Whole-Heart Tissue Engineering and Cardiac Patches: Challenges and Promises.

Despite all the advances in preventing, diagnosing, and treating cardiovascular disorders, they still account for a significant part of mortality and morbidity worldwide. The advent of tissue engineering and regenerative medicine has provided novel therapeutic approaches for the treatment of various diseases. Tissue engineering relies on three pillars: scaffolds, stem cells, and growth factors. Gene and cell therapy methods have been introduced as primary approaches to cardiac tissue engineering. Although the application of gene and cell therapy has resulted in improved regeneration of damaged cardiac tissue, further studies are needed to resolve their limitations, enhance their effectiveness, and translate them into the clinical setting. Scaffolds from synthetic, natural, or decellularized sources have provided desirable characteristics for the repair of cardiac tissue. Decellularized scaffolds are widely studied in heart regeneration, either as cell-free constructs or cell-seeded platforms. The application of human- or animal-derived decellularized heart patches has promoted the regeneration of heart tissue through in vivo and in vitro studies. Due to the complexity of cardiac tissue engineering, there is still a long way to go before cardiac patches or decellularized whole-heart scaffolds can be routinely used in clinical practice. This paper aims to review the decellularized whole-heart scaffolds and cardiac patches utilized in the regeneration of damaged cardiac tissue. Moreover, various decellularization methods related to these scaffolds will be discussed.

Off-the-shelf acellular fetal skin scaffold as a novel alternative to buccal mucosa graft: the development and characterization of human tissue-engineered fetal matrix in rabbit model of hypospadiasis.

AIM: In this study, we aimed to develop a novel alternative to buccal mucosal graft from the acellular human fetal skin to manage hypospadias in a rabbit model. We optimized the decellularization protocol to develop and characterize the human tissue-engineered fetal dermal matrix as an "off-the-shelf" natural biomaterial. MATERIAL AND METHODS: Human fetal skin was obtained at 16-19 weeks gestational age with respect to a signed informed consent from parents under the university ethical committee approval. The dissected full-thickness fetal skin tissues were placed into SDS and Triton X-100 in different dosages to achieve the optimum decellularization protocol. Histopathology of the acellular fetal matrix was assessed by Hematoxylin & Eosin (H&E) and DAPI staining to confirm the removal of all cell materials, Masson's trichrome staining for collagen evaluation, DNA quantification for confirmation of DNA content, and scanning electron microscopy (SEM) for evaluation of scaffold microstructure. Immunohistochemistry (IHC) staining was used to detect specific dermal markers, namely vimentin, type I collagen, cytokeratin (CK)19. The prepared dermal scaffolds were then grafted on the 8 rabbit models of hypospadias. The rabbits underwent evaluations at 1, 2, 3, and 6 months postoperatively. RESULTS: H&E, Masson's trichrome, DAPI staining, and SEM confirmed the significant removal of cells; meanwhile, the ECM was completely preserved. At the time of biopsy, after 2, 4, and 6 months, no evidence of inflammation, fibrosis, necrosis, or rejection was observed. The grafted dermal scaffolds appeared histologically and anatomically normal. It was observed that the scaffolds were recellularized by circulating CD 34 + bone marrow stem cells (BMSCs) inside the body, implicating the body as a natural bioreactor. CONCLUSION: The application of acellular fetal skin (AFS) is a safe and feasible method that can decrease surgical time in a complex hypospadias reconstruction. Moreover, AFS demonstrated excellent angiogenesis characteristics and migration of the stem cells to the scaffold observed during the course of treatment. Novel natural AFS scaffold without cell seeding is an excellent alternative to buccal mucosal graft; hence, it can overcome the limitations concerning the graft size and prevent the creation of wounds in oral mucosal tissue.

Pretreatment with frequent topical betamethasone in Ahmed glaucoma valve implantation.

OBJECTIVE: To evaluate the efficacy of pretreatment with topical betamethasone in Ahmed glaucoma valve (AGV) implantation. DESIGN: Randomized clinical trial. PARTICIPANTS: Sixty-two eyes from 62 patients undergoing AGV. METHODS: We randomly assigned patients undergoing AGV to 2 arms of the study. The case group received AGV implantation with preoperative betamethasone eye drops, and the control group did not receive preoperative betamethasone. Follow-up examinations were performed on postoperative day 1, at least weekly for 4 weeks, and then every 1 to 3 months. Our main outcome measure was the rate of success, defined as intraocular pressure (IOP) <15 mm Hg and IOP ≤18 mm Hg. RESULTS: We analyzed 62 eyes divided to case (n = 33) and control (n = 29) groups. The success rate was significantly higher in the intervention group than in the control group at 12 months postoperatively when considering either IOP < 15 or IOP < 18 mm Hg as success (p < 0.001) and also at 6 months when considering IOP < 18 mm Hg as success (p < 0.041). The reduction in the number of antiglaucoma medications used postoperatively was significantly higher in the betamethasone group at follow-up at 1 and 3 months and 1 year. CONCLUSION: Pretreatment with topical betamethasone in AGV implantations increases the success rate and reduces the need for medications.

National and provincial population-based incidence and mortality of skin cancer in Iran; 1990-2016.

PURPOSE: To estimate the national and provincial estimates of incidence, mortality and burden of skin cancer in Iran from 1990 to 2016. METHODS: The data for incidence and mortality rates were collected from the National and Subnational Burden of Diseases (NASBOD) project. We employed a two-stage spatiotemporal model to estimate cancer incidence based on sex, age, province and year. The national and subnational age and gender specific trends were calculated from 1990 to 2016. Mortality-to-incidence ratio (MIR) was considered as an indicator of cancer care quality. RESULTS: At the national level, the age standardized incidence rate (ASIR) of skin cancer decreased 1.29 times, from 23.6 (95% uncertainty interval [UI], 17.1-31.1) per 100 000 persons in 1990 to 18.2 (95% UI, 15.8-20.6) in 2016; a similar trend was seen in both males and females. The highest ASIR was seen in 2000. National estimates of the age standardized mortality rate (ASMR) steadily decreased from 2.8 per 100 000 persons (95% UI, 1.9-4.1) in 1990 to 0.2 (95% UI, 0.1-0.3) per 100 000 persons in 2015. The MIR decreased continuously from 1990 to 2015 in all provinces and among both genders. The age standardized rate of years of life lost also decreased 8.7 times, from 30.1 (95% UI, 20.2-45.1) in 1990 to 3.5 (95% UI, 2.3-5.3) in 2015. CONCLUSIONS: During the study period, skin cancer ASIR, ASMR and burden steadily decreased among the Iranian population. The declining MIR for all provinces from 1990 to 2015 was a proxy of early detection and high-quality medical care for skin cancer in Iran. These results can be beneficial to policymakers and health planners to make correct decisions and determine proper resource allocation.

Serum ferritin levels and irregular use of iron chelators predict liver iron load in patients with major beta thalassemia: a cross-sectional study.

AIM: To determine whether serum ferritin, liver transaminases, and regularity and type of iron chelation protocol can be used to predict liver iron load as assessed by T2* magnetic resonance imaging (MRI) in patients with beta thalassemia major (TM). METHODS: This cross-sectional study, conducted from March 1, 2014 to March 1, 2015, involved 90 patients with beta TM on regular packed red blood cell transfusion. Liver and cardiac iron load were evaluated with T2* MRI. Compliance with iron-chelating agents, deferoxamine or deferasirox, and regularity of their use, as well as serum ferritin and liver transaminase levels were assessed. RESULTS: Patients with high serum ferritin were 2.068 times (95% confidence interval 1.26-3.37) more likely to have higher liver or cardiac iron load. High serum aspartate aminotransferases and irregular use of iron chelating agents, but not their type, predicted higher cardiac iron load. In a multiple regression model, serum ferritin level was the only significant predictor of liver and myocardial iron load. CONCLUSIONS: Higher serum ferritin strongly predicted the severity of cardiac and liver iron load. Irregular use of chelator drugs was associated with a higher risk of cardiac and liver iron load, regardless of the type of chelating agent.

White Matter Changes Correlates of Peripheral Neuroinflammation in Patients with Parkinson's Disease.

Neuroinflammatory pathology has long been identified to contribute to the pathology of Parkinson disease. Early microstructural changes in white matter tracts might give a clue for earlier detection of PD. We investigated through diffusion MRI connectometry the structural correlates of white matter tracts of 81 patients with PD with whole blood neutrophil-to-lymphocyte ratio (NLR), controlling for age and sex. Diffusion data were reconstructed in the MNI space using q-space diffeomorphic reconstruction to obtain the spin distribution function. The spin distribution function (SDF) values were used in DMRI connectometry analysis. The connectometry analyses identified white matter QA of the following fibers to be correlated with NLR score after adjustment for age and sex: bilateral cingulum, body and left crus of fornix, bilateral corticospinal tract (CST), and body and splenium of corpus callosum (CC) and superior cerebellar peduncle with decreased connectivity related to NLR (FDR = 0.04542). Keeping with emerging evidence on the role of neuroinflammation in PD pathology, these results with functional relevance to prodromal Parkinson disease, bring new insights to pivotal role of peripheral inflammation in CNS neurodegeneration.

Exploring white matter microstructure and olfaction dysfunction in early parkinson disease: diffusion MRI reveals new insight.

Olfaction dysfunction is considered as a robust marker of prodromal Parkinson disease (PD). Measurement of olfaction function as a screening test is unsatisfactory due to long lead time interval and low specificity for detection of PD. Use of imaging markers might yield more accurate predictive values and provide bases for combined use of imaging and clinical markers for early PD. Diffusion MRI connectometry was conducted on 85 de novo PD patients in and 36 healthy controls to find: first, white matter tracts with significant difference in quantitative anisotropy between PD groups with various degrees of olfaction dysfunction and second, second fibers with correlation with University of Pennsylvania Smell Identification Test (UPSIT) score in each group using a multiple regression analysis considering age, sex, GDS and MoCA score. Local connectomes were determined in seven of all the possible comparisons, correcting for false discovery rate (FDR). PD patients with anosmia and normal olfaction had the highest number of fibers with decreased connectivity in left inferior longitudinal fasciculus, bilateral fornix, bilateral middle cerebellar peduncle (MCP), bilateral cingulum, bilateral corticospinal tract (CST) and body, genu and splenium of corpus callosum (CC) (FDR = 0.0013). In multiple regression analysis, connectivity in the body, genu and splenium of CC and bilateral fornix had significant negative correlation (FDR between 0.019 and 0.083), and bilateral cingulum and MCP had significant positive correlation (FDR between 0.022 and 0.092) with UPSIT score. White matter connectivity in healthy controls could not be predicted by UPSIT score using the same model. The results of this study provide compelling evidence that microstructural degenerative changes in these areas underlie the clinical phenotype of prodromal olfaction dysfunction in PD and that diffusion parameters of these areas might be able to serve as signature markers for early detection of PD. This is the first report that confirms a discriminative role for UPSIT score in identifying PD specific changes in white matter microstructure. Our results open a window to identify microstructural signatures of prodromal PD in white matter.

Epigenetics and pathogenesis of systemic sclerosis; the ins and outs.

The pathogenesis of many diseases is influenced by environmental factors which can affect human genome and be inherited from generation to generation. Adverse environmental stimuli are recognized through the epigenetic regulatory complex, leading to gene expression alteration, which in turn culminates in disease outcomes. Three epigenetic regulatory mechanisms modulate the manifestation of a gene, namely DNA methylation, histone changes, and microRNAs. Both epigenetics and genetics have been implicated in the pathogenesis of systemic sclerosis (SSc) disease. Genetic inheritance rate of SSc is low and the concordance rate in both monozygotic (MZ) and dizygotic (DZ) twins is little, implying other possible pathways in SSc pathogenesis scenario. Here, we provide an extensive overview of the studies regarding different epigenetic events which may offer insights into the pathology of SSc. Furthermore, epigenetic-based interventions to treat SSc patients were discussed.

Sequential language learning and language immersion in bilingualism: diffusion MRI connectometry reveals microstructural evidence.

Study of bilingual brain has provided evidence for probable advantageous outcomes of early second language learning and brain structural correlates to these outcomes. DMRI connectometry is a novel approach that tracts fibers based on correlation of the adjacent voxels with a variable of interest or group differences. Using the data deposited by Pliatsikas et al., we investigated through diffusion MRI connectometry and correlation analysis, the structural differences in white matter tracts of 20 healthy sequential bilingual adults who used English as a second language on a daily basis, compared to 25 age matched in fiber differentiation analyses. Connectometry results revealed increased connectivity in corpus callosum (CC), bilateral cingulum, arcuate fasciculus (AF), and left IFOF of sequential bilingual adults. All the above fibers except cingulum had positive association with language immersion period. We introduce cingulum as a tract with increased connectivity in late bilingual adults. We also found an increase in white matter connectivity conventional language-related fibers such as AF, and areas that had been shown in previous studies addressing WM differences between early or late bilinguals and monolinguals, inferior frontooccipital fasciculus, and CC. Pliatsikas reported a confounding effect for the immersion period, as a regressor in TBSS model. Through DMRI connectometry and correlation analysis, we showed that quantitative anisotropy of all of the significant fibers from connectometry analysis, except cingulum, had direct correlation with the duration of immersion period of the bilingual group into the second language.

Analysis of killer cell immunoglobulin-like receptors (KIRs) and their HLA ligand genes polymorphisms in Iranian patients with systemic sclerosis.

Genetic factors have a great role in the pathogenesis of autoimmune diseases by cooperating with environmental stimuli. Killer immunoglobulin-like receptors (KIRs) are cell surface proteins on NK cells whose association with major histocompatibility complex-I regulates their killing function. The aim of this study was to provide information on the possible association between KIR and human leukocyte antigen (HLA) genes with systemic sclerosis disease in Iranian population. A total of 279 systemic sclerosis patients and 451 healthy controls were enrolled in this case-control study in order to determine the presence or absence of 19 KIR genes and 6 specific HLA class I ligands. DNA was analyzed by polymerase chain reaction using the specific sequence primer method (PCR-SSP). Among 11 discovered KIR genotypes, 6 genotypes showed a considerable role and 4 genotypes could preclude the risk of systemic sclerosis (SSc) disease. The gene-gene interactions were also analyzed, and significant confounding effects were seen between involved genes in these two combinations: "KIR3DL1; HLA-BW4-Thr80" and "KIR3DL1 -HLA-BW4-A1." None of single KIR genes showed significant effect on the risk of SSc. We conclude that there is an important relationship between KIR genes and their HLA ligands with incidence rate of systemic sclerosis in Iranian population. The powerful role of a number of discovered KIR/HLA compounds such as activating KIR genotype 3 and HLA-BW4-A1 confirmed the provocative hypothesis of the interplay between activating or inhibitory KIR genes with HLA ligands as a critical index of systemic sclerosis predisposition.

Association Study of CD226 and CD247 Genes Single Nucleotide Polymorphisms in Iranian Patients with Systemic Sclerosis.

CD247 and CD226 play important roles in signaling of lymphocytes. Single nucleotide polymorphisms (SNPs) of genes encoding CD247 and CD226 have been associated with the risk of several autoimmune disorders. This study aimed to evaluate the possible association between CD226 and CD247 genes SNPs and risk of systemic sclerosis (SSc) in Iranian population. Study participants were 455 SSc patients and 455 age, sex and ethnic -matched healthy individuals. Genotyping of rs2056626 and rs763361 at CD247 and CD226 genes, respectively, was carried out using TaqMan MGB-based allelic discrimination real-time PCR. Neither alleles nor genotypes of both SNPs showed significant association with the risk of SSc. Furthermore, association analysis of the genotypes with clinical manifestations of the disease revealed that rs763361 variants were associated with the forced vital capacity (FVC) in SSc patients. Our results suggest that genetic variants of CD226 and CD247 genes may not be a contributing factor in pathogenesis of SSc in Iranian population.