On the role of peripheral sensory and gut mu opioid receptors: Peripheral analgesia and tolerance

There is growing evidence on the role of peripheral \ub5-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, \u3b2-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance

Fertility preservation in childhood cancer: Endocrine activity in prepubertal human testis xenografts exposed to a pubertal hormone environment

Survivors of childhood cancer are at risk for long-term treatment-induced health sequelae, including gonadotoxicity and iatrogenic infertility. At present, for prepubertal boys there are no viable clinical options to preserve future reproductive potential. We investigated the effect of a pubertal induction regimen with gonadotrophins on prepubertal human testis xenograft development. Human testis tissue was obtained from patients with cancer and non-malignant haematological disorders (n = 6; aged 1–14 years) who underwent testis tissue cryopreservation for fertility preservation. Fresh and frozen-thawed testis fragments were transplanted subcutaneously or intratesticularly into immunocompromised mice. Graft-bearing mice received injections of vehicle or exogenous gonadotrophins, human chorionic gonadotrophin (hCG, 20 IU), and follicle-stimulating hormone (FSH, 12.5 IU) three times a week for 12 weeks. The gross morphology of vehicle and gonadotrophin-exposed grafts was similar for both transplantation sites. Exposure of prepubertal human testis tissue xenografts to exogenous gonadotrophins resulted in limited endocrine function of grafts, as demonstrated by the occasional expression of the steroidogenic cholesterol side-chain cleavage enzyme (CYP11A1). Plasma testosterone concentrations (0.13 vs. 0.25 ng/mL; p = 0.594) and seminal vesicle weights (10.02 vs. 13.93 mg; p = 0.431) in gonadotrophin-exposed recipient mice were comparable to vehicle-exposed controls. Regardless of the transplantation site and treatment, initiation and maintenance of androgen receptor (AR) expression were observed in Sertoli cells, indicating commitment towards a more differentiated status. However, neither exogenous gonadotrophins (in castrated host mice) nor endogenous testosterone (in intact host mice) were sufficient to repress the expression of markers associated with immature Sertoli cells, such as anti-Müllerian hormone (AMH) and Ki67, or to induce the redistribution of junctional proteins (connexin 43, CX43; claudin 11, CLDN11) to areas adjacent to the basement membrane. Spermatogonia did not progress developmentally but remained the most advanced germ cell type in testis xenografts. Overall, these findings demonstrate that exogenous gonadotrophins promote partial activation and maturation of the somatic environment in prepubertal testis xenografts. However, alternative hormone regimens or additional factors for pubertal induction are required to complete the functional maturation of the spermatogonial stem cell (SSC) niche

EXPERIENCES OF DRUG USERS IN IIA CLASS JAIL YOGYAKARTA

United Nations Office on Drugs and Crime (UNODC) estimated that about 149-272 million people or 3.3 % - 6.1 % of world population aged 15-64 years used drugs (even once) during their life time. This estimation will increase with time (BNN, 2011). The number of prisoners suffering HIV/AIDS in recent years were increasing as well if compared to its numbers in the year 2011 from 787 people to 1042 people. It was estimated that in the year 2015, the number of drug users in Indonesia would increase to 5.8 million people, since the number of drug users at the present time were reached 4 million people. For the time being, in Yogyakarta second A class drug jail , the number of drug users were 256 people; this number were constant; its mean that if there was prisoner got his / her freedom, another prisoner was incoming. Data from BNN in August 2013 years, 70% of 4 million drug users in Indonesia were workers (productive aged). Aim; To discovered population research experiences that cause them used drugs and depend on its. Research method: This was qualitative research with phenomenological approach. Data gathering technique were deep interview and FGD toward 30 respondents. Data were analyzed using reduction, data display, and conclusion drawing/verification. The majority of respondents mentioned that they used drugs because of they wanted to know and the influence of friends. Drugs, kinds of sabu, used to increase energy and ganja were used to obtain peacefulness. Drugs users wanted to use its forever; therefore, they wanted to stop because of punishment to be in jail not because of the drugs had negative effects to the body. The majority of respondents mentioned that to stop using drugs must be self motivated; on the contrary, the obstacle to stop using drugs because of missing sensation to use it. They named it suggest. Using drugs were conducted by research population because of environmental influence, to increase energy and to obtain peacefulness. Keywords : The experiences of drug use

Rapid access clinic for unexplained lymphadenopathy and suspected malignancy: prospective analysis of 1000 patients.

Background:In patients presenting with peripheral lymphadenopathy, it is critical to effectively identify those with underlying cancer who require urgent specialist care. Methods:We analyzed a large dataset of 1000 consecutive patients with unexplained lymphadenopathy referred between 2001 and 2009 to the Royal Marsden Hospital (RMH) rapid access lymph node diagnostic clinic (LNDC). Results:Cancer was diagnosed in 14% of patients. Factors predictive for malignant disease were male sex, age, supraclavicular and multiple site involvement. Cancer-associated symptoms were present for a median of 8 weeks. The median time from referral to start of cancer therapy was 53 days. Fine needle aspiration (FNA) was performed in 83% of patients with malignancies. Sensitivity and specificity of FNA were limited (50 and 87%, respectively for any malignancy; 30 and 79%, respectively for lymphoma). The vast majority of cancer patients received diagnostic biopsies on the basis of suspicious clinical and ultrasound findings; the FNA result contributed to establishing the diagnosis in only 4 cases. Conclusions:In conclusion, we demonstrate that Oncologist-led rapid access clinics are successful concepts to assess patients with unexplained lymphadenopathy. Our data suggest that a routine use of FNA should be reconsidered in this setting

Brain signal variability as a window into the bidirectionality between music and language processing: moving from a linear to a nonlinear model

There is convincing empirical evidence for bidirectional transfer between music and language, such that experience in either domain can improve mental processes required by the other. This music-language relationship has been studied using linear models (e.g., comparing mean neural activity) that conceptualize brain activity as a static entity. The linear approach limits how we can understand the brain’s processing of music and language because the brain is a nonlinear system. Furthermore, there is evidence that the networks supporting music and language processing interact in a nonlinear manner. We therefore posit that the neural processing and transfer between the domains of language and music are best viewed through the lens of a nonlinear framework. Nonlinear analysis of neurophysiological activity may yield new insight into the commonalities, differences, and bidirectionality between these two cognitive domains not measurable in the local output of a cortical patch. We thus propose a novel application of brain signal variability (BSV) analysis, based on mutual information and signal entropy, to better understand the bidirectionality of music-to-language transfer in the context of a nonlinear framework. This approach will extend current methods by offering a nuanced, network-level understanding of the brain complexity involved in music-language transfer

Pitch expertise is not created equal: Cross-domain effects of musicianship and tone language experience on neural and behavioural discrimination of speech and music

Psychophysiological evidence supports a music-language association, such that experience in one domain can impact processing required in the other domain. We investigated the bidirectionality of this association by measuring event-related potentials (ERPs) in native English-speaking musicians, native tone language (Cantonese) nonmusicians, and native English-speaking nonmusician controls. We tested the degree to which pitch expertise stemming from musicianship or tone language experience similarly enhances the neural encoding of auditory information necessary for speech and music processing. Early cortical discriminatory processing for music and speech sounds was characterized using the mismatch negativity (MMN). Stimuli included \u27large deviant\u27 and \u27small deviant\u27 pairs of sounds that differed minimally in pitch (fundamental frequency, F0; contrastive musical tones) or timbre (first formant, F1; contrastive speech vowels). Behavioural F0 and F1 difference limen tasks probed listeners\u27 perceptual acuity for these same acoustic features. Musicians and Cantonese speakers performed comparably in pitch discrimination; only musicians showed an additional advantage on timbre discrimination performance and an enhanced MMN responses to both music and speech. Cantonese language experience was not associated with enhancements on neural measures, despite enhanced behavioural pitch acuity. These data suggest that while both musicianship and tone language experience enhance some aspects of auditory acuity (behavioural pitch discrimination), musicianship confers farther-reaching enhancements to auditory function, tuning both pitch and timbre-related brain processes