S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

Highly specific σ2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response.

The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

ephrin-B2 promotes nociceptive plasticity and hyperalgesic priming through EphB2-MNK-eIF4E signaling in both mice and humans.

Ephrin-B-EphB signaling can promote pain through ligand-receptor interactions between peripheral cells, like immune cells expressing ephrin-Bs, and EphB receptors expressed by DRG neurons. Previous studies have shown increased ephrin-B2 expression in peripheral tissues like synovium of rheumatoid and osteoarthritis patients, indicating the clinical significance of this signaling. The primary goal of this study was to understand how ephrin-B2 acts on mouse and human DRG neurons, which express EphB receptors, to promote pain and nociceptor plasticity. We hypothesized that ephrin-B2 would promote nociceptor plasticity and hyperalgesic priming through MNK-eIF4E signaling, a critical mechanism for nociceptive plasticity induced by growth factors, cytokines and nerve injury. Both male and female mice developed dose-dependent mechanical hypersensitivity in response to ephrin-B2, and both sexes showed hyperalgesic priming when challenged with PGE2 injection either to the paw or the cranial dura. Acute nociceptive behaviors and hyperalgesic priming were blocked in mice lacking MNK1 (Mknk1 knockout mice) and by eFT508, a specific MNK inhibitor. Sensory neuron-specific knockout of EphB2 using Pirt-Cre demonstrated that ephrin-B2 actions require this receptor. In Ca2+-imaging experiments on cultured DRG neurons, ephrin-B2 treatment enhanced Ca2+ transients in response to PGE2 and these effects were absent in DRG neurons from MNK1-/- and EphB2-PirtCre mice. In experiments on human DRG neurons, ephrin-B2 increased eIF4E phosphorylation and enhanced Ca2+ responses to PGE2 treatment, both blocked by eFT508. We conclude that ephrin-B2 acts directly on mouse and human sensory neurons to induce nociceptor plasticity via MNK-eIF4E signaling, offering new insight into how ephrin-B signaling promotes pain.

Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain.

Dysfunction in regulation of mRNA translation is an increasingly recognized characteristic of many diseases and disorders, including cancer, diabetes, autoimmunity, neurodegeneration, and chronic pain. Approximately 50 million adults in the United States experience chronic pain. This economic burden is greater than annual costs associated with heart disease, cancer, and diabetes combined. Treatment options for chronic pain are inadequately efficacious and riddled with adverse side effects. There is thus an urgent unmet need for novel approaches to treating chronic pain. Sensitization of neurons along the nociceptive pathway causes chronic pain states driving symptoms that include spontaneous pain and mechanical and thermal hypersensitivity. More than a decade of preclinical research demonstrates that translational mechanisms regulate the changes in gene expression that are required for ongoing sensitization of nociceptive sensory neurons. This review will describe how key translation regulation signaling pathways, including the integrated stress response, mammalian target of rapamycin, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase-interacting kinases, impact the translation of different subsets of mRNAs. We then place these mechanisms of translation regulation in the context of chronic pain states, evaluate currently available therapies, and examine the potential for developing novel drugs. Considering the large body of evidence now published in this area, we propose that pharmacologically manipulating specific aspects of the translational machinery may reverse key neuronal phenotypic changes causing different chronic pain conditions. Therapeutics targeting these pathways could eventually be first-line drugs used to treat chronic pain disorders. SIGNIFICANCE STATEMENT: Translational mechanisms regulating protein synthesis underlie phenotypic changes in the sensory nervous system that drive chronic pain states. This review highlights regulatory mechanisms that control translation initiation and how to exploit them in treating persistent pain conditions. We explore the role of mammalian/mechanistic target of rapamycin and mitogen-activated protein kinase-interacting kinase inhibitors and AMPK activators in alleviating pain hypersensitivity. Modulation of eukaryotic initiation factor 2α phosphorylation is also discussed as a potential therapy. Targeting specific translation regulation mechanisms may reverse changes in neuronal hyperexcitability associated with painful conditions.

Astrocytes show increased levels of Ero1α in multiple sclerosis and its experimental autoimmune encephalomyelitis animal model.

Multiple sclerosis (MS) and its animal models are characterized by cellular inflammation within the central nervous system (CNS). The sources and consequences of this inflammation are currently not completely understood. Critical signs and mediators of CNS inflammation are reactive oxygen species (ROS) that promote inflammation. ROS originate from a variety of redox-reactive enzymes, one class of which catalyses oxidative protein folding within the endoplasmic reticulum (ER). Here, the unfolded protein response and other signalling mechanisms maintain a balance between ROS producers such as ER oxidoreductin 1α (Ero1α) and antioxidants such as glutathione peroxidase 8 (GPx8). The role of ROS production within the ER has so far not been examined in the context of MS. In this manuscript, we examined how components of the ER redox network change upon MS and experimental autoimmune encephalomyelitis (EAE). We found that unlike GPx8, Ero1α increases within both MS and EAE astrocytes, in parallel with an imbalance of other oxidases such of GPx7, and that no change was observed within neurons. This imbalance of ER redox enzymes can reduce the lifespan of astrocytes, while neurons are not affected. Therefore, Ero1α induction makes astrocytes vulnerable to oxidative stress in the MS and EAE pathologies.

Endoplasmic reticulum stress in the dorsal root ganglia regulates large-conductance potassium channels and contributes to pain in a model of multiple sclerosis.

Neuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post-mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of mice with EAE and relieving ER stress with a chemical chaperone, 4-phenylbutyric acid (4-PBA), reduced pain hypersensitivity. In vitro, 4-PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca2+ transients in putative DRG nociceptors. We went on to assess disease-mediated changes in the functional properties of Ca2+ -sensitive BK-type K+ channels in DRG neurons. We found that the conductance-voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.

Endoplasmic reticulum-mitochondria interplay in chronic pain: The calcium connection.

Chronic pain is a debilitating condition that affects roughly a third to a half of the world's population. Despite its substantial effect on society, treatment for chronic pain is modest, at best, notwithstanding its side effects. Hence, novel therapeutics are direly needed. Emerging evidence suggests that calcium plays an integral role in mediating neuronal plasticity that underlies sensitization observed in chronic pain states. The endoplasmic reticulum and the mitochondria are the largest calcium repositories in a cell. Here, we review how stressors, like accumulation of misfolded proteins and oxidative stress, influence endoplasmic reticulum and mitochondria function and contribute to chronic pain. We further examine the shuttling of calcium across the mitochondrial-associated membrane as a mechanism of cross-talk between the endoplasmic reticulum and the mitochondria. In addition, we discuss how endoplasmic reticulum stress, mitochondrial impairment, and calcium dyshomeostasis are implicated in various models of neuropathic pain. We propose a novel framework of endoplasmic reticulum-mitochondria signaling in mediating pain hypersensitivity. These observations require further investigation in order to develop novel therapies for chronic pain.

Delay between onset of indication and definitive surgery for tracheal trauma.

Tracheal stenosis is rare but a recognized complication after traumatic injury or prolonged intubation. We assessed the time lag between onset of indication for tracheal reconstruction surgery following trauma and actual surgical intervention. We reviewed our operative records for all patients undergoing tracheal reconstruction over the past 10 years. Files were reviewed retrospectively to collect all the relevant data. Surgically all patients were operated via cervical approach. Series 12 cases were identified with an equal split between external trauma and iatrogenic tracheal trauma from prolonged intubation. On, an average patients presented 185 days after initial indication of surgery however there was a wide range of time lag which leads to the importance of early diagnosis of such injuries to reduce delay of definitive management.

Profiling the microRNA signature of the peripheral sensory ganglia in experimental autoimmune encephalomyelitis (EAE).

BACKGROUND: Multiple sclerosis is an autoimmune disease with a distinct female bias, as well as a high prevalence of neuropathic pain in both sexes. The dorsal root ganglia (DRG) contain the primary sensory neurons that give rise to pain, and damage to these neurons may lead to neuropathic pain. Here, we investigate the sex differences of the DRG transcriptome in a mouse model of MS. METHODS: Next-generation sequencing was used to establish RNA and microRNA profiles from the DRG of mice with MOG35-55-induced EAE, a model of CNS inflammation that mimics aspects of MS. Differential expression and multiple meta-analytic approaches were used to compare expression profiles in immunized female and male mice. Differential expression of relevant genes and microRNAs were confirmed by qPCR. RESULTS: Three thousand five hundred twenty genes and 29 microRNAs were differentially expressed in the DRG of female mice with MOG35-55-EAE, while only 189 genes and 3 microRNAs were differentially expressed in males with MOG35-55-EAE. Genes related to the immune system were uniquely regulated in immunized female mice. Direct comparison of sex within disease indicates significant differences in interferon and phagosomal pathways between the sexes. miR-21a-5p is the primary dysregulated microRNA in both sexes, with females having additional dysregulated microRNAs, including miR-122-5p. CONCLUSIONS: This study provides evidence that females are uniquely affected by MOG35-55-EAE and that this difference may result from additional signaling not present in the male. The altered transcriptome of females correlates with other studies finding hyperactivity of pain-sensing neurons and suggests underlying sex-specific pathways for neuropathic pain.

Single stage cricoid split laryngoplasty with costochondral rib grafting is a novel approach to treat subglottic stenosis in a paediatric patient: A case report.

INTRODUCTION AND IMPORTANCE: Subglottic stenosis (SGS) appears to be a commonly encountered condition in the paediatric age group. Single stage cricoid split laryngoplasty with costochondral rib grafting in paediatric patients is a unique, innovative, and advanced operation in nature. Morbidity and mortality rates can be minimized with early diagnosis and prompt treatment. PRESENTATION OF CASE: Presenting the case of a 13-month-old child diagnosed with Grade II SGS who was managed for cricoid split laryngoplasty with a costochondral rib graft. It was a unique strategy for providing infants and neonates with symptomatic SGS with a safe and efficient substitute for long-term tracheostomy. When healing was completed, the patient regained the function of their airway. The approach was successful, and preventable to long-term tracheostomy. DISCUSSION: Performing this procedure early in children has shown higher rates of success and it is safe and effective. Further extensive research and studies need to be conducted in this domain, and every patient's status should be reviewed time and again to tend to their specific needs, and the choice of procedure should be made optimally based on clinical evaluations. CONCLUSION: Successful management of a 13-month-old child with Grade II subglottic stenosis through cricoid split laryngoplasty with costochondral rib grafting is a challenging and novel approach to treating single-stage SGS.

Clinical phenotype and management of sound-induced pain: Insights from adults with pain hyperacusis.

Pain hyperacusis, also known as noxacusis, causes physical pain in response to everyday sounds that do not bother most people. How sound causes excruciating pain that can last for weeks or months in otherwise healthy individuals is not well understood, resulting in a lack of effective treatments. To address this gap, we identified the most salient physical and psychosocial consequences of debilitating sound-induced pain and reviewed the interventions that sufferers have sought for pain relief to gain insights into the underlying mechanisms of the condition. Adults (n = 32) with pain hyperacusis attended a virtual focus group to describe their sound-induced pain. They completed three surveys to identify common symptoms and themes that defined their condition and to describe their use of pharmaceutical and non-pharmaceutical therapies for pain relief. All participants endorsed negative effects of pain hyperacusis on psychosocial and physical function. Most reported sound-induced burning (80.77%), stabbing (76.92%), throbbing (73.08%), and pinching (53.85%) that occurs either in the ear or elsewhere in the body (i.e., referred pain). Participants reported using numerous pharmaceutical and non-pharmaceutical interventions to alleviate their pain with varying degrees of pain relief. Benzodiazepines and nerve blockers emerged as the most effective analgesic options while non-pharmaceutical therapies were largely ineffective. Symptoms of pain hyperacusis and therapeutic approaches are largely consistent with peripheral mechanistic theories of pain hyperacusis (e.g., trigeminal nerve involvement). An interdisciplinary approach to clinical studies and the development of animal models is needed to identify, validate, and treat the pathological mechanisms of pain hyperacusis.

Assessment of anxiety in parents of children undergoing tonsillectomy under general anaesthesia: A cross-sectional study.

Background and Aims: Surgery in the pediatric age group entails a significant amount of anxiety for parents. Due to anxiety, parents are unable to take care of their children, which could affect the child's well-being and contributes to poor outcomes. The primary objective of this study is to determine the frequency of preoperative anxiety in parents before the surgery of their children. Methods: It is a cross-sectional descriptive study that included either parent of 147 children of American Society of Anaesthesiology (ASA) I & II, aged 1-12 years undergoing tonsillectomy over the period of 1 year. Each parent's demographic data were recorded and requested to answer a proforma containing the Amsterdam Preoperative Anxiety Information Scale (APAIS) for assessing anxiety on a 5-point Likert scale. Median interquartile range (IQR), and frequency (%) were used to report the normal, skewed, and categorical variables. APAIS anxiety and information scores were compared by using either the Mann-Whitney U-test or the Kruskal-Wallis test. Furthermore, anxiety scores were grouped (present/absent) with a cut-off score of 11 for the presence of anxiety, and multivariate logistic regression was performed to explore the relationship between potential risk factors and the parent's anxiety. Results: Overall, anxiety was present in 59 (40.1%) respondents with 20 (33.9%) being fathers and 39 (66.1%) mothers. The median (IQR) for APAIS anxiety and information score were 9 ± 5 and 5 ± 2, respectively. Higher median anxiety scores were observed statistically significant in children under 5 years old, mother respondents, mothers aged 35 or younger, fathers under 40, and mothers with graduate or higher education (p < 0.05). Father respondents (AOR = 0.3, 95% CI = 0.1-0.8, p = 0.01), and mother's education less than graduation (AOR = 0.2, 95% CI = 0.1-0.6, p = 0.006) were also found to be statistically significant predictors. Conclusion: There is a significant prevalence of anxiety in parents of children who underwent surgery under general anaesthesia, and mothers have showed significantly higher anxiety levels than fathers.

Challenges and strategies regarding anaesthetic management of twin pregnancy undergoing redo aortic valve replacement.

INTRODUCTION AND IMPORTANCE: Redo aortic valve replacement in twin pregnancy presents significant challenges because of the elevated risks for both maternal and fetal health. Mortality rates range from 12 % to 21 % in specialised centres, with previous cardiac surgeries further elevating the risk. Pregnancy complicates cardiac surgery, with fetal mortality rates as high as 16-33 %. PRESENTATION OF CASE: A 31-year-old woman, 15 weeks pregnant with twins and with a history of mechanical aortic valve replacement, presented with worsening breathlessness and grade III dyspnoea. Echocardiography revealed severe valve obstruction, necessitating redo-aortic valve replacement and posterior aortic root enlargement. Despite intraoperative challenges, including ventricular fibrillation and postoperative heart block, she underwent successful surgery and pacemaker implantation, with both mother and fetuses remaining stable. DISCUSSION: Optimal timing of surgery is crucial, considering fetal developmental vulnerability in the first trimester and maternal cardiac workload in the third trimester. Second-trimester risks are comparable to non-pregnant patients. A limited understanding of fetal-placental perfusion during bypass necessitates cautious management strategies, with emerging techniques like pulsatile perfusion showing promise. Anaesthesia selection prioritises fetal safety while monitoring fetal distress during surgery remains challenging. To achieve successful outcomes for both mother and babies in a twin pregnancy undergoing a redo aortic valve replacement, careful timing, appropriate surgical techniques, and meticulous perioperative care are essential. CONCLUSION: A multidisciplinary approach is crucial for managing twin pregnancy following redo aortic valve surgery. Careful planning, close monitoring, and specialised surgical and anaesthetic techniques are key to minimising risks to both mother and fetus.

Nerve Detection and Visualization Using Hyperspectral Imaging for Surgical Guidance.

During surgery of delicate regions, differentiation between nerve and surrounding tissue is crucial. Hyperspectral imaging (HSI) techniques can enhance the contrast between types of tissue beyond what the human eye can differentiate. Whereas an RGB image captures 3 bands within the visible light range (e.g., 400 nm to 700 nm), HSI can acquire many bands in wavelength increments that highlight regions of an image across a wavelength spectrum. We developed a workflow to identify nerve tissues from other similar tissues such as fat, bone, and muscle. Our workflow uses spectral angle mapper (SAM) and endmember selection. The method is robust for different types of environment and lighting conditions. We validated our workflow on two samples of human tissues. We used a compact HSI system that can image from 400 to 1700 nm to produce HSI of the samples. On these two samples, we achieved an intersection-over-union (IoU) segmentation score of 84.15% and 76.73%, respectively. We showed that our workflow identifies nerve segments that are not easily seen in RGB images. This method is fast, does not rely on special hardware, and can be applied in real time. The hyperspectral imaging and nerve detection approach may provide a powerful tool for image-guided surgery.

Loss of Sigma-2 Receptor/TMEM97 Is Associated with Neuropathic Injury-Induced Depression-Like Behaviors in Female Mice.

Previous studies have shown that ligands that bind to sigma-2 receptor/TMEM97 (s2R/TMEM97), a transmembrane protein, have anxiolytic/antidepressant-like properties and relieve neuropathic pain-like effects in rodents. Despite medical interest in s2R/TMEM97, little affective and pain behavioral characterization has been done using transgenic mice, which limits the development of s2R/TMEM97 as a viable therapeutic target. Using wild-type (WT) and global Tmem97 knock-out (KO) mice, we sought to identify the contribution of Tmem97 in modulating affective and pain-like behaviors using a battery of affective and pain assays, including open field, light/dark preference, elevated plus maze, forced swim test, tail suspension test, and the mechanical sensitivity tests. Our results demonstrate that female Tmem97 KO mice show less anxiety-like and depressive-like behaviors in light/dark preference and tail suspension tests but not in an open field, elevated plus maze, and forced swim tests at baseline. We next performed spared nerve injury in WT and Tmem97 KO mice to assess the role of Tmem97 in neuropathic pain-induced anxiety and depression. WT mice, but not Tmem97 KO mice, developed a prolonged neuropathic pain-induced depressive-like phenotype when tested 10 weeks after nerve injury in females. Our results show that Tmem97 plays a role in modulating anxiety-like and depressive-like behaviors in naive animals with a significant change in the presence of nerve injury in female mice. Overall, these data demonstrate that Tmem97 could be a target to alleviate affective comorbidities of pain disorders.

Predicting treatment-seeking for visual hallucinations among Parkinson's disease patients.

AIM: While much research has been conducted towards understanding the basis of visual hallucinations in Parkinson's disease, little has focused on characterizing the content and patients' emotional experience. These factors are likely very influential on a patient's decision to seek treatment, a critical aspect of any symptom from the clinical perspective. METHODS: A retrospective chart analysis was performed on Parkinson's disease patients seen in a community-based Parkinson's Disease and Movement Disorder Clinic between 2005 and 2010. RESULTS: The study consisted of 334 patients with Parkinson's disease, among whom 10.5% had visual hallucinations. Hoehn and Yahr disease stage (P = 0.001), concurrent presence of dementia (P = 0.001),and sex (P = 0.031) were significant onset predictors. The most significant determinant of treatment-seeking was emotional reaction, namely whether hallucinations were bothersome (P = 0.008). However, the specific type of content during hallucinations was sometimes more influential and contradicted emotional response. CONCLUSION: Although treatment-seeking can be predicted by how individuals feel about hallucinations, a patient's decision may not be logically consistent. We suggest that clinicians offer treatment based on patients' recollections and opinions.

Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decreases ISR activation in DRG neurons.

Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes mechanical hypersensitivity in mice by inducing the integrated stress response (ISR), which is characterized by phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant proteins that neutralize MGO. We hypothesized that activating Nrf2 using diroximel fumarate (DRF) would alleviate MGO-induced pain hypersensitivity. We pretreated male and female C57BL/6 mice daily with oral DRF prior to intraplantar injection of MGO (20 ng). DRF (100 mg/kg) treated animals were protected from developing MGO-induced mechanical and cold hypersensitivity. Using Nrf2 knockout mice we demonstrate that Nrf2 is necessary for the anti-nociceptive effects of DRF. In cultured mouse and human dorsal root ganglion (DRG) sensory neurons, we found that MGO induced elevated levels of p-eIF2α. Co-treatment of MGO (1 µM) with monomethyl fumarate (MMF, 10, 20, 50 µM), the active metabolite of DRF, reduced p-eIF2α levels and prevented aberrant neurite outgrowth in human DRG neurons. Our data show that targeting the Nrf2 antioxidant system with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.

Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response.

The Sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal anti-nociceptive effect is approximately 24 hours following dosing. We sought to understand this unique anti-neuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout (KO) mice for Tmem97, we find that a new σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce anti-nociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion (DRG) neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

Impact of progression of Parkinson's disease on drooling in various ethnic groups.

BACKGROUND/AIMS: Drooling or sialorrhea is a common non-motor symptom of Parkinson's disease (PD), and is reported by 35-75% of patients. Drooling is primarily due to impaired swallowing rather than hypersecretion of saliva. In this study, we examined the prevalence of drooling in PD and its relation to various factors such as age, stage of disease, gender and ethnicity. METHODS: A retrospective cohort chart analysis of 307 patients with idiopathic PD was conducted. These patients were seen in the Parkinson's Disease and Movement Disorders Clinic between 2005 and 2010. RESULTS: 123 (40%) patients exhibited drooling. No correlation between age and development of drooling was observed. However, gender was found to be a significant factor in developing sialorrhea. Males are twice as more likely to develop sialorrhea than females. In addition, drooling becomes more prevalent with disease progression; Hoehn and Yahr stage 4 patients being the most at risk. Ethnicity and immigration status have no relationship in developing drooling. CONCLUSIONS: Sialorrhea is seen in a significant number of PD patients. This study, to the best of our knowledge, is the most extensive clinical assessment of drooling in PD to date.

Prevalence and relation of dementia to various factors in Parkinson's disease.

AIMS: Parkinson's disease is a chronic neurodegenerative disorder characterized by bradykinesia, rigidity, and resting tremor. Dementia, among its non-motor symptoms, is a debilitating complication affecting intellectual functioning. The aim of the present study was to determine the prevalence of dementia in Parkinson's disease and its relation to age, gender and stage of the disease. METHODS: A retrospective chart analysis was performed on Parkinson's disease patients seen in a community-based Parkinson's disease and movement disorder clinic between 2005 and 2010. RESULTS: A total of 310 patients were included in this survey, among whom 61 patients (19.7%) with Parkinson's disease met the criteria for dementia. Age was found to be a significant factor in developing dementia, with 90% of patients with dementia aged ≥70. Gender, however, was not correlated with dementia in Parkinson's disease. On analysis of stage at which dementia developed, progression of the disease was positively correlated with prevalence of dementia. CONCLUSIONS: As age increases, the chances of developing dementia increase. Dementia, contrarily, is not selective between genders. The likelihood of developing dementia increases as the stage of disease advances. Further research is required in order to understand underlying mechanisms of dementia in Parkinson's disease.