Plos One
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The etiology of chronic prostatitis/chronic pelvic pain syndrome in men is unknown but may involve microbes and autoimmune mechanisms. We developed an infection model of chronic pelvic pain in NOD/ShiLtJ (NOD) mice with a clinical Escherichia coli isolate (CP-1) from a patient with chronic pelvic pain. We investigated pain mechanisms in NOD mice and compared it to C57BL/6 (B6) mice, a strain resistant to CP-1-induced pain. ⋯ Adoptive transfer of ex-vivo expanded IFN-γ or IL-17A-expressing cells was sufficient to induce pelvic pain in naïve NOD recipients. Pelvic pain was not abolished in NOD-IFN-γ-KO mice but was associated with an enhanced IL-17A immune response to CP1 infection. These findings demonstrate a novel role for Th1 and Th17-mediated adaptive immune mechanisms in chronic pelvic pain.
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Striatal transplantation of dopaminergic (DA) neurons or neural stem cells (NSCs) has been reported to improve the symptoms of Parkinson's disease (PD), but the low rate of cell survival, differentiation, and integration in the host brain limits the therapeutic efficacy. We investigated the therapeutic effects of intracranial co-transplantation of mesencephalic NSCs stably overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs) together with fetal DA neurons in the 6-OHDA rat model of PD. ⋯ In addition, survival and differentiation of mNSCs into DA neurons was significantly greater following co-transplantation of GDNF-mNSCs plus fetal DA neurons compared to the other treatment groups as indicated by the greater number of cell expressing both the mNSCs lineage tracer enhanced green fluorescent protein (eGFP) and the DA neuron marker tyrosine hydroxylase. The success of cell-based therapies for PD may be greatly improved by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress trophic factors such as GDNF that support differentiation into DA cells and their survival in vivo.
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Abuse of prescription opioid analgesics is a serious threat to public health, resulting in rising numbers of overdose deaths and admissions to emergency departments and treatment facilities. Absent adequate patient information systems, "doctor shopping" patients can obtain multiple opioid prescriptions for nonmedical use from different unknowing physicians. Our study estimates the prevalence of doctor shopping in the US and the amounts and types of opioids involved. ⋯ Our data did not provide information to make a clinical diagnosis of individuals. Very few of these patients can be classified with certainty as diverting drugs for nonmedical purposes. However, even patients with legitimate medical need for opioids who use large numbers of prescribers may signal dangerously uncoordinated care. To close the information gap that makes doctor shopping and uncoordinated care possible, states have created prescription drug monitoring programs to collect records of scheduled drugs dispensed, but the majority of physicians do not access this information. To facilitate use by busy practitioners, most monitoring programs should improve access and response time, scan prescription data to flag suspicious purchasing patterns and alert physicians and pharmacists. Physicians could also prevent doctor shopping by adopting procedures to screen new patients for their risk of abuse and to monitor patients' adherence to prescribed treatments.
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The discovery that paracetamol is metabolized to the potent TRPV1 activator N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) and that this metabolite contributes to paracetamol's antinociceptive effect in rodents via activation of TRPV1 in the central nervous system (CNS) has provided a potential strategy for developing novel analgesics. Here we validated this strategy by examining the metabolism and antinociceptive activity of the de-acetylated paracetamol metabolite 4-aminophenol and 4-hydroxy-3-methoxybenzylamine (HMBA), both of which may undergo a fatty acid amide hydrolase (FAAH)-dependent biotransformation to potent TRPV1 activators in the brain. Systemic administration of 4-aminophenol and HMBA led to a dose-dependent formation of AM404 plus N-(4-hydroxyphenyl)-9Z-octadecenamide (HPODA) and arvanil plus olvanil in the mouse brain, respectively. ⋯ In the rat, pharmacological inhibition of FAAH, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors, and chemical deletion of bulbospinal serotonergic pathways prevented the antinociceptive action of 4-aminophenol. Thus, the pharmacological profile of 4-aminophenol was identical to that previously reported for paracetamol, supporting our suggestion that this drug metabolite contributes to paracetamol's analgesic activity via activation of bulbospinal pathways. Our findings demonstrate that it is possible to construct novel antinociceptive drugs based on fatty acid conjugation as a metabolic pathway for the generation of TRPV1 modulators in the CNS.
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People who have a disease often experience stigma, a socially and culturally embedded process through which individuals experience stereotyping, devaluation, and discrimination. Stigma has great impact on quality of life, behavior, and life chances. We do not know whether or not migraine is stigmatizing. ⋯ In our model, adjusted stigma was similar for chronic migraine and epilepsy, which were greater than for episodic migraine. Stigma correlated most strongly with inability to work, and was greater for chronic migraine than epilepsy or episodic migraine because chronic migraine patients had less ability to work.