Journal of Clinical Medicine

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Open AccessCommentary

The State of Play with iPSCs and Spinal Cord Injury Models

by Stuart I. Hodgetts, Michael Edel and Alan R. Harvey

J. Clin. Med. 2015, 4(1), 193-203; https://doi.org/10.3390/jcm4010193 - 14 Jan 2015

Cited by 7 | Viewed by 6256

The application of induced pluripotent stem cell (iPSC) technologies in cell based strategies, for the repair of the central nervous system (with particular focus on the spinal cord), is moving towards the potential use of clinical grade donor cells. The ability of iPSCs [...] Read more.

The application of induced pluripotent stem cell (iPSC) technologies in cell based strategies, for the repair of the central nervous system (with particular focus on the spinal cord), is moving towards the potential use of clinical grade donor cells. The ability of iPSCs to generate donor neuronal, glial and astrocytic phenotypes for transplantation is highlighted here, and we review recent research using iPSCs in attempts to treat spinal cord injury in various animal models. Also discussed are issues relating to the production of clinical grade iPSCs, recent advances in transdifferentiation protocols for iPSC-derived donor cell populations, concerns about tumourogenicity, and whether iPSC technologies offer any advantages over previous donor cell candidates or tissues already in use as therapeutic tools in experimental spinal cord injury studies. Full article

(This article belongs to the Special Issue iPS Cells for Modelling and Treatment of Human Diseases)

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Open AccessReview

NLRP3 Inflammasome and Pathobiology in AMD

by Lucia Celkova, Sarah L. Doyle and Matthew Campbell

J. Clin. Med. 2015, 4(1), 172-192; https://doi.org/10.3390/jcm4010172 - 14 Jan 2015

Cited by 84 | Viewed by 13983

Abstract

Age-related macular degeneration (AMD) is the leading cause of central vision loss and blindness in the elderly. It is characterized by a progressive loss of photoreceptors in the macula due to damage to the retinal pigment epithelium (RPE). Clinically, it is manifested by [...] Read more.

Age-related macular degeneration (AMD) is the leading cause of central vision loss and blindness in the elderly. It is characterized by a progressive loss of photoreceptors in the macula due to damage to the retinal pigment epithelium (RPE). Clinically, it is manifested by drusen deposition between the RPE and underlying choroid and accumulation of lipofuscin in the RPE. End-stage disease is characterized by geographic atrophy (dry AMD) or choroidal neovascularization (wet AMD). The NLRP3 inflammasome has recently been implicated in the disease pathology. Here we review the current knowledge on the involvement of this multiprotein complex and its effector cytokines interleukin-1β (IL-1β) and IL-18 in AMD progression. We also describe cell death mechanisms that have been proposed to underlie RPE degeneration in AMD and discuss the role of autophagy in the regulation of disease progression. Full article

(This article belongs to the Special Issue Age-Related Macular Disease)

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Open AccessReview

Design of a Tumorigenicity Test for Induced Pluripotent Stem Cell (iPSC)-Derived Cell Products

by Shin Kawamata, Hoshimi Kanemura, Noriko Sakai, Masayo Takahashi and Masahiro J. Go

J. Clin. Med. 2015, 4(1), 159-171; https://doi.org/10.3390/jcm4010159 - 14 Jan 2015

Cited by 57 | Viewed by 11078

Abstract

Human Pluripotent Stem Cell (PSC)-derived cell therapy holds enormous promise because of the cells’ “unlimited” proliferative capacity and the potential to differentiate into any type of cell. However, these features of PSC-derived cell products are associated with concerns regarding the generation of iatrogenic [...] Read more.

Human Pluripotent Stem Cell (PSC)-derived cell therapy holds enormous promise because of the cells’ “unlimited” proliferative capacity and the potential to differentiate into any type of cell. However, these features of PSC-derived cell products are associated with concerns regarding the generation of iatrogenic teratomas or tumors from residual immature or non-terminally differentiated cells in the final cell product. This concern has become a major hurdle to the introduction of this therapy into the clinic. Tumorigenicity testing is therefore a key preclinical safety test in PSC-derived cell therapy. Tumorigenicity testing becomes particularly important when autologous human induced Pluripotent Stem Cell (iPSC)-derived cell products with no immuno-barrier are considered for transplantation. There has been, however, no internationally recognized guideline for tumorigenicity testing of PSC-derived cell products for cell therapy. In this review, we outline the points to be considered in the design and execution of tumorigenicity tests, referring to the tests and laboratory work that we have conducted for an iPSC-derived retinal pigment epithelium (RPE) cell product prior to its clinical use. Full article

(This article belongs to the Special Issue iPS Cells for Modelling and Treatment of Human Diseases)

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Open AccessCase Report

Three Adult Cases of Orbital Hidrocystoma Presenting with Blepharoptosis

by Lucieni B. Ferraz, John R. Burroughs, Larissa H. Satto, Kryscia L. Natsuaki, Roberta L. F. S. Meneguin, Mariangela E. A. Marques and Silvana A. Schellini

J. Clin. Med. 2015, 4(1), 150-158; https://doi.org/10.3390/jcm4010150 - 13 Jan 2015

Cited by 10 | Viewed by 10830

Abstract

Purpose: To report adult cases of superior orbital apocrine hidrocystoma. Methods: Retrospective case series of three patients with superior orbital apocrine hidrocystoma and blepharoptosis with review of the clinical aspects of each of the cases. Results: All three cases presented with blepharoptosis. Two [...] Read more.

Purpose: To report adult cases of superior orbital apocrine hidrocystoma. Methods: Retrospective case series of three patients with superior orbital apocrine hidrocystoma and blepharoptosis with review of the clinical aspects of each of the cases. Results: All three cases presented with blepharoptosis. Two of the cases had occult hidrocystoma, and one was visibly subcutaneous at presentation. Conclusions: Although rare and more common along the eyelid margin, apocrine hidrocystomas may occur in the orbit leading to secondary blepharoptosis and should be included within the differential diagnosis of orbital cysts. Physicians should therefore be aware of this possibility. Full article

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Open AccessReview

Pediatric AML: From Biology to Clinical Management

by Jasmijn D. E. De Rooij, C. Michel Zwaan and Marry Van den Heuvel-Eibrink

J. Clin. Med. 2015, 4(1), 127-149; https://doi.org/10.3390/jcm4010127 - 9 Jan 2015

Cited by 152 | Viewed by 17501

Abstract

Pediatric acute myeloid leukemia (AML) represents 15%–20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de novo [...] Read more.

Pediatric acute myeloid leukemia (AML) represents 15%–20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de novo entity, but in a minority, it is a secondary malignancy. The diagnostic classification of pediatric AML includes a combination of morphology, cytochemistry, immunophenotyping and molecular genetics. Outcome is mainly dependent on the initial response to treatment and molecular and cytogenetic aberrations. Treatment consists of a combination of intensive anthracycline- and cytarabine-containing chemotherapy and stem cell transplantation in selected genetic high-risk cases or slow responders. In general, ~30% of all pediatric AML patients will suffer from relapse, whereas 5%–10% of the patients will die due to disease complications or the side-effects of the treatment. Targeted therapy may enhance anti-leukemic efficacy and minimize treatment-related morbidity and mortality, but requires detailed knowledge of the genetic abnormalities and aberrant pathways involved in leukemogenesis. These efforts towards future personalized therapy in a rare disease, such as pediatric AML, require intensive international collaboration in order to enhance the survival rates of pediatric AML, while aiming to reduce long-term toxicity. Full article

(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)

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Open AccessEditorial

Acknowledgement to Reviewers of the Journal of Clinical Medicine in 2014

by Journal of Clinical Medicine Editorial Office

J. Clin. Med. 2015, 4(1), 124-126; https://doi.org/10.3390/jcm4010124 - 8 Jan 2015

Cited by 1 | Viewed by 3820

Abstract

The editors of the Journal of Clinical Medicine would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2014: [...] Full article

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Open AccessArticle

Scalable Electrophysiological Investigation of iPS Cell-Derived Cardiomyocytes Obtained by a Lentiviral Purification Strategy

by Stephanie Friedrichs, Daniela Malan, Yvonne Voss and Philipp Sasse

J. Clin. Med. 2015, 4(1), 102-123; https://doi.org/10.3390/jcm4010102 - 8 Jan 2015

Cited by 13 | Viewed by 10838

Abstract

Disease-specific induced pluripotent stem (iPS) cells can be generated from patients and differentiated into functional cardiomyocytes for characterization of the disease and for drug screening. In order to obtain pure cardiomyocytes for automated electrophysiological investigation, we here report a novel non-clonal purification strategy [...] Read more.

Disease-specific induced pluripotent stem (iPS) cells can be generated from patients and differentiated into functional cardiomyocytes for characterization of the disease and for drug screening. In order to obtain pure cardiomyocytes for automated electrophysiological investigation, we here report a novel non-clonal purification strategy by using lentiviral gene transfer of a puromycin resistance gene under the control of a cardiac-specific promoter. We have applied this method to our previous reported wild-type and long QT syndrome 3 (LQTS 3)-specific mouse iPS cells and obtained a pure cardiomyocyte population. These cells were investigated by action potential analysis with manual and automatic planar patch clamp technologies, as well as by recording extracellular field potentials using a microelectrode array system. Action potentials and field potentials showed the characteristic prolongation at low heart rates in LQTS 3-specific, but not in wild-type iPS cell-derived cardiomyocytes. Hence, LQTS 3-specific cardiomyocytes can be purified from iPS cells with a lentiviral strategy, maintain the hallmarks of the LQTS 3 disease and can be used for automated electrophysiological characterization and drug screening. Full article

(This article belongs to the Special Issue iPS Cells for Modelling and Treatment of Human Diseases)

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Open AccessReview

Hyponatremia in Patients with Cirrhosis of the Liver

by Mauro Bernardi, Carmen Serena Ricci and Luca Santi

J. Clin. Med. 2015, 4(1), 85-101; https://doi.org/10.3390/jcm4010085 - 31 Dec 2014

Cited by 24 | Viewed by 18505

Abstract

Hyponatremia is common in cirrhosis. It mostly occurs in an advanced stage of the disease and is associated with complications and increased mortality. Either hypovolemic or, more commonly, hypervolemic hyponatremia can be seen in cirrhosis. Impaired renal sodium handling due to renal hypoperfusion [...] Read more.

Hyponatremia is common in cirrhosis. It mostly occurs in an advanced stage of the disease and is associated with complications and increased mortality. Either hypovolemic or, more commonly, hypervolemic hyponatremia can be seen in cirrhosis. Impaired renal sodium handling due to renal hypoperfusion and increased arginine-vasopressin secretion secondary to reduced effective volemia due to peripheral arterial vasodilation represent the main mechanisms leading to dilutional hyponatremia in this setting. Patients with cirrhosis usually develop slowly progressing hyponatremia. In different clinical contexts, it is associated with neurological manifestations due to increased brain water content, where the intensity is often magnified by concomitant hyperammonemia leading to hepatic encephalopathy. Severe hyponatremia requiring hypertonic saline infusion is rare in cirrhosis. The management of asymptomatic or mildly symptomatic hyponatremia mainly rely on the identification and treatment of precipitating factors. However, sustained resolution of hyponatremia is often difficult to achieve. V2 receptor blockade by Vaptans is certainly effective, but their long-term safety, especially when associated to diuretics given to control ascites, has not been established as yet. As in other conditions, a rapid correction of long-standing hyponatremia can lead to irreversible brain damage. The liver transplant setting represents a condition at high risk for the occurrence of such complications. Full article

(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)

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Open AccessCase Report

Malignant Cardiac Tamponade from Non-Small Cell Lung Cancer: Case Series from the Era of Molecular Targeted Therapy

by Bob T. Li, Antonia Pearson, Nick Pavlakis, David Bell, Adrian Lee, David Chan, Michael Harden, Manu Mathur, David Marshman, Peter Brady and Stephen Clarke

J. Clin. Med. 2015, 4(1), 75-84; https://doi.org/10.3390/jcm4010075 - 30 Dec 2014

Cited by 15 | Viewed by 12913

Abstract

Cardiac tamponade complicating malignant pericardial effusion from non-small cell lung cancer (NSCLC) is generally associated with extremely poor prognosis. With improved systemic chemotherapy and molecular targeted therapy for NSCLC in recent years, the prognosis of such patients and the value of invasive cardiothoracic [...] Read more.

Cardiac tamponade complicating malignant pericardial effusion from non-small cell lung cancer (NSCLC) is generally associated with extremely poor prognosis. With improved systemic chemotherapy and molecular targeted therapy for NSCLC in recent years, the prognosis of such patients and the value of invasive cardiothoracic surgery in this setting have not been adequately examined. We report outcomes from a contemporary case series of eight patients who presented with malignant cardiac tamponade due to NSCLC to an Australian academic medical institution over an 18 months period. Two cases of cardiac tamponade were de novo presentations of NSCLC and six cases were presentations following previous therapy for NSCLC. The median survival was 4.5 months with a range between 9 days to alive beyond 17 months. The two longest survivors are still receiving active therapy at 17 and 15 months after invasive surgical pericardial window respectively. One survivor had a histological subtype of large cell neuroendocrine carcinoma and the other received targeted therapy for epidermal growth factor receptor mutation. These results support the consideration of active surgical palliation to treating this oncological emergency complicating NSCLC, including the use of urgent drainage, surgical creation of pericardial window followed by appropriate systemic therapy in suitably fit patients. Full article

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Open AccessArticle

Implications of Hyponatremia in Liver Transplantation

by Sertac Cimen, Sanem Guler, Subhashini Ayloo and Michele Molinari

J. Clin. Med. 2015, 4(1), 66-74; https://doi.org/10.3390/jcm4010066 - 29 Dec 2014

Cited by 6 | Viewed by 9547

Abstract

Although there are a limited number of quality studies, appropriate peri-operative management of serum electrolytes seems to reduce adverse outcomes in liver transplantation. Hyponatremia is defined as the presence of serum concentration of sodium equal ≤130 mmol/L and it is detected in approximately [...] Read more.

Although there are a limited number of quality studies, appropriate peri-operative management of serum electrolytes seems to reduce adverse outcomes in liver transplantation. Hyponatremia is defined as the presence of serum concentration of sodium equal ≤130 mmol/L and it is detected in approximately 20% of patients with end stage liver disease waiting for a liver transplant (LT). This paper will focus on the pathogenesis of dilutional hyponatremia and its significance in terms of both candidacy for LT and post-operative outcomes. Full article

(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)

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Open AccessReview

The Potential for iPS-Derived Stem Cells as a Therapeutic Strategy for Spinal Cord Injury: Opportunities and Challenges

by Mohamad Khazaei, Ahad M. Siddiqui and Michael G. Fehlings

J. Clin. Med. 2015, 4(1), 37-65; https://doi.org/10.3390/jcm4010037 - 29 Dec 2014

Cited by 26 | Viewed by 11602

Abstract

Spinal cord injury (SCI) is a devastating trauma causing long-lasting disability. Although advances have occurred in the last decade in the medical, surgical and rehabilitative treatments of SCI, the therapeutic approaches are still not ideal. The use of cell transplantation as a therapeutic [...] Read more.

Spinal cord injury (SCI) is a devastating trauma causing long-lasting disability. Although advances have occurred in the last decade in the medical, surgical and rehabilitative treatments of SCI, the therapeutic approaches are still not ideal. The use of cell transplantation as a therapeutic strategy for the treatment of SCI is promising, particularly since it can target cell replacement, neuroprotection and regeneration. Cell therapies for treating SCI are limited due to several translational roadblocks, including ethical and practical concerns regarding cell sources. The use of iPSCs has been particularly attractive, since they avoid the ethical and moral concerns that surround other stem cells. Furthermore, various cell types with potential for application in the treatment of SCI can be created from autologous sources using iPSCs. For applications in SCI, the iPSCs can be differentiated into neural precursor cells, neurons, oligodendrocytes, astrocytes, neural crest cells and mesenchymal stromal cells that can act by replacing lost cells or providing environmental support. Some methods, such as direct reprogramming, are being investigated to reduce tumorigenicity and improve reprogramming efficiencies, which have been some of the issues surrounding the use of iPSCs clinically to date. Recently, iPSCs have entered clinical trials for use in age-related macular degeneration, further supporting their promise for translation in other conditions, including SCI. Full article

(This article belongs to the Special Issue iPS Cells for Modelling and Treatment of Human Diseases)

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Open AccessCommunication

Hyponatremia and the Thyroid: Causality or Association?

by Kevin M. Pantalone and Betul A. Hatipoglu

J. Clin. Med. 2015, 4(1), 32-36; https://doi.org/10.3390/jcm4010032 - 26 Dec 2014

Cited by 16 | Viewed by 8737

Abstract

Thyroid disorders, particularly hypothyroidism, have historically been implicated in the development of serum hyponatremia. However, in more recent years, this paradigm has been challenged, and it has been suggested that the link between hypothyroidism and hyponatremia may merely be an association. This review [...] Read more.

Thyroid disorders, particularly hypothyroidism, have historically been implicated in the development of serum hyponatremia. However, in more recent years, this paradigm has been challenged, and it has been suggested that the link between hypothyroidism and hyponatremia may merely be an association. This review will focus on the thyroid and its link with serum hyponatremia, and review the available literature on the topic. Full article

(This article belongs to the Special Issue Hyponatremia: Advances in Diagnosis and Management)

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Open AccessReview

Role of Factor H and Related Proteins in Regulating Complement Activation in the Macula, and Relevance to Age-Related Macular Degeneration

by Simon J. Clark and Paul N. Bishop

J. Clin. Med. 2015, 4(1), 18-31; https://doi.org/10.3390/jcm4010018 - 26 Dec 2014

Cited by 36 | Viewed by 10263

Abstract

The recent revolution in age-related macular degeneration (AMD) genetics has demonstrated that genetic alterations affecting the alternative pathway of the complement cascade have a major influence on AMD risk. One of the two most important genetic loci is on chromosome 1 and contains [...] Read more.

The recent revolution in age-related macular degeneration (AMD) genetics has demonstrated that genetic alterations affecting the alternative pathway of the complement cascade have a major influence on AMD risk. One of the two most important genetic loci is on chromosome 1 and contains genes encoding complement factor H (FH) and the factor H related proteins (FHR proteins). In macular tissue, especially Bruch’s membrane, relatively high levels of a truncated splice variant of FH called factor H-like protein 1 (FHL-1) are present. Here we discuss how genetic variations may alter the amounts, or by altering their protein sequences, the functions of these proteins. In particular, the common Y402H polymorphism affects the ability of FHL-1 and FH to localize to Bruch’s membrane and the inner choroid because it alters the ability of these complement regulators to bind heparan sulphate (HS) in these structures. In addition, there is an age-related loss of HS from Bruch’s membrane. We hypothesize that a combination of poor binding of the 402H variants of FHL-1 and FH to Bruch’s membrane, combined with a decrease in binding due to age-related HS loss, eventually results in insufficient FHL-1 and FH binding to Bruch’s membrane. This could result in complement activation, inflammation and thereby predispose to AMD. Full article

(This article belongs to the Special Issue Age-Related Macular Disease)

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Open AccessReview

Clinical Results of Hypomethylating Agents in AML Treatment

by Marjan Cruijsen, Michael Lübbert, Pierre Wijermans and Gerwin Huls

J. Clin. Med. 2015, 4(1), 1-17; https://doi.org/10.3390/jcm4010001 - 25 Dec 2014

Cited by 38 | Viewed by 10680

Abstract

Epigenetic changes play an important role in the development of acute myeloid leukemia (AML). Unlike gene mutations, epigenetic changes are potentially reversible, which makes them attractive for therapeutic intervention. Agents that affect epigenetics are the DNA methyltransferase inhibitors, azacitidine and decitabine. Because of [...] Read more.

Epigenetic changes play an important role in the development of acute myeloid leukemia (AML). Unlike gene mutations, epigenetic changes are potentially reversible, which makes them attractive for therapeutic intervention. Agents that affect epigenetics are the DNA methyltransferase inhibitors, azacitidine and decitabine. Because of their relatively mild side effects, azacitidine and decitabine are particularly feasible for the treatment of older patients and patients with co-morbidities. Both drugs have remarkable activity against AML blasts with unfavorable cytogenetic characteristics. Recent phase 3 trials have shown the superiority of azacitidine and decitabine compared with conventional care for older AML patients (not eligible for intensive treatment). Results of treatment with modifications of the standard azacitidine (seven days 75 mg/m² SC; every four weeks) and decitabine (five days 20 mg/m² IV; every four weeks) schedules have been reported. Particularly, the results of the 10-day decitabine schedule are promising, revealing complete remission (CR) rates around 45% (CR + CRi (i.e., CR with incomplete blood count recovery) around 64%) almost comparable with intensive chemotherapy. Application of hypomethylating agents to control AML at the cost of minimal toxicity is a very promising strategy to “bridge” older patients with co-morbidities to the potential curative treatment of allogeneic hematopoietic cell transplantation. In this article, we discuss the role of DNA methyltransferase inhibitors in AML. Full article

(This article belongs to the Special Issue AML in the Molecular Age: From Biology to Clinical Management)

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J. Clin. Med., Volume 4, Issue 1 (January 2015) – 14 articles , Pages 1-203

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