Columnar Metaplasia of the Esophagus Presenting as Iron Deficiency Anemia in Children with Neurologic Impairment or Congenital Esophageal Atresia.

BACKGROUND Columnar metaplasia of the lower esophagus includes both gastric and intestinal metaplasia. Children with severe neurologic impairment and congenital esophageal atresia often have gastroesophageal reflux disease, which can lead to Barrett's esophagus, a form of lower esophageal columnar metaplasia and precursor to esophageal adenocarcinoma, with some, but not all, guidelines specifically requiring the presence of intestinal metaplasia for diagnosis. This case series illustrates how iron deficiency anemia may be the primary symptom of esophageal columnar metaplasia in such children and how upper endoscopy is essential in their initial and ongoing evaluation.

Delta opioid receptors in Nav1.8 expressing peripheral neurons partially regulate the effect of delta agonist in models of migraine and opioid-induced hyperalgesia.

Migraine is one of the most common pain disorders and causes disability in millions of people every year. Delta opioid receptors (DOR) have been identified as a novel therapeutic target for migraine and other headache disorders. DORs are present in both peripheral and central regions and it is unclear which receptor populations regulate migraine-associated effects.

Applications of Covariate Adjusted Nonparametric Methods to CCTRN Clinical Trials.

CCTRN is a Cardiovascular Cell Therapy Research Network. There were three randomized double blinded controlled stem cell clinical trials conducted in its first phase. The main results of these three clinical trials were published with conventional parametric models such as T test and nonparametric test such as Wilcoxon rank sum test without adjusting covariates.

A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial.

Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy.

Methods And Results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.

Delta opioid receptor regulation of calcitonin gene-related peptide dynamics in the trigeminal complex.

Migraine is highly prevalent and is the sixth leading cause worldwide for years lost to disability. Therapeutic options specifically targeting migraine are limited, and delta opioid receptor (DOP) agonists were recently identified as a promising pharmacotherapy. The mechanisms by which DOPs regulate migraine are currently unclear.

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial.

Background: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment.

Objectives: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC.

Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia.

Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders. DORs are broadly expressed in several peripheral and central regions important for pain processing and mood regulation; and it is unclear which receptors regulate headache associated symptoms. In a model of chronic migraine-associated pain using the human migraine trigger, nitroglycerin, we observed increased expression of DOR in cortex, hippocampus, and striatum; suggesting a role for these forebrain regions in the regulation of migraine.

Impaired therapeutic efficacy of bone marrow cells from post-myocardial infarction patients in the TIME and LateTIME clinical trials.

Implantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs.

Voluntary collective isolation as a best response to COVID-19 for indigenous populations? A case study and protocol from the Bolivian Amazon.

Indigenous communities worldwide share common features that make them especially vulnerable to the complications of and mortality from COVID-19. They also possess resilient attributes that can be leveraged to promote prevention efforts. How can indigenous communities best mitigate potential devastating effects of COVID-19? In Bolivia, where nearly half of all citizens claim indigenous origins, no specific guidelines have been outlined for indigenous communities inhabiting native communal territories.

Adaptive group-sequential design with population enrichment in phase 3 randomized controlled trials with two binary co-primary endpoints.

The use of co-primary endpoints in drug development allows investigators to capture an experimental intervention's multidimensional effect more comprehensively than a single primary endpoint. We propose the theoretical basis and development of an adaptive population enrichment design with co-primary endpoints, provide stage-wise boundary values for futility and efficacy, and discuss power under different efficacy configurations, subgroup prevalence, and analysis times using a pre-specified decision criterion. We considered a two-arm, two-stage, parallel group design where population enrichment occurs at the interim analysis by dropping any non-responsive subgroups.

Opioid-Induced Hyperalgesia Is Associated with Dysregulation of Circadian Rhythm and Adaptive Immune Pathways in the Mouse Trigeminal Ganglia and Nucleus Accumbens.

The benefits of opioid-based treatments to mitigate chronic pain can be hindered by the side effects of opioid-induced hyperalgesia (OIH) that can lead to higher consumption and risk of addiction. The present study advances the understanding of the molecular mechanisms associated with OIH by comparing mice presenting OIH symptoms in response to chronic morphine exposure (OIH treatment) relative to control mice (CON treatment). Using RNA-Seq profiles, gene networks were inferred in the trigeminal ganglia (TG), a central nervous system region associated with pain signaling, and in the nucleus accumbens (NAc), a region associated with reward dependency.

Plasma Urea Cycle Metabolites May Be Useful Biomarkers in Children With Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a disorder of the esophagus that has become increasingly recognized in children. Because these children undergo multiple endoscopies, discovering a non-invasive biomarker of disease activity is highly desirable. The aim of this study was to use targeted plasma metabolomics to identify potential biomarker candidates for EoE in a discovery phase.

Gene Network Dysregulation in the Trigeminal Ganglia and Nucleus Accumbens of a Model of Chronic Migraine-Associated Hyperalgesia.

The pharmacological agent nitroglycerin (NTG) elicits hyperalgesia and allodynia in mice. This model has been used to study the neurological disorder of trigeminovascular pain or migraine, a debilitating form of hyperalgesia. The present study validates hyperalgesia in an established mouse model of chronic migraine triggered by NTG and advances the understanding of the associated molecular mechanisms.

Delta opioid receptor agonists are effective for multiple types of headache disorders.

Headaches are highly disabling and are among the most common neurological disorders worldwide. Despite the high prevalence of headache, therapeutic options are limited. We recently identified the delta opioid receptor (DOR) as an emerging therapeutic target for migraine.

Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial.

Objectives: SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC).

Background: AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium.

The development of a mouse model of mTBI-induced post-traumatic migraine, and identification of the delta opioid receptor as a novel therapeutic target.

Background: Post-traumatic headache is the most common and long-lasting impairment observed following mild traumatic brain injury, and frequently has migraine-like characteristics. The mechanisms underlying progression from mild traumatic brain injury to post-traumatic headache are not fully understood. The aim of this study was to develop a mouse model of post-traumatic headache and identify mechanisms and novel targets associated with this disorder.

Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit Cardiac Stem Cells As Regenerative Therapy for Heart Failure).

Rationale: Autologous bone marrow mesenchymal stem cells (MSCs) and c-kit cardiac progenitor cells (CPCs) are 2 promising cell types being evaluated for patients with heart failure (HF) secondary to ischemic cardiomyopathy. No information is available in humans about the relative efficacy of MSCs and CPCs and whether their combination is more efficacious than either cell type alone.

Objective: CONCERT-HF (Combination of Mesenchymal and c-kit Cardiac Stem Cells As Regenerative Therapy for Heart Failure) is a phase II trial aimed at elucidating these issues by assessing the feasibility, safety, and efficacy of transendocardial administration of autologous MSCs and CPCs, alone and in combination, in patients with HF caused by chronic ischemic cardiomyopathy (coronary artery disease and old myocardial infarction).

Author Correction: Circulating Biomarkers to Identify Responders in Cardiac Cell therapy.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

TIME Trial: Effect of Timing of Stem Cell Delivery Following ST-Elevation Myocardial Infarction on the Recovery of Global and Regional Left Ventricular Function: Final 2-Year Analysis.

Rationale: The TIME trial (Timing in Myocardial Infarction Evaluation) was the first cell therapy trial sufficiently powered to determine if timing of cell delivery after ST-segment-elevation myocardial infarction affects recovery of left ventricular (LV) function.

Objective: To report the 2-year clinical and cardiac magnetic resonance imaging results and their modification by microvascular obstruction.

Methods And Results: TIME was a randomized, double-blind, placebo-controlled trial comparing 150 million bone marrow mononuclear cells versus placebo in 120 patients with anterior ST-segment-elevation myocardial infarctions resulting in LV dysfunction.

Soluble guanylyl cyclase is a critical regulator of migraine-associated pain.

Background Nitric oxide (NO) has been heavily implicated in migraine. Nitroglycerin is a prototypic NO-donor, and triggers migraine in humans. However, nitroglycerin also induces oxidative/nitrosative stress and is a source of peroxynitrite - factors previously linked with migraine etiology.

Animal Model of Chronic Migraine-Associated Pain.

Migraine is a debilitating condition that affects hundreds of millions of people worldwide. A subset of these patients experience chronic migraine, resulting in long-term disability and a severely lowered quality of life. The development of novel migraine therapies has been slow, partially due to the small number of predictive animal models.

Circulating Biomarkers to Identify Responders in Cardiac Cell therapy.

Bone marrow mononuclear cell (BM-MNC) therapy in ST-elevation acute myocardial infarction (STEMI) has no biological inclusion criteria. Here, we analyzed 63 biomarkers and cytokines in baseline plasma samples from 77 STEMI patients treated with BM-MNCs in the TIME and Late-TIME trials as well as 61 STEMI patients treated with placebo. Response to cell therapy was defined by changes in left ventricular ejection fraction, systolic/diastolic volumes, and wall motion indexes.

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells).

Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms.