Natural polyphenolic coffee extract administration relieves chronic nociplastic pain in a reserpine-induced fibromyalgia-like female mouse model.

INTRODUCTION: Nociplastic pain involves reflexive and nonreflexive pain responses and it is a core symptom of fibromyalgia (FM). The increasing prevalence of this health condition and the low rates of patients' quality of life, combined with the lack of suitable pharmacologic treatments, evidence the demand to research new alternatives. Polyphenols may be potential therapeutic candidates as they have been reported to exert pathological pain modulation in preclinical models. In that context, this work was aimed to study the antinociceptive effects of a polyphenolic extract obtained from decaffeinated ground roasted coffee, in the RIM6 FM-like mouse model. METHODS: To this end, RIM6 adult ICR-CD1 female mice were administered daily once a week with either 10 or 15 mg/kg of extract, and reflexive pain responses were evaluated for up to 3 weeks. At the end, the depressive-like behavior was assessed as a nonreflexive pain response, and spinal cord and serum samples were collected for immunohistochemical and toxicological analyses. RESULTS: These findings showed that the repeated administration of the coffee polyphenolic extract (CE) modulated reflexive pain responses, depressive-like behavior, and spinal cord gliosis in a dose-dependent manner, without signs of systemic toxicity. CONCLUSION: Thus, the CE may be a potential pharmacological treatment suitable to relieve nociplastic pain responses characteristic of FM.

Multi-scale dynamic imaging reveals that cooperative motility behaviors promote efficient predation in bacteria.

Many species, such as fish schools or bird flocks, rely on collective motion to forage, prey, or escape predators. Likewise, Myxococcus xanthus forages and moves collectively to prey and feed on other bacterial species. These activities require two distinct motility machines enabling adventurous (A) and social (S) gliding, however when and how these mechanisms are used has remained elusive. Here, we address this long-standing question by applying multiscale semantic cell tracking during predation. We show that: (1) foragers and swarms can comprise A- and S-motile cells, with single cells exchanging frequently between these groups; (2) A-motility is critical to ensure the directional movement of both foragers and swarms; (3) the combined action of A- and S-motile cells within swarms leads to increased predation efficiencies. These results challenge the notion that A- and S-motilities are exclusive to foragers and swarms, and show that these machines act synergistically to enhance predation efficiency.

Transient Reflexive Pain Responses and Chronic Affective Nonreflexive Pain Responses Associated with Neuroinflammation Processes in Both Spinal and Supraspinal Structures in Spinal Cord-Injured Female Mice.

Central neuropathic pain is not only characterized by reflexive pain responses, but also emotional or affective nonreflexive pain responses, especially in women. Some pieces of evidence suggest that the activation of the neuroimmune system may be contributing to the manifestation of mood disorders in patients with chronic pain conditions, but the mechanisms that contribute to the development and chronicity of CNP and its associated disorders remain poorly understood. This study aimed to determine whether neuroinflammatory factor over-expression in the spinal cord and supraspinal structures may be associated with reflexive and nonreflexive pain response development from acute SCI phase to 12 weeks post-injury in female mice. The results show that transient reflexive responses were observed during the SCI acute phase associated with transient cytokine overexpression in the spinal cord. In contrast, increased nonreflexive pain responses were observed in the chronic phase associated with cytokine overexpression in supraspinal structures, especially in mPFC. In addition, results revealed that besides cytokines, the mPFC showed an increased glial activation as well as CX3CL1/CX3CR1 upregulation in the neurons, suggesting the contribution of neuron-glia crosstalk in the development of nonreflexive pain responses in the chronic spinal cord injury phase.

Artificial Neural Networks Coupled with MALDI-TOF MS Serum Fingerprinting To Classify and Diagnose Pathological Pain Subtypes in Preclinical Models.

Pathological pain subtypes can be classified as either neuropathic pain, caused by a somatosensory nervous system lesion or disease, or nociplastic pain, which develops without evidence of somatosensory system damage. Since there is no gold standard for the diagnosis of pathological pain subtypes, the proper classification of individual patients is currently an unmet challenge for clinicians. While the determination of specific biomarkers for each condition by current biochemical techniques is a complex task, the use of multimolecular techniques, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), combined with artificial intelligence allows specific fingerprints for pathological pain-subtypes to be obtained, which may be useful for diagnosis. We analyzed whether the information provided by the mass spectra of serum samples of four experimental models of neuropathic and nociplastic pain combined with their functional pain outcomes could enable pathological pain subtype classification by artificial neural networks. As a result, a simple and innovative clinical decision support method has been developed that combines MALDI-TOF MS serum spectra and pain evaluation with its subsequent data analysis by artificial neural networks and allows the identification and classification of pathological pain subtypes in experimental models with a high level of specificity.

Central Neuropathic Pain Development Modulation Using Coffee Extract Major Polyphenolic Compounds in Spinal-Cord-Injured Female Mice.

It was recently shown that coffee polyphenolic extract exerts preventive effects on central neuropathic pain development, but it is unknown whether its beneficial effects are associated with only one of its major polyphenolic compounds or if the whole extract is needed to exert such effects. The main objective of this study was to determine whether the separate administration of major polyphenols from coffee extract exerts preventive effects on the development of central neuropathic pain in mice compared with the effects of the whole coffee extract. Thus, spinal-cord-injured female ICR-CD1 mice were daily treated with either coffee extract or its major polyphenolic compounds during the first week, and reflexive and nonreflexive pain responses were evaluated within the acute phase of spinal cord injury. In addition, the injury-induced gliosis and dorsal horn sprouting were evaluated with immunohistochemistry. The results showed that the coffee extract prevented spinal cord injury-induced neuropathic pain, whereas its major polyphenolic compounds resulted in reflexive pain response attenuation. Both preventive and attenuation effects were associated with gliosis and afferent fiber sprouting modulation. Overall, the results suggested that coffee extract effects may be associated with potential synergistic mechanisms exerted by its major polyphenolic compounds and not by the sole effect of only one of them.

Long-Lasting Nociplastic Pain Modulation by Repeated Administration of Sigma-1 Receptor Antagonist BD1063 in Fibromyalgia-like Mouse Models.

Sigma-1 receptor (σ1R) ligands have been shown to be effective at relieving neuropathic and inflammatory pain, but have not yet been tested in experimental models of fibromyalgia. The objective of this study was to evaluate the effect of a σ1R antagonist (BD1063) compared to pregabalin. ICR-CD1 female mice were subjected to either six repeated injections of reserpine, to cause reserpine-induced myalgia (RIM6), or acidified saline intramuscular injections (ASI). In these two models, we evaluated the effect of BD1063 and pregabalin on thermal hypersensitivity, anxiety-like and depression-like behaviors, and on spinal cord gliosis. BD1063 exerted an antinociceptive effect on both reflexive (thermal hyperalgesia) and nonreflexive (anxiety- and depression-like) pain behaviors, and reduced spinal astroglial and microglial reactivity, following repeated treatment for 2 weeks. Interestingly, the effects of BD1063 were long-term, lasting several weeks after treatment discontinuation in both fibromyalgia-like models. Similar results were obtained with pregabalin, but the effects on pain behaviors lasted for a shorter length of time, and pregabalin did not significantly modulate spinal glial reactivity. The inhibitory and long-lasting effect of pharmacological blockade of σ1Rs on both sensory and affective dimensions of nociplastic-like pain and spinal cord gliosis in two experimental models of fibromyalgia support the application of this therapeutic strategy to treat fibromyalgia.

Polyphenolic grape stalk and coffee extracts attenuate spinal cord injury-induced neuropathic pain development in ICR-CD1 female mice.

More than half of spinal cord injury (SCI) patients develop central neuropathic pain (CNP), which is largely refractory to current treatments. Considering the preclinical evidence showing that polyphenolic compounds may exert antinociceptive effects, the present work aimed to study preventive effects on SCI-induced CNP development by repeated administration of two vegetal polyphenolic extracts: grape stalk extract (GSE) and coffee extract (CE). Thermal hyperalgesia and mechanical allodynia were evaluated at 7, 14 and 21 days postinjury. Then, gliosis, ERK phosphorylation and the expression of CCL2 and CX3CL1 chemokines and their receptors, CCR2 and CX3CR1, were analyzed in the spinal cord. Gliosis and CX3CL1/CX3CR1 expression were also analyzed in the anterior cingulate cortex (ACC) and periaqueductal gray matter (PAG) since they are supraspinal structures involved in pain perception and modulation. GSE and CE treatments modulated pain behaviors accompanied by reduced gliosis in the spinal cord and both treatments modulated neuron-glia crosstalk-related biomolecules expression. Moreover, both extracts attenuated astrogliosis in the ACC and PAG as well as microgliosis in the ACC with an increased M2 subpopulation of microglial cells in the PAG. Finally, GSE and CE prevented CX3CL1/CX3CR1 upregulation in the PAG, and modulated their expression in ACC. These findings suggest that repeated administrations of either GSE or CE after SCI may be suitable pharmacologic strategies to attenuate SCI-induced CNP development by means of spinal and supraspinal neuroinflammation modulation.

Prognostic value of symptoms at lung cancer diagnosis: a three-year observational study.

BACKGROUND: Lung cancer is mainly diagnosed at advanced or locally advanced stages, usually when symptoms become evident. However, sometimes it may be diagnosed incidentally during routine care, while patients are still asymptomatic. Prognosis differences based on symptomatic presentation have been partially explored. Our aim was to analyze the prognostic value of the initial symptomatic state of the patients in a general lung cancer cohort. METHODS: Observational ambispective study including patients consecutively diagnosed with primary lung cancer between January 2016 and December 2018 via the lung cancer Fast Diagnostic Track (FDT). Patients were followed up until death or the end of the study in September 2019. Asymptomatic patients were compared with patients presenting symptoms. Overall survival (OS) of both groups was compared using the log-rank test. Cox regression analysis was performed to clarify the effect of the symptomatic status at diagnosis on survival. Additionally, propensity score (PS) matching analysis was performed. RESULTS: A total of 267 patients were analyzed; 83.5% were men, with a mean (SD) age at diagnosis of 68 (10.7) years. Incidental diagnosis was ascertained in 24.7% of cases. Asymptomatic patients presented more frequently stage I and II disease compared to symptomatic patients (51.5% vs. 14%), and exhibited a significantly better prognosis, with a 3-year OS of 63.6% (vs. 30.3%) and a median OS that was not reached during follow-up (vs. 10.3 months). With an adjusted multivariate Cox proportional hazard model, we obtained a HR (95% CI) of 2.63 (95% CI, 1.6-4.2; P<0.0001) associated with symptomatic presentation independently of age, sex, stage at diagnosis and ECOG scale. In addition, after performing the propensity score matching analysis, the Cox regression model continued to show a significantly worse prognosis for patients presenting with symptoms (P=0.041). CONCLUSIONS: Lung cancer patients who are asymptomatic at diagnosis exhibit a significantly better prognosis, regardless of the stage of the disease, underlining the importance of an early diagnosis.

Assessing sleep health in a European population: Results of the Catalan Health Survey 2015.

OBJECTIVE: To describe the overall sleep health of the Catalan population using data from the 2015 Catalan Health Survey and to compare the performance of two sleep health indicators: sleep duration and a 5-dimension sleep scale (SATED). METHODS: Multistage probability sampling representative of the non-institutionalized population aged 15 or more years, stratified by age, gender and municipality size, was used, excluding nightshift-workers. A total of 4385 surveys were included in the analyses. Associations between sleep health and the number of reported chronic diseases were assessed using non-parametric smoothed splines. Differences in the predictive ability of age-adjusted logistic regression models of self-rated health status were assessed. Multinomial logistic regression models were used to assess SATED determinants. RESULTS: Overall mean (SD) sleep duration was 7.18 (1.16) hours; and SATED score 7.91 (2.17) (range 0-10), lower (worse) scores were associated with increasing age and female sex. Alertness and efficiency were the most frequently impaired dimensions across age groups. SATED performed better than sleep duration when assessing self-rated health status (area under the curve = 0.856 vs. 0.798; p-value <0.001), and had a linear relationship with the number of reported chronic diseases, while the sleep duration relationship was u-shaped. CONCLUSIONS: Sleep health in Catalonia is associated with age and gender. SATED has some advantaged compared to sleep duration assessment, as it relates linearly to health indicators, has a stronger association with self-rated health status, and provides a more comprehensive assessment of sleep health. Therefore, the inclusion of multi-dimensional sleep health assessment tools in national surveys should be considered.

Glycine and L-arginine treatment causes hyperhomocysteinemia in cerebral creatine transporter deficiency patients.

Our aim was to monitor folate status in five creatine transporter deficient (CRTR) patients undergoing glycine/L-arginine (Gly/Arg) therapy after the finding of severe hyperhomocysteinemia in one of these cases.Five male patients (age range: 12-20; median = 13 years) genetically confirmed of CRTR deficiency, who were treated with oral glycine (200 mg/kg/day) and L-arginine (400 mg/kg/day) twice a day for 9 months. Clinical follow-up was done at baseline and every 3 months after the start of the therapy. Serum folate was assayed by automated procedures, and plasma total homocysteine (tHcys) by HPLC with fluorescence detection. The 677C→T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was analyzed by PCR.Case 1 presented severe hyperhomocysteinemia (81 µmol/L; control values <10.8) 3 months after Gly/Arg therapy. Three out of the other four cases disclosed mildly increased plasma tHcys values. Serum folate was normal in all cases before therapy, but 3 months after, a deficient status was detected in two cases and a clear decrement in the others when compared with baseline conditions. Two cases were homozygous for the 677C→T polymorphism of the MTHFR, presenting the highest plasma tHcys values. In all cases, after 3 months of folate supplementation (5 mg/day), both serum folate and tHcys concentrations returned to normal values.In conclusion, prior to the start of long-term Gly/Arg therapy, the monitoring of folate and plasma tHcys values, together with study of the 677C→T polymorphism of the MTHFR gene, seems necessary in order to correct hyperhomocysteinemia by means of folate supplementation.

Idebenone treatment in paediatric and adult patients with Friedreich ataxia: long-term follow-up.

BACKGROUND: Antioxidant therapy is a new therapeutical approach for patients with Friedreich ataxia. AIMS: To assess the effectiveness of long-term idebenone treatment in Friedreich ataxia patients. METHODS: An open-labelled prospective study. Ten paediatric patients (age range 8-18 years) and 14 adults (age range 18-46 years) with genetic diagnosis of Friedreich ataxia were treated with idebenone (5-20mg/kg/day) for 3-5 years. Neurological evolution was evaluated using the International Cooperative Ataxia Rating Scale (ICARS), and cardiological outcomes using echocardiography. RESULTS: In paediatric patients, no significant differences were observed in ICARS scores and echocardiographic measurements when comparing baseline status and after 5 years of follow-up. Concerning adult cases, ICARS scores showed a significant increase in neurological dysfunctions during 3 years of therapy (Wilcoxon test, p=0.005), while echocardiographic measurements remained unchanged. CONCLUSIONS: Our results indicate that longer-term idebenone treatment prevented progression of cardiomyopathy in both paediatric and adult patients, whereas its stabilizing effect on neurological dysfunction was present only in the paediatric population, mainly before puberty. This suggests that the age at which idebenone treatment is initiated may be an important factor in the effectiveness of the therapy.

Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy.

The clinical, nutritional, and neuropsychological data of 11 mild/moderate PKU patients after one year of treatment with BH4 are evaluated. BH4 monotherapy was introduced at 5 mg/kg/day in 14 PKU patients. In 11/14 patients, Phe tolerance increased significantly from 356+/-172 to 1546+/-192 mg/day (p=0.004), and special PKU formula was gradually reduced until complete removal. In them, mean plasma Phe concentrations remained below 360 micromol/L at 5 mg BH4/kg/day (7 mg/kg/day in one patient). BH4 therapy was stopped in three patients (V388M/P362T and R243Q/IVS10-11G>A genotypes) because it was not possible to improve Phe tolerance and to remove formula intake. Serum micronutrients were not significantly different at the start of treatment and at one year follow-up, except for selenium, which increased significantly after one year of therapy (p=0.017). Anthropometric, and nutritional measurements were within the age- and sex-specific percentiles for a healthy population after one year therapy. Neuropsychological follow-up indicated that intelligence scores persisted within normal limits. In terms of patients' genotype, we confirmed that the P275S mutation combined with R408W was associated with long-term BH4 responsiveness, while the combination of P362T/V388M, and R243Q/IVS10-11G>A resulted in poor metabolic control in long-term BH4 therapy. In summary, our data confirm that BH4 is a safe, and effective therapy in a selected group of mild, and moderate PKU patients who respond to the BH4 loading test. Low doses of BH4 in monotherapy permit withdrawal of the special formula and guarantee a good clinical and nutritional outcome with no adverse side effects in PKU patients.

Tetrahydrobiopterin responsiveness in patients with phenylketonuria.

OBJECTIVES: To investigate the BH4 response in a group of patients with phenylketonuria (PKU) in order to offer this alternative treatment to the responsive patients. DESIGN AND METHODS: The 24-h-long Phe/BH4 loading test was performed on 64 PKU patients requiring dietary treatment. RESULTS: All patients with mild-PKU and 75% of patients with moderate-PKU were BH4 responsive, while only 11% of classic-PKU patients showed good/partial response (P < 0.0001). The percentages of Phe decrease after the BH4 loading test were significantly different in the three PKU phenotypes (mild PKU: 67.9 +/- 18.7; moderate PKU: 37.4 +/- 16.8; and classical PKU: 21.9 +/- 13.7; ANOVA with Bonferroni correction: P < 0.0001). We report four mutations (P147S, D222G, P275S, and P362T) not previously associated with BH4 responsiveness, all of them combined with mutations with zero predicted residual activity. CONCLUSION: Both the percentage of Phe decrease and the Phe value achieved 24 h after BH4 loading are valuable data in predicting a response. We report four mutations not previously associated with BH4 responsiveness.

Retention rate and illicit opioid use during methadone maintenance interventions: a meta-analysis.

The efficacy of methadone maintenance in opioid addiction was assessed in terms of programme retention rate and reduction of illicit opioid use by means of a meta-analysis of randomised, controlled and double blind clinical trials. The results were compared with interventions using buprenorphine and levo-acetylmethadol (LAAM). Trials were identified from the PubMed database from 1966 to December 1999 using the major medical subject headings 'methadone' and 'randomised controlled trial'. Data for a total of 1944 opioid-dependent patients from 13 studies were analysed. Sixty-four percent of patients received methadone, administered either as fixed or adjusted doses. Thus, 890 patients received > or = 50 mg/day (high dose group) and 392 were given < 50 mg/day (low dose group). Of 662 controls, 131 received placebo, 350 buprenorphine (265 at doses > or = 8 mg/day and 85 at doses < 8 mg/day) and 181 LAAM. High doses of methadone were more effective than low doses in the reduction of illicit opioid use (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.26--2.36). High doses of methadone were significantly more effective than low doses of buprenorphine (< 8 mg/day) for retention rates and illicit opioid use, but similar to high doses of buprenorphine (> or = 8 mg/day) for both parameters. Patients treated with LAAM had more risk of failure of retention than those receiving high doses of methadone (OR 1.92, 95% CI 1.32--2.78). It is proposed that in agonist-maintenance programmes, oral methadone at doses of 50 mg/day or higher is the drug of choice for opioid dependence.