Unraveling malignant phenotype of peritumoral tissue: transcriptomic insights into early-stage breast cancer.

BACKGROUND: Early-stage invasive ductal carcinoma displays high survival rates due to early detection and treatments. However, there is still a chance of relapse of 3-15% after treatment. The aim of this study was to uncover the distinctive transcriptomic characteristics and monitoring prognosis potential of peritumoral tissue in early-stage cases. METHODS: RNA was isolated from tumoral, peritumoral, and non-tumoral breast tissue from surgical resection of 10 luminal early-stage invasive ductal carcinoma patients. Transcriptome expression profiling for differentially expressed genes (DEGs) identification was carried out through microarray analysis. Gene Ontology and KEGG pathways enrichment analysis were explored for functional characterization of identified DEGs. Protein-Protein Interactions (PPI) networks analysis was performed to identify hub nodes of peritumoral tissue alterations and correlated with Overall Survival and Relapse Free Survival. RESULTS: DEGs closely related with cell migration, extracellular matrix organization, and cell cycle were upregulated in peritumoral tissue compared to non-tumoral. Analyzing PPI networks, we observed that the proximity to tumor leads to the alteration of gene modules involved in cell proliferation and differentiation signaling pathways. In fact, in the peritumoral area were identified the top ten upregulated hub nodes including CDK1, ESR1, NOP58, PCNA, EZH2, PPP1CA, BUB1, TGFBR1, CXCR4, and CCND1. A signature performed by four of these hub nodes (CDK1, PCNA, EZH2, and BUB1) was associated with relapse events in untreated luminal breast cancer patients. CONCLUSIONS: In conclusion, our study characterizes in depth breast peritumoral tissue providing clues on the changes that tumor signaling could cause in patients with early-stage breast cancer. We propose that the use of a four gene signature could help to predict local relapse. Overall, our results highlight the value of peritumoral tissue as a potential source of new biomarkers for early detection of relapse and improvement in invasive ductal carcinoma patient's prognosis.

Cognitive reserve and executive functions in dual task gait performance in Parkinson's disease.

A higher level of education was correlated with less severe motor impairment in Parkinson's Disease (PD). Nevertheless, there is limited evidence on the relationship between cognitive reserve and motor performance in complex situations in PD. To investigate the association between cognitive reserve and the dual-task gait effect in PD. Additionally, we examined the relationship between executive function, clinical and sociodemographic variables and, dual-task gait effects. We conducted a cross-sectional study with 44 PD participants. We evaluated dual-task effect on cadence, stride length, and gait velocity. Dual-task effects were correlated with neurophysiological factors, including cognitive reserve (Cognitive Reserve Index Questionnaire), overall cognitive performance of executive functions, a specific executive function domain (Trail Making Test), and the global cognitive status (Montreal Cognitive Assessment and Mini-Mental State Examination). Age, gender, and disease severity were considered as variables to be examined for correlation. We found that cognitive reserve did not influence gait performance under dual-task conditions in this sample. However, executive functions, age, and disease severity were associated with the dual-task effect on gait. The overall cognitive performance with respect to the Trail Making Test showed an inverse relationship in the dual-task gait effect on cadence. Our study's findings have important implications for understanding the association between executive functions, age, and disease severity with the dual-task effect on gait in PD. Pre-life factors, such as education, occupation, and leisure activity, did not contribute to coping with complex gait situations in PD.

A gamified virtual environment intervention for gait rehabilitation in Parkinson's Disease: co-creation and feasibility study.

BACKGROUND: Treadmill gait training has been shown to improve gait performance in People with Parkinson's Disease (PwPD), and in combination with Virtual Reality, it can be an effective tool for gait rehabilitation. The addition of gamification elements can create a more stimulating and adherent intervention. However, implementation of new technologies in healthcare can be challenging. This study aimed to develop and evaluate the feasibility of a treadmill rehabilitation program in a Gamified Virtual Reality Environment (GVRE) for PwPD. METHODS: The GVRE was developed following a user-centered design approach, involving both PwPD and physiotherapists in the development and evaluation of the intervention. The intervention consisted of a walking simulation in three different environments (countryside, city, and park), which had a progressive increase in difficulty. To test its feasibility, three sessions were carried out with four PwPD and four physiotherapists. To assess the usability, the System Usability Scale (SUS), Assistive Technology Usability Questionnaire for people with Neurological diseases (NATU Quest) and Simulator Sickness Questionnaire (SSQ) were used. To assess the intervention's acceptability, feedback and in-game performance was collected from participants. RESULTS: Results showed the feasibility of the intervention, with a SUS score of 74.82 ± 12.62, and a NATU Quest score of 4.49 ± 0.62, and positive acceptability feedback. Participants showed clear preferences for naturalistic environments, and gamification elements were seen as positive. Difficulty settings worked as intended, but lowered enjoyment of the experience in some cases. CONCLUSIONS: This intervention was successfully shown as a feasible option for the training of gait under Dual Task conditions for PwPD. It offers a safe and replicable environment in which complex situations can be trained. However, further iterations of the intervention need to be improved in order to guarantee accurate tracking and a more realistic training progression. TRIAL REGISTRATION NUMBER: NCT05243394-01/20/2022.

Inhibition of Cancer Stem-like Cells by Curcumin and Other Polyphenol Derivatives in MDA-MB-231 TNBC Cells.

Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and is highly aggressive. Despite an initial positive response to chemotherapy, most patients experience rapid disease progression leading to relapse and metastasis. This is attributed to the presence of breast cancer stem cells (BCSCs) within the tumor, which are characterized by self-renewal, pluripotency, and resistance mechanisms. Targeting BCSCs has become critical as conventional therapies fail to eradicate them due to a lack of specific targets. Curcumin, a polyphenol derived from turmeric (Curcuma longa), exhibits anticancer effects against breast cancer cells and BCSCs. The use of curcumin derivatives has been suggested as an approach to overcome the bioavailability and solubility problems of curcumin in humans, thereby increasing its anticancer effects. The aim of this study was to evaluate the cellular and molecular effects of six synthetic compounds derived from the natural polyphenol epigallocatechin gallate (EGCG) (TL1, TL2) and curcumin derivatives (TL3, TL4, TL5, and TL6) on a TNBC mesenchymal stem-like cell line. The activity of the compounds against BCSCs was also determined by a mammosphere inhibition assay and studying different BCSC markers by Western blotting. Finally, a drug combination assay was performed with the most promising compounds to evaluate their potential synergistic effects with the chemotherapeutic agents doxorubicin, cisplatin, and paclitaxel. The results showed that compounds exhibited specific cytotoxicity against the TNBC cell line and BCSCs. Interestingly, the combination of the curcumin derivative TL3 with doxorubicin and cisplatin displayed a synergistic effect in TNBC cells.

High Concentrations of Genistein Decrease Cell Viability Depending on Oxidative Stress and Inflammation in Colon Cancer Cell Lines.

Genistein could play a crucial role in modulating three closely linked physiological processes altered during cancer: oxidative stress, mitochondrial biogenesis, and inflammation. However, genistein's role in colorectal cancer remains unclear. We aimed to determine genistein's effects in two colon cancer cells: HT29 and SW620, primary and metastatic cancer cells, respectively. After genistein treatment for 48 h, cell viability and hydrogen peroxide (H2O2) production were studied. The cell cycle was studied by flow cytometry, mRNA and protein levels were analyzed by RT-qPCR and Western blot, respectively, and finally, cytoskeleton remodeling and NF-κB translocation were determined by confocal microscopy. Genistein 100 µM decreased cell viability and produced G2/M arrest, increased H2O2, and produced filopodia in SW620 cells. In HT29 cells, genistein produced an increase of cell death, H2O2 production, and in the number of stress fibers. In HT29 cells, mitochondrial biogenesis was increased, however, in SW620 cells, it was decreased. Finally, the expression of inflammation-related genes increased in both cell lines, being greater in SW620 cells, where NF-κB translocation to the nucleus was higher. These results indicate that high concentrations of genistein could increase oxidative stress and inflammation in colon cancer cells and, ultimately, decrease cell viability.

A treadmill training program in a gamified virtual reality environment combined with transcranial direct current stimulation in Parkinson's Disease: Study protocol for a randomized controlled trial.

BACKGROUND: Parkinson's Disease (PD) affects movement and cognition, and physiotherapy, particularly treadmill gait training, has potential in addressing movement dysfunctions in PD. However, treadmill training falls short in addressing cognitive aspects and adherence. Virtual reality (VR) and gamification can enhance motor and cognitive retraining and improve adherence. People with Parkinson's Disease (PWPD) have decreased motor skill learning efficiency, but tDCS can improve motor and cognitive learning. METHODS: 78 participants with PD will be randomly allocated in a 1:1:1 ratio to one of three groups: (1) treadmill + Gamified Virtual Reality Environment (GVRE) + tDCS training group; (2) treadmill + GVRE training group or (3) treadmill training group. Participants will follow a 6-week, 12-session treadmill gait training plan, gradually increasing session duration from 20 to 45 minutes. Participants in (1) and (2) will undergo a GVRE training protocol, with (1) also receiving tDCS for the first 20 minutes of each session. Assessments will occur at baseline, post-intervention, and at a 6-week follow-up. The primary outcome measure will be gait speed during single and dual-task performance. Secondary measures will include additional gait parameters, executive tests for cognitive performance, and clinical outcomes for disease stage, cognitive status, and physical condition. DISCUSSION: This randomized clinical trial presents an innovative neurorehabilitation protocol that aims to improve gait and cognition in PWPD. The study also examines how tDCS can enhance motor and cognitive training. Results could contribute to enhancing the motor and cognitive state of PWPD through a GVRE and tDCS-based neurorehabilitation protocol. TRIAL REGISTRATION: NCT05243394. 28/02/2024 -v3.2.

Metformin: From Diabetes to Cancer-Unveiling Molecular Mechanisms and Therapeutic Strategies.

Metformin, a widely used anti-diabetic drug, has garnered attention for its potential in cancer management, particularly in breast and colorectal cancer. It is established that metformin reduces mitochondrial respiration, but its specific molecular targets within mitochondria vary. Proposed mechanisms include inhibiting mitochondrial respiratory chain Complex I and/or Complex IV, and mitochondrial glycerophosphate dehydrogenase, among others. These actions lead to cellular energy deficits, redox state changes, and several molecular changes that reduce hyperglycemia in type 2 diabetic patients. Clinical evidence supports metformin's role in cancer prevention in type 2 diabetes mellitus patients. Moreover, in these patients with breast and colorectal cancer, metformin consumption leads to an improvement in survival outcomes and prognosis. The synergistic effects of metformin with chemotherapy and immunotherapy highlights its potential as an adjunctive therapy for breast and colorectal cancer. However, nuanced findings underscore the need for further research and stratification by molecular subtype, particularly for breast cancer. This comprehensive review integrates metformin-related findings from epidemiological, clinical, and preclinical studies in breast and colorectal cancer. Here, we discuss current research addressed to define metformin's bioavailability and efficacy, exploring novel metformin-based compounds and drug delivery systems, including derivatives targeting mitochondria, combination therapies, and novel nanoformulations, showing enhanced anticancer effects.

Tumorspheres as In Vitro Model for Identifying Predictive Chemoresistance and Tumor Aggressiveness Biomarkers in Breast and Colorectal Cancer.

Chemoresistance remains a major challenge in the treatment of breast and colorectal cancer. For this reason, finding reliable predictive biomarkers of response to chemotherapy has become a significant research focus in recent years. However, validating in vitro results may be problematic due to the outcome heterogeneity. In this study, we evaluate the use of tumorspheres as an in vitro model for validating biomarkers of chemoresistance in breast and colorectal cancer. Our investigation highlights the crucial role of inflammation-related pathways in modulating the response to chemotherapy. Using in silico approaches, we identified specific markers elevated in responders versus non-responders patients. These markers were consistently higher in three-dimensional (3D) tumorsphere models compared to traditional adherent cell culture models. Furthermore, the number of tumorspheres from breast and colorectal cancer cells increased in response to cisplatin and oxaliplatin treatment, respectively, whereas cell viability decreased in adherent cell culture. This differential response underscores the importance of the 3D tumorsphere model in mimicking the tumor microenvironment more accurately than adherent cell culture. The enhanced chemoresistance observed in the 3D tumorspheres model and their correlation of data with the in silico study suggest that 3D culture models are a better option to approach the in vivo model and also to validate in silico data. Our findings indicate that tumorspheres are an ideal model for validating chemoresistance biomarkers and exploring the interplay between inflammation and chemoresistance in breast and colon cancer.

Asymmetric sleep in apneic human patients.

Unilateral sleep in marine mammals has been considered to be a defense against airway obstruction, as a sentinel for pod maintenance, and as a thermoregulatory mechanism. Birds also show asymmetric sleep, probably to avoid predation. The variable function of asymmetric sleep suggests a general capability for independence between brain hemispheres. Patients with obstructive sleep apnea share similar problems with diving mammals, but their eventual sleep asymmetry has received little attention. The present report shows that human sleep apnea patients also present temporary interhemispheric variations in dominance during sleep, with significant differences when comparing periods of open and closed airways. The magnitude of squared coherence, an index of interhemispheric EEG interdependence in phase and amplitude, rises in the delta EEG range during apneic episodes, while the phase lag index, a measure of linear and nonlinear interhemispheric phase synchrony, drops to zero. The L index, which measures generalized nonlinear EEG interhemispheric synchronization, increases during apneic events. Thus, the three indexes show significant and congruent changes in interhemispheric symmetry depending on the state of the airways. In conclusion, when confronted with a respiratory challenge, sleeping humans undergo small, but significant, breathing-related oscillations in interhemispheric dominance, similar to those observed in marine mammals. The evidence points to a relationship between cetacean unihemispheric sleep and their respiratory challenges.

Cognitive recovery and restoration of cell proliferation in the dentate gyrus in the 5XFAD transgenic mice model of Alzheimer's disease following 2-hydroxy-DHA treatment.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly. In the last years, abnormalities of lipid metabolism and in particular of docosahexaenoic acid (DHA) have been recently linked with the development of the disease. According to the recent studies showing how hydroxylation of fatty acids enhances their biological activity, here we show that chronic treatment with a hydroxylated derivative of DHA, the 2-hydroxy-DHA (2OHDHA) in the 5XFAD transgenic mice model of AD improves performance in the radial arm maze test and restores cell proliferation in the dentate gyrus, with no changes in the presence of beta amyloid (Aß) plaques. These results suggest that 2OHDHA induced restoration of cell proliferation can be regarded as a major component in memory recovery that is independent of Aß load thus, setting the starting point for the development of a new drug for the treatment of AD.

Mammalian NREM and REM sleep: Why, when and how.

This report proposes that fish use the spinal-rhombencephalic regions of their brain to support their activities while awake. Instead, the brainstem-diencephalic regions support the wakefulness in amphibians and reptiles. Lastly, mammals developed the telencephalic cortex to attain the highest degree of wakefulness, the cortical wakefulness. However, a paralyzed form of spinal-rhombencephalic wakefulness remains in mammals in the form of REMS, whose phasic signs are highly efficient in promoting maternal care to mammalian litter. Therefore, the phasic REMS is highly adaptive. However, their importance is low for singletons, in which it is a neutral trait, devoid of adaptive value for adults, and is mal-adaptive for marine mammals. Therefore, they lost it. The spinal-rhombencephalic and cortical wakeful states disregard the homeostasis: animals only attend their most immediate needs: foraging defense and reproduction. However, these activities generate allostatic loads that must be recovered during NREMS, that is a paralyzed form of the amphibian-reptilian subcortical wakefulness. Regarding the regulation of tonic REMS, it depends on a hypothalamic switch. Instead, the phasic REMS depends on an independent proportional pontine control.

Physiotherapists' experiences on assisting physiotherapy users during the COVID-19 pandemic with lockdown measures in Spain.

BACKGROUND: Physiotherapists had faced a new healthcare scenario characterised by the restrictions caused by the COVID-19 pandemic. PURPOSE: To explore the impact of the COVID-19 pandemic on the physiotherapy profession from the perspective of physiotherapists working in the public and private sectors. METHODS: Qualitative study based on semi-structured personal interviews with 16 physiotherapists working in public, private, or public-private partnership sectors in Spain. The data were collected between March and June 2020. Inductive qualitative content analysis was performed. RESULTS: The participants (13 women, 3 men; aged 24-44 years) had professional experience in diverse healthcare settings (primary, hospital, home, consultations, insurance companies, associations). Five categories were identified: (1) the impact of lockdown on the health of physiotherapy users; (2) managing the demand for physiotherapy services during lockdown; (3) introducing protocols and protective measures in physiotherapy consultations; (4) changes in therapeutic approaches; and (5) future expectations in the physiotherapy care model. Physiotherapists perceived that lockdown caused a decline in the functionality of people with chronic conditions, together with a reduction in the physiotherapy services. Difficulties in prioritising users considered urgent became evident, and the inclusion of prophylactic measures affected treatment duration differently depending on the care setting and the pandemic prompted the use of telerehabilitation. DISCUSSION: The pandemic affected the functional status of chronic physiotherapy users and made treatment time, quality of care and triage protocols visible. In physiotherapy, technological barriers need to be solved, such as digital literacy, families without resources, situations of dependency and cultural barriers.

The Birth of the Mammalian Sleep.

Mammals evolved from small-sized reptiles that developed endothermic metabolism. This allowed filling the nocturnal niche. They traded-off visual acuity for sensitivity but became defenseless against the dangerous daylight. To avoid such danger, they rested with closed eyes in lightproof burrows during light-time. This was the birth of the mammalian sleep, the main finding of this report. Improved audition and olfaction counterweighed the visual impairments and facilitated the cortical development. This process is called "The Nocturnal Evolutionary Bottleneck". Pre-mammals were nocturnal until the Cretacic-Paleogene extinction of dinosaurs. Some early mammals returned to diurnal activity, and this allowed the high variability in sleeping patterns observed today. The traits of Waking Idleness are almost identical to those of behavioral sleep, including homeostatic regulation. This is another important finding of this report. In summary, behavioral sleep seems to be an upgrade of Waking Idleness Indeed, the trait that never fails to show is quiescence. We conclude that the main function of sleep consists in guaranteeing it during a part of the daily cycle.

Use of Omics Technologies for the Detection of Colorectal Cancer Biomarkers.

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers with high mortality rates, especially when detected at later stages. Early detection of CRC can substantially raise the 5-year survival rate of patients, and different efforts are being put into developing enhanced CRC screening programs. Currently, the faecal immunochemical test with a follow-up colonoscopy is being implemented for CRC screening. However, there is still a medical need to describe biomarkers that help with CRC detection and monitor CRC patients. The use of omics techniques holds promise to detect new biomarkers for CRC. In this review, we discuss the use of omics in different types of samples, including breath, urine, stool, blood, bowel lavage fluid, or tumour tissue, and highlight some of the biomarkers that have been recently described with omics data. Finally, we also review the use of extracellular vesicles as an improved and promising instrument for biomarker detection.

Chronic melatonin treatment and its precursor L-tryptophan improve the monoaminergic neurotransmission and related behavior in the aged rat brain.

Melatonin has an important role in the aging process as a potential drug to relieve oxidative damage, a likely cause of age-associated brain dysfunction. As age advances, the nocturnal production of melatonin decreases potentially causing physiological alterations. The present experiments were performed to study in vivo the effects of exogenously administered melatonin chronically on monoaminergic central neurotransmitters serotonin (5-HT), dopamine (DA) and norepinephrine (NE) and behavioral tests in old rats. The accumulation of 5-hydroxy-tryptophan (5-HTP) and L-3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in rat brain. Also neurotransmitters 5-HT, DA and NE and some metabolites were quantified by HPLC. In control rats, an age-related decline was observed in neurochemical parameters. However, chronic administration of melatonin (1 mg/kg/day, diluted in drinking water, 4 wk) significantly reversed the age-induced deficits in all the monoaminergic neurotransmitters studied. Also, neurochemical parameters were analyzed after administration of melatonin biosynthesis precursor L-tryptophan (240 mg/kg/day, i.p., at night for 4 wk) revealing similar improvement effects to those induced by melatonin. Behavioral data corresponded well with the neurochemical findings since spatial memory test in radial-maze and motor coordination in rota-rod were significantly improved after chronic melatonin treatment. In conclusion, these in vivo findings suggest that melatonin and L-tryptophan treatments exert a long-term effect on the 5-HT, DA and NE neurotransmission by enhancing monoamine synthesis in aged rats, which might improve the age-dependent deficits in cognition and motor coordination.

Comparing the Behavioural Effects of Exogenous Growth Hormone and Melatonin in Young and Old Wistar Rats.

Growth hormone (GH) and melatonin are two hormones with quite different physiological effects. Curiously, their secretion shows parallel and severe age-related reductions. This has promoted many reports for studying the therapeutic supplementation of both hormones in an attempt to avoid or delay the physical, physiological, and psychological decay observed in aged humans and in experimental animals. Interestingly, the effects of the external administration of low doses of GH and of melatonin were surprisingly similar, as both hormones caused significant improvements in the functional capabilities of aged subjects. The present report aims at discerning the eventual difference between cognitive and motor effects of the two hormones when administered to young and aged Wistar rats. The effects were tested in the radial maze, a test highly sensitive to the age-related impairments in working memory and also in the rotarod test, for evaluating the motor coordination. The results showed that both hormones caused clear improvements in both tasks. However, while GH improved the cognitive capacity and, most importantly, the physical stamina, the effects of melatonin should be attributed to its antioxidant, anxiolytic, and neuroprotective properties.

[Analysis of heart rate as a risk factor associated with the progression of chronic renal failure]. / Análisis de la frecuencia cardíaca como factor de riesgo asociado a la progresión de la insuficiencia renal crónica.

BACKGROUND: An increased heart rate is associated with an increased risk of cardiovascular and non-cardiovascular death. However, the possible relationship between heart rate and the rate of progression of renal disease has not been assessed so far. PATIENTS AND METHOD: Twenty-four-hour ambulatory blood pressure and heart rate recordings at baseline conditions were obtained in 24 patients with non-diabetic chronic renal failure and hypertension. The rate of progression of renal disease was estimated on the basis of the slope of the reciprocal of serum creatinine concentration against time. RESULTS: After a mean follow-up of 38 months, the rate of progression of renal failure was 0.004 (0.039) dL/mg/month. Progression of renal disease showed no correlation with baseline ambulatory systolic or diastolic blood pressures, and did not differ between dipper and non-dipper patients. Twenty-four-hour (r = 0.40, p = 0.05) and day-time (r = 0.534, p = 0.007) heart rates showed a relationship with the progression of renal failure. Proteinuria displayed a correlation with night-time heart rate (r = 0.405, p = 0.05) but not with the progression of renal failure. CONCLUSIONS: Baseline ambulatory heart rate, especially day-time heart rate, is associated with the decline of renal function in non-diabetic patients with chronic renal failure, suggesting that heart rate is a risk factor (or marker) for renal disease progression. Prospective controlled studies with a larger sample of patients are needed to confirm these findings and to investigate the possible mechanisms involved in this association.

Improving effects of long-term growth hormone treatment on monoaminergic neurotransmission and related behavioral tests in aged rats.

An age-related decline in cognitive functions and physical performance has been associated with reductions in growth hormone (GH) secretion and brain neurotransmitter function. In vivo experiments were performed to study the long-term effects of exogenously administered GH on the central monoaminergic neurotransmitters serotonin, dopamine, and noradrenaline and behavioral tests in old Wistar rats. The accumulation of 5-hydroxytryptophan (5-HTP) and L-3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in vivo. Also, the content of the neurotransmitters serotonin, dopamine, and noradrenaline and some metabolites was measured by high-pressure liquid chromatography (HPLC) in the hippocampus and striatum, brain regions involved in adult memory processing and motor coordination. The age-related decline observed in all the neurochemical parameters in control rats was significantly reversed after repeated subcutaneous administration of GH (2 mg/kg per day, 4 weeks). Thus, GH treatment exerted a long-term effect on serotonin, dopamine, and noradrenaline neurotransmission by enhancing neurotransmitter synthesis and metabolism in aged rats. The results obtained after examining working memory tasks in the eight-radial maze and motor ability in the Rotarod treadmill in aged rats were consistent with these neurochemical data; both tests were significantly improved after chronic GH treatment. Overall, these in vivo findings suggest that the positive effects induced by GH on serotonin, dopamine, and noradrenaline neurotransmitters might explain, at least in part, the effects of chronic GH treatment in improving cognitive and motor ability in aged rats, and could aid in preventing or delaying deficits in monoamines associated with learning or motor disabilities.

Evolution of wakefulness, sleep and hibernation: from reptiles to mammals.

Thus far, most hypotheses on the evolutionary origin of sleep only addressed the probable origin of its main states, REM and NREM. Our article presents the origin of the whole continuum of mammalian vigilance states including waking, sleep and hibernation and the causes of the alternation NREM-REM in a sleeping episode. We propose: (1) the active state of reptiles is a form of subcortical waking, without homology with the cortical waking of mammals; (2) reptilian waking gave origin to mammalian sleep; (3) reptilian basking behaviour evolved into NREM; (4) post-basking risk assessment behaviour, with motor suspension, head dipping movements, eye scanning and stretch attending postures, evolved into phasic REM; (5) post-basking, goal directed behaviour evolved into tonic REM and (6) nocturnal rest evolved to shallow torpor. A small number of changes from previous reptilian stages explain these transformations.

An eight-gene blood expression profile predicts the response to infliximab in rheumatoid arthritis.

BACKGROUND: TNF alpha blockade agents like infliximab are actually the treatment of choice for those rheumatoid arthritis (RA) patients who fail standard therapy. However, a considerable percentage of anti-TNF alpha treated patients do not show a significant clinical response. Given that new therapies for treatment of RA have been recently approved, there is a pressing need to find a system that reliably predicts treatment response. We hypothesized that the analysis of whole blood gene expression profiles of RA patients could be used to build a robust predictor to infliximab therapy. METHODS AND FINDINGS: We performed microarray gene expression analysis on whole blood RNA samples from RA patients starting infliximab therapy (n = 44). The clinical response to infliximab was determined at week 14 using the EULAR criteria. Blood cell populations were determined using flow cytometry at baseline, week 2 and week 14 of treatment. Using complete cross-validation and repeated random sampling we identified a robust 8-gene predictor model (96.6% Leave One Out prediction accuracy, P = 0.0001). Applying this model to an independent validation set of RA patients, we estimated an 85.7% prediction accuracy (75-100%, 95% CI). In parallel, we also observed a significantly higher number of CD4+CD25+ cells (i.e. regulatory T cells) in the responder group compared to the non responder group at baseline (P = 0.0009). CONCLUSIONS: The present 8-gene model obtained from whole blood expression efficiently predicts response to infliximab in RA patients. The application of the present system in the clinical setting could assist the clinician in the selection of the optimal treatment strategy in RA.