Broad Spectrum Of Disorders Research Articles

Telomerase is essential for cardiac differentiation and sustained metabolism of human cardiomyocytes

Telomeres as the protective ends of linear chromosomes, are synthesized by the enzyme telomerase (TERT). Critically short telomeres essentially contribute to aging-related diseases and are associated with a broad spectrum of disorders known as telomeropathies. In cardiomyocytes, telomere length is strongly correlated with cardiomyopathies but it remains ambiguous whether short telomeres are the cause or the result of the disease. In this study, we employed an inducible CRISPRi human induced pluripotent stem cell (hiPSC) line to silence TERT expression enabling the generation of hiPSCs and hiPSC-derived cardiomyocytes with long and short telomeres. Reduced telomerase activity and shorter telomere lengths of hiPSCs induced global transcriptomic changes associated with cardiac developmental pathways. Consequently, the differentiation potential towards cardiomyocytes was strongly impaired and single cell RNA sequencing revealed a shift towards a more smooth muscle cell like identity in the cells with the shortest telomeres. Poor cardiomyocyte function and increased sensitivity to stress directly correlated with the extent of telomere shortening. Collectively our data demonstrates a TERT dependent cardiomyogenic differentiation defect, highlighting the CRISPRi TERT hiPSCs model as a powerful platform to study the mechanisms and consequences of short telomeres in the heart and also in the context of telomeropathies.

Antioxidant activity, total phenolic content, and total flavonoid content of potato milk – A novel functional beverage developed as an alternative to cow milk

The fundamental component of food functionality is antioxidant activity, which can scavenge and neutralize free radicals released by the body's biochemical system in response to toxic chemical exposure. The chemical composition of potato milk include 1 ± 0.087% total sugar, 0.3 ± 0.001% fat, 2.2 ± 0.0365% crude protein, 1.9 ± 0.234% dietary fiber, 0 ± 0.000% lactose, 1.031 ± 0.021 density, 92.66 ± 0.032% moisture, 7.34 ± 0.002% total milk solid, 7.04 ± 0.013% solid non fat. The sensory evaluation was carried out with a 7-point hedonic scale with 25 panelists, and the overall acceptability was 5.62 ± 1.54. Analysis of the antioxidant ability is vital to ascertain the functionality of the newly developed potato milk so that it can be employed as a biofunctional beverage. By using standard procedures, the following outcome was attained. The total phenolics present in the methanolic extract of potato milk were 620 ± 0.046 mM Gallic acid/ml at 500 µg/ml concentration. At 100 µg/ml, the total flavonoid content was 131.11 ± 0.046 mM Quercetin/ml, percentage inhibition in the ABTS assay was 88.6 ± 0.053%, according to DPPH activity was 86.16 ± 0.030%, the ferric-reducing antioxidant power was 205.2 ± 0.057 µM Fe (II)/ml, the CUPRAC of potato milk was found to be 203.67 ± 0.001 mM ascorbic acid/ml, the reducing power assay revealed a value of 132.55 ± 0.037 mM ascorbic acid/. At 250 µg/ml, the total antioxidant capacity was 289 ± 0.053 mM ascorbic acid/ml. Thus, the novel potato milk has significant antioxidant potential and may help to protect the body against a broad spectrum of disorders.

Characterization of a novel non-canonical splice site variant (c.886-5T>A) in NBAS and description of the associated phenotype.

Biallelic pathogenic variants in the neuroblastoma-amplified sequence (NBAS) gene manifest in a broad spectrum of disorders, including, but not limited to recurrent acute liver failure, skeletal dysmorphism, susceptibility to infections, and SOPH syndrome with its cardinal symptoms of short stature, optic atrophy, and Pelger-Huët anomaly. We aimed to present clinical and genetic characteristics of two sisters (20 and 15 years old) who were diagnosed with optic atrophy and cone dystrophy in childhood. Genome sequencing revealed two novel variants in NBAS in compound heterozygous state in both sisters, namely a 1-bp deletion predicted to result in a premature termination codon (c.5104del; p.(Met1702*)), and a non-canonical splice site variant of unclear significance (c.886-5T>A; p.?). Clinical examination and history revealed cone dystrophy, optic atrophy, and Pelger-Huët anomaly, but no short stature, recurrent acute liver failure, or susceptibility to infections. RNA analysis revealed that the c.886-5T>A variant results in two aberrant transcripts that are predicted to lead to in frame amino acid changes in the β-propeller region of the protein. We hypothesize that the phenotype of our subjects, which appears to be at the end of the spectrum of NBAS-related disorders, could be explained by residual protein function mediated by the non-canonical splice site variant c.886-5T>A. Our study contributes to the existing knowledge on the genotypic and phenotypic spectrum of NBAS-related disorders.

Venous Wall of Patients with Chronic Venous Disease Exhibits a Glycolytic Phenotype

Chronic venous disease (CVeD) is a rising medical condition characterized by a broad spectrum of disorders in the venous system. Varicose veins (VVs) represent a frequent clinical manifestation of CVeD, particularly in the lower limbs. Prior histopathological studies have defined a set of alterations observed in the venous wall of patients with VVs, affecting their structure and behavior. Metabolic changes in the veins appear to be a critical biological mechanism aiding our understanding of the pathogenesis of CVeD. In this sense, previous studies have identified a potential role of a glycolytic phenotype in the development of different vascular disorders; however, its precise role in CVeD remains to be fully explored. Thus, the aim of the present study was to analyze the gene and protein expression of glucose transporter 1 (GLUT-1) and the glycolytic enzymes PGK-1, ALD, GA3PDH and LDH in the VVs of patients with CVeD (n = 35) in comparison to those expressed in healthy subjects. Our results display enhanced gene and protein expression of GLUT-1, PGK-1, ALD, GA3PDH and LDH in patients with CVeD, suggesting a glycolytic switch of the venous tissue. Greater understanding of the impact of this glycolytic switch in patients with CVeD is required to define a possible pathophysiological role or therapeutic implications of these changes.

Leukodystrophies.

This article reviews the most common leukodystrophies and is focused on diagnosis, clinical features, and emerging therapeutic options. In the past decade, the recognition of leukodystrophies has exponentially increased, and now this class includes more than 30 distinct disorders. Classically recognized as progressive and fatal disorders affecting young children, it is now understood that leukodystrophies are associated with an increasing spectrum of neurologic trajectories and can affect all ages. Next-generation sequencing and newborn screening allow the opportunity for the recognition of presymptomatic and atypical cases. These new testing opportunities, in combination with growing numbers of natural history studies and clinical consensus guidelines, have helped improve diagnosis and clinical care. Additionally, a more granular understanding of disease outcomes informs clinical trial design and has led to several recent therapeutic advances. This review summarizes the current understanding of the clinical manifestations of disease and treatment options for the most common leukodystrophies. As early testing becomes more readily available through next-generation sequencing and newborn screening, neurologists will better understand the true incidence of the leukodystrophies and be able to diagnose children within the therapeutic window. As targeted therapies are developed, it becomes increasingly imperative that this broad spectrum of disorders is recognized and diagnosed. This work summarizes key advances in the leukodystrophy field.

Role of Basophils in a Broad Spectrum of Disorders.

Basophils are the rarest granulocytes and have long been overlooked in immunological research due to their rarity and similarities with tissue-resident mast cells. In the last two decades, non-redundant functions of basophils have been clarified or implicated in a broad spectrum of immune responses, particularly by virtue of the development of novel analytical tools for basophils. Basophils infiltrate inflamed tissues of patients with various disorders, even though they circulate in the bloodstream under homeostatic conditions. Depletion of basophils results in the amelioration or exaggeration of inflammation, depending on models of disease, indicating basophils can play either beneficial or deleterious roles in a context-dependent manner. In this review, we summarize the recent findings of basophil pathophysiology under various conditions in mice and humans, including allergy, autoimmunity, tumors, tissue repair, fibrosis, and COVID-19. Further mechanistic studies on basophil biology could lead to the identification of novel biomarkers or therapeutic targets in a broad range of diseases.

Curriculum for Vestibular Medicine (VestMed) proposed by the Bárány Society.

This document presents the initiative of the Bárány Society to improve diagnosis and care of patients presenting with vestibular symptoms worldwide.The Vestibular Medicine (VestMed) concept embraces a wide approach to the potential causes of vestibular symptoms, acknowledging that vertigo, dizziness, and unsteadiness are non-specific symptoms that may arise from a broad spectrum of disorders, spanning from the inner ear to the brainstem, cerebellum and supratentorial cerebral networks, to many disorders beyond these structures.The Bárány Society Vestibular Medicine Curriculum (BS-VestMed-Cur) is based on the concept that VestMed is practiced by different physician specialties and non-physician allied health professionals. Each profession has its characteristic disciplinary role and profile, but all work in overlapping areas. Each discipline requires good awareness of the variety of disorders that can present with vestibular symptoms, their underlying mechanisms and etiologies, diagnostic criteria and treatment options. Similarly, all disciplines require an understanding of their own limitations, the contribution to patient care from other professionals and when to involve other members of the VestMed community. Therefore, the BS-VestMed-Cur is the same for all health professionals involved, the overlaps and differences of the various relevant professions being defined by different levels of detail and depth of knowledge and skills.The BS-VestMed-Cur defines a Basic and an Expert Level Curriculum. The Basic Level Curriculum covers the VestMed topics in less detail and depth, yet still conveys the concept of the wide net approach. It is designed for health professionals as an introduction to, and first step toward, VestMed expertise. The Expert Level Curriculum defines a Focused and Broad Expert. It covers the VestMed spectrum in high detail and requires a high level of understanding. In the Basic and Expert Level Curricula, the range of topics is the same and runs from anatomy, physiology and physics of the vestibular system, to vestibular symptoms, history taking, bedside examination, ancillary testing, the various vestibular disorders, their treatment and professional attitudes. Additionally, research topics relevant to clinical practice are included in the Expert Level Curriculum. For Focused Expert proficiency, the Basic Level Curriculum is required to ensure a broad overview and additionally requires an expansion of knowledge and skills in one or a few specific topics related to the focused expertise, e.g. inner ear surgery. Broad Expert proficiency targets professionals who deal with all sorts of patients presenting with vestibular symptoms (e.g. otorhinolaryngologists, neurologists, audiovestibular physicians, physical therapists), requiring a high level of VestMed expertise across the whole spectrum. For the Broad Expert, the Expert Level Curriculum is required in which the minimum attainment targets for all the topics go beyond the Basic Level Curriculum. The minimum requirements regarding knowledge and skills vary between Broad Experts, since they are tuned to the activity profile and underlying specialty of the expert. The BS-VestMed-Cur aims to provide a basis for current and future teaching and training programs for physicians and non-physicians. The Basic Level Curriculum could also serve as a resource for inspiration for teaching VestMed to students, postgraduate generalists such as primary care physicians and undergraduate health professionals, or anybody wishing to enter VestMed. VestMed is considered a set of competences related to an area of practice of established physician specialties and non-physician health professions rather than a separate clinical specialty. This curriculum does not aim to define a new single clinical specialty. The BS-VestMed-Cur should also integrate with, facilitate and encourage translational research in the vestibular field.

JAK-STAT Pathway: A Novel Target to Tackle Viral Infections.

Modulation of the antiviral innate immune response has been proposed as a putative cellular target for the development of novel pan-viral therapeutic strategies. The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway is especially relevant due to its essential role in the regulation of local and systemic inflammation in response to viral infections, being, therefore, a putative therapeutic target. Here, we review the extraordinary diversity of strategies that viruses have evolved to interfere with JAK-STAT signaling, stressing the relevance of this pathway as a putative antiviral target. Moreover, due to the recent remarkable progress on the development of novel JAK inhibitors (JAKi), the current knowledge on its efficacy against distinct viral infections is also discussed. JAKi have a proven efficacy against a broad spectrum of disorders and exhibit safety profiles comparable to biologics, therefore representing good candidates for drug repurposing strategies, including viral infections.

Pain after adult deformity surgery

Adult spinal deformity is a broad spectrum of disorders that are becoming more prevalent with an ageing population. In those with moderate to severe deformity, surgical correction of spinal alignment is an increasingly common treatment and has demonstrated improvement in patients’ quality of life. Whilst continued research in risk stratification, advances in surgical techniques, and preoperative optimization has taken place, rates of adverse outcomes following surgery for adult spinal deformity are still frequent. Pain is a common complaint after spinal deformity correction; however, whether this pain is deemed a ‘normal’ amount, or a ‘pathological’ pain has not been well characterized in the literature. This paper aims to provide a framework for evaluating pain after spinal deformity correction surgery in order to guide clinical decision making.

Pulmonology approach in the investigation of chronic unexplained dyspnea.

ABSTRACTChronic unexplained dyspnea and exercise intolerance represent common, distressing symptoms in outpatients. Clinical history taking and physical examination are the mainstays for diagnostic evaluation. However, the cause of dyspnea may remain elusive even after comprehensive diagnostic evaluation-basic laboratory analyses; chest imaging; pulmonary function testing; and cardiac testing. At that point (and frequently before), patients are usually referred to a pulmonologist, who is expected to be the main physician to solve this conundrum. In this context, cardiopulmonary exercise testing (CPET), to assess physiological and sensory responses from rest to peak exercise, provides a unique opportunity to unmask the mechanisms of the underlying dyspnea and their interactions with a broad spectrum of disorders. However, CPET is underused in clinical practice, possibly due to operational issues (equipment costs, limited availability, and poor remuneration) and limited medical education regarding the method. To counter the latter shortcoming, we aspire to provide a pragmatic strategy for interpreting CPET results. Clustering findings of exercise response allows the characterization of patterns that permit the clinician to narrow the list of possible diagnoses rather than pinpointing a specific etiology. We present a proposal for a diagnostic workup and some illustrative cases assessed by CPET. Given that airway hyperresponsiveness and pulmonary vascular disorders, which are within the purview of pulmonology, are common causes of chronic unexplained dyspnea, we also aim to describe the role of bronchial challenge tests and the diagnostic reasoning for investigating the pulmonary circulation in this context.

Paradoxical Mitophagy Regulation by PINK1 and TUFm

Aberrant mitophagy has been implicated in a broad spectrum of disorders. PINK1, Parkin, and ubiquitin have pivotal roles in priming mitophagy. However, the entire regulatory landscape and the precise control mechanisms of mitophagy remain to be elucidated. Here, we uncover fundamental mitophagy regulation involving PINK1 and a non-canonical role of the mitochondrial Tu translation elongation factor (TUFm). The mitochondrion-cytosol dual-localized TUFm interacts with PINK1 biochemically and genetically, which is an evolutionarily conserved Parkin-independent route toward mitophagy. A PINK1-dependent TUFm phosphoswitch at Ser222 determines conversion from activating to suppressing mitophagy. PINK1 modulates differential translocation of TUFm because p-S222-TUFm is restricted predominantly to the cytosol, where it inhibits mitophagy by impeding Atg5-Atg12 formation. The self-antagonizing feature of PINK1/TUFm is critical for the robustness of mitophagy regulation, achieved by the unique kinetic parameters of p-S222-TUFm, p-S65-ubiquitin, and their common kinase PINK1. Our findings provide new mechanistic insights into mitophagy and mitophagy-associated disorders.

Abstract 2550: Lack of FGF21 accelerates NASH-HCC transition via up-regulation of hepatic SPHK1-S1P-HIPPO signaling in murine models

Abstract Background: Non-alcoholic fatty liver disease(NAFLD) encompasses a broad spectrum of disorders, ranging from non-progressive bland steatosis to non-alcoholic hepatitis (NASH), cirrhosis, and malignant transformation into hepatocellular carcinoma (HCC). Accumulating evidence indicates that lipid metabolic reprogramming mediates the transition from NASH to HCC, however the NASH related carcinogenesis and role of FGF21 played during NASH-HCC transition are largely unknown. while fibroblast growth factor 21 (FGF21) exerts a key role in lipid homeostasis and play a promising therapeutic candidate for the treatment of obesity and diabetes. Aim: To investigate the effect of FGF21 on lipid metabolic reprogramming during the NASH-HCC carcinogenetic transformation and to reveal the potential NASH-HCC mechanism. Methods: Three NASH-HCC transition models were established in FGF21 knockout (KO) mice, with treatment of DEN at aged 2 weeks at 40 mg/kg body weight (i.p.) and feeding, 1) high fat diet (HFD, 60% kcal% fat); 2) western-style high fat diet (WSHFD, 60% kcal% fat and 19% kcal% fructose); and 3) methionine/choline-deficient diet (MCD). The cellular and molecular events, in turn, de novo lipogenesis, sphingolipid metabolism, white adipose tissue (WAT) lipolysis, insulin resistance (IR), release of free fatty acids (FFAs), metabolites of gut flora, carcinogenesis signaling pathways and NASH-HCC initiation, were determined both in vivo and in vitro. The in vitro studies were performed using shRNA-FGF21 knock down hepatocyte and HCC cell lines. Results: Aberrant lipid components, gut microbiome, hepatic Hippo-YAP and NF-kB signaling were found consistently in the NASH-HCC tissues from FGF21-KO mice with 3 diets treatments, compared to the wild type controls. Increased de novo lipogenesis, FFAs overflow to the liver, and inflammation agents from the metabolites of gut flora upregulated the hepatic sphingosine Kinase 1 (SPHK1) expression and its product sphingosine-1-phosphate (S1P), subsequently induced YAP dephosphorylation and nuclear localization. rhFGF21 or SPHK1 inhibitor (SKI-II) treatment significantly decreased the tumor volumes via alleviation of FFAs and S1P productions. Use of curcumin to modulate gut microbiota resulted in suppression of NASH-HCC growth in mice. Conclusion: 1) lack of FGF21 played a key role in hepatic lipid metabolism disorder in liver; 2) lack of FGF21 accelerated the SPHK1-S1P-HIPPO signaling promoted NASH-HCC transition; 3) administration of rhFGF21 not only attenuates NASH, but also prevents HCC carcinogenetic transformation via down-regulation of the SPHK1-S1P-HIPPO axis. This work was supported by an Institutional Development Award (IDeA) from the NIGMS of the National Institutes of Health under grant number P20GM113226. Key Words: Fibroblast growth factor 21; Steatohepatities; Hepatocellular carcinoma; Free fatty acid; Sphingolipid Citation Format: Xiaoju Shi, Robert C. Martin, Youxi Yu, Yujia Chen, Xingtong Wang, Guangyi Wang, Guoyue Lv, Ping Zhang, Yan Li. Lack of FGF21 accelerates NASH-HCC transition via up-regulation of hepatic SPHK1-S1P-HIPPO signaling in murine models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2550.

Glycogen synthase kinase-3 promotes T helper type 17 differentiation by promoting interleukin-9 production.

T helper type 17 (Th17) cells are recognized as important contributors to the deleterious effects of several neurological and psychiatric diseases. Clarifying mechanisms that control the production of Th17 cells may therefore provide new strategies for developing novel interventions in a broad spectrum of disorders. Th17 cell differentiation is promoted by glycogen synthase kinase-3 (GSK3), but the mechanisms for this are only beginning to be understood. Using T-cell-selective depletion of GSK3β and multiple selective pharmacological GSK3 inhibitors, we found that GSK3 inhibition decreased C-C motif chemokine (ccl)20, C-C motif chemokine receptor (ccr)6, interleukin (IL)-9, Runt-related transcription factor (Runx)1, interferon regulatory factor (Irf)4 and c-maf mRNA expression after 2days of Th17 cell differentiation in vitro. These effects were found to be independent of the master regulator transcription factor retinoic acid receptor-related orphan receptor γT (RORγT), as GSK3 inhibition still reduced Th17 cell differentiation in RORγT-depleted cells. Because IL-9 was approximately ninefold down-regulated in GSK3β-/- CD4 cells, we tested if reintroduction of IL-9 during Th17 cell differentiation abolished the inhibition by GSK3 deficiency of Th17 cell differentiation. We found that IL-9 over-expression was sufficient to reverse the inhibition of Th17 cell differentiation by GSK3 inhibition or depletion. We found that IL-9 enhances Th17 cell differentiation in part through signal transducer and activator of transcription 3 (STAT3) activation, and IL-9 also enhances STAT3 binding to the IL-17a promoter. Altogether, these findings suggest that IL-9 might be an important mediator of GSK3β-dependent enhancement of Th17 cell differentiation.

Optokinetic Analysis in Patients With Spontaneous Horizontal Gaze-Evoked Nystagmus Without Radiological Neuropathology.

Gaze-evoked nystagmus is not rare among those who have acute balance problem and may indicate a cerebellar dysfunction that is associated with a broad spectrum of disorders. The aim of this study is to analyze optokinetic response in those patients. Eleven males and 7 females (age range: 25-60, 42.5 [9.75]) with gaze-evoked nystagmus were analyzed with optokinetic test (Micromed Inc). Nystagmus was elicited by a stimulator light spot moving across the patient's visual field at a target speed of 30 degree/second. Ten age-matched healthy participants served as controls. The gain and slow-phase velocity difference in oculomotor response from left and right stimulus was compared in patients and the control participants. One-way analysis of variance test was used for multiple variance analysis of the groups. Statistical significance was set at P < .05. Slow-phase velocity of gaze-evoked nystagmus was ranging between 6 and 19 degree/second. The mean slow-phase velocity of gaze-evoked nystagmus to the right and left was 8.1 (3.81) and 6.8 (4.67) degree/second, respectively. Optokinetic gain was out of normal limits in 10 (55.5%) patients. Comparison of mean gain difference between the patients and the normal participants was statistically significant (P = .025). No statistical difference was found in mean slow-phase velocity difference in optokinetic nystagmus between control participants and patients (P > .05 [.099]). An acute-onset balance problem may be associated with dysfunction of separate populations of neurons in the brainstem and cerebellum even if there is no radiological neuropathy since gaze-evoked nystagmus is a sign of neural integrator dysfunction. Patients with gaze-evoked nystagmus and optokinetic abnormalities may have disruption of cerebellar pathways and should be followed closely.

Evaluation of Bone Metabolism Biomarkers in Hemodialysis Chronic Kidney Disease

Metabolic bone disease (MBD) is a common complication of chronic kidney disease (CKD) and is a part of a broad spectrum of disorders of mineral metabolism that occur in this clinical setting and result in both skeletal and extraskletal consequences. This study was a cross sectional which conducted in Dialysis Unit in Tikrit Teaching Hospital in Tikrit city. The study started from January 2018 to August 2018 on study population age ranged from (18 – 68) years old The total of 60 subjects were separated to two groups as following: Control: This group consist of 30 healthy individuals (15 females and 15 males), and Hemodialysis (HD) (CKD) patients: This group consist of CKD 30 patients (15 females and 15 males). The results referred to the increased levels of Transforming growth factor- ? (TGF-?), Osteoprogestrin (OPG), Sclerostin (SOST), Osteocalcin (OC) and C-reactive protein (CRP) in CKD with HD with highly significant differences (P?0.01) when compared with control group. The bone metabolism biomarkers are increased in HD CKD patients who complicated to MBD.

Hypnosis and Psychoanalysis: Toward Undoing Freud’s Primal Category Mistake

Hypnosis predates psychoanalysis, when autohypnotic pathologies were identified through the lens of hypnosis, and labeled “hypnoid hysteria” in the language of the day. The broad spectrum of disorders then subsumed under that term is still reflected in ICD-10’s subset, “F44—Dissociative (Conversion) Disorders.” Freud initially embraced both hypnoid hysteria and hypnosis, but came to abandon hypnosis and, by extension, hypnoid hysteria as well. Since that fateful decision, which I term herein Freud’s “Inaugural Category Mistake,” references to both hypnosis and hypnoid pathology largely vanished from the psychoanalytic mainstream, thereby neglecting conditions afflicting a significant portion of the mentally ill, and needlessly restricting the therapeutic repertoire of psychoanalysis. This contribution argues that psychoanalysis could best re-embrace hypnosis and hypnoid pathology together, as a related pair, and would benefit from doing so. Two examples of the differences of understanding and interventions such a rapprochement might encourage are offered: (a) how hypnoid pathology alters the transference and countertransference; and (b) how the appropriate use of hypnosis alters the nature of interpretation.

Clinical, molecular, and pharmacological aspects of FMR1-related disorders

BackgroundFragile X syndrome, the most common inherited cause of intellectual disability, is associated with a broad spectrum of disorders across different generations of a single family. This study reviews the clinical manifestations of fragile X-associated disorders as well as the spectrum of mutations of the fragile X mental retardation 1 gene (FMR1) and the neurobiology of the fragile X mental retardation protein (FMRP), and also provides an overview of the potential therapeutic targets and genetic counselling. DevelopmentThis disorder is caused by expansion of the CGG repeat (>200 repeats) in the 5 prime untranslated region of FMR1, resulting in a deficit or absence of FMRP. FMRP is an RNA-binding protein that regulates the translation of several genes that are important in synaptic plasticity and dendritic maturation. It is believed that CGG repeat expansions in the premutation range (55–200 repeats) elicit an increase in mRNA levels of FMR1, which may cause neuronal toxicity. These changes manifest clinically as developmental problems such as autism and learning disabilities as well as neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS). ConclusionsAdvances in identifying the molecular basis of fragile X syndrome may help us understand the causes of neuropsychiatric disorders, and they will probably contribute to development of new and specific treatments.

Analyzing the "CareGap": assessing gaps in adherence to clinical guidelines in adult soft tissue sarcoma.

Clinical decision support systems (CDSSs) are gaining popularity as tools that assist physicians in optimizing medical care. These systems typically comply with evidence-based medicine and are designed with input from domain experts. Nonetheless, deviations from CDSS recommendations are abundant across a broad spectrum of disorders, raising the question as to why this phenomenon exists. Here, we analyze this gap in adherence to a clinical guidelines-based CDSS by examining the physician treatment decisions for 1329 adult soft tissue sarcoma patients in northern Italy using patient-specific parameters. Dubbing this analysis "CareGap", we find that deviations correlate strongly with certain disease features such as local versus metastatic clinical presentation. We also notice that deviations from the guideline-based CDSS suggestions occur more frequently for patients with shorter survival time. Such observations can direct physicians' attention to distinct patient cohorts that are prone to higher deviation levels from clinical practice guidelines. This illustrates the value of CareGap analysis in assessing quality of care for subsets of patients within a larger pathology.

Iodine status of adults in Taiwan 2005-2008, 5 years after the cessation of mandatory salt iodization.

Iodine deficiency causes a broad spectrum of disorders across all ages. Mandatory salt iodization in Taiwan successfully reduced the goiter rate from 21.6% to 4.3% in schoolchildren surveyed in 1971. The program continued until 2003 when salt iodization was changed from mandatory to voluntary. The purpose of this study was to investigate the iodine status of Taiwanese individuals after the change in the iodine policy. Urinary iodine (UI) was measured in samples from adults in the Nutrition and Health Survey in Taiwan 2005-2008. The median UI level was 100μg/L, and the percentage of populations with UI levels below 100μg/L and 50μg/L was 50.1% and 15.1%, respectively, indicating that the iodine status was borderline adequate. Men had a higher UI level than women (102μg/L vs. 98μg/L, p=0.003), and older individuals (age > 60 years) had a lower UI level than younger people, particularly in women. The iodine status of the population < 50 years was sufficient, but it was insufficient in older groups. Mild iodine insufficiency was noted in all areas of Taiwan except the Southern area and Penghu islands, with the lowest UI level of 79μg/L in the Mountain area. Although the UI level of women of childbearing age (19-44 years) was 103μg/L, there may be a risk of iodine deficiency during pregnancy. The iodine nutrition of the Taiwanese population in 2005-2008 was borderline adequate, with insufficiency in some subgroups. Further monitoring of the iodine status is necessary.

Inaugural Message from the Founding Editor-in-Chief.

Given the remarkable advances made over the last several decades in science and medicine, there could be no better and opportune time to launch the Journal of Translational Science (JTS). We have been fortunate to witness the integration of multiple areas of discovery in science and medicine to push the envelope for the diagnosis and treatment of disorders that can affect any region of the body. In developed countries such as the United States, life expectancy continues to increase and is accompanied by a one percent decrease in the age-adjusted death rate from the years 2000 through 2011. Yet, with the increasing growth and lifespan of the world's population, it is expected that the incidence of a number of disorders, such as metabolic disease, and neurodegenerative disorders, also will continue to grow. For example, the World Health Organization reports that diabetes mellitus will be ranked as the seventh leading cause of death by the year 2030. As a result, multiple novel therapeutic strategies are currently being advanced to treat disorders that currently have limited remedies. In particular, stem cell applications have quickly advanced and are being considered for numerous disorders that include cardiovascular disease, diabetes mellitus, cancer, inflammatory bowel disease, peripheral ischemia, graft versus host disease, and nervous system disorders. More than 40 years prior, the use of bone marrow transplantation set the stage for the treatment of hematological disorders and cancer with the use of stem cells. Presently, more than 50,000 bone marrow transplants are performed every year using autologous and allogeneic hematopoietic stem cells. In addition, unique cellular channels, such as the vanilloid (capsaicin) receptor TRPV1 (transient receptor potential, vanilloid subfamily member 1) and a member of the TRP superfamily of cation channels, are being pursued for a diverse spectrum of disorders that range from pain management to neuronal protection of the brain following stroke. Increasing consideration also is being directed to the field of microRNAs (miRNAs). MiRNAs consist of 19-25 nucleotides, are small non-coding ribonucleic acids (RNAs), and can control gene expression by silencing targeted messenger RNAs (mRNAs) translated by specific genes. With the explosion of new studies, miRNAs are reported to play critical roles in stem cell renewal, tissue repair, and potential disease progression in areas such as those of the cardiac, gastrointestinal, and nervous systems. Although these therapeutic strategies appear initially to be diverse, upon closer inspection each depends upon a “common signaling platform” that is intimately connected through cellular pathways that can significantly affect clinical outcome in patients. It is clear that cellular and genetic targets can easily impact multiple disease entities. The translation of these pathways into relevant clinical treatments can yield fruit for many disorders. JTS was conceived with this knowledge in mind. JTS is a novel open access journal that will focus upon the translation of cellular, molecular, and genetic pathways into clinical strategies for multiple medical disciplines that can impact a broad spectrum of disorders. These disorders can involve all aspects of translational research and medicine to include stem cells, degenerative diseases, aging, immune function, tumorigenesis, epigenetics, musculoskeletal function, cognition, behavior, metabolic function, and targets of the neuronal, cardiac, pulmonary, gastrointestinal, and vascular systems. JTS will provide a platform in today's scientific and medical literature to serve as an international forum for the healthcare and scientific communities worldwide to translate basic and clinical research studies into clinical therapies as well as report upon prognostics, novel therapeutic strategies, and biomarker development. JTS will offer multiple venues to present authors' thoughts and investigations as original research papers, review papers, clinical studies, editorials, expert opinion and perspective papers, commentaries, book reviews, and letters to the editor. Ultimately, JTS will promote a rigorous, fair, and constructive evaluation of all submitted articles. Papers will be processed in an extremely timely fashion so that all authors can follow the progress of the papers during the evaluation, copyediting, and publication phases. We are extremely excited with the launch of JTS and believe that the journal will fill a great void in the reporting of today's scientific and medical discoveries. JTS will serve as an international forum for the greatest degree of scholarship in the research and clinical communities worldwide to translate pioneering “bench to bedside” breakthroughs into successful clinical strategies. On behalf of the Editorial Team and the Editorial Board, welcome to JTS!