Diseases, Vol. 7, Pages 47: Cell and Gene Therapies for Mucopolysaccharidoses: Base Editing and Therapeutic Delivery to the CNS Although individually uncommon, rare diseases collectively account for a considerable proportion of disease impact worldwide. A group of rare genetic diseases called the mucopolysaccharidoses (MPSs) are characterized by accumulation of partially degraded glycosaminoglycans cellularly. MPS results in varied systemic symptoms and in some forms of the disease, neurodegeneration. Lack of treatment options for MPS with neurological involvement necessitates new avenues of therapeutic investigation. Cell and gene therapies provide putative alternatives and when coupled with genome editing technologies may provide long term or curative treatment. Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing technology and, more recently, advances in genome editing research, have allowed for the addition of base editors to the repertoire of CRISPR-based editing tools. The latest versions of base editors are highly efficient on-targeting deoxyribonucleic acid (DNA) editors. Here, we describe a number of putative guide ribonucleic acid (RNA) designs for precision correction of known causative mutations for 10 of the MPSs. In this review, we discuss advances in base editing technologies and current techniques for delivery of cell and gene therapies to the site of global degeneration in patients with severe neurological forms of MPS, the central nervous system, including ultrasound-mediated blood-brain barrier disruption.

Diseases, Vol. 7, Pages 46: Preoperatory Anxiety in Patients Undergoing Cardiac Surgery Anxiety is a feeling of discomfort produced in face of an unknown event, as an impending cardiac surgery, that can lead to inconveniences in the intervention and subsequent recovery. Being the purpose of this research to analyze pre-surgical anxiety, a descriptive cross-sectional study among patients undergoing cardiac surgery was carried out. Data about sociodemographic variables were collected and the level of anxiety prior to surgery was assessed using the STAI-S scale. Subsequently, descriptive data analyses were performed, relationships among variables were analyzed, and a binary logistic regression model was developed in order to analyze the role of the variables involved in the development of preoperative anxiety. Sixty subjects were finally included; more than 80% had a moderate to high level of anxiety. 26.7% underwent valve surgery and 47% underwent coronary artery bypass graft (CABG) surgery, in the latter case presenting higher levels of anxiety. Statistically significant relationships were found among the level of anxiety and (a) level of studies, (b) first surgical intervention, and (c) the rating given to their previous surgical experience. We concluded that preoperative anxiety in people undergoing cardiac surgery is high and yet it is an underestimated phenomenon. The relationship between the received information and their anxiety level is inversely proportional, so that people programmed for cardiac surgery should be provided with all the information they required, through an individualized intervention.

Diseases, Vol. 7, Pages 45: The Role of Depression and Anxiety in Frail Patients with Heart Failure An increased interest regarding the impact of frailty on the prognosis of cardiovascular disease (CVD) has been observed in the last decade. Frailty is a syndrome characterized by a reduced biological reserve that increases the vulnerability of an individual in relation to stressors. Among the patients with CVD, a higher incidence of frailty has been reported in those with heart failure (HF). Regardless of its conceptualizations, frailty is generally associated with negative outcomes in HF and an increased risk of mortality. Psychological factors, such as depression and anxiety, increase the risk of negative outcomes on the cardiac function and mortality. Depression and anxiety are found to be common factors impacting the heart disease and quality of life (QoL) in patients with HF. Depression is considered an independent risk factor of cardiac-related incidents and death, and a strong predictor of rehospitalization. Anxiety seems to be an adequate predictor only in conjunction with depression. The relationship between psychological factors (depression and anxiety) and frailty in HF has hardly been documented. The aim of this paper is to review the reported data from relevant studies regarding the impact of depression and anxiety, and their effects on clinical outcomes and prognosis in frail patients with HF.

Diseases, Vol. 7, Pages 44: Clinical Impact of the Increase in Immunosuppressive Cell-Related Gene Expression in Urine Sediment during Intravesical Bacillus Calmette-Guérin Background: The aim of this study is to evaluate the clinical impact of intravesical Bacillus Calmette-Guérin (BCG)-induced changes in blood/urinary immune markers. Methods: Time-course changes in blood/urinary clinical parameters and mRNA expression of 13 genes in urine sediment taken eight times during the treatment course of intravesical BCG (before, every 2 weeks for 8 weeks, and after) in 24 patients with non-muscle invasive bladder cancer. The genes examined include cellular markers of four immune checkpoint proteins (PD-L1, PD-L2, PD-1, and CTLA-4), immunosuppressive cells (regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells), pan-T lymphocytes, B lymphocytes, and neutrophils. Results: Significant transient increase in gene expression was observed for PD-L1, PD-1, FOXP3, and CD204 at 6–8 doses of BCG. The patients were stratified into two groups depending on the number of genes with increased mRNA expression. Fourteen (58%) had 0–1 genes upregulated, while 10 (42%) had 2–4 genes with increased expression. No patient in the 0–1 group experienced recurrence, while 70% of patients in the 2–4 group experienced recurrence (p value = 0.037, hazard ratio = 5.93). Conclusions: Our findings suggested that increases in more than one of PD-L1, PD-1, FOXP3, and CD204, expression in the urine sediments was associated with resistance to BCG treatment.

Diseases, Vol. 7, Pages 43: Epigenetics—Shedding Light on the Path Ahead for Material Sciences The harmonious regulation of bodily function is a necessity for healthy individuals. Looking from the viewpoint of material sciences, one can only marvel at the cellular factories, their renewal, and the overall control of messaging and control of responses. As aging progresses and/or pathologies arise, clinicians may be forced to look for replacement of organs/tissues with medical devices. Since all devices are tailored, a detailed understanding of developmental processes, including aberrant processes leading to pathologies, is crucial to provide clinicians with a suitable device. Although research in the field of epigenetics has produced effective therapeutics and diagnostic markers, our currently fragmented understanding of epigenetic processes as they relate to material development is inherently limited, with logical implications for the success of medical procedures. Here, we illustrate how material sciences for clinical applications, critically depend on all aspects of biomedical sciences, including the field of epigenetics.

Diseases, Vol. 7, Pages 42: Epigenetic Factors of Disease The development of tissues involves the direction of specific programs for gene expression among distinct cell types. These programs are often established in a heritable state by virtue of epigenetic mechanisms and corresponding pathways of cellular memory. Thus, the broad synchronization in patterns of gene expression ultimately dictates cellular consequences. Aberrations in these epigenetic mechanisms are known to be associated with a range of diseases. Herein, we highlight epigenetic factors that, when aberrantly expressed, lead to a broad range of diseases. Further, we call upon the community of biomedical researchers to share their findings related to the epigenetic factors of disease.

Diseases, Vol. 7, Pages 41: Epidemiological Trends and Resistance Associated with Stenotrophomonas maltophilia Bacteremia: A 10-Year Retrospective Cohort Study in a Tertiary-Care Hospital in Hungary Stenotrophomonas maltophilia has been recognized as an emerging nosocomial pathogen in invasive infections of immunocompromised, severely debilitated patients with significant underlying illnesses. The first-choice drug in these infections is sulfamethoxazole-trimethoprim (SMX/TMP), and resistance to this antimicrobial is a daunting challenge for clinicians. The aim of this study was to assess the prevalence of S. maltophilia bacteremia and SMX/TMP-resistance levels at a tertiary-care university hospital. A total of 175 episodes of S. maltophilia bacteremia were identified (2008–2012: n = 82, 2013–2017: n = 93; p = 0.061), 52% of affected patients were 60 years of age, and had recent surgery, severe injuries or underlying conditions (malignant hematologic diseases and solid tumors) in their history. Sixteen percent of isolates were resistant to SMX/TMP (2008–2012: n = 13.8%, 2013–2017: n = 17.2%; p = 0.076), and out of the resistant strains, 32.7% were also resistant to levofloxacin and colistin. Our findings on the SMX/TMP-resistance were similar to global literature data.

Diseases, Vol. 7, Pages 40: Electrochemical Methodology for Evaluating Skin Oxidative Stress Status (SOSS) For the purpose of human disease prevention, several methods have been developed, and are still developing, to assess the oxidative stress status (OSS) of individuals. In the present paper, we describe an approach based on electrochemical detection able to evaluate skin oxidative stress status (SOSS) as a PAOT (Pouvoir AntiOxydant Total)-Skin Score®. Normal reference values for the PAOT-Skin Score® were: 0–62.94 (n = 263). Intra- and inter-assay coefficients of variation were, respectively, 12.47 ± 4.29% and 7.0 ± 2.5%. Our technology showed increased skin antioxidant activity following topical application of reduced coeznyme Q10 cream or vitamin C intake as orange juice or supplements. Moreover, we found significant correlations between some blood oxidative stress biomarkers and the PAOT-Skin Score® (γ-tocopherol/α-tocopherol ratio (r = 0.43, p = 0.020); copper (r = −0.42, p = 0.022); copper/zinc ratio (r = −0.49, p = 0.006), and lipid peroxides (r = −0.43, p = 0.002)). In addition to being non–invasive, the present electrochemical methodology is also not expensive, fast, and easy to use.

Diseases, Vol. 7, Pages 39: Fibroblasts Collagen Production and Histological Alterations in Hereditary Gingival Fibromatosis Hereditary gingival fibromatosis is a disorder for which the etiology remains unknown. We aimed to evaluate the fibroblasts and histological alterations to give new clues. A father and a daughter of a family showing gingival hereditary fibromatosis were treated, and gingival biopsies were obtained. A histological study revealed dense fibrous tissue, basal lamina disruption, and epithelial cell migration into the connective tissue. Fibroblasts were cultured from the father and daughter and compared with those from a healthy control patient. The results of the biochemical analysis showed increased collagen synthesis, reduced antioxidant CoQ10 content, and high levels of lipid peroxidation. Additionally, fibroblasts culture incubation with the oxidant H2O2 increased collagen levels that have been reduced by the addition of the antioxidant CoQ10. We conclude that some fibroblasts metabolic alterations play a significant role in initiating and maintaining persistent fibrotic tissue. Oxidative stress influences the fibroblasts collagen production and could play a particular role in the pathogenesis of hereditary gingival fibromatosis.

Diseases, Vol. 7, Pages 38: A Rare Adverse Event of Rhabdomyolysis Caused by Sacubitril/Valsartan Rhabdomyolysis is caused by extensive damage to skeletal muscles resulting in elevated creatine phosphokinase (CPK), Lactate dehydrogenase (LDH), and aspartate aminotransferase (AST), leading to life-threatening consequences like acute renal failure, cardiac arrhythmias, and hyperthermia. A variety of causes for muscle damage are known, and one of the most common is drug-induced. Statins and many other agents are known to induce muscle damage, but here we report Entresto™ (Sacubitril/Valsartan) induced rhabdomyolysis which has not been previously reported as solely responsible in the literature.