserve the integrity of peripheral tissues.

The direct impact of chronic hepatitis B and hepatitis C on neurocognition remains elusive due to the frequent comorbidities, and the domains of the neurocognitive functions affected have rarely been investigated comprehensively. We cross-sectionally assessed the neurocognitive functions of the individuals with chronic hepatitis B, chronic hepatitis C, treated chronic hepatitis C with a sustained virologic response, and their healthy control counterparts. Laboratory examinations were used to investigate the impact of inflammation on neurocognition, exclude the medical conditions that could interfere with neurocognition assessment, and assess liver function and fibrotic severity of the liver of the participants. This study found the detrimental impact of chronic hepatitis B on language and executive functions. In contrast, individuals with chronic hepatitis C showed deficits in executive functions, psychomotor speed, memory, and attention. Successful elimination of hepatitis C resulted in improved liver function, but not neuropsychological test performance. Moreover, erythrocyte sedimentation rate level was found to mediate the deficits in the attention of individuals with chronic hepatitis C. These results demonstrate the neurocognitive deficits and the difference in the profiles of neurocognitive deficits in individuals with chronic hepatitis B and chronic hepatitis C. Our study also provided results suggesting the mediation by systemic inflammation on the attention deficit in individuals with chronic hepatitis C.

Background: Hypomimia is a clinical feature of Parkinson’s disease (PD). Based on the embodied simulation theory, the impairment of facial mimicry may worsen facial emotion recognition; however, the empirical results are inconclusive. Objective: We aimed to explore the worsening of emotion recognition by hypomimia. We further explored the relationship between the hypomimia, emotion recognition, and social functioning. Methods: A total of 114 participants were recruited. The patients with PD and normal controls (NCs) were matched for demographic characteristics. All the participants completed the Mini-Mental State Examination and the Chinese Multi-modalities Emotion Recognition Test. In addition to the above tests, the patients were assessed with the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale and Parkinson’s Disease Social Functioning Scale (PDSFS). Results: Patients with PD with hypomimia had worse recognition of disgust than NCs (p = 0.018). The severity of hypomimia was predictive of the recognition of disgust (β= –0.275, p = 0.028). Facial emotion recognition was predictive of the PDSFS score of PD patients (β= 0.433, p = 0.001). We also found that recognizing disgust could mediate the relationship between hypomimia and the PDSFS score (β= 0.264, p = 0.045). Conclusion: Patients with hypomimia had the worst disgust facial recognition. Hypomimia may affect the social function of PD patients, which is related to recognizing the expression of disgust. Emotion recognition training may improve the social function of patients with PD.

This study aimed to understand the impact of sex on the neurocognitive function of patients with Parkinson’s disease (PD). Ninety-four participants with idiopathic PD and 167 age-matched healthy individuals as normal controls (NCs) were recruited and underwent comprehensive neuropsychological assessments. Sex differences were found in NCs, but not in patients with PD. Among male participants, patients with PD showed worse performance on the Digit Symbol Substitution (DSS) (p &lt, 0.001) test and Symbol Search (SS) (p &lt, 0.001) than NCs. Among female participants, patients with PD showed worse performance on the category score of the Modified Wisconsin Card Sorting Test (p &lt, 0.001), SS (p &lt, 0.001), and pentagon copying (p &lt, 0.001) than NCs. After controlling for the effects of age and years of education, Hoehn and Yahr stage was found to predict the performance of the Color Trails Test part A (βA = 0.241, pA = 0.036), Stroop Color and Word Test (β = −0.245, p = 0.036), and DSS (β = −0.258, p = 0.035) in men with PD. These results indicate the differential effect of sex on the neurocognitive function among healthy aging and PD populations. The disappearance of sex differences, which is present in healthy aging, in patients with PD suggests a gradual loss of the neuroprotective effect of estrogen after the initiation of the neurodegenerative process. This study also found mental flexibility and visuospatial function to be the susceptible cognitive domains in women with PD, while the disease severity could predict the working memory and processing speed in men with PD.

Viral hepatitis is a devastating disease with the risk for cirrhosis and carcinogenicity. Regulatory T cells (Tregs) play important roles in the disease course of viral hepatitis via maintaining the balance between overt‐immune responses and viral replications. We hypothesized that genetic polymorphisms of Treg‐related genes, such as interleukin‐2, transforming growth factor‐β 1 (TGF‐β1), forkhead box P3 (FOXP3), and adenylyl cyclase type 9 modulate the hosts' immune regulation under circumstances of viral hepatitis. We examined the effect of five single nucleotide polymorphisms (SNPs) of Treg‐related genes on the levels of C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR), alanine aminotransferase, and non‐invasive hepatic fibrosis marker (Fibrosis‐4 index) in a total of 138 participants with viral hepatitis. The rs1800469 (a TGF‐β1 SNP) GG genotype is associated with higher serum CRP levels, and the rs3761547 (a FOXP3 SNP) C allele in the females is associated with higher ESR levels. Besides, female participants carrying the rs3761547 C allele had a significantly higher Fibrosis‐4 (FIB‐4) index than the females carrying the TT genotype, while the rs3761547 C allele had the opposite effect in males. With linear‐regression moderation analysis, we found that sex moderated the impact of the FOXP3 SNP on the levels of FIB‐4, whereas the FOXP3 SNP caused the opposite effect between males and females on the severity of hepatic fibrosis. These results provide evidence for the participation of TGF‐β1 and FOXP3 in the inflammatory responses associated with viral hepatitis, where FOXP3 function may be moderated by sex.

This study aimed to elucidate the role of sex in neurocognitive function in patients with Parkinson’s disease (PD). Ninety-four idiopathic PD and 167 healthy elderly as normal controls (NCs) were recruited and underwent comprehensive neuropsychological assessments. The sex difference were found in NCs but not in PD. In male, PD patients had worse performance on the Digit symbol substitution (DSS) (p

BACKGROUND Social functioning is crucial for the determinants of Parkinson's disease (PD) with dementia; however, there is no social functioning scale applicable to PD. OBJECTIVE This study aimed to develop a social functioning scale specific to PD (PDSFS) and provide a cut-off score to improve diagnosis accuracy. METHODS The items were developed through literature, interview patients, and PD expertise. After the pilot study, one hundred fifty-seven patients and 74 healthy participants were enrolled and completed the Mini-Mental State Examination, Clock Drawing Test, Activities of Daily Living, Neuropsychiatric Inventory, Adaptive Behavior Assessment System-Second Edition (ABAS-II) and part III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS The final PDSFS has 23 items. The exploratory factor analysis revealed three factors, including "Family Life, Hobbies and Self-Care", "Interpersonal Relationship and Recreational Leisure", and "Social Bond". The internal consistency coefficient was 0.883, and the test-retest reliability was 0.774, respectively. The total score of the PDSFS was significantly related to the total score of ABAS-II (r = 0.609, p

The neuropathology of Parkinson’s disease (PD) involves the frontal-subcortical circuit, an area responsible for processing affective theory of mind (ToM). Patients with PD are expected to experience deficits in the affective ToM. This study aims to investigate whether the ability to infer emotion in others is affected in either young-onset Parkinson’s disease (YOPD) or middle-onset PD (MOPD) patients and to test whether the impairments in affective ToM are associated with the motor symptoms. The affective ToM, global mental abilities, and clinical symptoms were assessed in a total of 107 MOPD, 30 YOPD, and 30 normal controls (NCs). The MOPD patients exhibited deficits in affective ToM to the negative and neutral valences, when compared to the participants in the NCs and YOPD group. By conducting gender-stratified analysis, the deficits in affective ToM was only found in female participants. After adjusting for demographic variables, the multiple linear regression model revealed that affective ToM predicted motor symptoms, especially in female MOPD patients. The present study may aid in the development of medical care programs by advocating for a more comprehensive therapeutic plan that includes continuous disease progression monitoring and social skills training for female MOPD patients or their caregivers.

Monoamine neurotransmitters play essential roles in the regulation of arousal and sleep. Impaired metabolism of monoamine neurotransmitters could result in the accumulation of neurotoxic aldehyde metabolites and, hence, neuronal degeneration. Aldehyde dehydrogenases play an important role in the metabolism of the neurotoxic aldehyde metabolites, including the aldehyde metabolites of dopamine, serotonin, and noradrenaline. Deficient aldehyde dehydrogenase 2 (ALDH2) has been suggested to result in the accumulation of these biogenic aldehydes. An ALDH2 single nucleotide polymorphism (SNP), rs671 (A), results in significantly reduced ALDH2 enzyme activity. A total of 83 Parkinson’s disease (PD) patients were recruited in this study. In addition to the genotypes of rs671, the patients were assessed with the PD sleep scale-2nd version (PDSS-2) and the Epworth sleepiness scale (ESS) for symptoms of daytime and nocturnal sleep disturbances. The patients carrying rs671 (A) had more frequent dozing while lying down to rest in the afternoon (ESS item5) (F = 7.308, p = 0.008) than the rs671 (GG) patients. The patients with rs671 (A) reported a trend toward more frequent difficulty staying asleep than the patients with rs671 (GG). (F = 3.278, p = 0.074). The results indicate that patients carrying allele rs671 (A) are more likely to experience impairment in the regulation of arousal and sleep. The results also support the hypothesis that the accumulation of neurotoxic monoamine neurotransmitter aldehyde metabolites secondary to reduced ALDH2 enzyme activity may cause more severe monoaminergic neuronal loss and, hence, more severe symptoms in the regulation of wakefulness and sleep.

Thermal and noxious stimuli are detected by specialized nerve endings, which transform the stimuli into electrical signals and transmit the signals into central nervous system to facilitate the perception of temperature and pain. Several members within the transient receptor potential (TRP) channel family serve as the sensors for temperature and noxious stimuli and are involved in the development of pathological pain, especially inflammatory pain. Various inflammatory mediators can sensitize and modulate the activation threshold of TRP channels and result in the development of inflammatory pain behaviors. A brief review of the role of TRP channels in nociception and the modulatory mechanisms of TRP channels by inflammatory mediators, focusing on TRPV1, TRPA1, and TRPM2, will be presented. Recent advances in the development of therapeutic strategies targeting against TRP channels will also be reviewed.

The abilities to detect warmth and heat are critical for the survival of all animals, both in order to be able to identify suitable thermal environments for the many different activities essential for life and to avoid damage caused by extremes of temperature. Several ion channels belonging to the TRP family are activated by non-noxious warmth or by heat and are therefore plausible candidates for thermal detectors, but identifying those that actually regulate warmth and heat detection in intact animals has proven problematic. TRPM2 has recently emerged as a likely candidate for the detector of non-noxious warmth, as it is expressed in sensory neurons, and mice show deficits in the detection of warmth when TRPM2 is genetically deleted. TRPM2 is a chanzyme, containing a thermally activated TRP ion channel domain attached to a C-terminal motif, derived from a mitochondrial ADP ribose pyrophosphatase, that confers on the channel sensitivity to ADP ribose and reactive oxygen species such as hydrogen peroxide. Several open questions remain. Male mammals prefer cooler environments than female, but the molecular basis of this sex difference is unknown. TRPM2 plays a role in regulating body temperature, but are other warmth-detecting mechanisms also involved? TRPM2 is expressed in autonomic neurons, but does it confer a sensory function in addition to the well-known motor functions of autonomic neurons? TRPM2 is thought to play important roles in the immune system, in pain and in insulin secretion, but the mechanisms are unclear. TRPM2 has to date received less attention than many other members of the TRP family but is rapidly assuming importance both in normal physiology and as a key target in disease pathology.

Objective The use of opiate substances, such as heroin and methadone, has been proven to cause executive function damage. The extent of damage may be mediated by the activity of enzyme aldehyde dehydrogenase 2 (ALDH2), which plays an important role in neurotransmitter dopamine metabolism. The single nucleotide polymorphism Glu487Lys distributes mostly in Asia and codes for ALDH2 with greatly reduced enzyme activity. The current study aims to explore the effect of ALDH2 on executive function in opiate users. Methods A total of 94 opiate users were recruited and 58 patients finished the neuropsychological assessment and blood genotyping. Results After co-variating the influence of age and the years of education, we found that participants with ALDH2 A allele performed worse on the Category Complete index of the Modified Wisconsin Card Sorting Test (F = 5.34, p = 0.02), suggesting an impaired planning ability in this group. We also found that ALDH2 A carriers went through the Trail 2 in Color Trails Test faster (F = 8.21, p = 0.01), in part suggesting better set-shifting abilities; however, impulsiveness and lack of planning associated with this study group may also explain the faster performances. Conclusions The role that ALDH2 plays in the pathology of cognitive impairment in opiate users may lead new focus in studies of the pathophysiology in opiate usage and its consequences on cognitive function.

Thermal and noxious stimuli are detected by specialized nerve endings, which transform the stimuli into electrical signals and transmit the signals into central nervous system to facilitate the perception of temperature and pain. Several members within the transient receptor potential (TRP) channel family serve as the sensors for temperature and noxious stimuli and are involved in the development of pathological pain, especially inflammatory pain. Various inflammatory mediators can sensitize and modulate the activation threshold of TRP channels and result in the development of inflammatory pain behaviors. A brief review of the role of TRP channels in nociception and the modulatory mechanisms of TRP channels by inflammatory mediators, focusing on TRPV1, TRPA1, and TRPM2, will be presented. Recent advances in the development of therapeutic strategies targeting against TRP channels will also be reviewed.

Thermally activated ion channels are known to detect the entire thermal range from extreme heat (TRPV2), painful heat (TRPV1, TRPM3 and ANO1), non-painful warmth (TRPV3 and TRPV4) and non-painful coolness (TRPM8) through to painful cold (TRPA1)1,2,3,4,5,6,7. Genetic deletion of each of these ion channels, however, has only modest effects on thermal behaviour in mice6,7,8,9,10,11,12, with the exception of TRPM8, the deletion of which has marked effects on the perception of moderate coolness in the range 10–25 °C13. The molecular mechanism responsible for detecting non-painful warmth, in particular, is unresolved. Here we used calcium imaging to identify a population of thermally sensitive somatosensory neurons which do not express any of the known thermally activated TRP channels. We then used a combination of calcium imaging, electrophysiology and RNA sequencing to show that the ion channel generating heat sensitivity in these neurons is TRPM2. Autonomic neurons, usually thought of as exclusively motor, also express TRPM2 and respond directly to heat. Mice in which TRPM2 had been genetically deleted showed a striking deficit in their sensation of non-noxious warm temperatures, consistent with the idea that TRPM2 initiates a ‘warm’ signal which drives cool-seeking behaviour. The neuronal mechanism for the detection of non-painful warm stimuli has remained unclear; mammalian TRPM2 ion channel is shown to be required for warmth detection in the non-noxious range of 33–38 °C, and surprisingly to mediate responses to warmth in the autonomic nervous system. Despite the identification of several members of the TRP family of ion channels as heat-sensitive, the neuronal mechanism for the detection of non-painful warm stimuli has remained unclear, because genetic deletion of obvious candidates, such as TRPV3 and TRPV4, has had no effect on thermosensation. Rather than working with cloned channels, as is commonly done, Chun-Hsiang Tan and Peter McNaughton studied the responses of actual sensory neurons to thermal stimuli, then used an RNA-sequencing strategy to identify TRPM2 as genetically required for warmth detection in the non-noxious range of 33–38 °C, and, surprisingly, to mediate warm sensations in the autonomic nervous system.

Neurotransmitter degradation has been proposed to cause the accumulation of neurotoxic metabolites. The metabolism of these metabolites involves aldehyde dehydrogenase 2 (ALDH2). The Asian-specific single nucleotide polymorphism rs671 causes reduced enzyme activity. This study aims to explore whether Parkinson’s disease (PD) patients with reduced ALDH2 activity owing to the rs671 polymorphism are at risk for neuropsychological impairments. A total of 139 PD patients were recruited. Each participant was assessed for medical characteristics and their ALDH2 genotype. The Mini-Mental State Examination (MMSE), the Clinical Dementia Rating Scale and the Frontal Behavioral Inventory were used to measure neuropsychological functions. We found that the MMSE scores were significantly lower in patients with inactive ALDH2 (U = 1873.5, p = 0.02). The presence of cognitive impairments was significantly more frequent in the inactive ALDH2 group (46.0%) than in the active ALDH2 group (26.3%) (χ2 = 5.886, p = 0.01). The inactive group showed significant deterioration in hobbies and exhibited more severe “disorganization” and “hyper-sexuality” behaviours. The additive effects of the allele on the development of cognitive impairments in PD patients may be an important finding that provides further insight into the pathogenic mechanism of cognitive dysfunction in PD.

Objective Memory formation is proposed to be a dual process that involves the simultaneous memorisation of both detailed information (item-specific memory) and gist information (gist memory). Memory deficits have been reported in patients with Parkinson's disease (PD); however, few studies have explicitly addressed the nature of these deficits. To obtain a detailed understanding of memory dysfunction in patients with PD, it is of crucial importance to establish whether item-specific memory and gist memory performance are impaired. The aim of this study is to explore whether gist memory and item-specific memory performance are still intact in patients with PD, as well as to determine which psychological mechanisms are responsible for memory formation. Setting Two hospitals in northern Taiwan. Participants Thirty-nine patients with PD and 28 normal controls were recruited. Each participant received a gist-based recognition test following the Deese-Roediger-McDermott paradigm, as well as neuropsychological tests and measures of clinical characteristics. Results Gist memory was impaired in patients with advanced-stage disease (Hoehn and Yahr (H&Y) stage: III) (F2,64=3.58, p=0.033), whereas item-specific memory was preserved throughout all disease stages. Correlation analysis showed that item-specific memory was related to executive functions in normal controls and early-stage patients with PD (H&Y stage: I–II); however, item-specific memory was related to episodic memory, rather than to executive functions, in advanced-stage patients with PD. Moreover, gist memory was related to episodic memory, but only in early-stage patients with PD. Conclusions We discovered that impaired gist memory is found in advanced-stage, but not in early-stage, patients with PD. Our findings suggest that the techniques used to take advantage of the relatively preserved gist memory in early-stage patients with PD, as well as the preserved item-specific memory in patients with PD of all stages, could be useful for memory rehabilitation programmes.

Animals must sense temperature in the external environment in order to find ambient temperatures appropriate for different activities, such as hunting or sleeping, and to avoid even brief exposure to damaging extremes of temperature. They must also sense their internal bodily temperature in order to regulate it. Some members of the TRP channel family are activated by thermal stimuli, and are consequently named the thermoTRPs; thermally sensitive ion channels are also found in the potassium and chloride channel families. When thermoTRP channels are expressed in a sensory neuron, channel opening in response to heat leads to depolarization and generation of action potentials. It is still an open question which channels are important for sensation of thermal stimuli in the external environment, and channels involved in the sensation of internal bodily temperature for the purposes of thermoregulation are even less understood. In this chapter we review the properties of thermosensitive ion channels and their roles in thermosensation and thermoregulation, with an emphasis on TRP channels.

To investigate the skin innervation and its clinical significance in late-stage chronic kidney disease (CKD).Case series.National Taiwan University Hospital, Taipei, Taiwan.Forty consecutive nondiabetic patients with late-stage CKD (14 female and 26 male; mean [SD] age, 60.7 [12.3] years), including 2 cases with stage 3 CKD, 6 with stage 4 CKD, and 32 with stage 5 CKD, ie, end-stage kidney disease.Clinical evaluation of neurological deficits, nerve conduction study, autonomic function tests, and a 3-mm-diameter skin biopsy specimen taken from the distal leg.Quantitation of epidermal innervation, parameters of nerve conduction study, R-R interval variability, and sympathetic skin response.Clinically, 21 patients (52.5%) were symptomatic with paresthesia over the limbs or autonomic symptoms. The intraepidermal nerve fiber (IENF) density was markedly reduced in patients with CKD compared with age- and sex-matched controls (mean [SD], 2.8 [2.0] vs 8.6 [2.8] fibers/mm; P.001). Skin denervation was observed in 27 patients (67.5%). Fifteen patients (37.5%) had abnormalities on nerve conduction studies, and 29 patients (72.5%) had abnormal results on autonomic function tests. By analysis with multiple regression models, the IENF density was negatively correlated with the duration of renal disease (P = .02). Additionally, the R-R interval variability at rest was linearly correlated with the IENF density (P = .02) and the absence of sympathetic skin responses at the soles was associated with reduced IENF density (P = .03).Small-fiber sensory and autonomic neuropathies constitute the major form of neuropathy in late-stage CKD. Furthermore, skin denervation was associated with the duration of renal disease.

A 53-year-old male patient developed insidious onset of length-dependent painful neuropathy on a background of encephalopathy during prolonged treatment with metronidazole for a cumulative dose of 146 g in 88 days. The reversible encephalopathy was documented with gradual resolution of hyperintense lesions in bilateral cerebellum and brainstem on brain MRI together with the improvement in symptoms of ataxia and dysarthria. The concomitant impairment of small-diameter sensory nerves posed a diagnostic challenge. The authors took advantage of serial skin biopsies to demonstrate reversible metronidazole-induced small-fibre sensory neuropathy, that is, skin denervation after metronidazole and corresponding skin reinnervation with the disappearance of sensory symptoms.

Rwei-Ling Yu,1 Chun-Hsiang Tan,2 Ruey-Meei Wu3 1Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Wolfson Centre for Age Related Diseases, King’s College London, London, UK; 3Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan Objectives: The aims of this study were to explore nocturnal disturbances in patients with Parkinson’s disease (PD) and to assess their impact on quality of life (QoL).Methods: A total of 211 patients with PD were recruited for this study, and each participant was evaluated using the mini-mental state examination, PD sleep scale – second version (PDSS-2), pittsburgh sleep quality index (PSQI), PD QoL questionnaire (PDQ), Epworth sleepiness scale, Hoehn and Yahr (H&Y) staging, and unified Parkinson’s disease rating scale (UPDRS). Multiple regression analyses were performed to determine the contribution of the predictive variables on QoL.Results: There were 56.4% males (mean age: 64.08years; disease duration: 6.02years; H&Y stage: 2.25; and UPDRS: 33.01) in this study. Our patients’ actual sleep time was 5.96±1.16hours and the average sleep efficiency was 82.93%±12.79%. Up to 64.4% of patients were classified as “poor” sleepers and 23.8% suffered from daytime sleepiness. The final stepwise regression model revealed that UPDRS parts I and II, the sleep disturbance and daytime dysfunction components of the PSQI, the PD symptoms at night subscale of the PDSS-2, and the levodopa equivalent dose were significant predictors of the PDQ score (R2=53, F7,165=28.746; P

An 82-year-old female with history of hypertension, atrial fibrillation and rectosigmoid cancer status postoperation without recurrence had a sudden onset of right hemiparesis and aphasia. She had regularly taken irbesartan, atenolol, propafenone and indapamide. On arrival at the emergency room, she was globally aphasic and had right hemiparesis, hemihypoaesthesia and homonymous hemianopia. Her initial National Institutes of Health Stroke Scale Score was 20. Head CT 65 min after onset of symptoms showed a left hyperdense middle cerebral artery sign. A left middle cerebral artery infarction was diagnosed. She received recombinant tissue plasminogen activator (rt-PA) (alteplase, 0.75 mg/kg) 140 min after onset of …