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J. Clin. Med., Volume 6, Issue 3 (March 2017)

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Cover Story (view full-size image) Smoking, high alcohol intake and obesity are factors that generate different pro-inflammatory [...] Read more.
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Open AccessFeature PaperReview
The History of Clotting Factor Concentrates Pharmacokinetics
J. Clin. Med. 2017, 6(3), 35; https://doi.org/10.3390/jcm6030035 - 20 Mar 2017
Cited by 7 | Viewed by 2105
Abstract
Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients’ home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak, [...] Read more.
Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients’ home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak, and purification by Mabs made the plasma-derived concentrates safer and purer. CFCs were considered equivalent to the other drugs and general rules and methods of pharmacokinetics (PK) were applied to their study. After the first attempts by graphical methods and calculation of In Vivo Recovery, compartment and non-compartment methods were applied also to the study of PK of CFCs. The bioequivalence of the new concentrates produced by means of recombinant DNA biotechnology was evaluated in head-to-head PK studies. Since the beginning, the large inter-patient variability of dose/response of replacement therapy was realized. PK allowed tailoring haemophilia therapy and PK driven prophylaxis resulted more cost effective. Unfortunately, the need of several blood samples and logistic difficulties made the PK studies very demanding. Recently, population PK (PopPK) has been applied to the prediction of CFCs dosing by Bayesian methodology. By PopPK also sparse data may allow evaluating the appropriateness of replacement therapy. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
Open AccessFeature PaperArticle
Italian Registry of Congenital Bleeding Disorders
J. Clin. Med. 2017, 6(3), 34; https://doi.org/10.3390/jcm6030034 - 19 Mar 2017
Cited by 6 | Viewed by 1874
Abstract
In Italy, the surveillance of people with bleeding disorders is based on the National Registry of Congenital Coagulopathies (NRCC) managed by the Italian National Institute of Health (Istituto Superiore di Sanità). The NRCC collects epidemiological and therapeutic data from the 54 Hemophilia Treatment [...] Read more.
In Italy, the surveillance of people with bleeding disorders is based on the National Registry of Congenital Coagulopathies (NRCC) managed by the Italian National Institute of Health (Istituto Superiore di Sanità). The NRCC collects epidemiological and therapeutic data from the 54 Hemophilia Treatment Centers, members of the Italian Association of Hemophilia Centres (AICE). The number of people identified with bleeding disorders has increased over the years, with the number rising from approx. 7000 in 2000 to over 11,000 in 2015. The NRCC includes 4020 patients with hemophilia A and 859 patients with hemophilia B. The prevalence of the rare type 3 vWD is 0.20/100,000 inhabitants. Less common congenital bleeding disorders include the following deficiencies: Factor I (fibrinogen), Factor II (prothrombin), Factor V, Factor VII, Factor X, Factor XI and Factor XIII, which affect 1953 patients. Hepatitis C Virus (HCV) infection affects 1561 patients, more than 200 of whom have two infections (HCV + HIV). Estimated hemophilia-related drug consumption in 2015 was approx. 550 million IU of FVIII for hemophilia A patients and approx. 70 million IU of FIX for hemophilia B patients. The NRCC, with its bleeding disorder data set, is a tool that can provide answers to fundamental questions in public health, monitoring care provision and drug treatment, as well as facilitating clinical and epidemiological research.
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(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
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Open AccessFeature PaperReview
Improving Communication between Physicians and Their Patients through Mindfulness and Compassion-Based Strategies: A Narrative Review
J. Clin. Med. 2017, 6(3), 33; https://doi.org/10.3390/jcm6030033 - 17 Mar 2017
Cited by 14 | Viewed by 3173
Abstract
Communication between physicians and patients is a key pillar of psychosocial support for enhancing the healing process of patients and for increasing their well-being and quality of life. Physicians and other health professionals might benefit from interventions that increase their self-care, awareness, compassion, [...] Read more.
Communication between physicians and patients is a key pillar of psychosocial support for enhancing the healing process of patients and for increasing their well-being and quality of life. Physicians and other health professionals might benefit from interventions that increase their self-care, awareness, compassion, and other-focused concern, and reduce the chances of distress and burnout. There is substantial evidence for the contribution of different management strategies to achieve these aims. The goal of this article is to review the potential effect of mindfulness and compassion-based strategies for the improvement of physician-patient interactions. The acquisition of the necessary skills by physicians requires continuous education. Future research will be useful for identifying more evidence on the cost-effectiveness of this type of intervention. Full article
(This article belongs to the Special Issue Psychosocial Interaction between Physicians and Patients)
Open AccessArticle
In Vitro and In Vivo Effects of Gracilaria verrucosa Extracts on Osteoclast Differentiation
J. Clin. Med. 2017, 6(3), 32; https://doi.org/10.3390/jcm6030032 - 14 Mar 2017
Cited by 9 | Viewed by 1879
Abstract
Bone remodeling, a physiological process characterized by bone formation by osteoblasts and bone resorption by osteoclasts, is important for the maintenance of healthy bone in adult humans. Osteoclasts play a critical role in bone erosion and osteoporosis and are bone-specific multinucleated cells generated [...] Read more.
Bone remodeling, a physiological process characterized by bone formation by osteoblasts and bone resorption by osteoclasts, is important for the maintenance of healthy bone in adult humans. Osteoclasts play a critical role in bone erosion and osteoporosis and are bone-specific multinucleated cells generated through differentiation of monocyte/macrophage lineage precursors. Receptor activator of NF-κB ligand (RANKL) has been reported to induce osteoclast differentiation. In this study, we explored whether Gracilaria verrucosa extracts (GE) could affect RANKL-mediated osteoclast differentiation. GE significantly inhibited RANKL-activated osteoclast differentiation by inhibiting protein expression of c-fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), vital factors in RANKL-mediated osteoclastogenesis. In addition, GE attenuated ovariectomy-induced bone loss in mice. In summary, GE can prevent osteoclastogenesis and hormone-related bone loss via blockage of c-fos-NFATc1 signaling. Our results suggest that GE may have therapeutic potential in the treatment of postmenopausal osteoporosis. Full article
(This article belongs to the Special Issue Bone Cell Biology and Transcriptional Regulation)
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Open AccessArticle
The Relationship between Mitochondrial Respiratory Chain Activities in Muscle and Metabolites in Plasma and Urine: A Retrospective Study
J. Clin. Med. 2017, 6(3), 31; https://doi.org/10.3390/jcm6030031 - 10 Mar 2017
Cited by 3 | Viewed by 1614
Abstract
The relationship between 114 cases with decreased enzymatic activities of mitochondrial respiratory chain (MRC) complexes I-V (C I-V) in muscle and metabolites in urine and plasma was retrospectively examined. Less than 35% disclosed abnormal plasma amino acids and acylcarnitines, with elevated alanine and [...] Read more.
The relationship between 114 cases with decreased enzymatic activities of mitochondrial respiratory chain (MRC) complexes I-V (C I-V) in muscle and metabolites in urine and plasma was retrospectively examined. Less than 35% disclosed abnormal plasma amino acids and acylcarnitines, with elevated alanine and low free carnitine or elevated C4-OH-carnitine as the most common findings, respectively. Abnormal urine organic acids (OA) were detected in 82% of all cases. In CI and CII defects, lactic acid (LA) in combination with other metabolites was the most common finding. 3-Methylglutaconic (3MGA) acid was more frequent in CIV and CV, while Tyrosine metabolites, mainly 4-hydroxyphenyllactate, were common in CI and IV defects. Ketones were present in all groups but more prominent in combined deficiencies. There was a significant strong correlation between elevated urinary LA and plasma lactate but none between urine Tyrosine metabolites and plasma Tyrosine or urinary LA and plasma Alanine. All except one of 14 cases showed elevated FGF21, but correlation with urine OA was weak. Although this study is limited, we conclude that urine organic acid test in combination with plasma FGF21 determination are valuable tools in the diagnosis of mitochondrial diseases. Full article
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Open AccessArticle
Novel Pharmacological Activity of Artesunate and Artemisinin: Their Potential as Anti-Tubercular Agents
J. Clin. Med. 2017, 6(3), 30; https://doi.org/10.3390/jcm6030030 - 10 Mar 2017
Cited by 8 | Viewed by 2063
Abstract
Tuberculosis is a major infectious disease that globally causes the highest human mortality. From this aspect, this study was carried out to evaluate novel pharmacological activities/effects of artesunate and artemisinin causing anti-tubercular activity/effects against Mycobacterium tuberculosis (Mtb). The anti-Mtb activities/effects of artesunate and [...] Read more.
Tuberculosis is a major infectious disease that globally causes the highest human mortality. From this aspect, this study was carried out to evaluate novel pharmacological activities/effects of artesunate and artemisinin causing anti-tubercular activity/effects against Mycobacterium tuberculosis (Mtb). The anti-Mtb activities/effects of artesunate and artemisinin were evaluated using different anti-Mtb indicator assays, such as the resazurin microtiter assay, the Mycobacteria Growth Indicator Tube (MGIT) 960 system assay, and the Ogawa slant medium assay, as well as in vivo tests. Artesunate showed selective anti-Mtb effects by strongly inhibiting the growth of Mtb compared to artemisinin, and consistently induced anti-Mtb activity/effects by effectively inhibiting Mtb in the MGIT 960 system and in Ogawa slant medium for 21 days with a single dose; its minimum inhibitory concentration was 300 µg/mL in in vitro testing. Furthermore, artesunate demonstrated an anti-tubercular effect/action with a daily dose of 3.5 mg/kg in an in vivo test for four weeks, which did not indicate or induce toxicity and side effects. These results demonstrate that artesunate effectively inhibits the growth and/or proliferation of Mtb through novel pharmacological activities/actions, as well as induces anti-Mtb activity. This study shows its potential as a potent candidate agent for developing new anti-tuberculosis drugs of an effective/safe next generation, and suggests novel insights into its effective use by repurposing existing drugs through new pharmacological activity/effects as one of the substantive alternatives for inhibiting tuberculosis. Full article
(This article belongs to the Special Issue Tuberculosis Treatment and Management)
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Open AccessReview
Oxidative Stress: A New Target for Pancreatic Cancer Prognosis and Treatment
J. Clin. Med. 2017, 6(3), 29; https://doi.org/10.3390/jcm6030029 - 09 Mar 2017
Cited by 23 | Viewed by 2875
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumors, and its incidence is rising worldwide. Survival can be improved when tumors are detected at an early stage; however, this cancer is usually asymptomatic, and the disease only becomes apparent [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumors, and its incidence is rising worldwide. Survival can be improved when tumors are detected at an early stage; however, this cancer is usually asymptomatic, and the disease only becomes apparent after metastasis. Several risk factors are associated to this disease. Chronic pancreatitis, diabetes, and some infectious disease are the most relevant risk factors. Incidence of PDAC has increased in the last decades. It is hypothesized it could be due to other acquired risk habits, like smoking, high alcohol intake, and obesity. Indeed, adipose tissue is a dynamic endocrine organ that secretes different pro-inflammatory cytokines, enzymes, and other factors that activate oxidative stress. Reactive oxygen species caused by oxidative stress, damage DNA, proteins, and lipids, and produce several toxic and high mutagenic metabolites that could modify tumor behavior, turning it into a malignant phenotype. Anti-oxidant compounds, like vitamins, are considered protective factors against cancer. Here, we review the literature on oxidative stress, the molecular pathways that activate or counteract oxidative stress, and potential treatment strategies that target reactive oxygen species suitable for this kind of cancer. Full article
(This article belongs to the Special Issue The Role of Oxidant Stress in Disease)
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Open AccessCase Report
Long-Term Vaptan Treatment of Idiopathic SIADH in an Octogenarian
J. Clin. Med. 2017, 6(3), 28; https://doi.org/10.3390/jcm6030028 - 08 Mar 2017
Cited by 2 | Viewed by 1991
Abstract
Hyponatremia is the most common and by far underestimated electrolyte disorder in clinical practice. Especially in elderly patients, treatment of symptomatic hyponatremia is challenging. Herein we describe the case of an octogenarian with recurrent symptomatic hyponatremia due to idiopathic syndrome of inappropriate antidiuretic [...] Read more.
Hyponatremia is the most common and by far underestimated electrolyte disorder in clinical practice. Especially in elderly patients, treatment of symptomatic hyponatremia is challenging. Herein we describe the case of an octogenarian with recurrent symptomatic hyponatremia due to idiopathic syndrome of inappropriate antidiuretic hormone release (SIADH). Fluid restriction was insufficient to prevent repeated episodes of hyponatremia complicated by falls and coma. After introduction of a low-dose therapy with tolvaptan, serum sodium levels as well as the clinical condition were stable under vaptan therapy, without any relapse for more than six years now. This case demonstrates that long-term tolvaptan treatment for hyponatremia caused by SIADH is safe and well tolerated, even in the elderly. Full article
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Open AccessReview
Biochemical Assessment of Coenzyme Q10 Deficiency
J. Clin. Med. 2017, 6(3), 27; https://doi.org/10.3390/jcm6030027 - 05 Mar 2017
Cited by 11 | Viewed by 2900
Abstract
Coenzyme Q10 (CoQ10) deficiency syndrome includes clinically heterogeneous mitochondrial diseases that show a variety of severe and debilitating symptoms. A multiprotein complex encoded by nuclear genes carries out CoQ10 biosynthesis. Mutations in any of these genes are responsible for [...] Read more.
Coenzyme Q10 (CoQ10) deficiency syndrome includes clinically heterogeneous mitochondrial diseases that show a variety of severe and debilitating symptoms. A multiprotein complex encoded by nuclear genes carries out CoQ10 biosynthesis. Mutations in any of these genes are responsible for the primary CoQ10 deficiency, but there are also different conditions that induce secondary CoQ10 deficiency including mitochondrial DNA (mtDNA) depletion and mutations in genes involved in the fatty acid β-oxidation pathway. The diagnosis of CoQ10 deficiencies is determined by the decrease of its content in skeletal muscle and/or dermal skin fibroblasts. Dietary CoQ10 supplementation is the only available treatment for these deficiencies that require a rapid and distinct diagnosis. Here we review methods for determining CoQ10 content by HPLC separation and identification using alternative approaches including electrochemical detection and mass spectrometry. Also, we review procedures to determine the CoQ10 biosynthesis rate using labeled precursors. Full article
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Open AccessArticle
Portal Vein Embolization: Impact of Chemotherapy and Genetic Mutations
J. Clin. Med. 2017, 6(3), 26; https://doi.org/10.3390/jcm6030026 - 01 Mar 2017
Cited by 12 | Viewed by 1945
Abstract
We characterized the effect of systemic therapy given after portal vein embolization (PVE) and before hepatectomy on hepatic tumor and functional liver remnant (FLR) volumes. All 76 patients who underwent right PVE from 2002–2016 were retrospectively studied. Etiologies included colorectal cancer (n [...] Read more.
We characterized the effect of systemic therapy given after portal vein embolization (PVE) and before hepatectomy on hepatic tumor and functional liver remnant (FLR) volumes. All 76 patients who underwent right PVE from 2002–2016 were retrospectively studied. Etiologies included colorectal cancer (n = 44), hepatocellular carcinoma (n = 17), cholangiocarcinoma (n = 10), and other metastases (n = 5). Imaging before and after PVE was assessed. Chart review revealed systemic therapy administration, SNaPshot genetic profiling, and comorbidities. Nine patients received systemic therapy; 67 did not. Tumor volume increased 28% in patients who did not receive and decreased −24% in patients who did receive systemic therapy (p = 0.026), with no difference in FLR growth (28% vs. 34%; p = 0.645). Among 30 patients with genetic profiling, 15 were wild type and 15 had mutations. Mutations were an independent predictor of tumor growth (p = 0.049), but did not impact FLR growth (32% vs. 28%; p = 0.93). Neither cirrhosis, hepatic steatosis, nor diabetes impacted changes in tumor or FLR volume (p > 0.20). Systemic therapy administered after PVE before hepatic lobectomy had no effect on FLR growth; however, it was associated with decreasing tumor volumes. Continuing systemic therapy until hepatectomy may be warranted, particularly in patients with genetic mutations. Full article
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Open AccessArticle
Mitochondrial Modification Techniques and Ethical Issues
J. Clin. Med. 2017, 6(3), 25; https://doi.org/10.3390/jcm6030025 - 24 Feb 2017
Cited by 7 | Viewed by 2927
Abstract
Current strategies for preventing the transmission of mitochondrial disease to offspring include techniques known as mitochondrial replacement and mitochondrial gene editing. This technology has already been applied in humans on several occasions, and the first baby with donor mitochondria has already been born. [...] Read more.
Current strategies for preventing the transmission of mitochondrial disease to offspring include techniques known as mitochondrial replacement and mitochondrial gene editing. This technology has already been applied in humans on several occasions, and the first baby with donor mitochondria has already been born. However, these techniques raise several ethical concerns, among which is the fact that they entail genetic modification of the germline, as well as presenting safety problems in relation to a possible mismatch between the nuclear and mitochondrial DNA, maternal mitochondrial DNA carryover, and the “reversion” phenomenon. In this essay, we discuss these questions, highlighting the advantages of some techniques over others from an ethical point of view, and we conclude that none of these are ready to be safely applied in humans. Full article
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Open AccessReview
The Roles of Histone Demethylase Jmjd3 in Osteoblast Differentiation and Apoptosis
J. Clin. Med. 2017, 6(3), 24; https://doi.org/10.3390/jcm6030024 - 23 Feb 2017
Cited by 3 | Viewed by 1992
Abstract
Posttranslational modifications including histone methylation regulate gene transcription through directly affecting the structure of chromatin. Trimethylation of histone 3 lysine 27 (H3K27me3) is observed at the promoters of a wide variety of important genes, especially for mammalian development, and contributes to gene silencing. [...] Read more.
Posttranslational modifications including histone methylation regulate gene transcription through directly affecting the structure of chromatin. Trimethylation of histone 3 lysine 27 (H3K27me3) is observed at the promoters of a wide variety of important genes, especially for mammalian development, and contributes to gene silencing. Demethylase Jumonji domain-containing 3 (Jmjd3) catalyzes the transition of H3K27me3 to H3K27me1, therefore from a repressive to an active status of gene expression. Jmjd3 plays important roles in cell differentiation, inflammation, and tumorigenesis by targeting distinct transcription factors. In this review, we summarize the pivotal roles of Jmjd3 in maintaining skeletal homeostasis through regulating osteoblast differentiation, maturation, and apoptosis. Full article
(This article belongs to the Special Issue Bone Cell Biology and Transcriptional Regulation)
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Open AccessFeature PaperReview
Role of Protein Phosphatase 2A in Osteoblast Differentiation and Function
J. Clin. Med. 2017, 6(3), 23; https://doi.org/10.3390/jcm6030023 - 23 Feb 2017
Cited by 5 | Viewed by 2569
Abstract
The reversible phosphorylation of proteins plays hugely important roles in a variety of cellular processes, such as differentiation, proliferation, and apoptosis. These processes are strictly controlled by protein kinases (phosphorylation) and phosphatases (de-phosphorylation). Here we provide a brief history of the study of [...] Read more.
The reversible phosphorylation of proteins plays hugely important roles in a variety of cellular processes, such as differentiation, proliferation, and apoptosis. These processes are strictly controlled by protein kinases (phosphorylation) and phosphatases (de-phosphorylation). Here we provide a brief history of the study of protein phosphorylation, including a summary of different types of protein kinases and phosphatases. One of the most physiologically important serine/threonine phosphatases is PP2A. This review provides a description of the phenotypes of various PP2A transgenic mice and further focuses on the known functions of PP2A in bone formation, including its role in osteoblast differentiation and function. A reduction in PP2A promotes bone formation and osteoblast differentiation through the regulation of bone-related transcription factors such as Osterix. Interestingly, downregulation of PP2A also stimulates adipocyte differentiation from undifferentiated mesenchymal cells under the appropriate adipogenic differentiation conditions. In osteoblasts, PP2A is also involved in the ability to control osteoclastogenesis as well as in the proliferation and metastasis of osteosarcoma cells. Thus, PP2A is considered to be a comprehensive factor in controlling the differentiation and function of cells derived from mesenchymal cells such as osteoblasts and adipocytes. Full article
(This article belongs to the Special Issue Bone Cell Biology and Transcriptional Regulation)
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