Ann N Y Acad Sci [journal]
- Normal and abnormal physiology, pharmacology, and anatomy of the gastroesophageal junction high-pressure zone. [JOURNAL ARTICLE]
- Ann N Y Acad Sci 2016 Jul 28.
The high-pressure zone of the gastroesophageal junction acts as a multifunctional valve that comprises different groups of smooth muscles located in the distal esophagus and the proximal stomach, in addition to the extrinsic crural diaphragm, composed of skeletal muscle. In this review article, we evaluate the current literature with respect to human subjects, discussing the anatomic locations and physiologic and pharmacologic processes controlling these muscles. These muscles work individually and as a group to prevent reflux of gastric contents while allowing anterograde passage of food and liquid and retrograde passage of gas. We also reviewed new findings with respect to abnormalities that are permissive of reflux of gastric contents into the esophagus, which may lead to gastroesophageal reflux disease.
- Eosinophilic esophagitis: current perspectives from diagnosis to management. [JOURNAL ARTICLE]
- Ann N Y Acad Sci 2016 Jul 28.
Eosinophilic esophagitis (EoE) is a chronic antigen-mediated immune disease of the esophagus characterized by symptoms related to esophageal dysfunction, as well as significant esophageal eosinophilia. Although dense eosinophilia is the hallmark of EoE, other characteristic histologic features have been described that may help distinguish EoE from other competing diagnoses, although none are specific to EoE. One or more foods and, at times, environmental allergens trigger EoE. Left untreated, esophageal inflammation in EoE may lead to esophageal remodeling and stricture formation. Symptoms in EoE vary with age, as they relate to the progression of the disease from an inflammatory to a fibrostenotic phenotype over time. There are currently no U.S. Food and Drug Administration-approved therapies for EoE. Current options include various dietary-restriction therapies, topical corticosteroids, and esophageal dilations. Several emerging therapies aiming at restoring the esophageal barrier function or targeting various inflammatory cells or their mediators are under investigation.
- Models to identify treatments for the acute and persistent effects of seizure-inducing chemical threat agents. [JOURNAL ARTICLE]
- Ann N Y Acad Sci 2016 Jul 28.
Exposures to seizure-inducing chemical threat agents are a major public health concern. Of particular need is improved treatment to terminate convulsions and to prevent the long-term neurological sequelae in survivors. We are studying the organophosphorus cholinesterase inhibitor diisopropyl fluorophosphate (DFP) and the GABA receptor inhibitor tetramethylenedisulfotetramine (TETS), which arguably encompass the mechanistic spectrum of seizure-inducing chemical threats, with the goal of identifying therapeutic approaches with broad-spectrum efficacy. Research efforts have focused on developing translational models and translational diagnostic approaches, including (1) in vivo models of DFP- and TETS-induced seizures for studying neuropathological mechanisms and identifying treatment approaches; (2) in vivo imaging modalities for noninvasive longitudinal monitoring of neurological damage and response to therapeutic candidates; and (3) higher-throughput in vitro platforms for rapid screening of compounds to identify potential antiseizure and neuroprotective agents, as well as mechanistically relevant novel drug targets. This review summarizes our progress toward realizing these goals and discusses best practices and mechanistic insights derived from our modeling efforts.
- The influence of tissue microenvironment on stem cell-based cartilage repair. [JOURNAL ARTICLE]
- Ann N Y Acad Sci 2016 Jul 27.
Mesenchymal stem/progenitor cells and induced pluripotent stem cells have become viable cell sources for prospective cell-based cartilage engineering and tissue repair. The development and function of stem cells are influenced by the tissue microenvironment. Specifically, the local tissue microenvironment can dictate how stem cells integrate into the existing tissue matrix and how successfully they can restore function to the damaged area in question. This review focuses on the microenvironmental features of articular cartilage and how they influence stem cell-based cartilage tissue repair. Also discussed are current tissue-engineering strategies used in combination with cell-based therapies, all of which are designed to mimic the natural properties of cartilage tissue in order to achieve a better healing response.
- Neurosteroids for the potential protection of humans against organophosphate toxicity. [JOURNAL ARTICLE]
- Ann N Y Acad Sci 2016 Jul 23.
This article describes the therapeutic potential of neurosteroids as anticonvulsant antidotes for chemical intoxication caused by organophosphate pesticides and nerve agents or gases like sarin and soman. Toxic manifestations following nerve agent exposure, as evident in chemical attacks in Japan and Syria, include hypersecretion, respiratory distress, tremors, convulsions leading to status epilepticus (SE), and death. Benzodiazepines, such as diazepam, are the current anticonvulsants of choice for controlling nerve agent-induced life-threatening seizures, SE, and brain injury. Benzodiazepines can control acute seizures when given early, but they are less effective for delayed treatment of SE, which is characterized by rapid desensitization of synaptic GABAA receptors, benzodiazepine resistance, and brain injury. Neurosteroid-sensitive extrasynaptic GABAA receptors, however, remain unaffected by such events. Thus, anticonvulsant neurosteroids may produce more effective protection than benzodiazepines against a broad spectrum of chemical agents, even when given late after nerve agent exposure.
- Cyanide and the human brain: perspectives from a model of food (cassava) poisoning. [JOURNAL ARTICLE]
- Ann N Y Acad Sci 2016 Jul 23.
Threats by fundamentalist leaders to use chemical weapons have resulted in renewed interest in cyanide toxicity. Relevant insights may be gained from studies on cyanide mass intoxication in populations relying on cyanogenic cassava as the main source of food. In these populations, sublethal concentrations (up to 80 μmol/l) of cyanide in the blood are commonplace and lead to signs of acute toxicity. Long-term toxicity signs include a distinct and irreversible spastic paralysis, known as konzo, and cognition deficits, mainly in sequential processing (visual-spatial analysis) domains. Toxic culprits include cyanide (mitochondrial toxicant), thiocyanate (AMPA-receptor chaotropic cyanide metabolite), cyanate (protein-carbamoylating cyanide metabolite), and 2-iminothiazolidine-4-carboxylic acid (seizure inducer). Factors of susceptibility include younger age, female gender, protein-deficient diet, and, possibly, the gut functional metagenome. The existence of uniquely exposed and neurologically affected populations offers invaluable research opportunities to develop a comprehensive understanding of cyanide toxicity and test or validate point-of-care diagnostic tools and treatment options to be included in preparedness kits in response to cyanide-related threats.
- Resting in darkness improves downbeat nystagmus: evidence from an observational study. [Journal Article]
- Ann N Y Acad Sci 2016 Jul; 1375(1):66-73.
Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real-world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post-resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three-dimensional video-oculography in brightness and darkness conditions, each following two 2-h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P < 0.01). The clinical relevance is to advise patients with DBN to rest in darkness.
- Deferoxamine ameliorates hepatosteatosis via several mechanisms in ob/ob mice. [Journal Article]
- Ann N Y Acad Sci 2016 Jul; 1375(1):52-65.
Hepatic iron accumulation may be responsible for the pathology of nonalcoholic fatty liver disease (NAFLD), which is both increasingly prevalent in conjunction with obesity and associated with comorbidities. The efficacy of iron reduction therapies, such as phlebotomy or dietary iron restriction, has been demonstrated in patient and animal models, including models of diabetes and obesity; however, the effects on and exact mechanisms responsible for iron depletion in NAFLD have not been clearly elucidated. Our study investigated the role of iron depletion by deferoxamine (DFO) treatment of ob/ob mice with hepatic steatosis. We found that DFO reduced hepatic iron deposition and regulated intracellular iron concentration in a homeostatic process following 15 days of treatment. Compared with vehicle treatment, DFO significantly improved hepatic steatosis by upregulating proteins related to lipid metabolism. Meanwhile, the reduction of free radical formation and proinflammatory cytokines, as well as the increase of hypoxia-inducible factor-1α pathway proteins and Bcl2/Bax ratio, further indicated that DFO was effective for liver protection and hepatic adaptation. These findings show that the intraperitoneal delivery of DFO provides a potential means of both preventing the progression of NAFLD and accelerating healing of hepatic steatosis, with the potential for rapid clinical application.
- Thrombopoietin induces hematopoiesis from mouse ES cells via HIF-1α-dependent activation of a BMP4 autoregulatory loop. [Journal Article]
- Ann N Y Acad Sci 2016 Jul; 1375(1):38-51.
Understanding the molecular mechanisms underlying hematopoietic differentiation of embryonic stem (ES) cells may help to ascertain the conditions for the in vitro generation of hematopoietic cells. Previously, we found that patients with congenital amegakaryocytic thrombocytopenia (CAMT), who develop pancytopenia early after birth, harbor mutations within the thrombopoietin (TPO) receptor, c-MPL. This knowledge, together with observations in vitro and in vivo, suggests that TPO/c-MPL signaling promotes early hematopoiesis. However, the mechanisms underlying TPO signaling are not fully elucidated. Here, we describe a direct connection between TPO and bone morphogenetic protein 4 (BMP4) signaling pathways in determining the hematopoietic fate of ES cells. Morphogen BMP4 is known to induce early hematopoietic differentiation of ES cells. Treatment of ES cells with TPO induced the autocrine production of BMP4 with concomitant upregulation of the BMP receptor BMPR1A, phosphorylation of SMAD1, 5, 8, and activation of specific BMP4 target genes; this was mediated by TPO-dependent binding of transcription factor HIF-1α to the BMP4 gene promoter. Treatment of ES cells with the BMP antagonist noggin substantially reduced TPO-dependent hematopoietic differentiation of ES cells. Thus, our findings contribute to the establishment of techniques for generating hematopoietic cells from ES cells.
- Musical cognition in Alzheimer's disease: application of the Montreal Battery of Evaluation of Amusia. [Journal Article]
- Ann N Y Acad Sci 2016 Jul; 1375(1):28-37.
The aim of this study was to assess certain musical abilities in 30 patients with Alzheimer's disease (AD) and 30 healthy controls by using the complete version of the Montreal Battery of Evaluation of Amusia (MBEA). This battery evaluates melodic (scale, contour, and interval) and temporal (rhythm and meter) perception of music and musical memory. We found that altered musical processing is a common feature in AD. Despite that, AD subjects show partially spared abilities for temporal organization of music, though not for melodic perception and musical memory. This peculiar dysfunctional pattern could depend on the neurodegenerative involvement of some specific areas for music perception and memory in the brains of AD patients. Further studies are needed to investigate the usefulness of additional musical tests like the MBEA on larger samples to confirm our preliminary data.