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J. Clin. Med., Volume 3, Issue 4 (December 2014) , Pages 1064-1574

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Open AccessReview
The Insulin-Like Growth Factor System in Obesity, Insulin Resistance and Type 2 Diabetes Mellitus
J. Clin. Med. 2014, 3(4), 1561-1574; https://doi.org/10.3390/jcm3041561
Received: 23 September 2014 / Revised: 21 November 2014 / Accepted: 5 December 2014 / Published: 22 December 2014
Cited by 25 | Viewed by 4097 | PDF Full-text (195 KB) | HTML Full-text | XML Full-text
Abstract
The insulin-like growth factor (IGF) system, acting in concert with other hormone axes, is important in normal metabolism. In obesity, the hyperinsulinaemia that accompanies peripheral insulin resistance leads to reduced growth hormone (GH) secretion, while total IGF-I levels are relatively unchanged due to [...] Read more.
The insulin-like growth factor (IGF) system, acting in concert with other hormone axes, is important in normal metabolism. In obesity, the hyperinsulinaemia that accompanies peripheral insulin resistance leads to reduced growth hormone (GH) secretion, while total IGF-I levels are relatively unchanged due to increased hepatic GH sensitivity. IGF-binding protein (IGFBP)-1 levels are suppressed in relation to the increase in insulin levels in obesity and low levels predict the development of type 2 diabetes several years later. Visceral adiposity and hepatic steatosis, along with a chronic inflammation, contribute to the IGF system phenotype in individuals with metabolic syndrome and type 2 diabetes mellitus, including changes in the normal inverse relationship between IGFBP-1 and insulin, with IGFBP-1 concentrations that are inappropriately normal or elevated. The IGF system is implicated in the vascular and other complications of these disorders and is therefore a potential therapeutic target. Full article
(This article belongs to the Special Issue Obesity, Diabetes and Metabolic Syndrome)
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Open AccessReview
Inflammation and Cell Death in Age-Related Macular Degeneration: An Immunopathological and Ultrastructural Model
J. Clin. Med. 2014, 3(4), 1542-1560; https://doi.org/10.3390/jcm3041542
Received: 5 September 2014 / Revised: 26 November 2014 / Accepted: 1 December 2014 / Published: 22 December 2014
Cited by 12 | Viewed by 3801 | PDF Full-text (758 KB) | HTML Full-text | XML Full-text
Abstract
The etiology of Age-related Macular Degeneration (AMD) remains elusive despite the characterization of many factors contributing to the disease in its late-stage phenotypes. AMD features an immune system in flux, as shown by changes in macrophage polarization with age, expression of cytokines and [...] Read more.
The etiology of Age-related Macular Degeneration (AMD) remains elusive despite the characterization of many factors contributing to the disease in its late-stage phenotypes. AMD features an immune system in flux, as shown by changes in macrophage polarization with age, expression of cytokines and complement, microglial accumulation with age, etc. These point to an allostatic overload, possibly due to a breakdown in self vs. non-self when endogenous compounds and structures acquire the appearance of non-self over time. The result is inflammation and inflammation-mediated cell death. While it is clear that these processes ultimately result in degeneration of retinal pigment epithelium and photoreceptor, the prevalent type of cell death contributing to the various phenotypes is unknown. Both molecular studies as well as ultrastructural pathology suggest pyroptosis, and perhaps necroptosis, are the predominant mechanisms of cell death at play, with only minimal evidence for apoptosis. Herein, we attempt to reconcile those factors identified by experimental AMD models and integrate these data with pathology observed under the electron microscope—particularly observations of mitochondrial dysfunction, DNA leakage, autophagy, and cell death. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
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Open AccessReview
iPS Cells for Modelling and Treatment of Retinal Diseases
J. Clin. Med. 2014, 3(4), 1511-1541; https://doi.org/10.3390/jcm3041511
Received: 22 September 2014 / Revised: 16 November 2014 / Accepted: 18 November 2014 / Published: 19 December 2014
Cited by 4 | Viewed by 3006 | PDF Full-text (2391 KB) | HTML Full-text | XML Full-text
Abstract
For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of [...] Read more.
For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of patient-specific induced pluripotent stem cells (iPSC) for deriving retinal lineages has added a powerful alternative tool for discovering new disease-causing mutations, studying genotype-phenotype relationships, performing therapeutics-toxicity screening and developing personalised cell therapy. This review article provides a clinical perspective on the current and potential benefits of iPSC for managing the most common blinding diseases of the eye: inherited retinal diseases and age-related macular degeneration. Full article
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Open AccessReview
The Use of Patient-Specific Induced Pluripotent Stem Cells (iPSCs) to Identify Osteoclast Defects in Rare Genetic Bone Disorders
J. Clin. Med. 2014, 3(4), 1490-1510; https://doi.org/10.3390/jcm3041490
Received: 2 September 2014 / Revised: 20 November 2014 / Accepted: 20 November 2014 / Published: 17 December 2014
Cited by 4 | Viewed by 2864 | PDF Full-text (282 KB) | HTML Full-text | XML Full-text
Abstract
More than 500 rare genetic bone disorders have been described, but for many of them only limited treatment options are available. Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies. Effectors [...] Read more.
More than 500 rare genetic bone disorders have been described, but for many of them only limited treatment options are available. Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies. Effectors for skeletal abnormalities of bone disorders may be abnormal bone formation directed by osteoblasts or anomalous bone resorption by osteoclasts, or both. Patient-specific induced pluripotent stem cells (iPSCs) can be generated from somatic cells of various tissue sources and in theory can be differentiated into any desired cell type. However, successful differentiation of hiPSCs into functional bone cells is still a challenge. Our group focuses on the use of human iPSCs (hiPSCs) to identify osteoclast defects in craniometaphyseal dysplasia. In this review, we describe the impact of stem cell technology on research for better treatment of such disorders, the generation of hiPSCs from patients with rare genetic bone disorders and current protocols for differentiating hiPSCs into osteoclasts. Full article
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Open AccessReview
Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions
J. Clin. Med. 2014, 3(4), 1466-1489; https://doi.org/10.3390/jcm3041466
Received: 21 September 2014 / Revised: 27 November 2014 / Accepted: 28 November 2014 / Published: 15 December 2014
Cited by 3 | Viewed by 2459 | PDF Full-text (203 KB) | HTML Full-text | XML Full-text
Abstract
Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an [...] Read more.
Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attractive therapeutic target. Various tyrosine kinase inhibitors (TKIs) have been developed targeting FLT3, but in spite of initial optimism the first generation TKIs tested in clinical studies generally induce only partial and transient hematological responses. The limited treatment efficacy generally observed may be explained by numerous factors; extensively pretreated and high risk cohorts, suboptimal pharmacodynamic and pharmacokinetic properties of the compounds, acquired TKI resistance, or the possible fact that inhibition of mutated FLT3 alone is not sufficient to avoid disease progression. The second-generation agent quizartinb is showing promising outcomes and seems better tolerated and with less toxic effects than traditional chemotherapeutic agents. Therefore, new generations of TKIs might be feasible for use in combination therapy or in a salvage setting in selected patients. Here, we sum up experiences so far, and we discuss the future outlook of targeting dysregulated FLT3 signaling in the treatment of AML. Full article
Open AccessReview
The Legal Past, Present and Future of Prenatal Genetic Testing: Professional Liability and Other Legal Challenges Affecting Patient Access to Services
J. Clin. Med. 2014, 3(4), 1437-1465; https://doi.org/10.3390/jcm3041437
Received: 26 August 2014 / Revised: 16 September 2014 / Accepted: 17 September 2014 / Published: 15 December 2014
Cited by 6 | Viewed by 2678 | PDF Full-text (162 KB) | HTML Full-text | XML Full-text
Abstract
This chapter is an overview of the current status of the law in the United States regarding prenatal genetic testing with an emphasis on issues related to professional liability and other challenges affecting patient access to prenatal genetic testing. The chapter discusses the [...] Read more.
This chapter is an overview of the current status of the law in the United States regarding prenatal genetic testing with an emphasis on issues related to professional liability and other challenges affecting patient access to prenatal genetic testing. The chapter discusses the roles that federal regulations, promulgated by the Centers for Medicare and Medicaid Services (CMS), the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC), play in the regulation of prenatal genetic tests. The chapter discusses tort litigation based on allegations of malpractice in the provision of prenatal genetic testing and how courts have analyzed issues related to causation, damages and mitigation of damages. The chapter provides reference information regarding how individual states address causes of action under the tort theories of wrongful birth and wrongful life. The chapter concludes with a discussion of future legal issues that may affect clinical prenatal genetic testing services arising from the continued expansion of prenatal genetic testing, legal restrictions on access to abortion and the potential development of embryonic treatments. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 1)
Open AccessReview
Induced Pluripotent Stem Cells Derived from Alzheimer’s Disease Patients: The Promise, the Hope and the Path Ahead
J. Clin. Med. 2014, 3(4), 1402-1436; https://doi.org/10.3390/jcm3041402
Received: 14 August 2014 / Revised: 12 November 2014 / Accepted: 14 November 2014 / Published: 12 December 2014
Cited by 7 | Viewed by 6091 | PDF Full-text (522 KB) | HTML Full-text | XML Full-text
Abstract
The future hope of generated induced pluripotent stem cells (iPS cells) from Alzheimer’s disease patients is multifold. Firstly, they may help to uncover novel mechanisms of the disease, which could lead to the development of new and unprecedented drugs for patients and secondly, [...] Read more.
The future hope of generated induced pluripotent stem cells (iPS cells) from Alzheimer’s disease patients is multifold. Firstly, they may help to uncover novel mechanisms of the disease, which could lead to the development of new and unprecedented drugs for patients and secondly, they could also be directly used for screening and testing of potential new compounds for drug discovery. In addition, in the case of familial known mutations, these cells could be targeted by use of advanced gene-editing techniques to correct the mutation and be used for future cell transplantation therapies. This review summarizes the work so far in regards to production and characterization of iPS cell lines from both sporadic and familial Alzheimer’s patients and from other iPS cell lines that may help to model the disease. It provides a detailed comparison between published reports and states the present hurdles we face with this new technology. The promise of new gene-editing techniques and accelerated aging models also aim to move this field further by providing better control cell lines for comparisons and potentially better phenotypes, respectively. Full article
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Open AccessCase Report
Herpes Simplex Virus (HSV-1) Encephalitis Mimicking Glioblastoma: Case Report and Review of the Literature
J. Clin. Med. 2014, 3(4), 1392-1401; https://doi.org/10.3390/jcm3041392
Received: 4 September 2014 / Revised: 13 October 2014 / Accepted: 13 November 2014 / Published: 12 December 2014
Cited by 1 | Viewed by 2657 | PDF Full-text (360 KB) | HTML Full-text | XML Full-text
Abstract
Glioblastoma multiforme (GBM) often presents as a brain mass with encephalitis. In a patient with GBM, subsequent presentation with new onset encephalitis may be due to another GBM or Herpes simplex virus 1 (HSV-1) encephalitis. We present a case of HSV-1 encephalitis mimicking [...] Read more.
Glioblastoma multiforme (GBM) often presents as a brain mass with encephalitis. In a patient with GBM, subsequent presentation with new onset encephalitis may be due to another GBM or Herpes simplex virus 1 (HSV-1) encephalitis. We present a case of HSV-1 encephalitis mimicking GBM in a patient with previous GBM. Full article
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Open AccessBrief Report
High Prevalence of Asymptomatic Sexually Transmitted Infections among Men Who Have Sex with Men
J. Clin. Med. 2014, 3(4), 1386-1391; https://doi.org/10.3390/jcm3041386
Received: 23 September 2014 / Revised: 17 October 2014 / Accepted: 20 October 2014 / Published: 12 December 2014
Cited by 4 | Viewed by 2157 | PDF Full-text (127 KB) | HTML Full-text | XML Full-text
Abstract
Background: Men who have sex with men (MSM) are disproportionately affected by sexually transmitted infection. The aim of this cross-sectional study is to prospectively detect the prevalence of chlamydia trachomatis (CT), neisseria gonorrhoeae (NG), mycoplasma genitalium (MG), and high risk human papillomavirus (HR-HPV), [...] Read more.
Background: Men who have sex with men (MSM) are disproportionately affected by sexually transmitted infection. The aim of this cross-sectional study is to prospectively detect the prevalence of chlamydia trachomatis (CT), neisseria gonorrhoeae (NG), mycoplasma genitalium (MG), and high risk human papillomavirus (HR-HPV), and syphilis in a population of asymptomatic sexually active MSM. Methods: Rectal, pharyngeal, and urine samples for CT, NG, MG, and HR-HPV were analyzed in 116 MSM patients attending the clinic for their routine follow-up during the period the study was conducted: 99 patients were issued from the clinic routine follow-up for their HIV infection, and 17 attended the clinic because they were sexual partners of an HIV infected male. Results: An STI was found in 16% of the patients (19/116), with at least one bacterial strain (CT, NG, or MG) found in one site (the pharynx, rectum, or urine). Conclusions: In this study, 16% of the MSM reporting recent RAI were asymptomatic carriers of rectal CT, NG, or MG. According to the high prevalence of asymptomatic STIs found in our MSM population and in other studies, prevention efforts in the form of counseling about the risk of STI need to be done in the population of MSM. Full article
Open AccessReview
Differentiating SIADH from Cerebral/Renal Salt Wasting: Failure of the Volume Approach and Need for a New Approach to Hyponatremia
J. Clin. Med. 2014, 3(4), 1373-1385; https://doi.org/10.3390/jcm3041373
Received: 7 July 2014 / Revised: 26 August 2014 / Accepted: 9 September 2014 / Published: 8 December 2014
Cited by 13 | Viewed by 4785 | PDF Full-text (122 KB) | HTML Full-text | XML Full-text
Abstract
Hyponatremia is the most common electrolyte abnormality. Its diagnostic and therapeutic approaches are in a state of flux. It is evident that hyponatremic patients are symptomatic with a potential for serious consequences at sodium levels that were once considered trivial. The recommendation to [...] Read more.
Hyponatremia is the most common electrolyte abnormality. Its diagnostic and therapeutic approaches are in a state of flux. It is evident that hyponatremic patients are symptomatic with a potential for serious consequences at sodium levels that were once considered trivial. The recommendation to treat virtually all hyponatremics exposes the need to resolve the diagnostic and therapeutic dilemma of deciding whether to water restrict a patient with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or administer salt and water to a renal salt waster. In this review, we briefly discuss the pathophysiology of SIADH and renal salt wasting (RSW), and the difficulty in differentiating SIADH from RSW, and review the origin of the perceived rarity of RSW, as well as the value of determining fractional excretion of urate (FEurate) in differentiating both syndromes, the high prevalence of RSW which highlights the inadequacy of the volume approach to hyponatremia, the importance of changing cerebral salt wasting to RSW, and the proposal to eliminate reset osmostat as a subtype of SIADH, and finally propose a new algorithm to replace the outmoded volume approach by highlighting FEurate. This algorithm eliminates the need to assess the volume status with less reliance on determining urine sodium concentration, plasma renin, aldosterone and atrial/brain natriuretic peptide or the BUN to creatinine ratio. Full article
(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)
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Open AccessReview
Opportunities and Limitations of Modelling Alzheimer’s Disease with Induced Pluripotent Stem Cells
J. Clin. Med. 2014, 3(4), 1357-1372; https://doi.org/10.3390/jcm3041357
Received: 27 August 2014 / Revised: 31 October 2014 / Accepted: 12 November 2014 / Published: 5 December 2014
Cited by 9 | Viewed by 3833 | PDF Full-text (350 KB) | HTML Full-text | XML Full-text
Abstract
Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) has opened the way for patient-specific disease modelling. Following their differentiation into neuronal cell types, iPSC have enabled the investigation of human neurodegenerative diseases, such as Alzheimer’s disease (AD). While human iPSCs certainly [...] Read more.
Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) has opened the way for patient-specific disease modelling. Following their differentiation into neuronal cell types, iPSC have enabled the investigation of human neurodegenerative diseases, such as Alzheimer’s disease (AD). While human iPSCs certainly provide great opportunities to repeatedly interrogate specific human brain cell types of individuals with familial and sporadic forms of the disease, the complex aetiology and timescale over which AD develops in humans poses particular challenges to iPSC-based AD models. Here, we discuss the current state-of-play in the context of these and other iPSC model-related challenges and elaborate on likely future developments in this field of research. Full article
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Open AccessArticle
Endophenotypes for Age-Related Macular Degeneration: Extending Our Reach into the Preclinical Stages of Disease
J. Clin. Med. 2014, 3(4), 1335-1356; https://doi.org/10.3390/jcm3041335
Received: 4 September 2014 / Revised: 7 November 2014 / Accepted: 12 November 2014 / Published: 28 November 2014
Cited by 3 | Viewed by 2392 | PDF Full-text (468 KB) | HTML Full-text | XML Full-text
Abstract
The key to reducing the individual and societal burden of age-related macular degeneration (AMD)-related vision loss, is to be able to initiate therapies that slow or halt the progression at a point that will yield the maximum benefit while minimizing personal risk and [...] Read more.
The key to reducing the individual and societal burden of age-related macular degeneration (AMD)-related vision loss, is to be able to initiate therapies that slow or halt the progression at a point that will yield the maximum benefit while minimizing personal risk and cost. There is a critical need to find clinical markers that, when combined with the specificity of genetic testing, will identify individuals at the earliest stages of AMD who would benefit from preventive therapies. These clinical markers are endophenotypes for AMD, present in those who are likely to develop AMD, as well as in those who have clinical evidence of AMD. Clinical characteristics associated with AMD may also be possible endophenotypes if they can be detected before or at the earliest stages of the condition, but we and others have shown that this may not always be valid. Several studies have suggested that dynamic changes in rhodopsin regeneration (dark adaptation kinetics and/or critical flicker fusion frequencies) may be more subtle indicators of AMD-associated early retinal dysfunction. One can test for the relevance of these measures using genetic risk profiles based on known genetic risk variants. These functional measures may improve the sensitivity and specificity of predictive models for AMD and may also serve to delineate clinical subtypes of AMD that may differ with respect to prognosis and treatment. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
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Open AccessCorrection
Correction: Grömminger, S., et al. Fetal Aneuploidy Detection by Cell-Free DNA Sequencing for Multiple Pregnancies and Quality Issues with Vanishing Twins. J. Clin. Med. 2014, 3, 679-692
J. Clin. Med. 2014, 3(4), 1333-1334; https://doi.org/10.3390/jcm3041333
Received: 21 November 2014 / Revised: 24 November 2014 / Accepted: 24 November 2014 / Published: 24 November 2014
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Abstract
The authors wish to make the following corrections to this paper [1]: On page 683 at the end of Section 3.2. lines 13–14, the word “no” is missing. The correct sentence should be: “There has been no evidence of false-negative NIPT results so [...] Read more.
The authors wish to make the following corrections to this paper [1]: On page 683 at the end of Section 3.2. lines 13–14, the word “no” is missing. The correct sentence should be: “There has been no evidence of false-negative NIPT results so far in the pregnancies included in this study.”[...] Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 2)
Open AccessArticle
Hyponatremia in Patients with Spontaneous Intracerebral Hemorrhage
J. Clin. Med. 2014, 3(4), 1322-1332; https://doi.org/10.3390/jcm3041322
Received: 29 August 2014 / Revised: 28 October 2014 / Accepted: 31 October 2014 / Published: 20 November 2014
Cited by 4 | Viewed by 2605 | PDF Full-text (144 KB) | HTML Full-text | XML Full-text
Abstract
Hyponatremia is the most frequently encountered electrolyte abnormality in critically ill patients. Hyponatremia on admission has been identified as an independent predictor of in-hospital mortality in patients with spontaneous intracerebral hemorrhage (sICH). However, the incidence and etiology of hyponatremia (HN) during hospitalization in [...] Read more.
Hyponatremia is the most frequently encountered electrolyte abnormality in critically ill patients. Hyponatremia on admission has been identified as an independent predictor of in-hospital mortality in patients with spontaneous intracerebral hemorrhage (sICH). However, the incidence and etiology of hyponatremia (HN) during hospitalization in a neurointensive care unit following spontaneous intracerebral hemorrhage (sICH) remains unknown. This was a retrospective analysis of consecutive patients admitted to Detroit Receiving Hospital for sICH between January 2006 and July 2009. All serum Na levels were recorded for patients during the ICU stay. HN was defined as Na <135 mmol/L. A total of 99 patients were analyzed with HN developing in 24% of sICH patients. Patients with HN had an average sodium nadir of 130 ± 3 mmol/L and an average time from admission to sodium <135 mmol/L of 3.9 ± 5.7 days. The most common cause of hyponatremia was syndrome of inappropriate antidiuretic hormone (90% of HN patients). Patients with HN were more likely to have fever (50% vs. 23%; p = 0.01), infection (58% vs. 28%; p = 0.007) as well as a longer hospital length of stay (14 (8–25) vs. 6 (3–9) days; p < 0.001). Of the patients who developed HN, fifteen (62.5%) patients developed HN in the first week following sICH. This shows HN has a fairly high incidence following sICH. The presence of HN is associated with longer hospital length of stays and higher rates of patient complications, which may result in worse patient outcomes. Further study is necessary to characterize the clinical relevance and treatment of HN in this population. Full article
(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)
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Open AccessReview
Fundus Autofluorescence and RPE Lipofuscin in Age-Related Macular Degeneration
J. Clin. Med. 2014, 3(4), 1302-1321; https://doi.org/10.3390/jcm3041302
Received: 28 August 2014 / Revised: 4 November 2014 / Accepted: 6 November 2014 / Published: 17 November 2014
Cited by 15 | Viewed by 3996 | PDF Full-text (1342 KB) | HTML Full-text | XML Full-text
Abstract
Genes that increase susceptibility to age-related macular degeneration (AMD) have been identified; however, since many individuals carrying these risk alleles do not develop disease, other contributors are involved. One additional factor, long implicated in the pathogenesis of AMD, is the lipofuscin of retinal [...] Read more.
Genes that increase susceptibility to age-related macular degeneration (AMD) have been identified; however, since many individuals carrying these risk alleles do not develop disease, other contributors are involved. One additional factor, long implicated in the pathogenesis of AMD, is the lipofuscin of retinal pigment epithelium (RPE). The fluorophores that constitute RPE lipofuscin also serve as a source of autofluorescence (AF) that can be imaged by confocal laser ophthalmoscopy. The AF originating from lipofuscin is excited by the delivery of short wavelength (SW) light. A second autofluorescence is emitted from the melanin of RPE (and choroid) upon near-infrared (NIR-AF) excitation. SW-AF imaging is currently used in the clinical management of retinal disorders and the advantages of NIR-AF are increasingly recognized. Here we visit the damaging properties of RPE lipofuscin that could be significant when expressed on a background of genetic susceptibility. To advance interpretations of disease-related patterns of fundus AF in AMD, we also consider the photochemical and spectrophotometric features of the lipofuscin compounds responsible for generating the fluorescence emission. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
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Open AccessArticle
The Future of Prenatal Diagnosis and Screening
J. Clin. Med. 2014, 3(4), 1291-1301; https://doi.org/10.3390/jcm3041291
Received: 18 August 2014 / Revised: 13 October 2014 / Accepted: 14 October 2014 / Published: 14 November 2014
Cited by 3 | Viewed by 2023 | PDF Full-text (57 KB) | HTML Full-text | XML Full-text
Abstract
The future of prenatal diagnosis and screening lies in developing clinical approaches and laboratory technologies applicable to genetic analyses and therapeutic interventions during embryonic development. Full article
(This article belongs to the Special Issue Prenatal Genetic Screening and Diagnosis-Part 1)
Open AccessReview
Review of Tolvaptan’s Pharmacokinetic and Pharmacodynamic Properties and Drug Interactions
J. Clin. Med. 2014, 3(4), 1276-1290; https://doi.org/10.3390/jcm3041276
Received: 22 August 2014 / Revised: 15 October 2014 / Accepted: 24 October 2014 / Published: 12 November 2014
Cited by 12 | Viewed by 2872 | PDF Full-text (189 KB) | HTML Full-text | XML Full-text
Abstract
Tolvaptan is an arginine vasopressin (AVP) antagonist that acts to increase excretion of free water (aquaresis) in patients without introducing electrolyte abnormalities or worsening renal function. It works via blockade of vasopressin-2 receptors at the renal collecting duct. Since the approval of tolvaptan [...] Read more.
Tolvaptan is an arginine vasopressin (AVP) antagonist that acts to increase excretion of free water (aquaresis) in patients without introducing electrolyte abnormalities or worsening renal function. It works via blockade of vasopressin-2 receptors at the renal collecting duct. Since the approval of tolvaptan for the treatment of hypervolemic and euvolemic hyponatremia in 2009, new studies have been reported to better characterize its pharmacokinetic and pharmacodynamic profile of tolvaptan. This paper is a review of both these clinical studies, as well as previous literature, in order to help guide appropriate clinical use of tolvaptan in patients. With appropriate monitoring of serum sodium, tolvaptan may be safely dose escalated from 15 mg once daily to a maximum effective dose of 60 mg once daily for multiple days, to achieve optimal aqauretic effects. In terms of drug interactions, co-administration of moderate to potent CYP3A4 inhibitors and inducers should be avoided. Tolvaptan should also be co-administered with caution and proper monitoring in the presence of P-glycoprotein substrate and strong inhibitors. Co-administration of tolvaptan with diuretic therapy did not appear to alter the aquaretic effect of tolvaptan; and was shown to be safe and well tolerated. Full article
(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)
Open AccessReview
Physiopathological, Epidemiological, Clinical and Therapeutic Aspects of Exercise-Associated Hyponatremia
J. Clin. Med. 2014, 3(4), 1258-1275; https://doi.org/10.3390/jcm3041258
Received: 21 August 2014 / Revised: 24 October 2014 / Accepted: 24 October 2014 / Published: 12 November 2014
Cited by 3 | Viewed by 3060 | PDF Full-text (334 KB) | HTML Full-text | XML Full-text
Abstract
Exercise-associated hyponatremia (EAH) is dilutional hyponatremia, a variant of inappropriate antidiuretic hormone secretion (SIADH), characterized by a plasma concentration of sodium lower than 135 mEq/L. The prevalence of EAH is common in endurance (<6 hours) and ultra-endurance events (>6 hours in duration), in [...] Read more.
Exercise-associated hyponatremia (EAH) is dilutional hyponatremia, a variant of inappropriate antidiuretic hormone secretion (SIADH), characterized by a plasma concentration of sodium lower than 135 mEq/L. The prevalence of EAH is common in endurance (<6 hours) and ultra-endurance events (>6 hours in duration), in which both athletes and medical providers need to be aware of risk factors, symptom presentation, and management. The development of EAH is a combination of excessive water intake, inadequate suppression of the secretion of the antidiuretic hormone (ADH) (due to non osmotic stimuli), long race duration, and very high or very low ambient temperatures. Additional risk factors include female gender, slower race times, and use of nonsteroidal anti-inflammatory drugs. Signs and symptoms of EAH include nausea, vomiting, confusion, headache and seizures; it may result in severe clinical conditions associated with pulmonary and cerebral edema, respiratory failure and death. A rapid diagnosis and appropriate treatment with a hypertonic saline solution is essential in the severe form to ensure a positive outcome. Full article
(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)
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Open AccessReview
Age-Related Macular Degeneration: A Disease of Systemic or Local Complement Dysregulation?
J. Clin. Med. 2014, 3(4), 1234-1257; https://doi.org/10.3390/jcm3041234
Received: 4 August 2014 / Revised: 20 October 2014 / Accepted: 22 October 2014 / Published: 3 November 2014
Cited by 10 | Viewed by 2761 | PDF Full-text (753 KB) | HTML Full-text | XML Full-text
Abstract
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. The role of complement in the development of AMD is now well-established. While some studies show evidence of complement dysregulation within the eye, others have demonstrated elevated systemic complement [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. The role of complement in the development of AMD is now well-established. While some studies show evidence of complement dysregulation within the eye, others have demonstrated elevated systemic complement activation in association with AMD. It is unclear which one is the primary driver of disease. This has important implications for designing novel complement-based AMD therapies. We present a summary of the current literature and suggest that intraocular rather than systemic modulation of complement may prove more effective. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
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Open AccessArticle
Hyponatraemia in Emergency Medical Admissions—Outcomes and Costs
J. Clin. Med. 2014, 3(4), 1220-1233; https://doi.org/10.3390/jcm3041220
Received: 16 August 2014 / Revised: 6 October 2014 / Accepted: 10 October 2014 / Published: 29 October 2014
Cited by 3 | Viewed by 2125 | PDF Full-text (1018 KB) | HTML Full-text | XML Full-text
Abstract
Healthcare systems in the developed world are struggling with the demand of emergency room presentations; the study of the factors driving such demand is of fundamental importance. From a database of all emergency medical admissions (66,933 episodes in 36,271 patients) to St James’ [...] Read more.
Healthcare systems in the developed world are struggling with the demand of emergency room presentations; the study of the factors driving such demand is of fundamental importance. From a database of all emergency medical admissions (66,933 episodes in 36,271 patients) to St James’ Hospital, Dublin, Ireland, over 12 years (2002 to 2013) we have explored the impact of hyponatraemia on outcomes (30 days in-hospital mortality, length of stay (LOS) and costs). Identified variables, including Acute Illness Severity, Charlson Co-Morbidity and Chronic Disabling Disease that proved predictive univariately were entered into a multivariable logistic regression model to predict the bivariate of 30 days in-hospital survival. A zero truncated Poisson regression model assessed LOS and episode costs and the incidence rate ratios were calculated. Hyponatraemia was present in 22.7% of episodes and 20.3% of patients. The 30 days in-hospital mortality rate for hyponatraemic patients was higher (15.9% vs. 6.9% p < 0.001) and the LOS longer (6.3 (95% CI 2.9, 12.2) vs. 4.0 (95% CI 1.5, 8.2) p < 0.001). Both parameters worsened with the severity of the initial sodium level. Hospital costs increased non-linearly with the severity of initial hyponatraemia. Hyponatraemia remained an independent predictor of 30 days in-hospital mortality, length of stay and costs in the multi-variable model. Full article
(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)
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Open AccessArticle
Incidence, Etiology and Outcomes of Hyponatremia after Transsphenoidal Surgery: Experience with 344 Consecutive Patients at a Single Tertiary Center
J. Clin. Med. 2014, 3(4), 1199-1219; https://doi.org/10.3390/jcm3041199
Received: 30 July 2014 / Revised: 23 September 2014 / Accepted: 27 September 2014 / Published: 28 October 2014
Cited by 10 | Viewed by 2401 | PDF Full-text (839 KB) | HTML Full-text | XML Full-text
Abstract
Hyponatremia is often seen after transsphenoidal surgery and is a source of considerable economic burden and patient-related morbidity and mortality. We performed a retrospective review of 344 patients who underwent transsphenoidal surgery at our institution between 2006 and 2012. Postoperative hyponatremia was seen [...] Read more.
Hyponatremia is often seen after transsphenoidal surgery and is a source of considerable economic burden and patient-related morbidity and mortality. We performed a retrospective review of 344 patients who underwent transsphenoidal surgery at our institution between 2006 and 2012. Postoperative hyponatremia was seen in 18.0% of patients at a mean of 3.9 days postoperatively. Hyponatremia was most commonly mild (51.6%) and clinically asymptomatic (93.8%). SIADH was the primary cause of hyponatremia in the majority of cases (n = 44, 71.0%), followed by cerebral salt wasting (n = 15, 24.2%) and desmopressin over-administration (n = 3, 4.8%). The incidence of postoperative hyponatremia was significantly higher in patients with cardiac, renal and/or thyroid disease (p = 0.0034, Objective Risk (OR) = 2.60) and in female patients (p = 0.011, OR = 2.18) or patients undergoing post-operative cerebrospinal fluid drainage (p = 0.0006). Treatment with hypertonic saline (OR = −2.4, p = 0.10) and sodium chloride tablets (OR = −1.57, p = 0.45) was associated with a non-significant trend toward faster resolution of hyponatremia. The use of fluid restriction and diuretics should be de-emphasized in the treatment of post-transsphenoidal hyponatremia, as they have not been shown to significantly alter the time-course to the restoration of sodium balance. Full article
(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)
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Open AccessReview
Obesity as an Early Symptom of the AMIS Syndrome
J. Clin. Med. 2014, 3(4), 1178-1198; https://doi.org/10.3390/jcm3041178
Received: 15 August 2014 / Revised: 24 September 2014 / Accepted: 30 September 2014 / Published: 28 October 2014
Cited by 2 | Viewed by 2136 | PDF Full-text (2038 KB) | HTML Full-text | XML Full-text
Abstract
We review evidence that the AMIS (Absence of Meal-induced Insulin Sensitization) syndrome describes a paradigm fundamental to development of obesity. The hypoglycemic response to a pulse of insulin is doubled after a meal as a result of Hepatic Insulin Sensitizing Substance (HISS), released [...] Read more.
We review evidence that the AMIS (Absence of Meal-induced Insulin Sensitization) syndrome describes a paradigm fundamental to development of obesity. The hypoglycemic response to a pulse of insulin is doubled after a meal as a result of Hepatic Insulin Sensitizing Substance (HISS), released from the liver to act selectively on muscle, heart and kidney. In the absence of HISS action, the hypoglycemic response to insulin is the same as in the fasted state, and only half of what it should be. Postprandial hyperglycemia ensues, with compensatory hyperinsulinemia, resultant hyperlipidemia and elevated free radical stress. Storage of nutrient energy shifts from glycogen in muscle to fat. Chronic AMIS results in adiposity, occurs with age, is accelerated with sucrose supplement, and prevented by a synergistic antioxidant. Exercise reverses AMIS, as do pharmaceuticals that mimic the “feeding signals”. The AMIS syndrome develops as a sequence of pathologies based on the consequences of absence of HISS action, including adiposity as the earliest symptom. Cardiac dysfunction, hypertension, hypercholesterolemia, and fatty liver are related to lack of HISS action. The AMIS syndrome hypothesis is mechanistic-based and accounts for the major pathologies associated with prediabetes, obesity, diabetes and metabolic syndrome. AMIS can be diagnosed, prevented and treated. Full article
(This article belongs to the Special Issue Obesity, Diabetes and Metabolic Syndrome)
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Open AccessReview
Effects of Hyponatremia on the Brain
J. Clin. Med. 2014, 3(4), 1163-1177; https://doi.org/10.3390/jcm3041163
Received: 25 July 2014 / Revised: 18 September 2014 / Accepted: 10 October 2014 / Published: 28 October 2014
Cited by 17 | Viewed by 4834 | PDF Full-text (1254 KB) | HTML Full-text | XML Full-text
Abstract
Hyponatremia is a very common electrolyte disorder, especially in the elderly, and is associated with significant morbidity, mortality and disability. In particular, the consequences of acute hyponatremia on the brain may be severe, including permanent disability and death. Also chronic hyponatremia can affect [...] Read more.
Hyponatremia is a very common electrolyte disorder, especially in the elderly, and is associated with significant morbidity, mortality and disability. In particular, the consequences of acute hyponatremia on the brain may be severe, including permanent disability and death. Also chronic hyponatremia can affect the health status, causing attention deficit, gait instability, increased risk of falls and fractures, and osteoporosis. Furthermore, an overly rapid correction of hyponatremia can be associated with irreversible brain damage, which may be the result of the osmotic demyelination syndrome. This review analyzes the detrimental consequences of acute and chronic hyponatremia and its inappropriate correction on the brain and the underlying physiopathological mechanisms, with a particular attention to the less known in vivo and in vitro effects of chronic hyponatremia. Full article
(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)
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Open AccessReview
Comparing ESC and iPSC—Based Models for Human Genetic Disorders
J. Clin. Med. 2014, 3(4), 1146-1162; https://doi.org/10.3390/jcm3041146
Received: 10 February 2014 / Revised: 29 September 2014 / Accepted: 30 September 2014 / Published: 24 October 2014
Cited by 10 | Viewed by 3421 | PDF Full-text (1255 KB) | HTML Full-text | XML Full-text
Abstract
Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in [...] Read more.
Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in modeling multiple genetic diseases. The isolation of human embryonic stem cells (ESCs) from diseased blastocysts, the derivation of induced pluripotent stem cells (iPSCs) from patients’ somatic cells, and the new technologies for genome editing of pluripotent stem cells have opened a new window of opportunities in the field of disease modeling, and enabled studying diseases that couldn’t be modeled in the past. Importantly, despite the high similarity between ESCs and iPSCs, there are several fundamental differences between these cells, which have important implications regarding disease modeling. In this review we compare ESC-based models to iPSC-based models, and highlight the advantages and disadvantages of each system. We further suggest a roadmap for how to choose the optimal strategy to model each specific disorder. Full article
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Open AccessReview
iPSC-Based Models to Unravel Key Pathogenetic Processes Underlying Motor Neuron Disease Development
J. Clin. Med. 2014, 3(4), 1124-1145; https://doi.org/10.3390/jcm3041124
Received: 30 July 2014 / Revised: 19 September 2014 / Accepted: 22 September 2014 / Published: 17 October 2014
Cited by 4 | Viewed by 2897 | PDF Full-text (1386 KB) | HTML Full-text | XML Full-text
Abstract
Motor neuron diseases (MNDs) are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs) and/or lower motor neurons (LMNs). The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include [...] Read more.
Motor neuron diseases (MNDs) are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs) and/or lower motor neurons (LMNs). The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include sporadic and familial amyotrophic lateral sclerosis (sALS-fALS), while the most common infantile MND is represented by spinal muscular atrophy (SMA). No effective treatment is ccurrently available for MNDs, as for the vast majority of neurodegenerative disorders, and cures are limited to supportive care and symptom relief. The lack of a deep understanding of MND pathogenesis accounts for the difficulties in finding a cure, together with the scarcity of reliable in vitro models. Recent progresses in stem cell field, in particular in the generation of induced Pluripotent Stem Cells (iPSCs) has made possible for the first time obtaining substantial amounts of human cells to recapitulate in vitro some of the key pathogenetic processes underlying MNDs. In the present review, recently published studies involving the use of iPSCs to unravel aspects of ALS and SMA pathogenesis are discussed with an overview of their implications in the process of finding a cure for these still orphan disorders. Full article
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Open AccessReview
Clinical Potentials of Cardiomyocytes Derived from Patient-Specific Induced Pluripotent Stem Cells
J. Clin. Med. 2014, 3(4), 1105-1123; https://doi.org/10.3390/jcm3041105
Received: 31 July 2014 / Revised: 15 September 2014 / Accepted: 17 September 2014 / Published: 15 October 2014
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Abstract
The lack of appropriate human cardiomyocyte-based experimental platform has largely hindered the study of cardiac diseases and the development of therapeutic strategies. To date, somatic cells isolated from human subjects can be reprogramed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into [...] Read more.
The lack of appropriate human cardiomyocyte-based experimental platform has largely hindered the study of cardiac diseases and the development of therapeutic strategies. To date, somatic cells isolated from human subjects can be reprogramed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into functional cardiomyocytes. This powerful reprogramming technology provides a novel in vitro human cell-based platform for the study of human hereditary cardiac disorders. The clinical potential of using iPSCs derived from patients with inherited cardiac disorders for therapeutic studies have been increasingly highlighted. In this review, the standard procedures for generating patient-specific iPSCs and the latest commonly used cardiac differentiation protocols will be outlined. Furthermore, the progress and limitations of current applications of iPSCs and iPSCs-derived cardiomyocytes in cell replacement therapy, disease modeling, drug-testing and toxicology studies will be discussed in detail. Full article
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Open AccessArticle
Neurosurgical Hyponatremia
J. Clin. Med. 2014, 3(4), 1084-1104; https://doi.org/10.3390/jcm3041084
Received: 3 August 2014 / Revised: 11 September 2014 / Accepted: 22 September 2014 / Published: 14 October 2014
Cited by 6 | Viewed by 2905 | PDF Full-text (1051 KB) | HTML Full-text | XML Full-text
Abstract
Hyponatremia is a frequent electrolyte imbalance in hospital inpatients. Acute onset hyponatremia is particularly common in patients who have undergone any type of brain insult, including traumatic brain injury, subarachnoid hemorrhage and brain tumors, and is a frequent complication of intracranial procedures. Acute [...] Read more.
Hyponatremia is a frequent electrolyte imbalance in hospital inpatients. Acute onset hyponatremia is particularly common in patients who have undergone any type of brain insult, including traumatic brain injury, subarachnoid hemorrhage and brain tumors, and is a frequent complication of intracranial procedures. Acute hyponatremia is more clinically dangerous than chronic hyponatremia, as it creates an osmotic gradient between the brain and the plasma, which promotes the movement of water from the plasma into brain cells, causing cerebral edema and neurological compromise. Unless acute hyponatremia is corrected promptly and effectively, cerebral edema may manifest through impaired consciousness level, seizures, elevated intracranial pressure, and, potentially, death due to cerebral herniation. The pathophysiology of hyponatremia in neurotrauma is multifactorial, but most cases appear to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Classical treatment of SIADH with fluid restriction is frequently ineffective, and in some circumstances, such as following subarachnoid hemorrhage, contraindicated. However, the recently developed vasopressin receptor antagonist class of drugs provides a very useful tool in the management of neurosurgical SIADH. In this review, we summarize the existing literature on the clinical features, causes, and management of hyponatremia in the neurosurgical patient. Full article
(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)
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Open AccessReview
Human iPS Cell-Derived Germ Cells: Current Status and Clinical Potential
J. Clin. Med. 2014, 3(4), 1064-1083; https://doi.org/10.3390/jcm3041064
Received: 30 July 2014 / Revised: 17 September 2014 / Accepted: 22 September 2014 / Published: 13 October 2014
Cited by 9 | Viewed by 5789 | PDF Full-text (1088 KB) | HTML Full-text | XML Full-text
Abstract
Recently, fertile spermatozoa and oocytes were generated from mouse induced pluripotent (iPS) cells using a combined in vitro and in vivo induction system. With regard to germ cell induction from human iPS cells, progress has been made particularly in the male germline, demonstrating [...] Read more.
Recently, fertile spermatozoa and oocytes were generated from mouse induced pluripotent (iPS) cells using a combined in vitro and in vivo induction system. With regard to germ cell induction from human iPS cells, progress has been made particularly in the male germline, demonstrating in vitro generation of haploid, round spermatids. Although iPS-derived germ cells are expected to be developed to yield a form of assisted reproductive technology (ART) that can address unmet reproductive needs, genetic and/or epigenetic instabilities abound in iPS cell generation and germ cell induction. In addition, there is still room to improve the induction protocol in the female germline. However, rapid advances in stem cell research are likely to make such obstacles surmountable, potentially translating induced germ cells into the clinical setting in the immediate future. This review examines the current status of the induction of germ cells from human iPS cells and discusses the clinical potential, as well as future directions. Full article
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J. Clin. Med. EISSN 2077-0383 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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