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Staple diets that are deficient in thiamine can result in low body thiamine levels, which may be subclinical or may manifest as a thiamine-deficiency syndrome. In many communities in the developing countries of Africa, the staple diets of polished rice or processed cassava are deficient in thiamine, and thus the communities are at high risk for marginal or frank thiamine deficiency unless their diets are supplemented by other sources of thiamine, such as protein meals and vegetables. African communities with large numbers of individuals in low socioeconomic strata are more likely to subsist on a monotonous diet of rice or cassava with minimal or no protein supplementation and are therefore particularly at risk of thiamine-deficiency disorders. Indeed, there is evidence of widespread biochemical thiamine deficiency from community-based studies in Africa. The protean manifestations of thiamine deficiency disorders in the developing countries of Africa are presented in this paper. We present evidence supporting the contention that there is a diagnosis and treatment gap for thiamine-deficiency disorders in Africa. We discuss research and clinical options for bridging the putative diagnosis and treatment gap for thiamine-deficiency disorders in the developing countries of Africa. [ABSTRACT FROM AUTHOR]

This review documents the remarkable progress systemic lupus erythematosus (SLE) has made in the past 40 years especially in Asia. It provides a kaleidoscope in terms of prevalence, ethnic and regional variations, disease manifestation, treatment strategies, and outcome. From a seminal paper on the use of intravenous cyclophosphamide in 1964 from Singapore to the use of mycophenolate mofetil in 2000 from Hong Kong and Guangzhou, the prognosis of lupus has changed dramatically in the last few decades. With more targeted therapies and better translational research, this progress is set to continue in the coming years. From an acute fulminating illness, lupus has now evolved to one with a chronic, relapsing course. The main causes of morbidity and mortality are now either treatment-related or patient-related rather than the disease itself. The present time is one of unprecedented growth of new therapeutic approaches and reevaluation of past treatment modalities. With improving socioeconomic conditions in the region, we anticipate further rapid progress in disease outcome. Although living with the wolf is still an ordeal for our patients, optimism has now replaced nihilism in the lupus world. There is light at the end of the tunnel. [ABSTRACT FROM AUTHOR]

The aim of this article is to present an overview of some contemporary ideas concerning the status of music therapy research in Ibero-American countries, with a focus on assessment and clinical evaluation of music therapy clinical practice. [ABSTRACT FROM AUTHOR]

Recent years have witnessed a dramatic increase in publications implicating free radicals and oxidative stress in virtually every aspect of biology and medicine, Redox Neurology may be defined as the study of the roles of free radicals, transition metals, oxidative stress, and antioxidant defenses in diseases of the nervous system. In this position paper, an argument is presented for recognition of this field as an emerging subspecialty within medical neurology. A program for postresidency fellowship training in Redox Neurology that integrates laboratory experience with specialized clinical practice is proposed, Opportunities for research and teaching careers in the redox neurosciences are outlined. The paper concludes with a forecast of several research themes likely to preoccupy this nascent discipline in the days ahead. [ABSTRACT FROM AUTHOR]

There has been an upsurge of multidisciplinary research since the adoption of a standardized definition of osteonecrosis of the jaw (ONJ) and the first bisphosphenate-related ONJ conference in 2007 held at the New York Academy of Sciences. This series of papers revisits topics presented at the conference in addition to covering recent advances in the history, mechanisms, clinical management, and prevention of bisphosphonate-related ONJ. [ABSTRACT FROM AUTHOR]

Over the last 20 years, the Nestl'e Research Center in Switzerland and the International Center for Diarrhoeal Diseases Research in Bangladesh have explored the efficacy of alternative biological agents for the treatment of diarrheal diseases. This paper reviews the work of this collaborative effort, particularly on Escherichia coli phage therapy (PT), and discusses the development of the project, starting with the isolation of T4-like coliphages from the stool of diarrhea patients, their pilot plant amplification and purification, and the constitution and testing of a cocktail of T4-like phages in mice. A series of phase I clinical trials has demonstrated the safety of PT. Oral phage given without protection survived gastric passage and was recovered in the feces. Oral T4 phage cocktail was then tested in parallel to a commercial phage product in a phase II randomized, placebo-controlled single-center trial in Bangladeshi children hospitalized with acute E. coli diarrhea. It was found that oral phage did not perform better than the current standard of care by oral rehydration/zinc treatment. Furthermore, fecal E. coli pathogen titers were low and mixed infections were found to be frequent. Microbiota analysis showed a correlation between diarrhea and increased levels of Streptococcus, which raises fundamental questions on the causative agent of diarrhea that may explain PT clinical failure. [ABSTRACT FROM AUTHOR]

Fecal microbiota transplantation (FMT) is an emerging therapeutic option for Clostridium difficile infections that are refractory to conventional treatment. FMT introduces fecal microbes into the patient's intestine that prevent the recurrence of C. difficile, leading to rapid expansion of bacteria characteristic of healthy microbiota. However, the long-termeffects of FMT remain largely unknown. The C. difficile patient described in this paper revealed protracted microbiota adaptation processes from 6 to 42 months post-FMT. Ultimately, bacterial communities were donor similar, suggesting sustainable stool engraftment. Since little is known about the consequences of transmitted viruses during C. difficile infection, we also interrogated virome changes. Our approach allowed identification of about 10 phage types per sample that represented larger viral communities, and phages were found to be equally abundant in the cured patient and donor. The healthy microbiota appears to be characterized by low phage abundance. Although viruses were likely transferred, the patient established a virome distinct from the donor. Surprisingly, the patient had sequences of algal giant viruses (chloroviruses) that have not previously been reported for the human gut. Chloroviruses have not been associated with intestinal disease, but their presence in the oropharynx may influence cognitive abilities. The findings suggest that the virome is an important indicator of health or disease. A better understanding of the role of viruses in the gut ecosystem may uncover novel microbiota-modulating therapeutic strategies. [ABSTRACT FROM AUTHOR]

The majority of hematopoietic stem cells (HSCs) are maintained in a quiescent state to minimize premature exhaustion induced by various stresses. However, quiescent HSCs are vulnerable to mutagenesis because of attenuated DNA repair and DNA damage response programs. Basal abundant expression of prosurvival BCL-2 proteins further endows HSCs with high resistance to apoptosis. In contrast, HSCs elicit strong activation of p53 upon DNA damage, resulting in enhanced activation of proapoptotic BCL-2 signals through p53. ASPP1, an apoptosis-stimulating protein of p53, is highly expressed in HSCs and preserves HSC pool integrity via selective induction of apoptosis. In this paper, we discuss the role of p53 and mitochondrial apoptosis in HSC regulation and introduce the current understanding of how p53 activity is regulated to achieve a good balance between maintaining the HSC pool and preventing hematological malignancies. [ABSTRACT FROM AUTHOR]

Bipolar disorders are common psychiatric disorders that affect 1-5% of the population worldwide. Major advances in the epidemiology, pathophysiology, and treatment of the disorders have recently occurred. The majority of published reports, however, originate from theWestern hemisphere, mostly Europe and the United States. There is a shortage of data from the Arab world on bipolar disorders. In an era of globalization and rapid communication, it is not clear to what extent research findings pertaining to one part of the world are by necessity applicable to other parts. Psychiatric disorders are known to be affected by the culture in which they occur, and knowledge of variations in illness presentation in different ethnic groups is also increasing. However, knowledge of variations affecting Arab populations remains quite limited. This paper provides a critical review of the literature on bipolar affective disorders in the Arab world, pointing to major gaps in knowledge and future opportunities to fill these gaps. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments forMDDprimarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant inMDD.We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with theNIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants. [ABSTRACT FROM AUTHOR]

Over the last few decades, neuroimaging techniques have advanced the identification of structural, functional, and neurochemical brain abnormalities that are associated with the increased risk, clinical course, and treatment outcomes of major depressive disorder (MDD). This paper reviews specific neuroimaging abnormalities that, on the basis of early studies, may discriminate between MDD patients who do or do not respond to current therapeutic modalities, such as antidepressants, cognitive behavioral therapy, or novel therapies. Differences in gray matter volume, white matter coherence, brain activity via structural and functional magnetic resonance imaging techniques, and concentrations of specific brain metabolites (as measured with magnetic resonance spectroscopy), are potential biomarkers discussed in this review. Given the heterogeneity of MDD, larger, multisite studies with increased statistical power will be needed to identify more precise imaging biomarkers of treatment response in MDD. [ABSTRACT FROM AUTHOR]

Meniere's disease is a poorly understood, disabling syndrome causing spells of vertigo, hearing fluctuation, tinnitus, and aural fullness. In this paper, we present a review of the histopathology, cytochemistry, and imaging of Meniere's disease. Histopathology is significant for neuroepithelial damage with hair cell loss, basement membrane thickening, and perivascular microvascular damage. Cytochemical alterations are significant for altered AQP4 and AQP6 expression in the supporting cell, and altered cochlin and mitochondrial protein expression. Current developments include imaging techniques to determine the degree and presence of endolymphatic hydrops, and future studies will endeavor to correlate the observance of hydrops with clinical findings. [ABSTRACT FROM AUTHOR]

Wilson's disease is an autosomal recessively inherited copper overload disorder that leads to hepatic and/or neurologic symptoms. More than a century after the first description of Wilson's disease, the available medical treatment options have not been standardized. The efficacy of the commonly used drugs is satisfactory for hepatic disease, but disappointing in the neurologic patients, including the risk of neurologic deterioration after the initiation of chelation therapy. An approach to overcome this problem is the careful and systematic assessment of biochemical response patterns and the quantitative monitoring of symptoms using validated rating scales. Standardized dosage strategies that address changes in copper pools might improve adherence and reduce side effects. Such an approach may reduce long-term morbidity. In this paper, we discuss considerations for an effective medical treatment and requirements for future studies in Wilson's disease. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) are being employed in clinical trials to facilitate engraftment and to treat steroid-resistant acute graft-versus-host disease after hematopoietic stem cell transplantation, as well as to repair tissue damage in inflammatory/degenerative disorders, in particular, in inflammatory bowel diseases (IBDs). When entering the clinical arena, a few potential risks of MSC therapy have to be taken into account: (i) immunogenicity of the cells, (ii) biosafety of medium components, (iii) risk of ectopic tissue formation, and (iv) potential in vitro transformation of the cells during expansion. This paper analyzes the main risks connected with the use of MSCs in cellular therapy approaches, and reports on some of the most intriguing findings on the use of MSCs in the context of regenerative medicine. Experimental studies in animal models and phase I/II clinical trials on the use of MSCs for the treatment of IBDs and other inflammatory/degenerative conditions are reviewed. [ABSTRACT FROM AUTHOR]

In music therapy for nonfluent aphasia patients who have difficulty producing meaningful words, phrases, and sentences, various benefits of singing have been identified: strengthened breathing and vocal ability, improved articulation and prosody of speech, and increased verbal and nonverbal communicative behaviors. This paper will introduce these various techniques used in clinical music therapy, and summarize findings based on our recent study to illustrate the strength of different techniques emphasizing rhythm, pitch, memory, and vocal/oral motor components dealing with different symptoms. The efficacy of each component is enhanced or diminished by the choice of music and the way it is interactively delivered. This indicates that neural mechanisms underlying speech improvement vary greatly with available acoustic and social cues in aphasic brain. [ABSTRACT FROM AUTHOR]

The 21st century will see improvements in the quality of human life. The development of new therapeutic technologies will prevent prevalent diseases and enable recovery from currently incurable diseases. The development of cell and tissue replacement therapies using stem cells and their progenitors will accelerate the development of causative treatments. The effort expended thus far in developing cell therapies has revealed many technical limitations. Thus, we must explore conceptual changes in the feasibility of stem cell therapy. This paper introduces the current limitations to stem cell engineering and ways to overcome these limitations, which will provide new insight into their clinical application. [ABSTRACT FROM AUTHOR]

The paper highlights the role of different HLA class II molecules in hepatic and lymphoproliferative HCV-related disorders. HLA molecules have been reviewed, according to an in silico cluster classification, based on the sequence, the biochemical structure of the pockets, and the functional characteristics of the HLA II molecules. Thus, by reducing the complexity of HLA II polymorphism, charateristics that unite different HLA molecules with specific HCV-associated pathologies may be recognized with greater case. Results show that HLA clusters associated with better dlimination of the virus are protective against HCC development, while the same clusters are associated with a higher risk of developing cryoglobulinemic syndrome and the concomitant NHL. These data added further acknowledgements on pathogenetic mechanisms associated with HCV infection. Results also highlight differences of NHL occurring in HCV-positive subjects, with or without a concomitant type II autoimmune cryoglobulinemic syndrome, suggesting that cryoglobulinemic background associated with NHL should be considered in the evaluation of the effectiveness of new therapies in the course of HCV-associated NHLs. [ABSTRACT FROM AUTHOR]

Aminoguanidine (AG), a prototype therapeutic dicarbonyl scavenger, is the most potent drug available today to inhibit the formation of advanced glycation endproducts (AGEs) and to reverse glycation-mediated damage in normal aging. This paper examines the ability of AG to cause damage to supercoiled plasmid DNA in the presence of the transition metal, Fe+3. Damage to DNA was dependent on the concentrations of both the transition metal and AG. We could detect hydroxyl radical as well as hydrogen peroxide during the incubation of AG with Fe+3. Thus this finding further cautions against the indiscriminate use of AG in clinical prophylaxis in diabetes and questions its use as a therapeutic agent. [ABSTRACT FROM AUTHOR]

To maximize the safety and efficacy of human hormone replacement therapy, it is suggested that exact molecular copies of human hormones ("bio-identical" hormones) be administered in physiologic quantities and proportions, following physiologic timing and routes of administration. It is also suggested that physicians return to the practice of monitoring hormone therapy by precise laboratory measurement levels of the hormones administered. This paper also presents clinical and laboratory data concerning appropriate proportions of bio-identical estrogens, the physiologic and supraphysiologic nature of commonly employed doses, estrogen levels achieved by varying routes of administration, and the significant effects of iodine on estrogen metabolism and cobalt on estrogen excretion. [ABSTRACT FROM AUTHOR]

Simple diagnostic or therapeutic procedures can produce tremendous benefits for dizzy patients. To see how new ideas in the laboratory evolve into benefits for patients, an attempt to analyze how the corresponding information is distributed was made. To quantify that flow of information, a number of new scientific publications, citation numbers, and a number of new books on relevant subjects were looked at. For vertigo, this approach was facilitated by the fact that the diagnostic procedures for benign paroxysmal positioning vertigo (BPPV) and for canal paresis can be traced back to seminal publications. Results indicate that the current way of disseminating new information used here is working well, and that new ideas on diagnosis and treatment are readily available to practitioners. However, the application of new methods is limited by the availability of the required technology. It is conjectured that the technological requirements have become more complex over time, leading to a slower uptake of new technology. [ABSTRACT FROM AUTHOR]

To test the hypothesis that relaxin is an important factor supporting implantation, two approaches have been carried out using a human-relevant animal model, the marmoset monkey. First, uterine mRNA transcription and protein expression during the implantation phase in the conceptive and nonconceptive cycles were examined. Second, functional parameters were analyzed to assess the in vivo effects of exogenous applied relaxin throughout implantation. Relaxin and its receptor, RXFP1, were highly upregulated shortly before and during the physical process of implantation, indicating that relaxin is an important factor for remodeling and immunotolerance. The action of relaxin on the uterus was accompanied by an increase of estrogen-associated factors and macrophage infiltration, suggesting redundant systems necessary for successful implantation. The data from relaxin-treated animals supported those obtained from naive tissues in terms of increases in angiogenesis as well as earlier and faster growth of the uterus and placenta in the relaxin-treated marmoset monkey group, resulting in parturition 7–10 days earlier than the control group, but not pathological. In general, relaxin is very effective in preparing the endometrium for implantation. These findings should encourage further clinical research regarding introducing relaxin for pathological pregnancies, such as early pregnancy failure or insufficient placenta. [ABSTRACT FROM AUTHOR]

The introduction of acid inhibition in clinical practice has revolutionized the management of acid‐related diseases, leading to the virtual abolition of elective surgery for ulcer disease and relegating antireflux surgery to patients with gastroesophageal reflux disease (GERD) not adequately managed by medical therapy. Proton pump inhibitors (PPIs) are the antisecretory drugs of choice for the treatment of reflux disease. However, these drugs still leave some unmet clinical needs in GERD. PPI‐refractoriness is common, and persistent symptoms are observed in up to 40–55% of daily PPI users. Potassium‐competitive acid blockers (P‐CABs) clearly overcome many of the drawbacks and limitations of PPIs, achieving rapid, potent, and prolonged acid suppression, offering the opportunity to address many of the unmet needs. In recent years, it has been increasingly recognized that impaired mucosal integrity is involved in the pathogenesis of GERD. As a consequence, esophageal mucosal protection has emerged as a new, promising therapeutic avenue. When P‐CABS are used as add‐on medications to standard treatment, a growing body of evidence suggests a significant additional benefit, especially in the relief of symptoms not responding to PPI therapy. On the contrary, reflux inhibitors are considered a promise unfulfilled, and prokinetic agents should only be used on a case‐by‐case basis. [ABSTRACT FROM AUTHOR]

Coordination between the nervous and innate immune systems to maintain bone homeostasis is largely uncharacterized. The present study investigated the sensory–immune interaction in resting alveolar bone and healing socket by surgical sensory denervation. Bone histomorphometry and immunohistochemistry showed that sensory denervation resulted in moderate suppression of bone remodeling, with a proinflammatory milieu manifested by increased neutrophil recruitment and possible alternations in macrophage phenotypes along the resting bone surface. This denervation effect intensified when bone remodeling was triggered by tooth extraction, as revealed by disrupted temporospatial variations in macrophage subpopulations and neutrophil infiltration, which were closely associated with a dramatic decline in socket bone filling and residual ridge height. Antagonism of calcitonin gene‐related peptide (CGRP) brought about similar antianabolic and proinflammatory effects as sensory denervation, suggesting that sensory nerves may monitor the bony milieu by CGRP. Depletion of macrophages, rather than neutrophils, ruled out CGRP effects, illustrating that macrophages were the primary immune mechanism that linked sensory innervation, innate immunity, and bone. The data support that sensory innervation is required for control of innate immune responses and maintenance of bone homeostasis. Sensory neuropeptides, such as CGRP, are a possible target for the development of proanabolic treatments in bone disease by modulating innate immune responses. [ABSTRACT FROM AUTHOR]

Abstract: Pregnancy places acute demands on maternal physiology, including profound changes in glucose homeostasis. Gestation is characterized by an increase in insulin resistance, counterbalanced by an adaptive increase in pancreatic β cell production of insulin. Failure of normal adaptive responses of the islet to increased maternal and fetal demands manifests as gestational diabetes mellitus (GDM). The gestational changes and rapid reversal of islet adaptations following parturition are at least partly driven by an anticipatory program rather than post‐factum compensatory adaptations. Here, I provide a comprehensive review of the cellular and molecular mechanisms underlying normal islet adaptation during pregnancy and how dysregulation may lead to GDM. Emerging areas of interest and understudied areas worthy of closer examination in the future are highlighted. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) is a highly neurotoxic gas. Acute exposure can lead to neurological sequelae among survivors. A drug for treating neurological sequelae in survivors of acute H2S intoxication is needed. Using a novel mouse model we evaluated the efficacy of cobinamide (Cob) for increasing survival of, and reducing neurological sequalae in, mice exposed to sublethal doses of H2S. There were two objectives: (1) to determine the dose-response efficacy of Cob and (2) to determine the effective therapeutic time window of Cob. To explore objective 1, mice were injected intramuscularly with Cob at 0, 50, or 100 mg/kg at 2 min after H2S exposure. For objective 2, mice were injected intramuscularly with 100 mg/kg Cob at 2, 15, and 30 min after H2S exposure. For both objectives, mice were exposed to 765 ppm of H2S gas. Cob significantly reduced H2S-induced lethality in a dose-dependent manner ( P < 0.05). Cob-treated mice exhibited significantly fewer seizures and knockdowns compared with the H2S-exposed group. Cob also reversed H2S-induced weight loss, behavioral deficits, neurochemical changes, cytochrome c oxidase enzyme inhibition, and neurodegeneration in a dose- and time-dependent manner ( P < 0.01). Overall, these findings show that Cob increases survival and is neuroprotective in a mouse model of H2S-induced neurological sequelae. [ABSTRACT FROM AUTHOR]

Prodrugs of resveratrol are under development. Among the long-term goals, still largely elusive, are (1) modulating physical properties (e.g., water-soluble derivatives bearing polyethylene glycol chains), (2) changing distribution in the body (e.g., galactosyl derivatives restricted to the intestinal lumen), (3) increasing absorption from the gastrointestinal tract (e.g., derivatives imitating the natural substrates of endogenous transporters), and (4) hindering phase II metabolism (e.g., temporarily blocking the hydroxyls), all contributing to (5) increasing bioavailability. The chemical bonds that have been tested for functionalization include carboxyester, acetal, and carbamate groups. A second approach, which can be combined with the first, seeks to reinforce or modify the biochemical activities of resveratrol by concentrating the compound at specific subcellular sites. An example is provided by mitochondria-targeted derivatives. These proved to be pro-oxidant and cytotoxic in vitro, selectively killing fast-growing and tumor cells when supplied in the low micromolar range. This suggests the possibility of anticancer applications. [ABSTRACT FROM AUTHOR]

Resveratrol is probably the most investigated plant secondary metabolite ever. An epidemiological study known as the French paradox showed a correlation between red wine intake and low mortality due to coronary heart diseases, and the red wine substance resveratrol was claimed to play a key role. Since then, several hundred resveratrol studies have been conducted to demonstrate its antioxidant and other beneficial properties. In the foodomics era, considering a complex foodome including over 25,000 substances that make up the human diet, it appears to be outdated to pursue the hunt for biological activities one function/compound at a time. First, nature is multivariate, and the effect of any one molecule will have to be modulated by its carrying matrix, its bioavailability, and synergies with other molecules. Second, a large number of targeted studies have the tendency to become biased, as they tend to retain only the data that the researchers think are relevant and thus increase the chances of spurious correlations. In this concise review, we retrace the research toward a more inductive, holistic, and multivariate path. [ABSTRACT FROM AUTHOR]

Cancer, a growing health problem worldwide, affects millions of people every year. The overall survival rates of most cancers have been prolonged owing to the efforts of clinicians and scientists. However, some tumors develop resistance to chemoradiotherapeutic agents, and the cancer research community continues to search for effective sensitizers. Resveratrol, a natural polyphenolic phytoalexin, has shown promising effects in inhibiting proliferation and cancer progression in several tumor models. However, its molecular mechanisms and applications in chemotherapy and radiotherapy have yet to be fully determined. In this concise review, we highlight the role and related molecular mechanisms of resveratrol in cancer treatment. In particular, we focus on the role of resveratrol in the tumor microenvironment and the sensitization of cancer cells for chemotherapy and radiotherapy. Resveratrol shows promising efficacies in cancer treatment and may be applied in clinical therapy, but it requires further clinical study. [ABSTRACT FROM AUTHOR]

Replacement of the esophagus in children can be performed in cases of malformations, injuries, or acquired conditions. The new esophagus should allow normal oral feeding, with little or no gastroesophageal reflux, and be able to work well for the lifetime of the patient. For over a century, many substitutes have been used, such as segments of colon, the entire stomach, gastric tubes, or parts of the small bowel, but none are perfect or function like a normal esophagus. Esophageal replacements are demanding challenges for pediatric surgeons. Here, I review the different techniques and the pitfalls related to these procedures on the basis of our experience of more than 300 esophageal replacements in children performed since 1989. [ABSTRACT FROM AUTHOR]

Achalasia is an esophageal motility disorder associated with abnormalities in peristalsis and lower esophageal sphincter (LES) relaxation. The etiology of the disease remains elusive. It is often misdiagnosed initially as gastroesophageal reflux disease. Patients with achalasia often complain of dysphagia to solids and liquids but may focus on regurgitation as the primary symptom, leading to the early misdiagnosis. Chest pain, weight loss, and occasional vomiting may be additional symptoms encountered in those with achalasia. The disease may be suspected on the basis of clinical presentation, but diagnosis depends on classic findings using high-resolution manometry, showing either failed or simultaneous contractions with associated normal or high LES pressures with no or incomplete relaxation with swallows. There are no cures for achalasia, and, in most patients, treatments have to be repeated over time. Definitive treatment options in achalasia include pneumatic dilation, surgical myotomy, and the new technique of per-oral endoscopic myotomy. Botulinum toxin (Botox) or other medical therapies are often reserved for those who cannot have definitive therapies owing to comorbid conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The term 'Esophagiome' is meant to imply a holistic, multiscale treatment of esophageal function from cellular and muscle physiology to the mechanical responses that transport and mix fluid contents. The development and application of multiscale mathematical models of esophageal function are central to the Esophagiome concept. These model elements underlie the development of a 'virtual esophagus' modeling framework to characterize and analyze function and disease by quantitatively contrasting normal and pathophysiological function. Functional models incorporate anatomical details with sensory-motor properties and functional responses, especially related to biomechanical functions, such as bolus transport and gastrointestinal fluid mixing. This brief review provides insight into Esophagiome research. Future advanced models can provide predictive evaluations of the therapeutic consequences of surgical and endoscopic treatments and will aim to facilitate clinical diagnostics and treatment. [ABSTRACT FROM AUTHOR]

The 21st century offers new advances in diagnostic procedures and protocols in the management of esophageal diseases. This review highlights the most recent advances in esophageal diagnostic technologies, including clinical applications of novel endoscopic devices, such as ultrathin endoscopy and confocal laser endomicroscopy for diagnosis and management of Barrett's esophagus; novel parameters and protocols in high-resolution esophageal manometry for the identification and better classification of motility abnormalities; innovative connections between esophageal motility disorder diagnosis and detection of gastroesophageal reflux disease (GERD); impedance-pH testing for detecting the various GERD phenotypes; performance of distensibility testing for better pathophysiological knowledge of the esophagus and other gastrointestinal abnormalities; and a modern view of positron emission tomography scanning in metastatic disease detection in the era of accountability as a model for examining other new technologies. We now have better tools than ever for the detection of esophageal diseases and disorders, and emerging data are helping to define how well these tools change management and provide value to clinicians. This review features novel insights from multidisciplinary perspectives, including both surgical and medical perspectives, into these new tools, and it offers guidance on the use of novel technologies in clinical practice and future directions for research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine (vitamin B1). Throughout the last century, research showed that thiamine deficiency is associated with neurological problems, including cognitive deficits and encephalopathy. Multiple similarities exist between classical thiamine deficiency and Alzheimer's disease (AD) in that both are associated with cognitive deficits and reductions in brain glucose metabolism. Thiamine-dependent enzymes are critical components of glucose metabolism that are reduced in the brains of AD patients and by thiamine decline, and a decrease in their levels could account for the reduction in glucose metabolism. In preclinical models, reduced thiamine can drive AD-like abnormalities, including memory deficits, neuritic plaques, and hyperphosphorylation of tau. Furthermore, excess thiamine diminishes AD-like pathologies. In addition to dietary deficits, drugs or other manipulations that interfere with thiamine absorption can cause thiamine deficiency. Elucidating the reasons why the brains of AD patients are functionally thiamine deficient and determining the effects of thiamine restoration may provide critical information to help treat patients with AD. [ABSTRACT FROM AUTHOR]

All psychiatric disorders have suffered from a dearth of truly novel pharmacological interventions. In bipolar disorder, lithium remains a mainstay of treatment, six decades since its effects were serendipitously discovered. The lack of progress reflects several factors, including ignorance of the disorder's pathophysiology and the complexities of the clinical phenotype. After reviewing the current status, we discuss some ways forward. First, we highlight the need for a richer characterization of the clinical profile, facilitated by novel devices and new forms of data capture and analysis; such data are already promoting a reevaluation of the phenotype, with an emphasis on mood instability rather than on discrete clinical episodes. Second, experimental medicine can provide early indications of target engagement and therapeutic response, reducing the time, cost, and risk involved in evaluating potential mood stabilizers. Third, genomic data can inform target identification and validation, such as the increasing evidence for involvement of calcium channel genes in bipolar disorder. Finally, new methods and models relevant to bipolar disorder, including stem cells and genetically modified mice, are being used to study key pathways and drug effects. A combination of these approaches has real potential to break the impasse and deliver genuinely new treatments. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a B cell malignancy resulting in osteolytic lesions and fractures. In the disease state, bone healing is limited owing to increased osteoclastic and decreased osteoblastic activity, as well as an MM-induced forward-feedback cycle where bone-embedded growth factors further enhance tumor progression as bone is resorbed. Recent work on somatic mutation in MM tumors has provided insight into cytogenetic changes associated with this disease; the initiating driver mutations causing MM are diverse because of the complexity and multitude of mutations inherent in MM tumor cells. This manuscript provides an overview of MM pathogenesis by summarizing cytogenic changes related to oncogenes and tumor suppressors associated with MM, reviewing risk factors, and describing the disease progression from monoclonal gammopathy of undetermined significance to overt MM. It also highlights the importance of the bone marrow microenvironment (BMM) in the establishment and progression of MM, as well as associated MM-induced bone disease, and the relationship of the bone marrow to current and future therapeutics. This review highlights why understanding the basic biology of the healthy and diseased BMM is crucial in the quest for better treatments and work toward a cure for genetically diverse diseases such as MM. [ABSTRACT FROM AUTHOR]

Resveratrol (RSV) is a naturally occurring plant polyphenol that has potential to attenuate osteoporosis with distinct pathologies. This review evaluates preclinical evidence regarding the efficacy and safety of RSV as a therapeutic bone agent using different rat models. Limitations of these animal models are discussed, and suggestions for strengthening the experimental design of future studies are provided. The ovariectomized rat model of postmenopausal osteoporosis reported that RSV supplementation attenuated estrogen deficiency-induced bone loss and trabecular structural deterioration. RSV safety was indicated by the absence of stimulation of estrogen-sensitive tissue. Providing RSV to rats aged >6 months attenuated age-related bone mass loss and structural deterioration but produced inconsistent effects on bones in rats aged <6 months. The hindlimb-suspension rat model of disuse osteoporosis reported that RSV attenuated bone loss in old rats, but higher doses and longer duration supplementation before mechanical loading were required for younger rats. Limitations common to studies using rat models of osteoporosis include requirements to include animals that are skeletally mature, longer study durations, and to adjust for potential confounding effects due to altered body weight and endocrine function. Strengthening experimental design can contribute to translation of animal results to clinically relevant recommendations for humans. [ABSTRACT FROM AUTHOR]

Resveratrol is an ingredient widely researched, with growing evidence of health-promoting effects. However, the reactions of supplement or food consumers to resveratrol has not been researched, and the ingredient is yet unknown to most consumers. We used respective literature and our own resveratrol consumer studies with Danish and U.S. consumers to look at current findings and future research directions for three questions. (1) Which factors determine consumer interest in a yet unknown functional ingredient such as resveratrol? (2) How should resveratrol be marketed as a new functional ingredient to be understood and favorably perceived? (3) What could be the effects of adoption of an ingredient such as resveratrol on the healthy lifestyle of a consumer? Literature and first results indicate that personal relevance and familiarity are crucial factors; however, consumers show little interest in resveratrol and lack relevant knowledge, especially in Denmark. Favorable attitudes were explained by health outcome expectations, use of complementary and alternative medicine, and interest in the indulgence dimension of food. Nonscientifically phrased communication led to more favorable attitudes in Danish consumers; scientifically phrased communication, though, made U.S. consumers more likely to retain favorable attitudes in the presence of contradictory evidence. We discuss future research directions in different cultural backgrounds and market contexts and for different foods. [ABSTRACT FROM AUTHOR]

Chemoprevention of human cancer(s) is a viable option for cancer control, especially when chemopreventive intervention is involved during the early stages of the carcinogenesis process. Naturally occurring bioactive food components, such as dietary polyphenols, have shown good antioxidant activity and other beneficial activities. In addition, compounds belonging to the polyphenolic chemical class may play promising roles in cancer prevention. Among them, the phytoalexin resveratrol has demonstrated antiproliferative effects, as well as the ability to inhibit initiation and promotion of induced cancer progression in a wide variety of tumor models. However, resveratrol, like other natural polyphenols, is an extremely photosensitive compound with low chemical stability and limited bioavailibility, which limit the therapeutic application of its beneficial effects. In this context, the development of innovative formulation strategies able to overcome physicochemical and pharmacokinetic limitations of this compound could be beneficial. This may be achieved via nanotechnology approaches utilizing suitable carriers that allow slow, sustained, and controlled release of the encapsulated agent. This review focuses on the recent developments of novel nanoformulations used to deliver sustained levels of resveratrol. [ABSTRACT FROM AUTHOR]

Lifestyle, particularly diet, is a risk factor for prostate cancer. Dietary polyphenols such as resveratrol possess anticancer properties and therefore have chemopreventive and therapeutic potential. Resveratrol has pleiotropic effects, exerting its biological activity through multiple pathways and targets, including those associated with cancer. Numerous studies have demonstrated the anticancer effects of resveratrol and, to a lesser extent, its analogs, in tissue culture, while in vivo observations are limited. Here, we provide a concise summary of our results on epigenetic mechanisms of resveratrol and analogs mediated through regulation of chromatin modifier metastasis-associated protein 1 (MTA1) and microRNAs (miRNAs), and highlight the anticancer effects of these compounds in preclinical models of prostate cancer. We suggest that the identified stilbene responsive mechanism-based biomarkers, such as MTA1 and oncogenic miRNAs, may become indicative of treatment efficacy in prostate cancer. Resveratrol analogs with better bioavailability, conferring superior pharmacological potencies and greater anticancer effects, may become stronger candidates for clinical development. [ABSTRACT FROM AUTHOR]

This review presents recent evidence implicating microRNAs (miRNAs) in the beneficial effects of resveratrol (trihydroxystilbene), a nonflavonoid plant polyphenol, with emphasis on its anti-inflammatory effects. Many diseases and pathologies have been linked, directly or indirectly, to inflammation. These include infections, injuries, atherosclerosis, diabetes mellitus, obesity, cancer, osteoarthritis, age-related macular degeneration, demyelination, and neurodegenerative diseases. Resveratrol can both decrease the secretion of proinflammatory cytokines (e.g., IL-6, IL-8, and TNF-α) and increase the production of anti-inflammatory cytokines; it also decreases the expression of adhesion proteins (e.g., ICAM-1) and leukocyte chemoattractants (e.g., MCP-1). Resveratrol's primary targets appear to be the transcription factors AP-1 and NF-κB, as well as the gene COX2. Although no mechanistic link between any particular miRNA and resveratrol has been identified, resveratrol effects depend at least in part upon the modification of the expression of a variety of miRNAs that can be anti-inflammatory (e.g., miR-663), proinflammatory (e.g., miR-155), tumor suppressing (e.g., miR-663), or oncogenic (e.g., miR-21). [ABSTRACT FROM AUTHOR]

To enhance their water solubility and pharmacological activities, the stilbenes resveratrol, pterostilbene, and piceatannol were glycosylated to their monoglucosides (β-glucosides) and diglycosides (β-maltosides) by cultured cells and cyclodextrin glucanotransferase (CGTase). Cultured cells of Phytolacca americana and glucosyltransferase ( PaGT) were capable of glucosylation of resveratrol to its 3- and 4′-β-glucosides. Pterostilbene was slightly transformed into its 4′-β-glucoside by P. americana cells. Piceatannol was readily converted into piceatannol 4′-β-glucoside, with the highest yield among the three substrates. The 3- and 4′-β-glucosides of resveratrol were subjected to further glycosylation by CGTase to give 3- and 4′-β-maltoside derivatives. The inhibitory action of resveratrol and pterostilbene toward histamine release induced with compound 48/80 from rat peritoneal mast cells was improved by β-glucosylation and/or β-maltosylation (i.e., the inhibitory activity for histamine release of the 3- and 4′-β-glucosides of resveratrol, the 3- and 4′-β-maltosides of resveratrol, and the 4′-β-glucoside of pterostilbene was higher than that of the corresponding aglycones, resveratrol and pterostilbene, respectively). In addition, the phosphodiesterase (PDE) inhibitory activity of resveratrol and pterostilbene was enhanced by β-glucosylation and/or β-maltosylation (i.e., the PDE inhibitory activities of the 3- and 4′-β-glucosides of resveratrol, the 4′-β-maltoside of resveratrol, and the 4′-β-glucoside of pterostilbene were higher than those of the corresponding aglycones, resveratrol and pterostilbene, respectively). [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PCa), which is now the fourth most frequent cause of cancer-related death, has a median survival of less than 6 months and a 5-year survival rate of <6%. The hallmarks of this cancer include poor outcome, short survival duration, and resistance to therapy. The poor prognosis of PCa is related to its local recurrence, lymph node and liver metastases, and peritoneal dissemination. Recent studies have indicated that resveratrol has cancer-chemopreventive and anticancer activities. In this short review we summarize the chemopreventive and treatment effects of resveratrol in PCa, as follows: resveratrol inhibits the proliferation of pancreatic cancer cells; induces apoptosis and cell cycle arrest; inhibits metastasis and invasion of PCa cells; inhibits the proliferation and viability of PCa stem cells; enhances the chemoradiosensitization of PCa cells; and can affect diabetes mellitus in addition to PCa. On the basis of these data, resveratrol may be considered a potential anticancer agent for the treatment of PCa. [ABSTRACT FROM AUTHOR]

Cognitive impairment in late-life depression is prevalent, disabling, and heterogeneous. Although mild cognitive impairment in depression does not usually progress to dementia, accurate assessment of cognition is vital to prognosis and treatment planning. For example, executive dysfunction often accompanies late-life depression, influences performance across cognitive domains, and is associated with poor antidepressant treatment outcomes. Here, we review howassessment can capture dysfunction across cognitive domains and discuss cognitive trajectories frequently observed in late-life depression in the context of the neurobiology of this disorder. We also review the efficacy of a sample of interventions tailored to specific cognitive profiles. [ABSTRACT FROM AUTHOR]

Neuroscience has made tremendous progress delineating the cellular and molecular processes important for understanding neuronal development and behavior, but this knowledge has been slow to translate to new treatments for psychiatric illness. To accelerate this transfer of knowledge to the human condition requires the wide-scale adoption of biomarkers that can bridge preclinical and clinical discoveries, and serve as surrogate measures of efficacy before commencing expensive phase III studies. Several biomarker methodologies, including imaging, electroencephalography (EEG), and blood transcriptomics/proteomics, are now showing promise. From an industry perspective, we highlight the utility of quantitative EEG as one example of a translatable biomarker applicable to psychiatric drug development and discuss recent insights into glutamate system dysfunction in schizophrenia and depression gained through translational studies of the drug ketamine. [ABSTRACT FROM AUTHOR]

Depression is a heterogeneous disorder and, similar to other spectrum disorders, its manifestation varies by age of onset, severity, comorbidity, treatment responsiveness, and other factors. A laboratory blood test based on specific biomarkers for major depressive disorder (MDD) and its subgroups could increase diagnostic accuracy and expedite the initiation of treatment. We identified candidate blood biomarkers by examining genome-wide expression differences in the blood of animal models representing both the genetic and environmental/stress etiologies of depression. Human orthologs of the resulting transcript panel were tested in pilot studies. Transcript abundance of 11 blood markers differentiated adolescent subjects with early-onset MDD from adolescents with no disorder (ND). A set of partly overlapping transcripts distinguished adolescent patients who had comorbid anxiety disorders from those with only MDD. In adults, blood levels of nine transcripts discerned subjects with MDD from ND controls. Even though cognitive behavioral therapy (CBT) resulted in remission of some patients, the levels of three transcripts consistently signaled prior MDD status. A coexpression network of transcripts seems to predict responsiveness to CBT. Thus, our approach can be developed into clinically valid diagnostic panels of blood transcripts for different manifestations of MDD, potentially reducing diagnostic heterogeneity and advancing individualized treatment strategies. [ABSTRACT FROM AUTHOR]

There are currently eight groups of drugs for the pharmacotherapy of vertigo, nystagmus, and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications; antidepressants, anticonvulsants, aminopyridines, and acetyl- dl-leucine ('the eight A's'). In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but there is not sufficient current evidence for a general recommendation. There is also insufficient evidence that 48 or 144 mg/day betahistine has an effect in Ménière's disease. Therefore, higher dosages are currently recommended; in animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one yet not randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There are so far no RCTs on vestibular migraine, so currently no treatment can be recommended. Acetyl- dl-leucine improves cerebellar ataxia (three observational studies); it also accelerates central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl- dl-leucine (ALCAT). [ABSTRACT FROM AUTHOR]

Mal de Debarquement Syndrome (MdDS) is an enigmatic neurotological disorder with high morbidity, psychosocial burden, and few treatment options. Fortunately, there has been recent growth in scientific interest in understanding the biological basis of and in treating MdDS. Recent studies using functional neuroimaging have shown increased glucose metabolism in the left entorhinal cortex (EC) and amygdala in the setting of decreased prefrontal and temporal cortex metabolism in subjects with persistent MdDS. The EC is a key player in processing and gating spatial information to be stored in the hippocampus and is a major driver of brain oscillations. A limbic focus may also be key to spontaneous MdDS-like symptoms occurring in individuals with a history of anxiety or chronic stress. Treatment with repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex can decrease the rocking dizziness of MdDS, with successful responses associated with decreases in the coherence between brain networks with nodes in the parietal and occipital lobes. A new theory of MdDS is proposed as pathology secondary to entrainment of intrinsic brain networks driven by oscillatory motion exposure coupled with an inability to subsequently desynchronize the activity of these nodes. Future treatment strategies may be directed toward unyoking these networks. [ABSTRACT FROM AUTHOR]