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BioRxiv : the Preprint Server For... Feb 2024Placebo analgesia is a widely observed clinical phenomenon. Establishing a robust mouse model of placebo analgesia is needed for careful dissection of the underpinning...
Placebo analgesia is a widely observed clinical phenomenon. Establishing a robust mouse model of placebo analgesia is needed for careful dissection of the underpinning circuit mechanisms. However, previous studies failed to observe consistent placebo effects in rodent models of chronic pain. We wondered whether strong placebo analgesia can be reverse engineered using general anesthesia-activated neurons in the central amygdala (CeA ) that can potently suppress pain. Indeed, in both acute and chronic pain models, pairing a context with CeA -mediated pain relief produced robust context-dependent analgesia, exceeding that induced by morphine in the same paradigm. We reasoned that if the analgesic effect was dependent on reactivation of CeA neurons by conditioned contextual cues, the analgesia would still be an active treatment, rather than a placebo effect. CeA neurons indeed receive monosynaptic inputs from temporal lobe areas that could potentially relay contextual cues directly to CeA . However, in vivo imaging showed that CeA neurons were re-activated in the conditioned context, despite mice displaying a strong analgesic phenotype, supporting the notion that the cue-induced pain relief is true placebo analgesia. Our results show that conditioning with activation of a central pain-suppressing circuit is sufficient to engineer placebo analgesia, and that purposefully linking a context with an active treatment could be a means to harness the power of placebo for pain relief.
PubMed: 38405975
DOI: 10.1101/2024.02.12.579946 -
Advanced Drug Delivery Reviews Jul 2024
Topics: Humans; Fungi; Antifungal Agents; Theranostic Nanomedicine; Mycoses; Drug Delivery Systems
PubMed: 38782093
DOI: 10.1016/j.addr.2024.115343 -
Annual Review of Neuroscience Jul 2023Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are... (Review)
Review
Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are strongest in pain, indicating that psychosocial factors directly influence pain. In this review, I focus on the neural and psychological mechanisms by which instructions, learning, and expectations shape subjective pain. I address new experimental designs that help researchers tease apart the impact of these distinct processes and evaluate the evidence regarding the neural mechanisms by which these cognitive factors shape subjective pain. Studies reveal that expectations modulate pain through parallel circuits that include both pain-specific and domain-general circuits such as those involved in affect and learning. I then review how expectations, learning, and verbal instructions impact clinical outcomes, including placebo analgesia and responses to pharmacological treatments, and discuss implications for future work.
Topics: Humans; Motivation; Pain; Analgesia; Learning; Placebo Effect
PubMed: 36917820
DOI: 10.1146/annurev-neuro-101822-122427 -
Small (Weinheim An Der Bergstrasse,... Jun 2024Microneedles (MNs) have maintained their popularity in therapeutic and diagnostic medical applications throughout the past decade. MNs are originally designed to gently... (Review)
Review
Microneedles (MNs) have maintained their popularity in therapeutic and diagnostic medical applications throughout the past decade. MNs are originally designed to gently puncture the stratum corneum layer of the skin and have lately evolved into intelligent devices with functions including bodily fluid extraction, biosensing, and drug administration. MNs offer limited invasiveness, ease of application, and minimal discomfort. Initially manufactured solely from metals, MNs are now available in polymer-based varieties. MNs can be used to create systems that deliver drugs and chemicals uniformly, collect bodily fluids, and are stimulus-sensitive. Although these advancements are favorable in terms of biocompatibility and production costs, they are insufficient for the therapeutic use of MNs. This is the first comprehensive review that discusses individual MN functions toward the evolution and development of smart and multifunctional MNs for a variety of novel and impactful future applications. The study examines fabrication techniques, application purposes, and experimental details of MN constructs that perform multiple functions concurrently, including sensing, drug-molecule release, sampling, and remote communication capabilities. It is highly likely that in the near future, MN-based smart devices will be a useful and important component of standard medical practice for different applications.
Topics: Needles; Humans; Drug Delivery Systems; Animals; Theranostic Nanomedicine; Microinjections
PubMed: 38385813
DOI: 10.1002/smll.202308479 -
Luminescence : the Journal of... Jan 2024Specific biomarker-activatable probes have revolutionized theranostics, being beneficial for precision medicine. Hypoxia is a critical pathological characteristic... (Review)
Review
Specific biomarker-activatable probes have revolutionized theranostics, being beneficial for precision medicine. Hypoxia is a critical pathological characteristic prevalent in numerous major diseases such as cancers, cardiovascular disorders, inflammatory diseases, and acute ischemia. Aggregation-induced emission luminogens (AIEgens) have emerged as a promising tool to tackle the biomedical issues. Of particular significance are the hypoxia-responsive AIEgens, representing a kind of crucial probe capable of delicately sensing and responding to the hypoxic microenvironment, thereby enhancing the precision of disease diagnosis and treatment. In this review, we summarize the recent advances of hypoxia-responsive AIEgens for varied biomedical applications. The hypoxia-responsive structures based on AIEgens, such as azobenzene, nitrobenzene, and N-oxide are presented, which are in response to the reduction property to bring about significant alternations in response spectra and/or fluorescence intensity. The bioapplications including imaging and therapy of tumor and ischemia diseases are discussed. Moreover, the review sheds light on the future challenges and prospects in this field. This review aims to provide comprehensive guidance and understanding into the development of activatable bioprobes, especially the hypoxia-responsive AIEgens for improving the diagnosis and therapy outcome of related diseases.
Topics: Humans; Precision Medicine; Theranostic Nanomedicine; Neoplasms; Optical Imaging; Ischemia; Fluorescent Dyes; Tumor Microenvironment
PubMed: 38286609
DOI: 10.1002/bio.4659 -
JAMA Network Open Oct 2023Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer.
OBJECTIVE
To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK. A total of 755 patients were screened for inclusion; 484 did not meet the inclusion criteria, and 1 declined to participate. A total of 270 patients were randomly assigned to 4 groups (selenium plus placebo, vitamin E plus placebo, selenium plus vitamin E, and placebo plus placebo) in a double-blind fashion between July 17, 2007, and October 10, 2011. Eligibility included initial diagnosis of NMIBC (stages Ta, T1, or Tis); randomization within 12 months of first transurethral resection was required.
INTERVENTIONS
Oral selenium (200 μg/d of high-selenium yeast) and matched vitamin E placebo, vitamin E (200 IU/d of d-alfa-tocopherol) and matched selenium placebo, selenium and vitamin E, or placebo and placebo.
MAIN OUTCOME AND MEASURES
Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022).
RESULTS
The study randomized 270 patients (mean [SD] age, 68.9 [10.4] years; median [IQR] age, 69 [63-77] years; 202 male [75%]), with 65 receiving selenium and vitamin E placebo, 71 receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos. Median overall follow-up was 5.5 years (IQR, 5.1-6.1 years); 228 patients (84%) were followed up for more than 5 years. Median treatment duration was 1.5 years (IQR, 0.9-2.5 years). The study was halted because of slow accrual. For selenium (n = 134) vs no selenium (n = 136), there was no difference in RFI (hazard ratio, 0.92; 95% CI, 0.65-1.31; P = .65). For vitamin E (n = 140) vs no vitamin E (n = 130), there was a statistically significant detriment to RFI (hazard ratio, 1.46; 95% CI, 1.02-2.09; P = .04). No significant differences were observed for progression-free interval or overall survival time with either supplement. Results were unchanged after Cox proportional hazards regression modeling to adjust for known prognostic factors. In total, 1957 adverse events were reported; 85 were serious adverse events, and all were considered unrelated to trial treatment.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of selenium and vitamin E, selenium supplementation did not reduce the risk of recurrence in patients with NMIBC, but vitamin E supplementation was associated with an increased risk of recurrence. Neither selenium nor vitamin E influenced progression or overall survival. Vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required.
TRIAL REGISTRATION
isrctn.org Identifier: ISRCTN13889738.
Topics: Humans; Male; Aged; Vitamin E; Selenium; Non-Muscle Invasive Bladder Neoplasms; Prospective Studies; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms
PubMed: 37847504
DOI: 10.1001/jamanetworkopen.2023.37494 -
Clinical and Experimental Medicine Jan 2024Humanity is suffering from cancer which has become a root cause of untimely deaths of individuals around the globe in the recent past. Nanotheranostics integrates... (Review)
Review
Humanity is suffering from cancer which has become a root cause of untimely deaths of individuals around the globe in the recent past. Nanotheranostics integrates therapeutics and diagnostics to monitor treatment response and enhance drug efficacy and safety. We hereby propose to discuss all recent cancer imaging and diagnostic tools, the mechanism of targeting tumor cells, and current nanotheranostic platforms available for cancer. This review discusses various nanotheranostic agents and novel molecular imaging tools like MRI, CT, PET, SPEC, and PAT used for cancer diagnostics. Emphasis is given to gold nanoparticles, silica, liposomes, dendrimers, and metal-based agents. We also highlight the mechanism of targeting the tumor cells, and the limitations of different nanotheranostic agents in the field of research for cancer treatment. Due to the complexity in this area, multifunctional and hybrid nanoparticles functionalized with targeted moieties or anti-cancer drugs show the best feature for theranostics that enables them to work on carrying and delivering active materials to the desired area of the requirement for early detection and diagnosis. Non-invasive imaging techniques have a specificity of receptor binding and internalization processes of the nanosystems within the cancer cells. Nanotheranostics may provide the appropriate medicine at the appropriate dose to the appropriate patient at the appropriate time.
Topics: Humans; Drug Delivery Systems; Theranostic Nanomedicine; Gold; Metal Nanoparticles; Neoplasms
PubMed: 38240834
DOI: 10.1007/s10238-023-01262-3 -
Advanced Science (Weinheim,... Jun 2024Traumatic brain injuries (TBI) and stroke are major causes of morbidity and mortality in both developing and developed countries. The complex and heterogeneous...
Traumatic brain injuries (TBI) and stroke are major causes of morbidity and mortality in both developing and developed countries. The complex and heterogeneous pathophysiology of TBI and cerebral ischemia-reperfusion injury (CIRI), in addition to the blood-brain barrier (BBB) resistance, is a major barrier to the advancement of diagnostics and therapeutics. Clinical data showed that the severity of TBI and stroke is positively correlated with the number of neutrophils in peripheral blood and brain injury sites. Furthermore, neutrophil extracellular traps (NETs) released by neutrophils correlate with worse TBI and stroke outcomes by impairing revascularization and vascular remodeling. Therefore, targeting neutrophils to deliver NETs inhibitors to brain injury sites and reduce the formation of NETs can be an optimal strategy for TBI and stroke therapy. Herein, the study designs and synthesizes a reactive oxygen species (ROS)-responsive neutrophil-targeting delivery system loaded with peptidyl arginine deiminase 4 (PAD4) inhibitor, GSK484, to prevent the formation of NETs in brain injury sites, which significantly inhibited neuroinflammation and improved neurological deficits, and improved the survival rate of TBI and CIRI. This strategy may provide a groundwork for the development of targeted theranostics of TBI and stroke.
Topics: Extracellular Traps; Brain Injuries, Traumatic; Neutrophils; Animals; Mice; Disease Models, Animal; Stroke; Protein-Arginine Deiminase Type 4; Humans; Reactive Oxygen Species; Male; Theranostic Nanomedicine
PubMed: 38520727
DOI: 10.1002/advs.202308719 -
Inflammatory Bowel Diseases Apr 2024Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo endoscopic and histological response rates in Crohn's disease (CD) clinical trials.
METHODS
MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to April 2022 to identify placebo-controlled studies of pharmacological interventions for CD. Endoscopic response, remission, and mucosal healing rates for participants assigned to placebo in induction and maintenance studies were pooled using a random-effects model. Point estimates and associated 95% confidence intervals (CIs) were calculated.
RESULTS
In total, 16 studies (11 induction, 3 maintenance, 2 induction and maintenance) that randomized 1646 participants to placebo were eligible. For induction trials, the pooled placebo endoscopic response, endoscopic remission, and mucosal healing rates in participants assigned to placebo were 13% (95% CI, 10-16; I2 = 14.1%; P = .14), 6% (95% CI, 3-11; I2 = 74.7%; P < .001), and 6% (95% CI, 4-9; I2 = 26.9%; P = .29), respectively. The pooled endoscopic remission rate in patients who were bio-naïve was 10% (95% CI, 4-23) compared with only 4% (95% CI, 3-7) in bio-experienced patients. For maintenance trials, the pooled endoscopic response, remission, and mucosal healing rates were 7% (95% CI, 1-31; I2 = 78.2%; P = .004), 11% (95% CI, 4-27; I2 = 70.8%; P = .06), and 7% (95% CI, 3-15; I2 = 29.7; P = .23), respectively. Only 3 trials assessed histological outcomes.
CONCLUSIONS
Endoscopic placebo rates vary according to trial phase and prior biologic exposure. These contemporary data will serve to inform CD trial design, sample size calculation, and end point selection for future trials.
Topics: Humans; Crohn Disease; Endoscopy; Remission Induction; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 37002875
DOI: 10.1093/ibd/izad052 -
Experimental Neurology Jun 2024The intricate functional interactions between mitochondria and lysosomes play a pivotal role in maintaining cellular homeostasis and proper cellular functions. This... (Review)
Review
The intricate functional interactions between mitochondria and lysosomes play a pivotal role in maintaining cellular homeostasis and proper cellular functions. This dynamic interplay involves the exchange of molecules and signaling, impacting cellular metabolism, mitophagy, organellar dynamics, and cellular responses to stress. Dysregulation of these processes has been implicated in various neurodegenerative diseases. Additionally, mitochondrial-lysosomal crosstalk regulates the exosome release in neurons and glial cells. Under stress conditions, neurons and glial cells exhibit mitochondrial dysfunction and a fragmented network, which further leads to lysosomal dysfunction, thereby inhibiting autophagic flux and enhancing exosome release. This comprehensive review synthesizes current knowledge on mitochondrial regulation of cell death, organelle dynamics, and vesicle trafficking, emphasizing their significant contributions to neurodegenerative diseases. Furthermore, we explore the emerging field of nanomedicine in the management of neurodegenerative diseases. The review provides readers with an insightful overview of nano strategies that are currently advancing the mitochondrial-lysosome-extracellular vesicle axis as a therapeutic approach for mitigating neurodegenerative diseases.
Topics: Humans; Lysosomes; Extracellular Vesicles; Neurodegenerative Diseases; Mitochondria; Animals; Theranostic Nanomedicine
PubMed: 38508481
DOI: 10.1016/j.expneurol.2024.114757