Post-stroke dysphagia and ambient air pollution are associated with dementia.

Introduction: This cohort study aimed to explore the potential association between ambient air pollution and dementia incidence in adults who have experienced a stroke. Additionally, the study aimed to determine dysphagia as a predictive factor for the subsequent development of dementia in patients with stroke. Materials and methods: This retrospective nested case-control study used data from the Kaohsiung Medical University Hospital Database in Taiwan. Data collected include average ambient air pollution concentrations within 3 months and 1 year after the index dysphagia date. The primary outcome includes incident dementia in patients with or without dysphagia. Logistic regression analysis was performed to examine the association between significant air pollution exposure and the risk of dementia while controlling for baseline demographic characteristics (age and sex), and comorbidities. Results: The univariable regression models revealed a higher likelihood of dementia diagnosis in patients with dysphagia (odds ratio = 1.493, 95% confidence interval = 1.000-2.228). The raw odds ratios indicated a potential link between air pollution exposure and elevated dementia risks in the overall study population and patients with stroke without dysphagia, except for O3. Particulate matter (PM)2.5 and nitrogen oxides (NOx) exhibited significant effects on the risk of dementia in the stepwise logistic regression models. Conclusion: The presence of dysphagia following a stroke may pose a risk of developing dementia. Additionally, PM2.5 and NOx exposure appears to elevate the risk of dementia in patients with stroke.

Acidosis-related pain and its receptors as targets for chronic pain.

Sensing acidosis is an important somatosensory function in responses to ischemia, inflammation, and metabolic alteration. Accumulating evidence has shown that acidosis is an effective factor for pain induction and that many intractable chronic pain diseases are associated with acidosis signaling. Various receptors have been known to detect extracellular acidosis and all express in the somatosensory neurons, such as acid sensing ion channels (ASIC), transient receptor potential (TRP) channels and proton-sensing G-protein coupled receptors. In addition to sense noxious acidic stimulation, these proton-sensing receptors also play a vital role in pain processing. For example, ASICs and TRPs are involved in not only nociceptive activation but also anti-nociceptive effects as well as some other non-nociceptive pathways. Herein, we review recent progress in probing the roles of proton-sensing receptors in preclinical pain research and their clinical relevance. We also propose a new concept of sngception to address the specific somatosensory function of acid sensation. This review aims to connect these acid-sensing receptors with basic pain research and clinical pain diseases, thus helping with better understanding the acid-related pain pathogenesis and their potential therapeutic roles via the mechanism of acid-mediated antinociception.

Oxidative stress involves phenotype modulation of morbid soreness symptoms in fibromyalgia.

OBJECTIVES: Muscle soreness occurs after exercise and also in musculoskeletal diseases, such as fibromyalgia (FM). However, the nosography and pathoetiology of morbid soreness in FM remain unknown. This study aimed to investigate the morbid soreness of FM, evaluate its therapeutic responses and probe its pathophysiology with metabolomics profiling. METHODS: Patients with newly diagnosed FM were prospectively recruited and completed self-report questionnaires pertaining to musculoskeletal symptoms. The phenotypes and metabotypes were assessed with variance, classification and correlation analyses. RESULTS: Fifty-one patients and 41 healthy controls were included. Soreness symptoms were prevalent in FM individuals (92.2%). In terms of manifestations and metabolomic features, phenotypes diverged between patients with mixed pain and soreness symptoms (FM-PS) and those with pain dominant symptoms. Conventional treatment for FM did not ameliorate soreness severity despite its efficacy on pain. Moreover, despite the salient therapeutic efficacy on pain relief in FM-PS cases, conventional treatment did not improve their general disease severity. Metabolomics analyses suggested oxidative metabolism dysregulation in FM, and high malondialdehyde level indicated excessive oxidative stress in FM individuals as compared with controls (p=0.009). Contrary to exercise-induced soreness, lactate levels were significantly lower in FM individuals than controls, especially in FM-PS. Moreover, FM-PS cases exclusively featured increased malondialdehyde level (p=0.008) and a correlative trend between malondialdehyde expression and soreness intensity (r=0.337, p=0.086). CONCLUSIONS: Morbid soreness symptoms were prevalent in FM, with the presentation and therapeutic responses different from FM pain conditions. Oxidative stress rather than lactate accumulation involved phenotype modulation of the morbid soreness in FM. TRIAL REGISTRATION NUMBER: NCT04832100.

The association between white matter changes and development of malignant middle cerebral artery infarction: A case-control study.

ABSTRACT: Disrupted blood-brain barrier (BBB) in patients with ischemic stroke plays a critical role in malignant middle cerebral artery infarction (MMI) development.Cerebral white matter changes (WMC), particularly in the deep subcortical area or in severe one, may be also underlain by disrupted BBB. It is unclear whether the presence of WMC with potential premorbid disruption of BBB makes patients susceptible to MMI. Therefore, this study aimed to clarify any putative relationship between the MMI and WMC in terms of their severity and locations.In this case-control study, patients with infarction in the middle cerebral artery territory were retrospectively reviewed. Brain magnetic resonance images were analyzed according to Fazekas scale, and identified WMC were divided into periventricular WMC (PV-WMC) and deep subcortical WMC (deep-WMC). Patients were scored as having WMC, PV-WMC, deep-WMC, severe PV-WMC, and severe deep-WMC according to the severity and locations. Patients were defined as having MMI if either a progressive conscious disturbance or signs of uncal herniation was recorded in combination with a midline shift >5 mm identified on the follow-up computed tomography.Among 297 patients admitted between July 2009 and February 2015, 92 patients were eligible for final analysis. Compared to patients without MMI, patients with MMI had a higher score of National Institutes of Health Stroke Scale, a larger infarct volume, and an increasingly greater proportion of severe PV-WMC, deep-WMC, and severe deep-WMC, respectively. After adjustment for sex, age, infarct volume, and history of hypertension, severe deep-WMC (odds ratio [OR] = 6.362, 95% confidence interval [CI] = 1.444-28.023, P = .0144) and severe PV-WMC (odds ratio = 5.608, 95% confidence interval = 1.107-28.399, P = .0372) were significantly associated with MMI development.MMI and WMC are significantly associated such that MMI development is more likely when PV-WMC or deep-WMC is more severe. We hypothesize that Fazekas scale-defined severe deep-WMC and PV-WMC may be considered as clinically approachable predictors of MMI development. These findings support that the WMC with potential premorbid disrupted BBB may make patients susceptible to MMI, and further prospective study should be conducted to clarify this hypothesis.

Activation of acid-sensing ion channel 3 by lysophosphatidylcholine 16:0 mediates psychological stress-induced fibromyalgia-like pain.

OBJECTIVES: Fibromyalgia is commonly considered a stress-related chronic pain disorder, and daily stressors are known triggers. However, the relation between stress and pain development remains poorly defined by clinical approaches. Also, the aetiology remains largely unknown. METHODS: We used a newly developed mouse model and lipidomic approaches to probe the causation and explore the biological plausibility for how perceived stress translates into chronic non-inflammatory pain. Clinical and lipidomic investigations of fibromyalgia were conducted for human validation. RESULTS: Using non-painful sound stimuli as psychological stressors, we demonstrated that mice developed long-lasting non-inflammatory hyperalgesia after repeated and intermittent sound stress exposure. Elevated serum malondialdehyde level in stressed mice indicated excessive oxidative stress and lipid oxidative damage. Lipidomics revealed upregulation of lysophosphatidylcholine 16:0 (LPC16:0), a product of lipid oxidisation, in stressed mice. Intramuscular LPC16:0 injection triggered nociceptive responses and a hyperalgesic priming-like effect that caused long-lasting hypersensitivity. Pharmacological or genetic inhibition of acid-sensing ion channel 3 impeded the development of LPC16:0-induced chronic hyperalgesia. Darapladib and antioxidants could effectively alleviate the stress-induced hyperalgesia by inhibiting LPC16:0 synthesis. Clinical investigations showed that excessive oxidative stress and LPC16:0 expression also exist in patients with fibromyalgia. Moreover, LPC16:0 expression was correlated with pain symptoms in patients with high oxidative stress and disease severity. CONCLUSIONS: Our study provides experimental evidence for the causal effect of psychological stressors on chronic pain development. The findings identify a possible pathophysiological mechanism of stress-induced chronic non-inflammatory pain at molecular, behavioural and clinical levels that might indicate a new therapeutic approach for fibromyalgia.

Evaluating soreness symptoms of fibromyalgia: Establishment and validation of the Revised Fibromyalgia Impact Questionnaire with Integration of Soreness Assessment.

BACKGROUND: Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain. A common complaint is soreness. However, until now, no assessment tool is available to address soreness and evaluate its impact on disease severity. We aimed to establish a questionnaire for soreness assessment and to evaluate its validity in fibromyalgia patients. METHODS: Patients diagnosed with fibromyalgia per the American College of Rheumatology criteria (2011) were recruited. The Revised Fibromyalgia Impact Questionnaire with an integration of Soreness Assessment (FIQRS) was established by adding five items pertinent to soreness sensation to the existing FIQR. The participants were asked to evaluate their soreness symptoms by filling out the FIQRS twice. The test-retest reliability and internal consistency were assessed. Construct validity was evaluated by correlations with the FIQR and fibromyalgia symptom severity (SS) score. RESULTS: Sixty-two patients with fibromyalgia were recruited, including 57 females (91.9%; mean age: 51.4 years). The intraclass correlation coefficient (ICC) of test-retest reliability was 0.92 for the FIQRS overall score. The Cronbach's α of all the items in the FIQRS was 0.93. The correlation coefficient of the FIQRS total score with the FIQR was 0.97 (p < 0.0001) and that with the fibromyalgia SS scale was 0.52 (p < 0.0001). CONCLUSION: The FIQRS has good reliability and internal consistency for the assessment of disease impact on fibromyalgia patients, thus providing a reliable tool for soreness evaluation. Future studies are warranted for further validation regarding its correlation with other psychometric properties and life quality measurements.

Quasi-Static Current Measurement with Field-Modulated Spin-Valve GMR Sensors.

A non-contact current measurement device comprised of a GMR sensor and a ferrite ring core was investigated. The sensor chip employed a high-sensitivity spin-valve full-bridge GMR sensor of which the direct output has non-negligible hysteresis and a limited linear range. By applying an AC modulation current to modulate the output of the GMR sensor, the hysteresis was reduced, and the linear range was over ±0.5 A. The resolution for DC and quasi-static current measurement was 0.1 mA at a 10 Hz bandwidth. The output in proportion to the measured current was obtained either by demodulating the current-sensitive AC signal or by employing the filtered output of the intrinsically nonlinear spin-valve response. The proposed current sensing scheme is suitable for quasi-static current measurement from DC to over 100 Hz.

Sensing acidosis: nociception or sngception?

BACKGROUND: Sensing tissue acidosis is an important function of the somatosensory nervous system to response to noxious stimuli. MAIN BODY: In the pain clinic, acid or soreness sensation is a characteristic sensory phenotype of various acute and chronic pain syndromes, such as delayed onset muscle soreness, fibromyalgia, and radicular pain. However, soreness sensation is a sign of successful analgesia for acupuncture and noxipoint therapy. Thus, the nature of acid or soreness sensation is not always nociceptive (or painful) and could be anti-nociceptive. To facilitate the investigation of the molecular and neurobiological mechanisms of soreness sensation, we propose a concept called "sngception (sng- ception)" to describe the response of the somatosensory nervous system to sense tissue acidosis and to distinguish it from nociception. "Sng" is a Taiwanese word that represents the state of soreness while at the same time imitates the natural vocalization of humans feeling sore. CONCLUSION: Here we propose sngception as a specific somatosensory function that transmits the acid sensation from the peripheral to the central nervous system. Sngception could partially overlap with nociception, but it could also transmit antinociception, proprioception, and pruriception.

Identification of a cono-RFamide from the venom of Conus textile that targets ASIC3 and enhances muscle pain.

Acid-sensing ion channels (ASICs) are proton-gated Na+ channels that are expressed throughout the nervous system. ASICs have been implicated in several neuronal disorders, like ischemic stroke, neuronal inflammation, and pathological pain. Several toxins from venomous animals have been identified that target ASICs with high specificity and potency. These toxins are extremely useful in providing protein pharmacophores and to characterize function and structure of ASICs. Marine cone snails contain a high diversity of toxins in their venom such as conotoxins, which are short polypeptides stabilized by disulfide bonds, and conopeptides, which have no or only one disulfide bond. Whereas conotoxins selectively target specific neuronal proteins, mainly ion channels, the targets of conopeptides are less well known. Here, we perform an in vitro screen of venoms from 18 cone snail species to identify toxins targeting ASICs. We identified a small conopeptide of only four amino acids from the venom of Conus textile that strongly potentiated currents of ASIC3, which has a specific role in the pain pathway. This peptide, RPRFamide, belongs to the subgroup of cono-RFamides. Electrophysiological characterization of isolated dorsal root ganglion (DRG) neurons revealed that RPRFamide increases their excitability. Moreover, injection of the peptide into the gastrocnemius muscle strongly enhanced acid-induced muscle pain in mice that was abolished by genetic inactivation of ASIC3. In summary, we identified a conopeptide that targets the nociceptor-specific ion channel ASIC3.

Clinical and radiological findings suggesting disorders other than tolosa-hunt syndrome among ophthalmoplegic patients: a retrospective analysis.

OBJECTIVE: To investigate clinical and radiological features of Tolosa-Hunt syndrome (THS) and examine their diagnostic value, and to propose clinical and radiological features that indicate other symptomatic painful ophthalmoplegias (SPOs) in order to distinguish them from THS. BACKGROUND: Clinical presentations of THS are nonspecific and may overlap with many etiologies. Therefore, excluding other SPOs is essential for correct diagnosis. At the present time, the predictive value of the current International Classification of Headache Disorders (ICHD) criteria is not well established, and specific imaging markers that can discriminate SPOs from THS are lacking. METHODS: Patients referred with painful ophthalmoplegia over 12 years were recruited retrospectively and allocated into THS or SPO groups. Typical symptoms (episodic unilateral orbital pain preceding or developing with diplopia) and imaging of THS (inflammatory lesions in the cavernous sinus/orbit by magnetic resonance imaging) were proposed based on ICHD-3 beta criteria and previous literature. Atypical clinical and radiological features suggesting alternative diagnoses were also proposed to predict SPO. Initial presentations and imaging findings were registered and correlated with diagnostic outcomes. The predictive value of clinical and imaging findings was then evaluated. RESULTS: Of the 61 referred cases, 25 were classified as THS and 36 as SPO. Of the SPO cases, 52.8% manifested typical THS symptoms at onset. Patients with SPOs were prone to have atypical symptoms (47.2%) and radiographical findings (82.1%) in comparison to those with THS (4.0% and 4.2%, respectively; both P < .001). Both typical symptoms and imaging findings predicted a diagnosis of THS with high sensitivity (95.8% and 100%, respectively) but low specificity (47.2% and 28.6%, respectively). High sensitivity (82.1%) and specificity (95.8%) were achieved using atypical imaging features to predict SPO. CONCLUSION: A diagnosis of THS based strictly on clinical presentations or imaging results is not completely reliable. Identification of atypical imaging features may have a useful role in discriminating SPOs and thus avoid erroneous diagnoses of THS. Future studies with larger sample sizes are warranted to evaluate their validity in general population.

Painful ophthalmoplegia with normal cranial imaging.

BACKGROUND: Painful ophthalmoplegia with normal cranial imaging is rare and confined to limited etiologies. In this study, we aimed to elucidate these causes by evaluating clinical presentations and treatment responses. METHODS: Cases of painful ophthalmoplegia with normal cranial MRI at a single center between January 2001 and June 2011 were retrospectively reviewed. Diagnoses of painful ophthalmoplegia were made according to the recommendations of the International Headache Society. RESULTS: Of the 58 painful ophthalmoplegia cases (53 patients), 26 (44.8%) were diagnosed as ocular diabetic neuropathy, 27 (46.6%) as benign Tolosa-Hunt syndrome (THS), and 5 (8.6%) as ophthalmoplegic migraine (OM). Patients with ocular diabetic neuropathy were significantly older (62.8 ± 7.8 years) than those with benign THS (56.3 ± 12.0 years) or OM (45.8 ± 23.0 years) (p < 0.05). Cranial nerve involvement was similar among groups. Pupil sparing was dominant in each group. Patients with benign THS and OM responded exquisitely to glucocorticoid treatment with resolved diplopia, whereas patients with ocular diabetic neuropathy didn't (p < 0.05). Patients with OM recovered more rapidly than the other groups did (p < 0.05). Overall, most patients (94.8%) recovered completely during the follow-up period. CONCLUSIONS: Ocular diabetic neuropathy and benign THS accounted for most of the painful ophthalmoplegias in patients with normal cranial imaging. Patient outcomes were generally good.

A comparison of benign and inflammatory manifestations of Tolosa-Hunt syndrome.

BACKGROUND: Tolosa-Hunt syndrome (THS) manifests as a benign or an inflammatory type disease. The nosography differences between these types remain to be elucidated. We aimed to analyze and compare the clinical presentations of benign and inflammatory THS. METHODS: The ward patients who presented with THS from January 1990 to May 2011 were retrospectively reviewed. THS was diagnosed according to the recommendations of the International Headache Society. RESULTS: Of the 53 THS cases (49 patients), 30 (56.6%) were classified as benign and 23 (43.4%) as inflammatory THS. There were strong similarities between the groups in terms of clinical manifestations, laboratory findings, responses to glucocorticoid treatment, and outcomes. However, patients with inflammatory THS tended to be younger (mean age, 43.4 years; P 0.05) and have optic nerve dysfunction (56.5%; P 0.05) and longer disease duration (2.3 ± 1.0 months; P 0.05) compared to those with benign THS (mean age, 56.4 years; mean disease duration, 1.6 ± 0.7 months). The patients with additional involvement of both the optic nerve and the second division of the trigeminal nerve experienced a longer disease duration ( P 0.05). Additionally, patients with orbital pseudotumors had diplopia that responded poorly to treatment with glucocorticoids ( P 0.05). High-dose (>0.5 mg/kg/day) and low-dose (≤0.5 mg/kg/day) prednisolone were equally effective in relieving symptoms in both groups ( P > 0.05). CONCLUSION: Benign and inflammatory THS were highly similar in terms of nosography. The responses to glucocorticoid treatment were generally good except in patients with orbital pseudotumors.

Features of varicella zoster virus myelitis and dependence on immune status.

BACKGROUND: Myelitis is a rare complication of varicella zoster virus (VZV) infection and is more prevalent in immunocompromised individuals. Clinical features, outcomes, and presentations vary. The aim of the current study was to compare the clinical presentations of our patients with those reported in the literature, and to evaluate the differences in clinical features between immunocompromised and immunocompetent patients. METHODS: A review of the literature on VZV myelitis was carried out by searching PUBMED from 1980 to 2012. Clinical features of our cases and those in the literature were compared. RESULTS: There were 5 cases at our hospital and 26 were reported in the literature. Seventeen patients were immunocompromised (54.8%), and most had acquired immune deficiency syndrome (AIDS). Typical presentations (skin lesions followed by myelopathy at the corresponding level) were observed in 14 patients (45.2%). The immunocompromised patients were prone to atypical presentations (p<0.05). Outcomes were good in immunocompetent patients and relatively poor in immunocompromised patients (p<0.05). Anti-herpetic agents had no statistically significant effect on outcomes in immunocompromised patients (p=0.280), but could reduce mortality rate in AIDS patients (p<0.05). CONCLUSION: Immunocompromised individuals are susceptible to this disease, and prone to atypical presentations and poorer outcomes. Timely recognition and anti-herpes therapy may be beneficial to the outcomes. In the AIDS patients, anti-herpes therapy can reduce mortality effectively.