From acute to chronic pain: tapentadol in the progressive stages of this disease entity

OBJECTIVE: Chronic pain is now recognized as a neural disease, which results from a maladaptive functional and structural transformation process occurring over time. In its chronic phase, pain is not just a symptom but also a disease entity. Therefore, pain must be properly addressed, as many patients still report unsatisfactory pain control despite on-going treatment. The selection of the therapy - taking into account the pathophysiological mechanisms of pain - and the right timing can result in a successful analgesic outcome. This review will present the functional and structural modifications leading to chronification of pain, focusing on the role of tapentadol in this setting. MATERIALS AND METHODS: For inclusion in this review, research studies were retrieved via a keyword-based query of multiple databases (MEDLINE, Embase, Cochrane). The search was last updated in November 2016; no limitations were applied. RESULTS: Functional and structural abnormalities of the nervous system associated with pain chronification have been reported in several conditions, including osteoarthritis, chronic back pain, chronic pelvic pain and fibromyalgia. Correct identification and treatment of pain in recurrent/progressive stage is crucial to prevent chronification and related changes in neural structures. Among analgesic drugs, tapentadol, with its dual mechanism of action (opioid agonist and noradrenaline reuptake blocker), has recently resulted active in pain control at both central and spinal level. CONCLUSIONS: Tapentadol represents a suitable candidate for patients at early progressive stage of pain who have developed neuroplasticity with modification of pain pathways. The availability of different doses of tapentadol may help clinicians to tailor treatment based on the individual need of each patient, with the aim to enhance therapeutic appropriateness in the treatment of musculoskeletal and neuropathic pain

Circulating Cell-Free DNA in Dogs with Mammary Tumors: Short and Long Fragments and Integrity Index

Circulating cell-free DNA (cfDNA) has been considered an interesting diagnostic/prognostic plasma biomarker in tumor-bearing subjects. In cancer patients, cfDNA can hypothetically derive from tumor necrosis/apoptosis, lysed circulating cells, and some yet unrevealed mechanisms of active release. This study aimed to preliminarily analyze cfDNA in dogs with canine mammary tumors (CMTs). Forty-four neoplastic, 17 non-neoplastic disease-bearing, and 15 healthy dogs were recruited. Necrosis and apoptosis were also assessed as potential source of cfDNA on 78 CMTs diagnosed from the 44 dogs. The cfDNA fragments and integrity index significantly differentiated neoplastic versus non-neoplastic dogs (P<0.05), and allowed the distinction between benign and malignant lesions (P<0.05). Even if without statistical significance, the amount of cfDNA was also affected by tumor necrosis and correlated with tumor size and apoptotic markers expression. A significant (P<0.01) increase of Bcl-2 in malignant tumors was observed, and in metastatic CMTs the evasion of apoptosis was also suggested. This study, therefore, provides evidence that cfDNA could be a diagnostic marker in dogs carrying mammary nodules suggesting that its potential application in early diagnostic procedures should be further investigated

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Gene set analysis exploiting the topology of a pathway

BACKGROUND: Recently, a great effort in microarray data analysis is directed towards the study of the so-called gene sets. A gene set is defined by genes that are, somehow, functionally related. For example, genes appearing in a known biological pathway naturally define a gene set. The gene sets are usually identified from a priori biological knowledge. Nowadays, many bioinformatics resources store such kind of knowledge (see, for example, the Kyoto Encyclopedia of Genes and Genomes, among others). Although pathways maps carry important information about the structure of correlation among genes that should not be neglected, the currently available multivariate methods for gene set analysis do not fully exploit it. RESULTS: We propose a novel gene set analysis specifically designed for gene sets defined by pathways. Such analysis, based on graphical models, explicitly incorporates the dependence structure among genes highlighted by the topology of pathways. The analysis is designed to be used for overall surveillance of changes in a pathway in different experimental conditions. In fact, under different circumstances, not only the expression of the genes in a pathway, but also the strength of their relations may change. The methods resulting from the proposal allow both to test for variations in the strength of the links, and to properly account for heteroschedasticity in the usual tests for differential expression. CONCLUSIONS: The use of graphical models allows a deeper look at the components of the pathway that can be tested separately and compared marginally. In this way it is possible to test single components of the pathway and highlight only those involved in its deregulation

The CUORE cryostat: an infrastructure for rare event searches at millikelvin temperatures

The CUORE experiment is the world's largest bolometric experiment. The detector consists of an array of 988 TeO2 crystals, for a total mass of 742 kg. CUORE is presently taking data at the Laboratori Nazionali del Gran Sasso, Italy, searching for the neutrinoless double beta decay of 130Te. A large custom cryogen-free cryostat allows reaching and maintaining a base temperature of about 10 mK, required for the optimal operation of the detector. This apparatus has been designed in order to achieve a low noise environment, with minimal contribution to the radioactive background for the experiment. In this paper, we present an overview of the CUORE cryostat, together with a description of all its sub-systems, focusing on the solutions identified to satisfy the stringent requirements. We briefly illustrate the various phases of the cryostat commissioning and highlight the relevant steps and milestones achieved each time. Finally, we describe the successful cooldown of CUORE

Sex-dependent effect of inflammatory pain on negative affective states is prevented by kappa opioid receptors blockade in the nucleus accumbens shell

Pain comorbidities include several psychological disorders, such as anxiety and anhedonia. However, the way pain affects male and female individuals and by which mechanism is not well understood. Previous research shows that pain induces alterations in the dynorphinergic pathway within the mesocorticolimbic system (MCLS), together with a relationship between corticotropin-releasing system and dynorphin release in the MCLS. Here, we analyse the sex and time course-dependent effects of pain on negative affect. Additionally, we study the implication of dynorphinergic and corticotropin releasing factor in these pain related behaviours. We used behavioural pharmacology and biochemical tools to characterise negative affective states induced by inflammatory pain in male and female rats, and the alterations in the dynorphinergic and the corticotropin systems within the MCLS. Female rats showed persistent anxiety-like and reversible anhedonia-like behaviours derived from inflammatory pain. Additionally, we found alterations in dynorphin and corticotropin releasing factor in NAc and amygdala, which suggests sex-dependent dynamic adaptations. Finally blockade on the kappa opioid receptor in the NAc confirmed its role in pain-induced anxiety-like behaviour in female rats. Our results show sex and time-dependent anxiety- and anhedonia-like behaviours induced by the presence of pain in female rats. Furthermore, we replicated previous data, pointing to the KOR/DYN recruitment in the NAc as a key neurological substrate mediating pain-induced behavioural alterations. This research studies the mechanisms underlying these behaviours, to better understand the emotional dimension of pain

Gray Matter Pathology in MS: A 3-Year Longitudinal Study in a Pediatric Population

RESULTS: At T0, GMf did not differ between cMS and NC (P .18), while it was lower in patients with aMS compared with both NCs (P .001) and patients with cMS (P .001). The number of patients with CLs, as well as CL number and volume, were higher in patients with aMS than in those with cMS (P .001). At T3, -GMf was higher in both patients with cMS (1.6% 0.5%; range 0.7%–3.4%; P .001) and aMS (1.6% 0.6%; range 0.6%–3.4%; P .001) compared with NCs (0.7% 0.2%; range 0.4%–1.1%), whereas no difference was observed between patients with cMS and aMS (P .93). -GMf significantly correlated with increased CL volume (cMS: r 0.46; aMS: r 0.48) and with the appearance of new CLs (cMS: r 0.51; aMS: r 0.49). CONCLUSIONS: Our findings suggest that focal (CLs) and diffuse (atrophy) GM damage are strictly associated with the biologic onset of MS, and proceed linearly and partly independently of WM pathology. ABBREVIATIONS: aMS adult-onset multiple sclerosis; CL cortical lesion; cMS childhoodonset multiple sclerosis; EDSS Expanded Disability Status Scale; GM gray matter; GMf gray matter fraction; -GMf delta gray matter fraction; -GMf_1 delta gray matter fraction at T1; -GMf_2 delta gray matter fraction at T2; -GMf_3 delta gray matter fraction at T3; NC healthy control; T0 baseline; T2WMLV T2 white matter lesion volum

Safe use of opioids in chronic kidney disease and hemodialysis patients. ips and tricks for non pain specialist

Abstract: In patients suffering from moderate-to-severe chronic kidney disease (CKD) or end-stage renal disease (ESRD), subjected to hemodialysis (HD), pain is very common, but often underestimated. Opioids are still the mainstay of severe chronic pain management; however, their prescription in CKD and HD patients is still significantly low and pain is often under-treated. Altered pharmacokinetics and the lack of clinical trials on the use of opioids in patients with renal impairment increase physicians’ concerns in this specific population. This narrative review focused on the correct and safe use of opioids in patients with CKD and HD. Morphine and codeine are not recommended, because the accumulation of their metabolites may cause neurotoxic symptoms. Oxycodone and hydromorphone can be safely used, but adequate dosage adjustments are required in CKD. In dialyzed patients, these opioids should be considered as second-line agents and patients should be carefully mon- itored. According to different studies, buprenorphine and fentanyl could be considered first- line opioids in the management of pain in CKD; however, fentanyl is not appropriate in patients undergoing HD. Tapentadol does not need dosage adjustment in mild-to-moderate renal impairment conditions; however, no data are available on its use in ESRD. Opioid- related side effects may be exacerbated by common comorbidities in CKD patients. Opioid- induced constipation can be managed with peripherally-acting-μ-opioid-receptor-antagonists (PAMORA). Unlike the other PAMORA, naldemedine does not require any dose adjustment in CKD and HD patients. Accurate pain diagnosis, opioid titration and tailoring are manda- tory to minimize the risks and to improve the outcome of the analgesic therapy

Holographic quark matter with colour superconductivity and a stiff equation of state for compact stars

We present a holographic model of QCD with a first order chiral restoration phase transition with chemical potential, mu. The first order behaviour follows from allowing a discontinuity in the dual description as the quarks are integrated out below their constituent mass. The model predicts a deconfined yet massive quark phase at intermediate densities (350 MeV< mu <500 MeV), above the nuclear density phase, which has a very stiff equation of state and a speed of sound close to one. We also include a holographic description of a colour superconducting condensate in the chirally restored vacuum and study the resulting equation of state. They provides a well behaved first order transition from the deconfined massive quark phase at very high density (mu>500 MeV). We solve the Tolman-Oppenheimer-Volkoff equations with the resulting equations of state and find stable hybrid stars with quark cores. We compute the tidal deformability for these hybrid stars and show they are consistent with LIGO/Virgo data on a neutron star collision. Our holographic model shows that quark matter could be present at the core of such compact stars.Comment: 17 pages, 14 figure