Inhibition of adenylyl cyclase 1 (AC1) and exchange protein directly activated by cAMP (EPAC) restores ATP-sensitive potassium (K) channel activity after chronic opioid exposure.

Prolonged exposure to Gαi/o receptor agonists such as opioids can lead to a sensitization of adenylyl cyclases (ACs), resulting in heterologous sensitization or cyclic AMP (cAMP) overshoot. The molecular consequences of cAMP overshoot are not well understood, but this adaptive response is suggested to play a critical role in the development of opioid tolerance and withdrawal. We found that genetic reduction of AC1 and simultaneous upregulation of ATP-sensitive potassium (K) channel subunits, SUR1 or Kir6.

Pharmacologically enabling the degradation of Na V 1.8 channels to reduce neuropathic pain.

In phase II clinical trials, Na V 1.8 channels were identified as viable targets to treat acute pain. Results were modest, however, and Na V 1.

Loss of ATP-Sensitive Potassium Channel Expression and Function in the Nervous System Decreases Opioid Sensitivity in a High-Fat Diet-Fed Mouse Model of Diet-Induced Obesity.

During diabetes progression, β-cell dysfunction due to loss of potassium channels sensitive to ATP, known as KATP channels, occurs, contributing to hyperglycemia. The aim of this study was to investigate if KATP channel expression or activity in the nervous system was altered in a high-fat diet (HFD)-fed mouse model of diet-induced obesity. Expression of two KATP channel subunits, Kcnj11 (Kir6.

Comparing the prognostic performance of iBOX and biopsy-proven acute rejection for long-term kidney graft survival.

Biopsy-proven acute rejection (BPAR) occurs in approximately 10% of kidney transplant recipients in the first year, making superiority trials unfeasible. iBOX, a quantitative composite of estimated glomerular filtration rate, proteinuria, antihuman leukocyte antigen donor-specific antibody, and + full/- abbreviated kidney histopathology, is a new proposed surrogate endpoint. BPAR's prognostic ability was compared with iBOX in a pooled cohort of 1534 kidney transplant recipients from 4 data sets, including 2 prospective randomized controlled trials.

The Banff 2022 Kidney Meeting Work Plan: Data-driven refinement of the Banff Classification for renal allografts.

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized.

Applying propensity methods to the United States transplant registry for external real-world evidence control arms for 5-year survival in the BENEFIT study.

To address the challenges of assessing the impact of a reasonably likely surrogate endpoint on long-term graft survival in prospective kidney transplant clinical trials, the Transplant Therapeutics Consortium established a real-world evidence workgroup evaluating the scientific value of using transplant registry data as an external control to supplement the internal control group. The United Network for Organ Sharing retrospectively simulated the use of several distinct contemporaneous external control groups, applied multiple cause inference methods, and compared treatment effects to those observed in the BENEFIT study. Applying BENEFIT study enrollment criteria produced a smaller historical cyclosporine control arm (n = 153) and a larger, alternative (tacrolimus) historical control arm (n = 1069).

Qualifying a novel clinical trial endpoint (iBOX) predictive of long-term kidney transplant outcomes.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials.

Loss of ATP-sensitive channel expression and function decreases opioid sensitivity in a mouse model of type 2 diabetes.

During diabetes, β-cell dysfunction due to loss of potassium channels sensitive to ATP, known as K channels occurs progressively over time contributing to hyperglycemia. K channels are additionally present in the central and peripheral nervous systems and are downstream targets of opioid receptor signaling. The aim of this study is to investigate if K channel expression or activity in the nervous system changes in diabetic mice and if morphine antinociception changes in mice fed a high fat diet (HFD) for 16 weeks compared to controls.

K Channel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine-Induced Hypersensitivity, and Precipitated Withdrawal in Mice.

Previous studies show ATP-sensitive potassium (K) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of K channels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociceptive activity of novel K channel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP.

Reduced activity of adenylyl cyclase 1 attenuates morphine induced hyperalgesia and inflammatory pain in mice.

Opioid tolerance, opioid-induced hyperalgesia during repeated opioid administration, and chronic pain are associated with upregulation of adenylyl cyclase activity. The objective of this study was to test the hypothesis that a reduction in adenylyl cyclase 1 (AC1) activity or expression would attenuate morphine tolerance and hypersensitivity, and inflammatory pain using murine models. To investigate opioid tolerance and opioid-induced hyperalgesia, mice were subjected to twice daily treatments of saline or morphine using either a static (15 mg/kg, 5 days) or an escalating tolerance paradigm (10-40 mg/kg, 4 days).

DYSPHAGIA OCCURRENCE IN COVID-19-POSITIVE PATIENTS IN TWO HOSPITALS IN BRAZIL.

Background: COVID-19 comprises a respiratory infection resulting from contamination by SARS-CoV-2, with acute respiratory failure being one of its main characteristics, leading to a high frequency of orotracheal intubation (OTI), which in turn increases the risk for dysphagia. Since this can lead to pulmonary impairment, knowing the real occurrence of dysphagia in part of the Brazilian population and its associations allows early and effective clinical management of the multidisciplinary team in relation to patients.

Objective: To verify the occurrence of dysphagia in COVID-19-positive adult patients in two Brazilian reference hospitals in the care of the pandemic.

Loss of SUR1 subtype K channels alters antinociception and locomotor activity after opioid administration.

Opioid signaling can occur through several downstream mediators and influence analgesia as well as reward mechanisms in the nervous system. K channels are downstream targets of the μ opioid receptor and contribute to morphine-induced antinociception. The aim of the present work was to assess the role of SUR1-subtype K channels in antinociception and hyperlocomotion of synthetic and semi-synthetic opioids.

Pruriception and neuronal coding in nociceptor subtypes in human and nonhuman primates.

In humans, intradermal administration of β-alanine (ALA) and bovine adrenal medulla peptide 8-22 (BAM8-22) evokes the sensation of itch. Currently, it is unknown which human dorsal root ganglion (DRG) neurons express the receptors of these pruritogens, MRGPRD and MRGPRX1, respectively, and which cutaneous afferents these pruritogens activate in primate. In situ hybridization studies revealed that MRGPRD and MRGPRX1 are co-expressed in a subpopulation of TRPV1+ human DRG neurons.

The Relationship Between Trauma Exposure and Adult Tobacco Use: Analysis of the National Epidemiologic Survey on Alcohol and Related Conditions (III).

Introduction: Previous research has examined cigarette smoking in trauma exposed populations. However, the relationships between trauma exposure and use of other tobacco products (eg, cigars, e-cigarettes) and specific trauma exposure characteristics that may be associated with tobacco use are understudied.

Aims And Methods: Using the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (N = 36 151 adults), we conducted weighted bivariate analyses of tobacco use among participants with no trauma exposure, trauma exposure, and trauma exposure with post-traumatic stress disorder (trauma + PTSD), stratified by tobacco product use.

Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain.

Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance.

Morphine Efficacy, Tolerance, and Hypersensitivity Are Altered After Modulation of SUR1 Subtype K Channel Activity in Mice.

ATP-sensitive potassium (K) channels are found in the nervous system and are downstream targets of opioid receptors. K channel activity can effect morphine efficacy and may beneficial for relieving chronic pain in the peripheral and central nervous system. Unfortunately, the K channels exists as a heterooctomers, and the exact subtypes responsible for the contribution to chronic pain and opioid signaling in either dorsal root ganglia (DRG) or the spinal cord are yet unknown.

The orotrigeminal system.

The trigeminal sensory nerve fiber branches supply afferent information from the skin and mucous membranes of the face and head and the oral cavity regarding information on temperature, touch, and pain. Under normal conditions, the trigeminal nerve serves to provide important information from nerve fibers and tissues using specialized receptors sensitive for irritant and painful stimuli. The current scientific consensus indicates that nerve endings responsible for chemical and thermal sensitivity of the skin and mucous membranes are the same nerves responsible for nociception.

Smoke-free and tobacco-free colleges and universities in the United States.

Objective: To describe the number and proportion of accredited, degree-granting institutions with 100% smoke-free and 100% tobacco-free protections across the USA and by state.

Methods: Data on postsecondary education institutions from the US Department of Education National Center for Education Statistics Integrated Postsecondary Education Data System 2015, and smoke-free and tobacco-free campus protections from the American Nonsmokers' Rights Foundation's Smokefree and Tobacco-Free Colleges and Universities List 2017, were integrated to calculate the number and proportion of: (1) smoke-free and tobacco-free accredited, degree-granting institutions and (2) students and staff protected by campus policies and state laws. Campus protections are given a 100% smoke-free designation if smoking is not allowed on campus anywhere, at any time; 100% tobacco-free designations extend smoke-free protections to include non-combustible products such as smokeless tobacco.

Modulation of SUR1 K Channel Subunit Activity in the Peripheral Nervous System Reduces Mechanical Hyperalgesia after Nerve Injury in Mice.

The ATP-sensitive K channel (K) is involved in hypersensitivity during chronic pain and is presumed to be a downstream target of mu opioid receptors. Multiple subtypes of K channels exist in the peripheral and central nervous system and their activity may be inversely correlated to chronic pain phenotypes in rodents. In this study, we investigated the different K channel subunits that could be involved in neuropathic pain in mice.

Chemogenic Subqualities of Mouthfeel.

Mouthfeel refers to the physical or textural sensations in the mouth caused by foods and beverages that are essential to the acceptability of many edible products. The sensory subqualities contributing to mouthfeel are often chemogenic in nature and include heat, burning, cooling, tingling, and numbing. These "chemesthetic" sensations are a result of the chemical activation of receptors that are associated with nerve fibers mediating pain and mechanotransduction.

Demonstrating Higher Incidence of Advanced Breast Malignancies in Our Young Hispanic Population.

Historically, the Hispanic population in the United States has had a lower incidence of cancer than the matched non-Hispanic population, despite disparities in access to health care, screening, and prevention. Our experience in Austin, Texas, directly contradicts this. We have seen a disproportionate amount of young Hispanic patients with advanced malignancies, particularly of the breast.

Laboratory measures of coagulation among trauma patients on NOAs: results of the AAST-MIT.

Background: Warfarin is associated with poor outcomes after trauma, an effect correlated with elevations in the international normalized ratio (INR). In contrast, the novel oral anticoagulants (NOAs) have no validated laboratory measure to quantify coagulopathy. We sought to determine if use of NOAs was associated with elevated activated partial thromboplastin time (aPTT) or INR levels among trauma patients or increased clotting times on thromboelastography (TEG).