Splicing accuracy varies across human introns, tissues and age.

Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigated mis-splicing using RNA-sequencing data from ~14K control samples and 42 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that mis-splicing occurs at different rates across introns and tissues and that these splicing inaccuracies are primarily affected by the abundance of core components of the spliceosome assembly and its regulators. Using publicly available data on short-hairpin RNA-knockdowns of numerous spliceosomal components and related regulators, we found support for the importance of RNA-binding proteins in mis-splicing. We also demonstrated that age is positively correlated with mis-splicing, and it affects genes implicated in neurodegenerative diseases. This in-depth characterisation of mis-splicing can have important implications for our understanding of the role of splicing inaccuracies in human disease and the interpretation of long-read RNA-sequencing data.

Effect of trunk exercise upon lumbar IVD height and vertebral compliance when performed supine with 1 g at the CoM compared to upright in 1 g.

BACKGROUND: Spinal unloading in microgravity is associated with stature increments, back pain, intervertebral disc (IVD) swelling and impaired spinal kinematics. The aim of this study was to determine the effect of lateral stabilization, trunk rotation and isometric abdominal exercise upon lumbar IVD height, and both passive and active vertebral compliance when performed supine on a short-arm human centrifuge (SAHC)-a candidate microgravity countermeasure-with 1 g at the CoM, compared to that generated with equivalent upright exercise in 1 g. METHODS: 12 (8 male) healthy subjects (33.8 ± 7 years, 178.4 ± 8.2 cm, 72.1 ± 9.6 kg) gave written informed consent. Subjects performed three sets of upper body trunk exercises either when standing upright (UPRIGHT), or when being spun on the SAHC. Lumbar IVD height and vertebral compliance (active and passive) were evaluated prior to SAHC (PRE SAHC) and following the first SAHC (POST SPIN 1) and second Spin (POST SPIN 2), in addition to before (PRE UPRIGHT), and after upright trunk exercises (POST UPRIGHT). RESULTS: No significant effect upon IVD height (L2-S1) when performed UPRIGHT or on the SAHC was observed. Trunk muscle exercise induced significant (p < 0.05) reduction of active thoracic vertebral compliance when performed on the SAHC, but not UPRIGHT. However, no effect was observed in the cervical, lumbar or across the entire vertebral column. On passive or active vertebral compliance. CONCLUSION: This study, the first of its kind demonstrates that trunk exercise were feasible and tolerable. Whilst trunk muscle exercise appears to have minor effect upon IVD height, it may be a candidate approach to mitigate-particularly active-vertebral stability on Earth, and in µg via concurrent SAHC. However, significant variability suggests larger studies including optimization of trunk exercise and SAHC prescription with MRI are warranted. TRIAL REGISTRATION: North Rhine ethical committee (Number: 6000223393) and registered on 29/09/2020 in the German Clinical Trials Register (DRKS00021750).

Preliminary study of the Craniofacial Pain and Disability Inventory-11: validation for patients with head and neck cancer.

BACKGROUND: Cancer involves numerous physical, psychological and emotional changes and has a negative impact on patients. Although there are a wide variety of questionnaires for general use in patients with cancer, very few are available that assess the pain, disability and craniomandibular functionality of patients with head and neck cancer (HNC) in a more specific manner. The purpose of this study is to present the preliminary behavior of the CF-PDI in its reduced version adapted for patients with HNC. MATERIAL AND METHODS: A total of 61 patients with HNC were included in a study to preliminarily analyze the internal consistency of the instrument, the convergent validity and the floor and ceiling effects. All the patients completed the informed consent document and a battery of 5 questionnaires: The Numerical Rating Scale (NRS), the Tampa Scale for Kinesiophobia for Temporomandibular Disorders (TSK-TMD), the Pain Catastrophizing Scale (PCS), the Quality of Life Questionnaire in patients with HNC (QLQ-HN) and the reduced version of the Craniofacial Pain and Disability Inventory (CF-PDI-11). Patients also performed 2 physical tests: measurements of the pain threshold on the masseter muscle and on the distal phalanx of the first finger; and the maximum mouth opening in neutral head position. RESULTS: Cronbach's α coefficient showed a very high internal consistency of 0.92. In terms of convergent validity, a statistically significant correlation was found between the CF-PDI-11 and the following variables: NRS, TSK-TMD, PCS, QLQ-HN, the threshold of pain in the distal phalanx of the first finger and the maximum interincisal opening. However, 21.3% of patients obtained the lowest possible score. The strongest correlation was found between the CF-PDI-11 and the QLQ-HN (r = 0.85, p <0.01). CONCLUSIONS: The preliminary version of the CF-PDI-11 shows that it could be a valid and reliable instrument to measure pain, disability and quality of life in patients with HNC.

Blunted Pain Modulation Response to Induced Stress in Women with Fibromyalgia with and without Posttraumatic Stress Disorder Comorbidity: New Evidence of Hypo-Reactivity to Stress in Fibromyalgia?

There is evidence regarding the presence of alterations in both the stress response and the endogenous pain modulation systems of people with fibromyalgia (FM). However, research on pain modulation under induced stress on FM patients is scarce and contradictory. The present study analyzes stress-induced changes in pain and intolerance thresholds among FM patients, examining the possible existence of differences linked to PTSD comorbidity and gaining insights into the role of cardiovascular reactivity. Eighteen women diagnosed with FM and comorbid PTSD (FM + PTSD), 18 women diagnosed with FM and no PTSD (FM-PTSD), and 38 healthy women (HC) were exposed to the Social Stress Test task. Pressure pain thresholds and intolerance thresholds were measured before and during stress induction, and after a recovery period, while systolic blood pressure and heart rate were simultaneously recorded. Overall, while pain thresholds decreased during stress and recovery for HC, no significant changes were observed for women with FM. The intolerance threshold decreased for HC during stress, but was maintained at basal level during recovery. FM-PTSD women exhibited a delayed response, with a drop at recovery. For FM + PTSD, tolerance levels remained unchanged. In addition, cardiovascular reactivity did not seem to explain these results. This performance of the pain modulation system seems to follow the same pattern of hypoactive responsiveness under stressors that has previously been observed in FM patients on the autonomic and neuroendocrine axes. Such a hypoactive pattern may involve a non-adaptive response that may contribute to the development and maintenance of chronic pain.

Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis.

Different cellular mechanisms have been described as being potentially involved in the progression of neurodegeneration in Parkinson's disease, although their role is still unclear. The present study aimed to identify in detail, through differentially expressed genes analysis by bioinformatics approaches, the molecular mechanisms triggered after a systemic insult in parkinsonian mice. To address this objective, we combined a dextran sodium sulfate (DSS)-induced ulcerative colitis experimental mice model with an acute 1-methyl-4-phenyl-1,2,3,6-tetradropyridine (MPTP) intoxication. The animals were divided into four experimental groups based on the different treatments: (i) control, (ii) DSS, (iii) MPTP and (iv) MPTP + DSS. The data obtained by microarray and functional enrichment analysis point out the implication of different molecular mechanisms depending on the experimental condition. We see, in the striatum of animals intoxicated only with DSS, dysfunction processes related to the blood. On the other hand, oxidative stress processes are more prominent at the MPTP intoxicated mice. Finally, differentially expressed genes within the MPTP + DSS show functional enrichment in inflammation and programmed cell death. Interestingly, we identify a significant synergistic negative effect of both toxins since the expression of differentially expressed genes (DEGs) related to balanced cellular homeostasis was not enough to prevent processes associated with cell death. This work provides detailed insights into the involvement of systemic inflammation, triggered after an insult in the colon, in the progression of the degeneration in Parkinsonism. In this way, we will be able to identify promising therapeutic targets that prevent the contribution of inflammatory processes in the progression of Parkinson's disease.

A novel mobile application to determine mandibular and tongue laterality discrimination in women with chronic temporomandibular disorder.

BACKGROUND: Chronic pain from temporomandibular disorders (TMDs) is caused by a somatosensory disturbance due to sustained activation of central nervous system nociceptive pathways, which can induce changes in neuroplasticity in the thalamus, basal ganglia and limbic system, as well as disturbances in the somatosensory, prefrontal and orbitofrontal cortex and cognitive impairment. The main objective of this study was to determine the discrimination capacity of mandibular and tongue laterality between women with chronic TMDs and asymptomatic women. MATERIAL AND METHODS: This descriptive-comparative study examined 2 groups with a total of 30 women. All participants were between the ages of 23 and 66 years and were assigned to the chronic TMD group or the asymptomatic group according to the inclusion criteria. We employed a mobile application developed specifically for this study to measure the accuracy and reaction time (RT) of mandibular and tongue laterality discrimination. RESULTS: The chronic TMD group had a lower success rate in laterality discrimination (mean mandibular accuracy of 40% and mean tongue accuracy of 67%) than the asymptomatic group (mean mandibular accuracy of 61% and mean tongue accuracy of 90%). These results showed statistically significant differences between the groups for mandibular laterality discrimination (d, 1.14; p<0.01) and tongue laterality discrimination (d, 0.79; p=0.03). The asymptomatic group had faster RTs than the chronic TMD group. The data revealed statistically significant differences for the right mandibular RT (d, 0.89; p=0.02) and right tongue RT (d, 0.83; p=0.03). However, there were no significant differences for left mandibular and left tongue RT. CONCLUSIONS: We found that the women with chronic TMDs had a lower success rate and slower RTs in the discrimination of mandibular laterality when compared with the asymptomatic women.

Parkinson's disease: a short story of 200 years.

After Alzheimer's disease, Parkinson's disease (PD) is the second most prevalent and incidental neurodegenerative disorder, affecting more than 2% of the population older than 65 years old. Since it was first described 200 years ago by Dr James Parkinson, great steps have been made in the understanding of the pathology. However, the cause(s) that initiates and perpetuates the neurodegenerative process is (are) still not clear. Thus, early diagnosis is not available, nor are there efficient therapies that can stop neurodegeneration. PD clinical features are defined by motor (like bradykinesia, resting tremor, gait impairment) and non-motor symptoms (like constipation, apathy, fathigue, olfactory dysfunction, depression and cognitive decline) that get more severe as the disease advances. Neuropathological hallmarks comprise selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and Lewy bodies (LB) in different nuclei of the nervous system. Numerous studies have shown that these pathological features are aggravated by the confluence of other contributing factors, such as a genetic component, exposure to environmental toxins, mitochondrial dysfunction, increase of oxidative stress, calcium imbalance and chronic neuroinflammation, among others. Here, we provide a summary of the actual state of PD's pathology, the most studied molecular mechanisms, classic and novel therapeutic strategies and diagnosis methods, especially highlighting recent advances in these 200 years.

Validación y fiabilidad de la versión española de la escala autoadministrada de Evaluación de Signos y Síntomas Neuropáticos de Leeds (S-LANSS) / Validity and reliability of the Spanish-language version of the self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale

INTRODUCCIÓN: La escala autoadministrada de Evaluación de Signos y Síntomas Neuropáticos de Leeds (S-LANSS) es un instrumento diseñado para identificar a pacientes con dolor de características neuropáticas. OBJETIVO: Evaluar la validez y fiabilidad de la versión española del S-LANSS. MÉTODOS: Se incluyó un total de 182 pacientes con dolor crónico para evaluar la validez discriminante y convergente del S-LANSS, incrementándose la muestra hasta 321 pacientes para valorar la validez de constructo y la fiabilidad de la escala. Se utilizó como variable criterio la versión validada al español del ID-Pain. Todos los participantes cumplimentaron el cuestionario ID-Pain, el S-LANSS, y la Escala Numérica del Dolor. La validez discriminante se evaluó mediante el análisis del área bajo la curva de características operativas para el receptor, y la sensibilidad y especificidad. La validez de constructo se evaluó mediante un análisis factorial y mediante el análisis del odds-ratio de cada ítem del S-LANSS respecto a la puntuación total. La validez convergente y la fiabilidad se valoraron con la R de Pearson y el alfa de Cronbach respectivamente. RESULTADOS: El punto de corte óptimo del S-LANSS fue ≥ 12 puntos (área bajo la curva = 0,89; sensibilidad = 88,7; especificidad = 76,6). El S-LANSS presentó un factor y, además, cada ítem contribuyó significativamente a la puntuación total positiva del S-LANSS (p < 0,05). El S-LANSS mostró una relación significativa con el ID-Pain (R = 0,734) y un alfa de Cronbach de 0,71. CONCLUSIÓN: La versión española del S-LANSS es válida y fiable para identificar pacientes con dolor crónico con características neuropáticas

INTRODUCTION: The self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) scale is a tool designed to identify patients with pain with neuropathic features. OBJECTIVE: To assess the validity and reliability of the Spanish-language version of the S-LANSS scale. METHODS: Our study included a total of 182 patients with chronic pain to assess the convergent and discriminant validity of the S-LANSS; the sample was increased to 321 patients to evaluate construct validity and reliability. The validated Spanish-language version of the ID-Pain questionnaire was used as the criterion variable. All participants completed the ID-Pain, the S-LANSS, and the Numerical Rating Scale for pain. Discriminant validity was evaluated by analysing sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC). Construct validity was assessed with factor analysis and by comparing the odds ratio of each S-LANSS item to the total score. Convergent validity and reliability were evaluated with Pearson's r and Cronbach's alpha, respectively. RESULTS: The optimal cut-off point for S-LANSS was ≥12 points (AUC = .89; sensitivity = 88.7; specificity = 76.6). Factor analysis yielded one factor; furthermore, all items contributed significantly to the positive total score on the S-LANSS (P < .05). The S-LANSS showed a significant correlation with ID-Pain (r = .734, alfa = .71). CONCLUSION: The Spanish-language version of the S-LANSS is valid and reliable for identifying patients with chronic pain with neuropathic features

[Effectiveness of virtual immersion programmes in patients with Parkinson's disease. A systematic review]. / Efectividad de los programas de inmersion virtual en los pacientes con enfermedad de Parkinson. Revision sistematica.

INTRODUCTION: Parkinson disease (PD) is the second most common neurodegenerative disease. Virtual reality (VR) is being used in rehabilitation of neurological patients. To analyze the VR systems' therapeutically effectiveness through PD diagnosed subjects with variables of motor, quality of life and cognition. PATIENTS AND METHODS: Electronics database were used to look for articles: Medline, EMBASE, PEDro, CINAHL and Cochrane. The inclusion criteria were: randomized control trial (RCT) performed in PD with at least one VR variable included in the therapeutically treatment and diagnosed PD subjects. Four RCT were chosen showing all good methodology quality. Concordance between evaluators was moderate-high. VR was the main treatment in all of them. RESULTS: VR was more effective in balance improvement in PD subjects than conventional physiotherapy in two RCT. VR was not more effective in balance improvement in PD subjects than conventional physiotherapy in two RCT. Contradictory evidences where showed between the effectiveness of the VR programs versus conventional programs in the effectiveness of balance treatment with PD subjects. Non-motor variables improvement was not greater in subjects with VR treatments versus the ones with conventional physiotherapy in the four RCT. CONCLUSIONS: The treatments with VR cannot be assumed as more effectives than conventional physiotherapy through PD subjects in motor and psychosocial variables.

TITLE: Efectividad de los programas de inmersion virtual en los pacientes con enfermedad de Parkinson. Revision sistematica.Introduccion. La enfermedad de Parkinson (EP) es la segunda enfermedad neurodegenerativa mas frecuente. La tecnologia de realidad virtual (RV) ha adquirido una gran relevancia en la rehabilitacion en pacientes de origen neurologico. El objetivo es analizar la efectividad terapeutica de la RV en pacientes con EP en variables motoras, calidad de vida y cognicion. Pacientes y metodos. La busqueda de articulos se realizo utilizando bases de datos electronicas: Medline, EMBASE, PEDro, CINAHL y Cochrane. Los criterios de inclusion fueron estudios clinicos aleatorizados (ECA) en pacientes con EP donde al menos una intervencion terapeutica estuviera basada en programas de RV. Se seleccionaron cuatro ECA con calidad metodologica buena. La concordancia entre los evaluadores fue moderada-alta. En los cuatro ECA se realizo inmersion de RV como principal tratamiento. Resultados. Dos de los ECA revelaron que la RV es superior frente al tratamiento de fisioterapia convencional para la mejora del equilibrio. Dos de los ECA revelaron que la RV no es superior frente al tratamiento convencional en la mejora del equilibrio. Existe evidencia contradictoria de que los programas para la mejora del equilibrio basados en RV son mas eficaces que los basados en fisioterapia convencional. Las variables no motoras medidas en los diferentes ECA no se vieron mejoradas en los grupos tratados con RV frente a los tratados con fisioterapia convencional. Conclusiones. No se ha podido demostrar que la efectividad terapeutica de los sistemas de RV sea superior a los programas de fisioterapia convencional en pacientes con EP en variables motoras y psicosociales.

Electrical stimulation or MK-801 in the inferior colliculus improve motor deficits in MPTP-treated mice.

The inferior colliculus (IC) is an important midbrain relay station for the integration of descending and ascending auditory information. Additionally, the IC has been implicated in processing sensorimotor responses. Glutamatergic and GABAergic manipulations in the IC can improve motor deficits as demonstrated by the animal model of haloperidol-induced catalepsy. However, how the IC influences motor function remains unclear. We investigated the effects of either intracollicular deep brain stimulation (DBS) or microinjection of the glutamatergic antagonist MK-801 or the agonist NMDA in C57BL/6J mice chronically treated with saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After DBS or microinjections, the mice were submitted to rotarod and open field tests, respectively. DBS in the IC was effective to increase the time spent on the rotarod in MPTP-treated mice. After unilateral microinjection of MK-801, but not NMDA, MPTP-treated mice increased the distance travelled in the open field (p < 0.05). In conclusion, intracollicular DBS or MK-801 microinjection can improve motor performance in parkinsonian mice suggesting the IC as a new and non-conventional therapeutic target in motor impairment.

Validity and reliability of the Spanish-language version of the self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale. / Validación y fiabilidad de la versión española de la escala autoadministrada de Evaluación de Signos y Síntomas Neuropáticos de Leeds (S-LANSS).

INTRODUCTION: The self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) scale is a tool designed to identify patients with pain with neuropathic features. OBJECTIVE: To assess the validity and reliability of the Spanish-language version of the S-LANSS scale. METHODS: Our study included a total of 182 patients with chronic pain to assess the convergent and discriminant validity of the S-LANSS; the sample was increased to 321 patients to evaluate construct validity and reliability. The validated Spanish-language version of the ID-Pain questionnaire was used as the criterion variable. All participants completed the ID-Pain, the S-LANSS, and the Numerical Rating Scale for pain. Discriminant validity was evaluated by analysing sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC). Construct validity was assessed with factor analysis and by comparing the odds ratio of each S-LANSS item to the total score. Convergent validity and reliability were evaluated with Pearson's r and Cronbach's alpha, respectively. RESULTS: The optimal cut-off point for S-LANSS was ≥12 points (AUC=.89; sensitivity=88.7; specificity=76.6). Factor analysis yielded one factor; furthermore, all items contributed significantly to the positive total score on the S-LANSS (P<.05). The S-LANSS showed a significant correlation with ID-Pain (r=.734, α=.71). CONCLUSION: The Spanish-language version of the S-LANSS is valid and reliable for identifying patients with chronic pain with neuropathic features.

Alteration of the PAC1 Receptor Expression in the Basal Ganglia of MPTP-Induced Parkinsonian Macaque Monkeys.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-known neuropeptide with strong neurotrophic and neuroprotective effects. PACAP exerts its protective actions via three G protein-coupled receptors: the specific Pac1 receptor (Pac1R) and the Vpac1/Vpac2 receptors, the neuroprotective effects being mainly mediated by the Pac1R. The protective role of PACAP in models of Parkinson's disease and other neurodegenerative diseases is now well-established in both in vitro and in vivo studies. PACAP and its receptors occur in the mammalian brain, including regions associated with Parkinson's disease. PACAP receptor upregulation or downregulation has been reported in several injury models or human diseases, but no data are available on alterations of receptor expression in Parkinson's disease. The model closest to the human disease is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced macaque model. Therefore, our present aim was to evaluate changes in Pac1R expression in basal ganglia related to Parkinson's disease in a macaque model. Monkeys were rendered parkinsonian with MPTP, and striatum, pallidum, and cortex were evaluated for Pac1R immunostaining. We found that Pac1R immunosignal was markedly reduced in the caudate nucleus, putamen, and internal and external parts of the globus pallidus, while the immunoreactivity remained unchanged in the cortex of MPTP-treated parkinsonian monkey brains. This decrease was attenuated in some brain areas in monkeys treated with L-DOPA. The strong, specific decrease of the PACAP receptor immunosignal in the basal ganglia of parkinsonian macaque monkey brains suggests that the PACAP/Pac1R system may play an important role in the development/progression of the disease.