Trisomy 18 Syndrome

An MRI-only Three-dimensional Cephalometry Protocol based on the Integrated and Modular Architecture of the Human Head

Background: Currently, three-dimensional cephalometry measurements are mainly based on cone beam computed tomography (CBCT), which has limitations of ionizing radiation, lack of soft tissue information, and lack of standardization of median sagittal plane establishment.

Objectives: This study investigated magnetic resonance imaging (MRI)-only based 3D cephalometry measurement based on the integrated and modular characteristics of the human head.

Methods: Double U-Net CycleGAN was used for CT image synthesis from MRI. This method enabled the synthesis of a CT-like image from MRI and measurements were made using 3D slicer registration and fusion.

Results: A protocol for generating and optimizing MRI-based synthetic CT was described and found to meet the precision requirements of 3D head measurement using MRI midline positioning methods reported in neuroscience to establish the median sagittal plane. An MRI-only reference frame and coordinate system were established enabling an MRI-only cephalometric analysis protocol that combined the dual advantages of soft and hard tissue display. The protocol was devised using data from a single volunteer and validation data from a larger sample remains to be collected.

Conclusion: The reported method provided a new protocol for MRI-only cephalometric analysis of craniofacial growth and development, malformation occurrence, treatment planning, and outcomes.

Can Uterine Artery Pulsatility Index Predict Fetal Chromosomal Abnormality in Early Pregnancy Loss? A Retrospective Cohort Study

Background: Early pregnancy loss (EPL) or spontaneous loss of an intrauterine pregnancy within the first trimester occurs commonly worldwide. It is useful to predict the possibility of fetal chromosomal abnormalities using other cheap and easily available markers.

Objective: This study aimed to evaluate whether the uterine artery pulsatility index (UtA-PI) can predict fetal chromosomal abnormality in early pregnancy loss (EPL).

Methods: This was a retrospective cohort study including 148 women who underwent dilation and curettage for missed abortion. The UtA-PI was measured and evaluated by transvaginal ultrasound. Abnormal UtA-PI was identified through the mean of left and right UA-PI ≥ 90th percentiles of the relevant values for the corresponding gestational age. Copy number variation sequencing (CNV-seq) was performed on EPL cases without maternal cell contamination.

Results: 107 (72.3%) cases were classified with normal UtA-PI, while 41 (27.7%) cases were classified with abnormal UtA-PI. The fetal chromosomal abnormality rate was significantly higher in cases with normal UtA-PI than in those with abnormal UtA-PI (67.3% vs 22.0%, P = 7.1 × 10^-7). Compared to cases with abnormal UtA-PI, the risk of fetal chromosomal abnormalities in cases with normal UtA-PI increased with an odds ratio of 7.3 (95% confidence interval [CI]: 3.2‒17.0, P = 4 × 10^-7). The predictive value of normal UtA-PI alone for fetal chromosomal abnormalities was shown to have an area under the curve of 0.67‒0.71 in our population.

Conclusion: The UtA-PI seems to be lower and less likely to be elevated in EPL with fetal chromosomal abnormalities compared to those without aneuploidies. We suggest that UtA-PI should be examined in all EPL patients.

Perinatal Management of Pregnancies with Fetal Congenital Anomalies: A Guide to Obstetricians and Pediatricians

Background: Congenital anomalies are responsible for approximately 20% of all neonatal deaths worldwide. Improvements in antenatal screening and diagnosis have significantly improved the prenatal detection of birth defects; however, these improvements have not translated into the improved neonatal prognosis of babies born with congenital anomalies.

Objectives: An attempt has been made to summarise the prenatal interventions, if available, the optimal route, mode and time of delivery and discuss the minimum delivery room preparations that should be made if expecting to deliver a fetus with a congenital anomaly.

Methods: The recent literature related to the perinatal management of the fetus with prenatally detected common congenital anomalies was searched in English peer-reviewed journals from the PubMed database to work out an evidence-based approach for their management.

Results: Fetuses with prenatally detected congenital anomalies should be delivered at a tertiary care centre with facilities for neonatal surgery and paediatric intensive care if needed. There is no indication for preterm delivery in the majority of cases. Only a few congenital malformations, like highrisk sacrococcygeal teratoma, congenital lung masses with significant fetal compromise, fetal cerebral lesions or neural tube defects with Head circumference >40 cm or the biparietal diameter is ≥12 cm, gastroschisis with extracorporeal liver, or giant omphaloceles in the fetus warrant caesarean section as the primary mode of delivery.

Conclusion: The prognosis of a fetus with congenital anomalies can be significantly improved if planning for delivery, including the place and time of delivery, is done optimally. A multidisciplinary team should be available for the fetus to optimize conditions right from when it is born.

Leptotrichia trevisanii: Case Report and Review of the Literature on Patients with Leptotrichia trevisanii Bacteremia in Acute Myeloid Leukemia

Background: Leptotrichia spp. are fastidious facultative anaerobic, pencil-shaped, gramnegative rods that reside in the mouths, intestines, and female genital tracts of humans. Bacteremia and septic shock have been rarely reported in the immunocompromised host. We report a case of L. trevisanii bacteremia in a patient recently diagnosed with acute myeloid leukemia (AML) on chemotherapy.

Case Presentation: A 75-year-old male with a history of diabetes, chronic kidney disease, and coronary artery disease status post-CABG presented with neutropenic fevers and signs of sepsis after the initiation of chemotherapy. Blood cultures were ordered and extensive gene sequencing helped identify Leptotrichia trevisanii as the causative pathogen. Subsequently, the patient was successfully treated with empiric cefepime.

Discussion: Opportunistic pathogens are involved in a variety of diseases and have been isolated from immunocompromised patients undergoing transplantation or in patients with comorbidities, like leukemia, lymphoma, or neutropenia. L. trevisanii has been reported as a cause of bloodstream infections in patients with hematologic malignancies receiving chemotherapy.

Conclusion: This case highlights the key role that Leptotrichia trevisanii plays in the introduction of sepsis among immunocompromised patients, particularly with hematologic malignancies, like AML, on chemotherapy.

First Trimester Tricuspid Regurgitation: Clinical Significance

Tricuspid regurgitation is a cardiac valvular anomaly that consists of the return of blood to the right atrium during systole due to incomplete valve closure. This structure can be visualized on ultrasound between 11 and 14 weeks of gestation in most cases. Despite being a common finding, even in healthy fetuses, the presence of tricuspid regurgitation may be associated with chromosomal and structural abnormalities. The evaluation of tricuspid flow and the presence of regurgitation on first-trimester ultrasound has shown promising results regarding its role in the early detection of aneuploidies, congenital heart defects, and other adverse perinatal outcomes. This review article aims to demonstrate the importance of tricuspid regurgitation as a secondary marker, and consequently, significant benefits of its early detection when added to the combined first-trimester screening. Its value will be discussed, namely its sensitivity and specificity, alone and together with other current markers in the fetal assessment performed in the first-trimester ultrasound.

Stem Cells and Congenital Heart Disease: The Future Potential Clinical Therapy Beyond Current Treatment

Congenital heart disease (CHD) is the most common congenital anomaly in newborns. Current treatment for cyanotic CHD largely relies on the surgical intervention; however, significant morbidity and mortality for patients with CHD remain. Recent research to explore new avenues of treating CHD includes the utility of stem cells within the field. Stem cells have since been used to both model and potentially treat CHD. Most clinical applications to date have focused on hypoplastic left heart syndrome. Here, we examine the current role of stem cells in CHD and discuss future applications within the field.

Selenium-Derivative Compounds: A Review of New Perspectives in the Treatment of Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is one of the most prevalent types of dementia, affecting millions of older people worldwide. AD is stimulating efforts to develop novel molecules targeting its main features associated with a decrease in acetylcholine levels, an increase in oxidative stress and depositions of amyloid-β (Aβ) and tau protein. In this regard, selenium-containing compounds have been demonstrated as potential multi-targeted compounds in the treatment of AD. These compounds are known for their antioxidant and anticholinesterase properties, causing a decrease in Aβ aggregation.

Objective: In this review, we approach structure-activity relationships of each compound, associating the decrease of ROS activity, an increase of tau-like activity and inhibition of AChE with a decrease in the self-aggregation of Aβ.

Methods: We also verify that the molecular descriptors apol, nHBAcc and MlogP may be related to optimized pharmacokinetic properties for anti-AD drugs.

Results: In our analysis, few selenium-derived compounds presented similar molecular features to FDA-approved drugs.

Conclusion: We suggest that unknown selenium-derived molecules with apol, nHBAcc and MlogP like FDA-approved drugs may be better successes with optimized pharmacokinetic properties in future studies in AD.

Are Monocyte, %M and WBC Biomarkers in the First Trimester Screening Test?

Background: Differences in free beta HCG and PAPP-A values, which are among the biochemical parameters in the double screening test, are frequently used for pregnancy follow-up, allowing aneuploidy and triploidy risk to be determined. In recent studies, it is suggested that the modified hemogram indices have gained importance as a marker in the prognosis of diseases.

Objective: In this study, we aimed to determine the hematological parameters, which are routinely applied in the first trimester of pregnancy, have any value in predicting the risk increase in the double screening test and in early diagnosis.

Methods: Pregnant women who conceived spontaneously and had double screening tests were included in the study. CBC results that were studied together with the first trimester screening test were reported. The patients were divided into two groups according to the results of the screening test as the combined risk ratio.

Results: The mean age was found to be significantly higher in the high-risk group than in the low-risk group. Monocyte, % M and WBC values were significantly lower in the high-risk group (0,483±0,140, 5,58±1,44 and 8,75±2,12, respectively). There was no significant difference in NLR and PLR values compared between the groups. MPV values were lower and PAPP-A, PAPP-A MoM values were significantly lower in high-risk group compared to the low-risk group.

Conclusion: The findings support low Monocyte, % M and WBC values as a potential marker for the identification of high risk pregnancy in otherwise healthy pregnant women. The results indicate that CBC parameters commonly used in pregnancy can be used to predict the prognosis.

Clinical and Molecular Heterogeneity of Silver-Russell Syndrome and Therapeutic Challenges: A Systematic Review

Background: Silver-Russell syndrome (SRS) is a developmental disorder involving extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the clinical heterogeneity of SRS makes diagnosis a challenging task, the worldwide incidence of SRS could vary from 1:30,000 to 1:100,000. Although various chromosomal, genetic, and epigenetic mutations have been linked with SRS, the cause had only been identified in half of the cases.

Material and Methods: To have a better understanding of the SRS clinical presentation and mutation/ epimutation responsible for SRS, a systematic review of the literature was carried out using appropriate keywords in various scientific databases (PROSPERO protocol registration CRD42021273211). Clinical features of SRS have been compiled and presented corresponding to the specific genetic subtype. An attempt has been made to understand the recurrence risk and the role of model organisms in understanding the molecular mechanisms of SRS pathology, treatment, and management strategies of the affected patients through the analysis of selected literature.

Results: 156 articles were selected to understand the clinical and molecular heterogeneity of SRS. Information about detailed clinical features was available for 228 patients only, and it was observed that body asymmetry and relative macrocephaly were most prevalent in cases with methylation defects of the 11p15 region. In about 38% of cases, methylation defects in ICRs or genomic mutations at the 11p15 region have been implicated. Maternal uniparental disomy of chromosome 7 (mUPD7) accounts for about 7% of SRS cases, and rarely, uniparental disomy of other autosomes (11, 14, 16, and 20 chromosomes) has been documented. Mutation in half of the cases is yet to be identified. Studies involving mice as experimental animals have been helpful in understanding the underlying molecular mechanism. As the clinical presentation of the syndrome varies a lot, treatment needs to be individualized with multidisciplinary effort.

Conclusion: SRS is a clinically and genetically heterogeneous disorder, with most of the cases being implicated with a mutation in the 11p15 region and maternal disomy of chromosome 7. Recurrence risk varies according to the molecular subtype. Studies with mice as a model organism have been useful in understanding the underlying molecular mechanism leading to the characteristic clinical presentation of the syndrome. Management strategies often need to be individualized due to varied clinical presentations.

Screening and in Silico Functional Analysis of MiRNAs Associated with Acute Myeloid Leukemia Relapse

Background: Hematologic malignancies are among fatal diseases with different subtypes. Acute myeloid leukemia (AML) is a subtype showing a high invasion rate to different tissues.

Objective: AML patients, even after treatment, show an increased rate of recurrence, and this relapsed profile of AML has turned this malignancy into big challenges in the medical scope.

Methods: In the current study, we aimed to investigate hub-genes and potential signaling pathways in AML recurrence. Two expression profiles of genes and non-coding RNAs were extracted from the Gene Expression Omnibus (GEO) database. Target genes of identified miRNAs were predicted through bioinformatics tools. GO and KEGG pathway enrichment analyses were conducted to discover common target genes and differentially expressed genes. Protein‐protein interaction (PPI) network was constructed and visualized through the STRING online database and Cytoscape software, respectively. Hub-genes of constructed PPI were found through the CytoHubba plugin of Cytoscape software.

Results: As a result, 109 differentially expressed genes and 45 differentially expressed miRNAs were found, and the top enriched pathways were immune response, xhemokine activity, immune System, and plasma membrane. The hub-genes were TNF, IL6, TLR4, VEGFA, PTPRC, TLR7, TLR1, CD44, CASP1, and CD68.

Conclusion: The present investigation based on the in silico analysis and microarray GEO databases may provide a novel understanding of the mechanisms related to AML relapse.

MicroRNAs as Biomarkers for Birth Defects

It is estimated that 2-4% of live births will have a birth defect (BD). The availability of biomarkers for the prenatal detection of BDs will facilitate early risk assessment, prompt medical intervention and ameliorating disease severity. miRNA expression levels are often found to be altered in many diseases. There is, thus, a growing interest in determining whether miRNAs, particularly extracellular miRNAs, can predict, diagnose, or monitor BDs. These miRNAs, typically encapsulated in exosomes, are released by cells (including those of the fetus and placenta) into the extracellular milieu, such as blood, urine, saliva and cerebrospinal fluid, thereby enabling interaction with target cells. Exosomal miRNAs are stable, protected from degradation, and retain functionality. The observation that placental and fetal miRNAs can be detected in maternal serum, provides a strong rationale for adopting miRNAs as noninvasive prenatal biomarkers for BDs. In this mini-review, we examine the current state of research involving the use of miRNAs as prognostic and diagnostic biomarkers for BD.

Pediatrics for Disability: A Comprehensive Approach to Children with Syndromic Psychomotor Delay

Intellectual disability is the impairment of cognitive, linguistic, motor and social skills that occurs in the pediatric age and is also described by the term “mental retardation”. Intellectual disability occurs in 3-28 % of the general population due to a genetic cause, including chromosome aberrations. Among people with intellectual disabilities, the cause of the disability was identified as a single gene disorder in up to 12 %, multifactorial disorders in up to 4 %, and genetic disorders in up to 8.5 %. Children affected by a malformation syndrome associated with mental retardation or intellectual disability represent a care challenge for the pediatrician. A multidisciplinary team is essential to manage the patient, thereby controlling the complications of the syndrome and promoting the correct psychophysical development. This requires continuous follow-up of these children by the pediatrician, which is essential for both the clinical management of the syndrome and facilitating the social integration of these children.

Chromosome 9 Inversion: Pathogenic or Benign? A Comprehensive Systematic Review of all Clinical Reports

Background: Inversion of chromosome 9 (inv[9]) is known as one of the most common structural balanced chromosomal variations. Chromosome 9 is highly susceptible to structural rearrangements, specifically to pericentric inversions. Various investigators have posited that inv(9) with different breakpoints could be the cause of several abnormal conditions in individuals, whereas others have considered it a benign variant. To our knowledge, a consensus regarding the effects of this inversion has yet to emerge.

Objective: This study aims to discuss the pathogenic/benign effects of inv(9) in all possible clinical conditions detected in the occurrence of this abnormality.

Methods: Studies on inv(9) were collected via PubMed, MalaCards, Google Scholar, and NORD, along with the search terms of inv(9), pericentric inv(9), and chromosome 9 variants. Additionally, the incidence of inv(9) and the karyotype and clinical findings of individuals reported with this variant were investigated.

Results: The collection of the studies reviewed shows that inv(9) is associated with various conditions such as congenital anomalies, growth retardation, infertility, recurrent pregnancy loss, and cancer. The clinical features associated with this variant in humans vary between growth stages. Further, there have been no shared clinical findings in a specific period.

Conclusion: Although there is no conclusive evidence for the pathogenicity of this rearrangement, prenatal genetic counseling on inv(9) and further clinical and molecular studies would be helpful in chromosome 9-related problems.

Regulation of Microtubule: Current Concepts and Relevance to Neurodegenerative Diseases

Neurodevelopmental Disorders (NDDs) are abnormalities linked to neuronal structure and irregularities associated with the proliferation of cells, transportation, and differentiation. NDD also involves synaptic circuitry and neural network alterations known as synaptopathy. Microtubules (MTs) and MTs-associated proteins help to maintain neuronal health as well as their development. The microtubular dynamic structure plays a crucial role in the division of cells and forms mitotic spindles, thus take part in initiating stages of differentiation and polarization for various types of cells. The MTs also take part in cellular death, but MT-based cellular degenerations are not yet well excavated. In the last few years, studies have provided the protagonist activity of MTs in neuronal degeneration. In this review, we largely engrossed our discussion on the change of MT cytoskeleton structure, describing their organization, dynamics, transportation, and their failure causing NDDs. At the end of this review, we are targeting the therapeutic neuroprotective strategies on clinical priority and also try to discuss the clues for the development of new MT-based therapy as a new pharmacological intervention. This will be a new potential site to block not only neurodegeneration but also promotes the regeneration of neurons.

Prospects of Non-Coding Elements in Genomic DNA Based Gene Therapy

Gene therapy has made significant development since the commencement of the first clinical trials a few decades ago and has remained a dynamic area of research regardless of obstacles such as immune response and insertional mutagenesis. Progression in various technologies like next-generation sequencing (NGS) and nanotechnology has established the importance of non-- coding segments of a genome, thereby taking gene therapy to the next level. In this review, we have summarized the importance of non-coding elements, highlighting the advantages of using full- length genomic DNA loci (gDNA) compared to complementary DNA (cDNA) or minigene, currently used in gene therapy. The focus of this review is to provide an overview of the advances and the future of potential use of gDNA loci in gene therapy, expanding the therapeutic repertoire in molecular medicine.

Prenatal Diagnosis Preferences of Turkish Women and the Association of their Choices with Temperament

Objectives: The purpose of this study is to explain which choices Turkish women prefer for prenatal diagnosis more frequently and to find out if there is an association between temperament and decisions through the prenatal diagnostic steps or consistency of decision.

Materials and Methods: This is a cross-sectional study on pregnant women who were admitted to our outpatient clinic based on the responses to a self-administered questionnaire at the time of combined test or triple test as the first prenatal screening test. 198 pregnant women completed self-administered questionnaires comprising 131 questions including Temperament Evaluation of Memphis, Pisa, Paris, and San Diego questionnaire (TEMPS-A).

Results: Overall, 88.4% of women were willing to learn if there was an anomaly, whereas 4.5% did not, and 7.5% were uncertain. Of the included patients, 87.9% would decide on the screening tests to be performed, 23.2% had a positive attitude on diagnostic tests, and only 13.1% were in favour of termination. No association was found between the temperament scores and positive, negative, and indecisive attitudes of the patients. In addition, there was no relation between being decisive and indecisive, and the temperament scores except for cyclothymic scores. Indecisive attitude to termination was associated with higher cyclothymic scores (5 (1–13) for decisive patients, 7 (0–17) for indecisive patients, p=0.035).

Conclusion: We found that affective temperaments measured by the TEMPS-A are not related to the attitudes about prenatal screening or diagnostic tests or termination. Indecisive attitude to termination was associated with higher cyclothymic scores.

MALDI-ToF Mass Spectra Phenomic Analysis for Human Disease Diagnosis Enabled by Cutting-Edge Data Processing Pipelines and Bioinformatics Tools

Current methods for diagnosing human disease are still incapable of rapidly and accurately screening for multiple diseases simultaneously on a large scale, and at an affordable price. MALDI-ToF mass spectrometry is an ultra-sensitive, ultra-fast, lowcost, high-throughput technology that has the potential to achieve this goal, allowing human phenotype characterization and thus phenomic screening for multiple disease states. In this review, we will discuss the main advances achieved so far, putting forward targeted applications of MALDI-ToF mass spectrometry in the service of human disease detection. This review focuses on the methodological workflow as MALDI-ToF data processing for phenomic analysis, using state-of-the-art bioinformatic pipelines and software tools. The role of mathematical modelling, machine learning, and artificial intelligence algorithms for disease screening are considered. Moreover, we present some previously developed tools for disease diagnostics and screening based on MALDI-ToF analysis. We discuss the remaining challenges that are ahead when implementing MALDI-ToF into clinical laboratories. Differentiating a standard profile from a single disease phenotype is challenging, but the potential to simultaneously run multiple algorithm screens for different disease phenotypes may only be limited by computing power once this initial hurdle is overcome. The ability to explore the full potential of human clinical phenomics may be closer than imagined; this review gives an insight into the benefits this technology may reap for the future of clinical diagnostics.

The Relationship between Prenatal Diagnosis Indications and Abnormal Chromosomal Karyotypes: A Retrospective Cohort of 4646 Cases in Beijing from 2012-2019

Background and Objective: Chromosomal abnormalities are one of the genetic disorders caused by abnormal chromosome number or structure and can endanger multiple organs, morphology and function of the systems in the human body. This study aims to investigate the relationship between prenatal diagnosis indications and abnormal karyotypes to improve prenatal screening.

Methods: The karyotype analyses were carried out on 4646 pregnant women with prenatal diagnosis indications referred to the first medical center of Chinese PLA General Hospital from 2012 to 2019. The incidence, distribution, and statistical features of chromosomal abnormality of different prenatal diagnosis indications were analyzed, and the relationships with the prenatal diagnosis indications were assessed.

Results: A total of 351 fetal chromosomal abnormalities were detected in 4646 karyotypes, with an incidence of 7.6%. The chromosomal abnormality incidence in the single indication group, two indications group, and three indications group was 5.8%, 16.1%, and 70.0%, respectively, indicating a statistically significant difference (p < 0.05). Advanced maternal age (AMA), high-risk maternal serum screening (MSS), and non-invasive prenatal DNA testing (NIPT) were the important indications for predicting abnormal karyotype. The number of prenatal diagnosis indications was highly correlated with fetal chromosomal abnormalities. The overall incidence of chromosomal abnormalities showed a tendency to increase with age. The incidence of Trisomy 21 was 3.2%, accounting for 42.5% of all chromosomal abnormalities, and the incidence tended to increase with maternal age.

Conclusion: Prenatal karyotype analysis of pregnant women with prenatal diagnosis indications can effectively prevent the birth of defective children. AMA, MSS and NIPT were the important indications for predicting abnormal karyotype. In addition, the number of prenatal diagnosis indications is highly correlated with chromosomal abnormalities.

Different Methods for Molecular and Rapid Detection of Human Novel Coronavirus

Introduction: While PCR has been recognized as one of the appropriate ways to diagnose infectious diseases, Loop-mediated isothermal amplification (LAMP) which is a nucleic acid amplification method, can be considered as an alternative to PCR, and it is faster, cost-effective, and easier to perform than nested PCR.

Patients and Methods: Keywords were searched in PubMed/MEDLINE, Scopus and Institute for Scientific Information Web of Science, as well as the search engine of Google Scholar. Keywords included PCR, LAMP, RAA, RPA, Virus and COVID-19.

Results: LAMP technology has been extensively applied for the detection of human pathogenic bacteria, crop pests, pathogenic organisms and components in meat products. A new isotheral method, Recombinase polymerase amplification (RPA), can amplify the DNA as well as RPA. RPA involves benefits of isothermal PCR as well as simplicity and rapid amplification. Recombinase aided amplification (RAA) assay has been favorably used in the detection of bacterial and viral pathogens and solved the technical difficulties posed by DNA amplification methods because it does not need thermal denaturation of the template and involves a low and constant temperature.

Conclusion: Reverse transcription polymerase chain reaction, digital PCR, LAMP, nicking endonuclease amplification reaction, recombinase polymerase amplification, and clustered regularly interspaced short palindromic repeats are different nucleic acid amplification tests of COVID-19. LAMP methods can be more specific than qPCR and immunoassays. The LAMP assay can be applied for rapid detection of SARS-CoV, MERS-CoV, SARS-CoV-2, and influenza, because LAMP is a highly sensitive and specific DNA/RNA amplification technique.

Potential Phytotherapeutic Approaches for the Treatment of Alzheimer’s Disease: An Overview

Alzheimer’s disease is one of the most prevailing age-dependent neurodegenerative diseases and the most common cause of dementia. The pharmacological therapies available for the disease provide only symptomatic relief. Plants are being extensively investigated for Alzheimer’s as they are relatively safer and cheaper. This review summarizes recent findings suggesting anti- Alzheimer potential of the plants along with compounds or mechanisms responsible for their efficacy and their therapeutic targets. The findings of recent studies have revealed that the plants or the compounds isolated from them exhibit mitigative potential in Alzheimer’s disease by targeting amyloid beta, tau protein, cholinergic pathways via various enzymes like beta secretase, gamma secretase, acetylcholinesterase or receptors involved in these pathways. A number of putative compounds revealed from these studies can be investigated further for the mitigation of Alzheimer’s disease.

Role of Hydrogen Sulfide and Polysulfides in Neurological Diseases: Focus on Protein S-Persulfidation

Hydrogen sulfide (H2S) and hydrogen polysulfides are recognized as important signaling molecules that are generated physiologically in the body, including the central nervous system (CNS). Studies have shown that these two molecules are involved in cytoprotection against oxidative stress and inflammatory response. In the brain system, H2S and polysulfides exert multiple functions in both health and diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington's disease (HD), memory decline, and glioma. Mechanistically, S-Persulfidation (also known as S-sulfuration or S-sulfhydration) of target proteins is believed to be a fundamental mechanism that underlies H2S-regulated signaling pathways. Cysteine S-Persulfidation is an important paradigm of post translational protein modification in the process of H2S signaling. This model is established as a critical redox mechanism to regulate numerous biological functions, especially in H2S-mediated neuroprotection and neurogenesis. Although the current research of S-Persulfidation is still in its infancy, accumulative evidence suggests that protein S-Persulfidation may share similar characteristics with protein S-nitrosylation. In this review, we will provide a comprehensive insight into the S-Persulfidation biology of H2S and polysulfides in neurological ailments and presume potential avenues for therapeutic development in these disorders based on S-Persulfidation of target proteins.

Newborn Screening through TREC, TREC/KREC System for Primary Immunodeficiency with limitation of TREC/KREC. Comprehensive Review

Introduction: Newborn screening (NBS) by quantifying T cell receptor excision circles (TRECs) and Kappa receptor excision circles in neonatal dried blood spots (DBS) enables early diagnosis of different types of primary immune deficiencies. Global newborn screening for PID, using an assay to detect T-cell receptor excision circles (TREC) in dried blood spots (DBS), is now being performed in all states in the United States. In this review, we discuss the development and outcomes of TREC, TREC/KREC combines screening, and continued challenges to implementation.

Objective: To review the diagnostic performance of published articles for TREC and TREC/ KREC based NBS for PID and its different types.

Methods: Different research resources were used to get an approach for the published data of TREС and KREC based NBS for PID like PubMed, Scopus, Google Scholar, Research gate EMBASE. We extracted TREC and KREC screening Publisher with years of publication, content and cut-off values, and a number of retests, repeat DBS, and referrals from the different published pilot, pilot cohort, Case series, and cohort studies.

Results: We included the results of TREC, combined TREC/KREC system based NBS screening from different research articles, and divided these results between the Pilot studies, case series, and cohort. For each of these studies, different parameter data are excluded from different articles. Thirteen studies were included, re-confirming 89 known SCID cases in case series and reporting 53 new SCID cases in 3.15 million newborns. Individual TREC contents in all SCID patients were <25 TRECs/μl (except in those evaluated with the New York State assay).

Conclusion: TREC and KREC sensitivity for typical SCID and other types of PID was 100 %. It shows its importance and anticipating the significance of implementation in different undeveloped and developed countries in the NBS program in upcoming years. Data adapting the screening algorithm for pre-term/ill infants reduce the amount of false-positive test results.

Pregnancy Among HIV-Serodiscordant Couples: Case Report of Vertical Transmission and Retrospective Case Series

Background: HIV transmission during pregnancy and breastfeeding among serodiscordant heterosexual couples represents an ongoing barrier to the elimination of vertical transmission of HIV-1 infection in Canada.

Objective: To report a case of vertical HIV transmission during breastfeeding and examine the prevalence of risk factors for HIV transmission in the pregnancy and postpartum periods among serodiscordant couples where the male partner is HIV positive and female partner HIV negative.

Methods: Case report and retrospective chart review of HIV-serodiscordant pregnant couples over an eight-year period in Edmonton, Canada.

Results: We report a case of maternal primary HIV infection during the postpartum period and vertical transmission to a nursing infant that went undetected until the infant presented with AIDS. We also report a series of 41 serodiscordant pregnant couples identified by our public health nurse between 2008 and 2016. Among HIV-infected male partners, 20 (49%) had a detectable viral load (VL) during their partner’s pregnancy and during breastfeeding, with median peak VL 4,700 copies/mL (range 49-120,000) and 5,100 copies/mL (range 40-120,000) during pregnancy and breastfeeding, respectively. None of the female partners seroconverted during pregnancy, but three seroconverted at 1.8, 2.4, and 6.9 years after delivery. No vertical transmission occurred.

Conclusion: Despite concerted attempts to minimize HIV transmission during pregnancy and breastfeeding in our well-resourced setting, residual transmission risk remains due to non-suppressed viral load within many HIV-serodiscordant pregnant couples.

Inflammaging of Female Reproductive System: A Molecular Landscape

Aging is a complex biological process, a major aspect of which is the accumulation of somatic changes throughout life. Cellular senescence is a condition in which cells undergo an irreversible cell cycle arrest in response to various cellular stresses. Once the cells begin to senesce, they become more resistant to any mutagens, including oncogenic factors. Inflammaging (inflammatory aging) is an age-related, chronic, and systemic inflammatory condition realized by cells with the Senescence-Associated Secretory Phenotype (SASP). These recently recognized senescent phenotypes associated with aging have been reported to promote better wound healing, embryonic development, as well as stimulation and extension of the tumor process. It is assumed that cellular senescence contributes to the age-related decline of reproductive function due to the association of senescent cells with aging and age-related diseases. Thus, SASPs have both positive and negative effects, depending on the biological context. SASP cell accumulation in tissues contributes to an age-related functional decline of the tissue and organ state. In this review, the term “cellular senescence” is used to refer to the processes of cells irreversible growth inhibition during their viable state, while the term “aging” is used to indicate the deterioration of tissues due to loss of function. Late reproductive age is associated with infertility and possible complications of the onset and maintenance of pregnancy. Senescent cells express pro-inflammatory cytokines, growth factors, and matrix metalloproteinases and some other molecules collectively called the Senescence-Associated Secretory Phenotype (SASP).

Therapies of Hematological Malignancies: An Overview of the Potential Targets and Their Inhibitors

Background: The term “hematological malignancy” means a cluster of cancer and tumor conditions, including leukemia, lymphoma, myeloproliferative neoplasm, lymphoproliferative disorders, etc., involved with circulatory organs like blood, bone marrow, lymph, and lymph nodes.

Introduction: The increase in the number of hematological malignancy-related cases in our modern society urges suitable treatment of such disease. In this current era, there is still a major deficiency in the number of suitable chemotherapeutic agents for the treatment of hematological malignancies.

Methods: The researchers were successful in identifying various cellular, extracellular proteins, and cytokines, as well as their involvement in different hematological malignancies via epigenetic modulation and regulation of other proteins and signaling pathways. Here, we have discussed the structural aspects, connection, and pathophysiological contributions of a group of different cellular and extracellular proteins that are regulated and/or have a significant influence on the progression of different hematological malignancies along with their potent inhibitors.

Result and Conclusion: The correlation of physiological proteins with cancerous hematological conditions has been discussed here. It can be crucial for the development of potent inhibitors as chemotherapeutic agents to contest such malignancies. This review will also be useful in the chemotherapeutic agent development by providing crucial information about such hematological malignancy-related proteins and their inhibitors. The repurposed drugs with potential for anticancer applications are also discussed.

Vitamins and Cognition: A Nutrigenomics Perspective

The rise in the prevalence of neurodegenerative and neurodevelopmental cognitive disorders combined with a lack of efficient therapeutic strategies has necessitated the need to develop alternate approaches. Dietary supplements are now being considered as a complementary and alternative medicine for cognitive impairments. Considerable evidence suggests the role of vitamins in modulating the genetic and epigenetic factors implicated in neuropsychiatric, neurodevelopmental and neurodegenerative disorders. In this review, we provide an overview of the implications of nutrigenomics with reference to vitamins that are suggested to boost cognitive functions (nootropic vitamins). Several vitamins have been found to possess antioxidant and anti-inflammatory properties which make them potential candidates in preventing or delaying age-related neurodegeneration and cognitive decline. Well-designed longitudinal studies are essential to examine the association between vitamins and cognitive functions. Future studies linking nutrition with advances in neuroscience, genomics and epigenomics would provide novel approaches to managing cognitive disorders.

Childhood Alopecia Areata: An Overview of Treatment and Recent Patents

Background: Alopecia Areata (AA) is a systemic autoimmune condition that usually starts in childhood.

Objective: This article aims to review genetics, therapy, prognosis, and recent patents for AA.

Methods: We used clinical queries and keywords “alopecia areata” AND “childhood” as a search engine. Patents were searched using the key term “alopecia areata” in Patents.google.com and freepatentsonline. com.

Results: Due to an immune-mediated damage to the hair follicles, hair is lost from the scalp and other areas of the body temporarily or even permanently. Children with AA are generally healthy. Evidence of genetic association and increased predisposition for AA was found by studying families with affected members. Pathophysiologically, T- lymphocytes attack hair follicles and cause inflammation and destruction of the hair follicles and hair loss. In mild cases, there would be well-demarcated round patchy scalp hair loss. The pathognomonic “exclamation mark hairs” may be seen at the lesion periphery. In more severe cases, the hair loss may affect the whole scalp and even the whole body. The clinical course is also variable, which may range from transient episodes of recurrent patchy hair loss to an indolent gradually deteriorating severe hair loss. The treatment of AA depends on factors including patients’ age, the extent of the hair loss, duration of disease, psychological impact, availability and side effect profile of the treatments. For localized patchy alopecia, topical application of corticosteroids and/or intralesional corticosteroids are the treatment of choice. Other topical treatments include minoxidil, anthralin, coal tar and immunotherapy. In severe resistant cases, systemic immunosuppressants may be considered. Although herbal medicine, acupuncture, complementary and alternative medicine may be tried on children in some Asian communities, the evidence to support these practices is lacking. To date, only a few recent patents exist in topical treatments, including Il-31, laser and herbal medications. Clinical efficacy is pending for these treatment modalities.

Conclusion: None of the established therapeutic options are curative. However, newer treatment modalities, including excimer laser, interleukin-31 antibodies and biologics, are evolving so that there may be significant advances in treatment in the near future. AA can be psychosocially devastating. It is important to assess the quality of life, degree of anxiety, social phobia and mood of the patients and their families. Psychological support is imperative for those who are adversely affected psychosocially.

Cardiovascular Complications in Patients with Klinefelter’s Syndrome

More than 70 years have passed since the first description of Klinefelter Syndrome (KS), the most frequent chromosome disorder causing male infertility and hypogonadism. KS is associated with increased cardiovascular (CV) mortality due to several comorbidities, including hypogonadism, as well as metabolic syndrome and type 2 diabetes, which are highly prevalent in these patients. Aside from metabolic disturbances, patients with KS suffer from both acquired and congenital CV abnormalities, cerebrovascular thromboembolic disease, subclinical atherosclerosis and endothelial dysfunction, which may all contribute to increased CV mortality. The mechanisms involved in this increased risk of CV morbidity and mortality are not entirely understood. More research is needed to better characterise the CV manifestations, elucidate the pathophysiological mechanisms and define the contribution of testosterone replacement to restoring CV health in KS patients. This review explores the complex association between KS, metabolic syndrome and CV risk in order to plan future studies and improve strategies to reduce mortality in this high-risk population.

Occipital Encephalocele: Cause, Incidence, Neuroimaging and Surgical Management

Aims: To review and present the current knowledge of incidence, signs and symptoms, diagnosis and treatment of the occipital encephalocele.

Background: Encephalocele (E) is a defect of the neural tube that refers to congenital malformations featured by skull defect and dura with extracranial spread of intracranial structures. Occipital encephalocele (OE) are the most common form of this congenital disorder and are manifested as a swelling of different sizes over the occipital bone in the midline. Proper diagnosis and treatment is highly important in the management of this congenital malformation of brain.

Objective: To review and present the current knowledge of incidence, signs and symptoms, diagnosis and treatment of the occipital encephalocele.

Methods: We conducted a search of case reports or case-series of patients by the use of electronic databases: Pub Med, Medline, Index Medicus, Scorpus. The key words were: encephalocele, occipital encephalocele, neural tube defect, congenital malformation. The search was updated to December 31, 2018. Papers published in English were the only source of information.

Results: Occipital encephalocelle are more frequent in females than in males. The incidence is between 1 in 3000 to 1 in 10,000 live births; approximately 90% of them involve the midline. Magnetic resonance imaging is the method of choice in diagnosis and surgery is the best option for the treatment of OE. Overall morbidity and mortality is still high in spite of advenced surgical management, but have been significantly improved in recent years thanks to sophisticated highresolution imaging, adequate and proper surgical treatment and decent post-operative care.

Conclusion: Occipital encephalocele is the most common form of encephalocele. The diagnosis is mostly based by the use of neuroimaging techniques. Operation is the best option for treatment. Overall morbidity and mortality is still high, but have been significantly improved in recent years thanks to sophisticated high-resolution imaging, adequate and proper surgical treatment and decent post-operative care.

Role of microRNAs in Chronic Lymphocytic Leukemia Pathogenesis

MicroRNAs (miRNAs) are a group of small endogenous non-coding RNAs involved in many cancers and various cellular processes such as cellular growth, DNA methylation, apoptosis, and differentiation. 13q14.3 chromosomal region contains miR-15 and miR-16 and deletion of this region is a commonly reported aberration in Chronic Lymphoblastic Leukemia (CLL), suggesting miRNAs involvement in CLL pathogenesis. MicroRNAs are known as oncogenes and tumor suppressors in CLL which may also serve as markers of onset and progression of the disease. The most prevalent form of leukemia diagnosed in adults in the western world, chronic lymphocytic leukemia, accounts for one-third of all leukemias. CLL is characterized by the presence of B Cell Malignant Clones in secondary lymphoid tissues, peripheral blood and bone marrow. The precise etiology of CLL is remained to be known, however, a number of Chromosomal Abnormalities such as deletions of 13q14.3, 11q and 17p and trisomy 12 have been detected. In this review, we offer our prospect on how miRNAs are involved in the CLL pathogenesis and disease progression. Further understanding of the underlying mechanisms and regulation of CLL pathogenesis has underscored the need for further research regarding their role in this disease.

Pharmacotherapy of Down’s Syndrome: When and Which?

Down Syndrome (DS) is an essential genetic disease that involves many other body systems along with cerebral functions. The postnatal approach to treat this genetic disease includes intervention on various related disorders (e.g., heart failure, respiratory, oral, ear, and hearing disorders). However, different proposed treatments do not significantly improve the quality of life of these subjects. Another approach to the treatment of DS considering the possibility to intervene on the embryo was recently introduced. As of this, the current study has reviewed different outcomes regarding DS treatment in an animal model, namely the Ts65Dn mouse. The obtained results encouraged spending more time, efforts, and resources in this field. Besides, various treatment strategies were tried to include genetic modification, treatment with vasoactive intestinal peptide derivatives or fluoxetine. However, the main obstacle to the use of these possible treatments is the ethical issues it raises. The progression of the pregnancy in spite of awareness that DS affects the unborn and prenatal treatment of DS injured embryo are relevant dilemmas. Thus, talented researchers should spend more efforts to improve the quality of life for people affected by DS, which will allow probably a better approach to the ethical issues.

Metabolic Routes in Inflammation: The Citrate Pathway and its Potential as Therapeutic Target

Significant metabolic changes occur in inflammation to respond to the new energetic needs of cells. Mitochondria are addressed not only to produce ATP, but also to supply substrates, such citrate, to produce pro-inflammatory molecules. In this context, most of the citrate is diverted from Krebs cycle and channeled into the “citrate pathway” leading to the increase in the export of citrate into cytosol by the Mitochondrial Citrate Carrier (CIC) followed by its cleavage into acetyl-CoA and oxaloacetate by ATP Citrate Lyase (ACLY). Acetyl- CoA is used to produce PGE2 and oxaloacetate to make NADPH needed for NO and ROS production. In addition, cytosolic citrate also provides precursors for itaconate synthesis. Citrate- derived itaconate acts as a negative regulator of inflammation by modulating the synthesis of the inflammatory mediators. Inhibition of CIC or ACLY by different synthetic and natural molecules results in the reduction of NO, ROS and PGE2 levels suggesting that the citrate pathway can be a new target to be addressed in inflammation. Beneficial effects can be obtained also in the oxidative stress and inflammatory conditions observed in Down syndrome.

Endothelial and Circulating Progenitor Cells in Hematological Diseases and Allogeneic Hematopoietic Stem Cell Transplantation

Background: Circulating endothelial cells (CECs), originated form endothelial progenitors (EPCs) are mature cells not associated with vessel walls and detached from the endothelium. Normally, they are present in insignificant amounts in the peripheral blood of healthy individuals. On the other hand, elevated CECs and EPCs levels have been reported in the peripheral blood of patients with different types of cancers and other diseases.

Objective: This review aims to provide an overview on the characterization of CECs and EPCs, to describe isolation methods and to identify the potential role of these cells in hematological diseases and hematopoietic stem cell transplantation.

Methods: We performed a detailed search of peer-reviewed literature using keywords related to CECs, EPCs, allogeneic hematopoietic stem cell transplantation, and hematological diseases (hemoglobinopathies, hodgkin and non-hodgkin lymphoma, acute leukemia, myeloproliferative syndromes, chronic lymphocytic leukemia).

Results: CECs and EPCs are potential biomarkers for several clinical conditions involving endothelial turnover and remodeling, such as in hematological diseases. These cells may be involved in disease progression and in the neoplastic process. Moreover, CECs and EPCs are probably involved in endothelial damage which is a marker of several complications following allogeneic hematopoietic stem cell transplantation.

Conclusion: This review provides information about the role of CECs and EPCs in hematological malignancies and shows their implication in predicting disease activity as well as improving HSCT outcomes.

CT and MR Imaging of the Encephalopathic Child

Background: Neonatal and paediatric encephalopathy can be a diagnostic challenge for clinicians. Potential aetiologies include hypoxic brain injury, stroke, infection, trauma, metabolic and electrolyte abnormalities, autoimmune conditions and drug ingestion. Radiology plays a key role in determining aetiology and, even when normal, directing further assessment.

Conclusion: We present a review of the neuroradiological manifestations of neonatal and paediatric encephalopathies which will aide paediatricians and radiologists in their assessment of children with this condition.

Induced Pluripotent Stem Cell Technology: A Paradigm Shift in Medical Science for Drug Screening and Disease Modeling

Background: Induced Pluripotent Stem Cell (IPSC) Technology is the most advanced research as it offers an attractive alternative for establishing patient-specific IPSCs to recapitulate phenotypes of not only monogenic diseases (viz. Thalassaemia, Sickle cell anemia, Haemophilia, Tay-Sachs disease), but also late-onset polygenic diseases (viz. Parkinson's disease, Alzheimer's disease, schizophrenia). Over the hindsight, numerous studies of the past and current scientists have led to the production, maturation and understanding of induced pluripotent stem cell technology and its use in basic and clinical research.

Methods: A systematic search of peer-reviewed scientific literature and clinical trials in public databases were carried out to summarize the evidence on the use of IPSC.

Results: Current review sheds light upon the use of patient-derived iPSC models in drug toxicity, screening and discovery which have been derived after referring to more than 200 articles in literature. Furthermore, their use as disease models was also studied signifying the versatility of iPSC lines.

Conclusion: Through this review, we describe the advent of iPSC technology, where we comprehensively cover the generation of iPSCs and their characterization along with their prospective applications using IPSC banks in disease modeling and drug screening.

Developmental Expression and Dysregulation of miR-146a and miR-155 in Down's Syndrome and Mouse Models of Down's Syndrome and Alzheimer's Disease

Background: miR-146a and miR-155 are key regulators of the innate immune response. We hypothesized that an inflammation-mediated dysregulation of these miRNAs may occur in patients with Down syndrome (DS) and Alzheimer's disease (AD).

Methods: The miRNA expression patterns were investigated by in situ hybridization in developing hippocampus from controls, patients with DS and in adults with AD pathology (DS and sporadic AD; sAD). Quantitative real-time PCR was employed to evaluate the miRNA levels in the hippocampus of sAD and in mouse models of DS and AD. Both miRNAs were expressed in prenatal human hippocampus. In DS we detected increased miR-146a expression in reactive astrocytes. Increased expression of miR-146a was found in the hippocampus of sAD and negatively correlated with its target IRAK-1. APP/PS1 mice showed a significant increase in the expression of both miRNAs at 11-13 months of age as compared to WT and mice at 3 months. A negative correlation between miR-146a levels and its target TRAF6 was observed in both Ts65Dn and APP/PS1 mice.

Conclusion: These findings suggest a possible involvement of miR-146a and miR-155 in brain development and neurodegeneration. In particular, we provide evidence of a dysregulation of these two immunomodulatory miRNAs in AD with a potential therapeutical implication, deserving further investigation.

Lithium Restores Age-related Olfactory Impairment in the Ts65Dn Mouse Model of Down Syndrome

Background & Objective: Down syndrome, a genetic condition caused by triplication of chromosome 21, is characterized by widespread neurogenesis reduction and cognitive impairment. Unlike other brain functions, smell is not impaired at early life stages and olfactory deterioration begins to appear in adulthood. Similarly to individuals with Down syndrome, in the Ts65Dn mouse model of Down syndrome smell function is normal at early life stages. Smell impairment only appears in adulthood associated with a reduction in the number of new granule neurons migrated to the olfactory bulb from the subventricular zone. Based on evidence that lithium positively impacts neurogenesis, the goal of current study was to establish whether treatment with lithium restores olfactory bulb neurogenesis and olfactory performance in middle-aged Ts65Dn mice.

Method: Euploid and Ts65Dn mice aged 13 months were treated with lithium chow or control chow for one month. Before the end of treatment, mice were injected with BrdU, in order to label proliferating cells. Results showed that in Ts65Dn mice lithium treatment restored the number of neural precursor cells in the subventricular zone of the lateral ventricle, rostral migratory stream and olfactory bulb. This effect was accompanied by restoration of olfactory performance. Unlike in olfactory neurogenic regions, treatment had no neurogenesis-enhancing effect on the subgranular zone of the hippocampal dentate gyrus, indicating that lithium has no generalized positive effect on the brain.

Conclusion: Results suggest that lithium may have a positive impact in brain disorders that, similarly to Down syndrome, are characterized by olfactory decline and neurogenesis impairment in the subventricular zone.

Biomarkers for Alzheimer's Disease Diagnosis

Objective: The dramatic increase in the population with dementia expected in the next decades is accompanied by the establishment of novel and innovated methods that will offer accurate and efficient detection of the disease in its early stages. While Alzheimer's disease is the most common cause of dementia, by the time it is typically diagnosed, substantial neuronal loss and neuropathological lesions can damage many brain regions. The aim of this study is to investigate the main risk factors that affect and increase Alzheimer's disease progression over time even in cases with no significant memory impairment present. Several potential markers are discussed such as oxidative stress, metal ions, vascular disorders, protein dysfunctions and alterations in the mitochondrial populations.

Conclusion: A multiparametric model of Alzheimer's biomarkers is presented according to the latest classification of the disease.

Congenital Malformations Attributed to Prenatal Exposure to Cyclophosphamide

Cyclophosphamide (CPA) remains one of the most widely prescribed anticancer drugs. It is also used in the treatment of rheumatoid arthritis, childhood nephrotic syndrome and systemic lupus erythematosus. It is a potent immunosuppressive agent. It is commonly used in blood and bone marrow transplantation. With the growing trend among women postponing childbearing, the number of women who are diagnosed with breast cancer is also increasing thus escalating the chances of exposure of the unborn child to antineoplastic drugs. A review of the literature provides strong evidence for the teratogenic effects on infants prenatally exposed to CPA. Both sporadic case reports and larger case series have demonstrated that babies with cyclophosphamide embryopathy are afflicted with intrauterine growth restriction, small for gestational age, and craniofacial malformations including eye anomalies, cleft/arched palate, hydrocephaly, micrognathia, low set microtia, hearing defects, craniosynostosis, and facial asymmetry. Also observed in these cases are limb defects such as radial, ulnar and tibial hypoplasia, club foot, digital defects of the hand and feet as well as vertebral fusion, brevicolis, and occasional Sprengel’s deformity. These anomalies vary in consistency of occurrence and severity of the phenotype across cases and lack the specificity of thalidomide embryopathy or rubella embryopathy. However, they do occur is no longer in doubt. First trimester of pregnancy seems to be particularly susceptible to fetal malformations, although CPA effects on fetuses of later stages of gestation (hearing defects, growth restriction for example) are also reported occasionally. One of the major concerns from a mechanistic point of view is our inability to dissect the teratogenic effects of CPA from those of other drugs administered together with CPA as combination therapy. Animal experiments have been of particular value in that they are able to circumvent the numerous extraneous variables inherent to human case reports. They have also revealed the detrimental effects of CPA on gametes, preimplantation embryos, organogenesis as well as their potential teratogenic mechanisms. Of particular importance are the role of genetic polymorphisms, male mediated teratogenesis, ovarian failure, preimplantation embryo loss, epigenetic modifications, proxidant-antioxidant imbalance, autophagy, apoptosis, microRNAs and postclosure neural tube defects induced by CPA -all of which are areas for further research in CPA teratogenesis.

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Homocysteine in Neurology: From Endothelium to Neurodegeneration

Vitamin B12 and folate are supplied via two major pathways, the conversion of homocysteine to methionine and the conversion of methyl malonyl coenzyme A to succinyl coenzyme A. Therefore, the defect in both the vitamins results in an increase in both serum homocysteine and methylmalonic acid. Hence, homocysteine, vitamin B12, and folate are closely linked together in the so-called one-carbon cycle, making vitamin B12 the necessary co-enzyme for the methyl donation from 5-methyl-tetra-hydrofolate in tetra-hydro-folate, necessary for methionine synthetase. Folate is a cofactor in one-carbon metabolism, and it promotes the remethylation of homocysteine, which can cause DNA strand breakage, oxidative stress and apoptosis. Vitamin B12 and folate are involved in nucleic acid synthesis and in the methylation reactions, and their deficit causes the inhibition of S-adenosylmethionine mediated methylation reactions, and through the related toxic effects of homocysteine, a possible direct alteration of the vascular endothelium and inhibition of N-methyl-D-Aspartate receptors take place. We discussed the possible and still controversial role of homocysteine accumulation in cerebral pathologies, starting from vascular events to neurodegeneration and to endothelium damage mechanism.

Tauopathies – Focus on Changes at the Neurovascular Unit

In the past, the blood-brain barrier (BBB) has been characterized mainly as a layer of endothelial cells forming the vessel/capillary wall of the brain. More recently, the BBB is considered to be a part of a highly dynamic and interactive system called the neurovascular unit (NVU), consisting of vascular cells, glial cells, and neurons.

The list of central nervous system (CNS) pathologies involving BBB dysfunction is rapidly growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic and neuronal dysfunction and loss. Such processes have been implicated in different diseases, including vascular dementias, stroke, Alzheimer´s disease (AD), Parkinson´s disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus.

Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of microtubule-associated protein tau in cells of the nervous system.

Increased microvascular permeability has been more typically related to cerebrovascular deposition of amyloid-β (Aβ), but in contrast very little is known about the connection between functional impairment of the BBB and the misfolded tau proteins. Here, we review what is known about tauopathies, the BBB, and the NVU.

Virological and Clinical Response to Interferon-Free Regimens in Patients with HCV-Related Mixed Cryoglobulinemia: Preliminary Results of a Prospective Pilot Study

Mixed Cryoglobulinemia (MC) is the most frequent extrahepatic manifestation of Hepatitis C virus (HCV) infection. MC is an autoimmune /B-cell lymphoproliferative disorder characterized by circulating immune-complexes, named cryoglobulins. MC patients exhibit symptoms due to a systemic vasculitis of small/medium size vessels (mixed cryoglobulinemia syndrome, MCS) in a percentage going from 5 to 30%. The first-line therapeutic option in MCS patients is the etiologic treatment and, in the past fifteen years, antiviral therapy with Pegylated-Interferon (Peg-IFN) plus Ribavirin (RBV) represented the standard of care. Lately, the arrival of direct acting antivirals (DAAs) significantly modified the cure of HCV infection, consenting the use of IFN-free regimens. Here we report a review of the literature about the role of antiviral treatment, following its evolution, in treating HCVrelated MC. Furthermore, we report the results, after 8 weeks of treatment, of a preliminary pilot prospective study, counting 17 patients with HCV-related MC with or without MCS, treated with new generation DAAs in IFN-free regimens. After 8 weeks of DAA administration, all the subjects were HCV RNA negative. Moreover, in 6/17 (35%) patients cryoglobulins disappeared and, on the whole, in all patients a decrease of the cryocrit values was observed (p<0.05). Furthermore, three MCS-HCV patients (30%) resulted to be complete clinical responders and 5 subjects (50%) partial clinical responders. Therefore, IFN-free anti-HCV treatment appears to be safe and effective in MC patients from virological and clinical points of view, thus supporting the importance of HCV eradication in leading MC remission.

HCV-Related Rheumatic Manifestations and Therapeutic Strategies

A number of hepatic and extra-hepatic autoimmune disorders may complicate a percentage of patients with hepatitis C virus (HCV) infection that is both hepatotropic and lymphotropic agent; the resulting clinical phenotypes can be grouped into the so-called HCV syndrome. This latter includes various rheumatic disorders that are frequently characterized by clinical or serological overlap; thus, a correct patients’ classification is necessary prior to decide the therapy.

The management of these conditions is particularly difficult, given the coexistence of viral infection and immunological alterations. In this scenario, cryoglobulinemic vasculitis represents the prototype of HCV-related rheumatic disorders that can be treated at different levels by means of etiological (antivirals) and/or pathogenetic and/or symptomatic treatments (rituximab, cyclophosphamide, steroids, plasmapheresis, etc). In clinical practice, the therapeutic strategy should take into account the specific symptoms combination and the severity/activity of the disease, according to each patient’s conditions. This review focuses on the clinico-diagnostic assessments and therapeutical approaches of some rheumatic disorders complicating HCV infection, mainly arthritis, sicca syndrome, and osteosclerosis; while, cryoglobulinemic vasculitis is comprehensively examined in another article of the present issue.

New Developments of Differentiation Therapy of Acute Myeloid Leukemia

Background: A typical feature of acute myeloid leukemia (AML) consists in the blockade of the cell differentiation process. Many experimental studies have shown that some chemical compounds induce the selective differentiation of hematopoietic cell lines, thus supporting the rationale of using these agents to treat AML by forcing these cells to undergo a process of terminal differentiation. From these studies emerged the potential of all-trans retinoic acid (ATRA) to induce the differentiation of acute promyelocytic cells (APLs) and to treat these patients. The introduction of ATRA in the therapy of these patients improved the treatment of APLs, providing evidence that ATRA, combined with standard chemotherapy or arsenic trioxide (ATO) gives a curative effect in most of these patients. Attempts to emulate the effects of ATRA using other differentiation agents have failed.

Results: The recent identification of new AML subsets classified according to specific molecular abnormalities and the development of agents selectively targeting these leukemia biomarkers led to a renewed interest for the differentiation therapy. It was shown that inhibition of mutant FLT3 or of mutant IDH1/2 exerts a significant anti-leukemia effect in part mediated by induction of cell differentiation. Preclinical studies strongly support the use of these inhibitors in combination with ATRA. On the other hand, recent observations indicate that various modulators of the epigenetic response (such as DNMT3A or LSD1 inhibitors) restore the sensitivity of non-APL AML blasts to the differentiative effect of ATRA.

Conclusion: These observations suggest new successful developments of AML differentiation therapy in the near future.

Polyphenols Beyond Barriers: A Glimpse into the Brain

Background: Ageing can be simply defined as the process of becoming older, which is genetically determined but also environmentally modulated. With the continuous increase of life expectancy, quality of life during ageing has become one of the biggest challenges of developed countries. The quest for a healthy ageing has led to the extensive study of plant polyphenols with the aim to prevent age-associated deterioration and diseases, including neurodegenerative diseases. The world of polyphenols has fascinated researchers over the past decades, and in vitro, cell-based, animal and human studies have attempted to unravel the mechanisms behind dietary polyphenols neuroprotection.

Methods: In this review, we compiled some of the extensive and ever-growing research in the field, highlighting some of the most recent trends in the area.

Results: The main findings regarding polypolyphenols neuroprotective potential performed using in vitro, cellular and animal studies, as well as human trials are covered in this review. Concepts like bioavailability, polyphenols biotransformation, transport of dietary polyphenols across barriers, including the blood-brain barrier, are here explored.

Conclusion: The diversity and holistic properties of polypolyphenol present them as an attractive alternative for the treatment of multifactorial diseases, where a multitude of cellular pathways are disrupted. The underlying mechanisms of polypolyphenols for nutrition or therapeutic applications must be further consolidated, however there is strong evidence of their beneficial impact on brain function during ageing. Nevertheless, only the tip of the iceberg of nutritional and pharmacological potential of dietary polyphenols is hitherto understood and further research needs to be done to fill the gaps in pursuing a healthy ageing.

Pregnancy-Associated Plasma Protein-A and its Role in Cardiovascular Disease. Biology, Experimental/Clinical Evidences and Potential Therapeutic Approaches

Pregnancy-Associated Plasma Protein-A (PAPP-A) is a zinc-binding metalloproteinase protein produced by placental syncytio-trophoblasts and secreted into the maternal circulation where its concentration progressively increases until term. In recent years, PAPP-A has been studied for its potential involvement in cardiovascular (CV) disease. However, all those studies did not provide a clear view to identify the pathophysiological links between PAPP-A plasma levels and the occurrence of CV events. In this review, starting from a complete description of PAPP-A structure and biology, we present an updated overview of experimental as well as clinical evidence on the role of this metalloproteinase in CV disease. Finally, we discuss possible therapeutic approaches to antagonize its potential detrimental CV effects.

Statins, Mevalonate Pathway and its Intermediate Products in Placental Development and Preeclampsia

The mevalonate pathway synthesizes intermediates and products such as cholesterol and nonsterol isoprenoids that are crucial for cell survival and function. In the human placenta, the prenylation of proteins, rather than cholesterol synthesis, represents the main "metabolic target" of mevalonate metabolism. Major cellular functions depend on isoprenylation including proliferation, migration, metabolism and protein glycosylation that are all crucial for proper development of the embryo and the placenta. Statins are inhibitors of HMG-CoA reductase, the enzyme that catalyzes the reduction of HMG-CoA to mevalonic acid by NADPH. In vitro experiments using human placental explants suggest that statins elicit a detrimental effect on placental growth. However, animal and epidemiologic studies show no increase of fetal malformations after exposure to statins during pregnancy. Moreover, emerging evidence from mouse studies suggest that statins may be useful in preventing serious pregnancy complications like preeclampsia.

Right Heart Catheterization Through Persistent Left Superior Vena Cava, an Extremely Rare Procedure and Review of Current Literature

Persistent left superior vena cava (PLSVC) is encountered occasionally during angiographic procedures. It usually coexists with right superior vena cava and drains to the right atrium through the coronary sinus, but multiple variations are described. Although PLSVC is extensively reported in the literature, there are very few articles addressing right heart catheterization in patients with isolated PLSVC. We present a patient with absent right superior vena cava and PLSVC draining to a dilated coronary sinus diagnosed during right heart catheterization in the setting of pulmonary hypertension. We were able to safely complete the procedure through the right internal jugular vein. Transthoracic echocardiography and chest CT scan were consistent with this finding. Although clinically silent most of the time, undiagnosed PLSVC can lead to catastrophic consequences when the patient undergoes invasive procedures. If PLSVC is suspected, the anatomy of the thoracic venous system must be identified before invasive cardiac procedures.

Genetic and Epigenetic Drug Targets in Myelodysplastic Syndromes

Background: Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders of hematopoietic system, characterized by genetic, epigenetic or microenvironmental alterations of aging hematopoietic stem cells. Pathophysiology of MDS comprises the suppression of normal hematopoiesis and reduced myeloid progenitor cells differentiation, with the main consequence of peripheral cytopenias and increased risk to evolution in acute myeloid leukemia (AML).

Method: This review summarizes the evolving understanding of the role of genetic and epigenetic alterations involved in pathogenesis and current and future strategies for therapeutic targeting in myelodysplastic syndromes.

Results: In addition to molecular characteristics, immune and microenvironmental factors in bone marrow of MDS patients may further modify the MDS manifestations, its clinical presentation, disease course, risk of transformation to AML and prognosis of MDS, as well as response to therapy. Current clinical response to therapy approaches are exerted both by epigenetic alterations and by induction of apoptosis.

Conclusion: Future treatment strategies in preclinical and clinical investigations are directed towards new dosing schedules of existing drugs, new genetic and epigenetic targets and combination of different agents, including hypomethylation agents and histone deacetylase inhibitors.

Rasburicase-Induced Methemoglobinemia in a Patient with Glucose-6- Phosphate Dehydrogenase Deficiency

Background: Rasburicase is commonly used in patients with hematologic malignancies for tumor lysis syndrome prophylaxis and management. Methemoglobinemia is a serious rare adverse effect of rasburicase, more common in patients with G6PD deficiency. Prompt diagnosis and appropriate management of this condition can make the difference between successful recovery and significant morbidity. Here we discuss the link of rasburicase with methemoglobinemia and the pathophysiology behind increased incidence of this side effect in G6PD deficient patients.

Methods: We report the case of a 73-year-old African American man who developed methemoglobinemia on rasburicase treatment, who was later confirmed to be G6PD deficient. We reviewed the literature using Pubmed and Google Scholar using the following key words: “methemoglobinemia”, “rasburicase”, “urate oxidase”, tumor lysis syndrome”, G6PD deficiency”, “hemolytic anemia” and “hyperuricemia”.

Results: Rasburicase-induced methemoglobinemia is more common in patients with G6PD deficiency, and rasburicase is therefore contraindicated in these patients. Clinical presentation includes cyanosis, pallor, methemoglobin levels of 8-12%, and oxygen saturation gap which is evident from ABG analysis, though pulse oximetry is normal. Treatment consists of oxygen supplementation, ascorbic acid and blood transfusion. Importantly, methylene blue is avoided as therapy in G6PD deficiency as it can worsen the methemoglobinemia.

Conclusion: Rasburicase-induced methemoglobinemia is a serious concern, especially in African- American patients. It should be considered when clinical signs and symptoms are present. Knowledge of this side effect is important in early diagnosis and successful management of the condition.

Medical and Dental Implications of Down Syndrome: A Review Part 1: General and Craniofacial Characteristic

Down syndrome (DS) is a genetic disorder characterized by the presence of three chromosomes instead of two, specifically chromosome No. 21. The special needs status of DS individuals makes them more prone to several medical conditions such as congenital heart disease, gastrointestinal tract anomalies, immunodeficiency, visual impairment, skeletal defects, audiological dysfunction, seizures, acute leukaemia and thyroid disorders. A thorough knowledge of the unusual medical and orofacial abnormalities and their implications is crucial for a successful dental preventive and treatment planning. This paper provides an updated review of DS definition, etiology, epidemiology, medical problems and dentofacial abnormalities.

Adaptive Behavior in Williams-Beuren Syndrome, Down Syndrome, and Autism Spectrum Disorder

Adaptive behavior (AB) is defined as the skills acquired in response to everyday life demands. AB profiles of genetic syndromes have been proposed, but the literature on them has not been conclusive, mainly due to the large number of these syndromes and marked within-profile variability. The aim of the present study was to analyze the different ABs observed in subjects with Williams-Beuren Syndrome (WBS), Down Syndrome (DS) and Autistic Spectrum Disorder (ASD) through a literature review using the PubMed and Scopus database. The results indicated that Socialization strongly affects WBS; however, this group demonstrated the greatest amount of difficulty in the domain of daily living. The DS group demonstrated better performance in Socialization and Daily Living compared to Communication. The ASD group displayed better performance in Daily Living and Communication and the worst performance in socialization. Although the reviewed studies appear to demonstrate controversial results related to how ABs occur in each group, the main skills and shortages remained similar to each corresponding diagnostic behavioral characteristic. We conclude that it is possible to build AB profiles in the analyzed diagnostic groups, and we believe that these profiles may facilitate the construction of intervention plans.

Blood-Brain Barrier ABC-transporter P-glycoprotein in Alzheimer's Disease: Still a Suspect?

Alzheimer’s disease is a neurodegenerative disorder and the most common form of dementia. One of the pathological hallmarks of the disease is amyloid deposition in the brain. The major cause of amyloid deposition in sporadic Alzheimer’s disease is thought to be decreased brain clearance of amyloid. There is compelling preclinical evidence that the blood-brain barrier, a structure that maintains homeostasis in the central nervous system and protects the brain from harmful substances, plays an important role in amyloid clearance. Indeed, several dedicated transporter systems are present at the blood-brain barrier which may have a role in brain amyloid clearance, such as P-glycoprotein (P-gp). In vitro experiments and animal studies indicated increased amyloid deposition when P-gp was eliminated by pharmacological blockade or by genetic modification. And as decreased P-gp expression has been found in AD brains, P-gp became more and more a suspect. Using an imaging technique called positron emission tomography, P-gp transporter function was found to be decreased in Alzheimer’s disease patients compared to healthy controls, further establishing the important role of P-gp in the pathogenesis of the disease. In this review, we summarize what is now known about P-gp in Alzheimer’s disease pathology, as these transporters may provide a novel target for therapeutic strategies.

Clinical Experience of Non-Invasive Prenatal Chromosomal Aneuploidy Testing in 190,277 Patient Samples

Objectives: To detect trisomy 21, 18, and 13 in 190,277 clinical samples from the medical diagnostic laboratories of ten hospitals.

Methods: The study assessed the clinical performance of non-invasive prenatal testing (NIPT) in detecting trisomy 21, 18, and 13 in 190,277 clinical samples using semiconductor sequencing technology.

Results: NIPT participants were at a mean gestation of 17.79 weeks (range, 9–36) and age of 31.12 years (range, 18–46) at the time of testing on average. There were 1,543 (0.81%) positive cases, including 1050 for trisomy 21, 316 for trisomy 18, and 177 for trisomy, 13. The overall sensitivity and specificity for detecting trisomy 21, 18 and 13 combined were 99.61% and 99.91% respectively, and the overall positive predictive value and negative predictive value (PPV and NPV) were 89.74% and 99.99%, respectively.

Conclusions: This was the first large clinical study for semiconductor sequencing technologies in NIPT application. Our findings indicate that NIPT has the potential to replace serum biochemistry screening and could be performed at the early gestational age of 9~12 weeks.

Multiple Targets for the Management of Alzheimer’s Disease

AD is a progressive and irreversible neurodegenerative disease and the most common cause of dementia in the elderly population. Βeta- amyloid cascade formation along with several cytoskeleton abnormalities succeeding to the hyperphosphorylation of microtubule-associated tau protein in neurons leads to the elicitation of several neurotoxic incidents. As an outcome of these phenomena, steady growth of dementia in aged population is becoming ubiquitous in both developed and developing countries. Thus, the key aspiration is to endow with stable daily life functionality to the person suffering from dementia and to cut down or slower the symptoms of disease leading to disruptive behavior. In sight of this, the proteins amyloid-beta, BACE-1, RAGE and AChE are being aimed for the treatment of AD successfully. Currently, there are several medicines for the treatment of AD under survey like Galangin, Cymserine, Tolserine, Bisnorcymserine and Huperzine A. The article emphasizes clinical and neurobiological aspects of AD. The purpose of this review article is to provide a brief introduction of AD along with the related concept of beta-secretase, beta amyloid and neurotransmitter in the progression of disease. In the present review, we summarize the available evidence on the new therapeutic approaches that target amyloid and neurotransmitter in the AD.

Functional and Clinical Significance of the Integrin Alpha Chain CD49d Expression in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphological appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. CD49d, the α chain of the α₄β₁ integrin heterodimer, is one of the main interactors between CLL cells and accessory cells in the microenvironmental sites and one of the main predictors of overall survival. In particular, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug-induced damages. Treatment strategies targeting the α4β1 integrin could represent an interesting option in CLL. In this context, the recombinant anti-CD49d antibody natalizumab demonstrated the potential to overcome stromal cell-induced resistance of B cell lymphoma cells against cytotoxic drugs and rituximab in vitro. Moreover, a specific interest for the CD49d molecule raises from the clinical activity of the recently proposed inhibitors of kinases downstream the BCR that has been recently related with the inside-out activation of the α4β1 integrin. In the review, we addressed in detail the role of CD49d in CLL cells, including clinical impact, relationship with specific cytogenetic features, and CD49d-dependent interactions in lymph node and bone marrow microenvironment responsible for growth- and survival- supporting signals, eventually influencing CLL prognosis and therapeutic options.

Antiphospholipid Antibody-Mediated Thrombotic Mechanisms in Antiphospholipid Syndrome: Towards Pathophysiology-Based Treatment

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by a persistently high titer of antiphospholipid antibodies (aPLs). In addition to pregnancy morbidity, arterial and/or venous thrombosis is another clinical feature of APS. Regardless of the type of APS, the thrombi formed by the induction of aPLs can lead to deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke and gangrene. Although the concept of APS was introduced approximately 32 years ago, its thrombogenic pathophysiology is still unclear. Therefore, patients are treated with anticoagulant and/or antiplatelet regimens just as in other thrombotic disorders even though the thrombotic pathophysiology is mainly aPLs-mediated. In this review, we provided an update of the cellular, auto-immune and genetic factors known to play important roles in the generation of thrombi. Current successful regimens are also outlined along with potential emerging treatment strategies that may lead to the optimum management of thrombotic APS patients.

Human Induced Pluripotent Stem Cells for Inherited Cardiovascular Diseases Modeling

Cardiovascular cells derived from patient specific induced Pluripotent Stem Cell (iPSC) harbor gene mutations associated with the pathogenesis of inherited cardiac diseases and congenital heart diseases (CHD). Numerous reports have demonstrated the utilization of human induced Pluripotent Stem Cell (hiPSC) to model cardiac diseases as a means of investigating their underlying mechanisms. So far, they have been shown to investigate the molecular mechanisms of many cardiac disorders, such as long-QT syndrome (LQT), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), LEOPARD syndrome (LS), arrhythmogenic cardiomyopathy (ACM), Friedreich ataxia (FRDA), Barth syndrome (BTHS), hypoplastic left heart syndrome (HLHS), Marfan syndrome (MFS) and other CHD. This article summarizes the growing body of research related to modeling various cardiac diseases using hiPSCs. Moreover, by reviewing the methods used in previous studies, we propose multiple novel applications of hiPSCs to investigate comprehensive cardiovascular disorders and facilitate drug discovery.

Neuropsychiatric Disturbances in Alzheimer’s Disease: What Have We Learned from Neuropathological Studies?

Neuropsychiatric symptoms (NPS) are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. The near universal prevalence of NPS in Alzheimer’s disease (AD), combined with their disabling effects on patients and caregivers, is contrasted by the fact that few effective and safe treatments exist, which is in part to be attributed to our incomplete understanding of the neurobiology of NPS. In this review, we describe the pathological alterations typical for AD, including spreading and evolution of burden, effect on the molecular and cellular integrity, functional consequences and atrophy of NPS-relevant brain regions and circuits in correlation with specific NPS assessments. It is thereby clearly established that NPS are fundamental expressions of the underlying neurodegenerative brain disease and not simply reflect the patients’ secondary response to their illness. Neuropathological studies, moreover, include a majority of end-stage patient samples, which may not correctly represent the pathophysiological environment responsible for particular NPS that may already be present in an early stage, or even prior to AD diagnosis. The burdensome nature and high prevalence of NPS, in combination with the absence of effective and safe pharmacotherapies, provide a strong incentive to continue neuropathological and neurochemical, as well as imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.

Molecular Basis of Familial and Sporadic Alzheimer's Disease

Alzheimer’s disease (AD) is a multifactorial disease with genetic (70%) and environmental (30%) causes. Among the genetic factors are genes associated with a family history of the disease (familial AD, FAD) and sporadic AD (SAD). The genes: APP (amyloid precursor protein), PSEN1 (Presenilin 1) and PSEN2 (Presenilin 2) are responsible for the presence of FAD. The APOE gene is responsible for the sporadic form of the disease. Other molecular factors related to the immunological cause (TREM2) of the disease are a disorder of the lipid (ABCA1, ABCA7) or biothiol (MTHFD1) metabolism and of the transport of metabolites (BIN1). Currently, it is believed that APOE is a risk factor for both SAD and late-onset FAD.

The pathomechanism of AD is most commonly explained as based on the amyloid cascade theory. This theory is related to the FAD, although there are reports indicating the probability of its occurrence in the SAD. It seems that the excessive deposition of β-amyloid (Aβ) peptides and intracellular neurofibrillary tangles of tau protein hyperphosphorylated forms contribute to the damage of both DNA and RNA. Furthermore, it is believed that RNA-interference can affect both the level of pathological proteins (Aβ, tau protein) and the onset and progress of AD.

It seems that a complete understanding of both FAD and SAD pathogenesis may contribute to the search for earlier clinical diagnosis and to an understanding of later occurrence of the disease, which may help modify its course and affect more effective therapy of this incurable neurological disease.

Connections Between Herpes Simplex Virus Type 1 and Alzheimer's Disease Pathogenesis

Alzheimer’s disease (AD) is currently one of the most studied neurodegenerative disorders in humans. First reported in 1907, the disease has a familial form which represents approximately 5% of cases, while the remaining, sporadic cases are of multifactorial etiology. The disease progression of the latter form has specific pathological and functional characteristics, which have unknown etiology. Several authors have proposed a viral etiology for AD, while others implicate many neurotropic infectious agents. This review compares research findings regarding pathways and effects of neuropathological viruses with the pathways and effects involved in the progression of AD. The similarities are striking and provide a compelling argument for a pathogen-based etiology of AD.

Identifying S100B as a Biomarker and a Therapeutic Target For Brain Injury and Multiple Diseases

The calcium binding protein S100B has attracted great attention as a biomarker for a variety of diseases. S100B is mainly expressed in glial cells and functions through intracellular and extracellular signaling pathways. The biological roles of S100B have been closely associated with its concentrations and its physiological states. The released S100B can bind to the receptor of advanced glycation end products and induce the initiation of multiple cell signaling transductions. The regulation of S100B bioactivities has been suggested through phosphoinositide 3 kinase/Akt, p53, mitogen-activated protein kinases, transcriptional factors including nuclear factor-kappaB, and cyclic adenosine monophosphate. The levels of S100B in the blood may function to predict the progress or the prognosis of many kinds of diseases, such as cerebrovascular diseases, neurodegenerative diseases, motor neuron diseases, traumatic brain injury, schizophrenia, depression, diabetes mellitus, myocardial infarction, cancer, and infectious diseases. Given that the activity of S100B has been implicated in the pathological process of these diseases, S100B should not be simply regarded as a biomarker, it may also function as therapeutic target for these diseases. Further elucidation of the roles of S100B may formulate innovative therapeutic strategies for multiple diseases.

Vaccination to Alzheimer Disease. Is it a Promising Tool or a Blind Way?

Alzheimer disease (AD) is an irreversible neurodegenerative disorder associated with cognitive dysfunction. The disease incidence has growing tendency worldwide with strong impact on healthcare funds. The fact that there is no effective therapy makes the disorder more serious. Currently, AD manifestation can be suppressed by having impact on enzyme acetylcholinesterase: donepezil, rivastigmine, and galantamine or ionotropic glutamate NMDA receptor ( memanitine). Contrary to the drugs effecting symptomatically, vaccination against amyloid plaques or neurofibrillary tangles and their precursors amyloid beta and hyperphosphorylated tau are expected to be more suitable. Huge numbers of works have been done on the issue. Unfortunately, the promising vaccines like the AN 1792 were halted during clinical trials because of adverse effects like meningoencephalitis. Monoclonal antibody specific to amyloid plaques, Bapineuzumab, was closest to the practical performance but the clinical trials were also stopped. The review summarizes facts about AD, opportunities in AD vaccination, and obstacles that limit the vaccination including reasons why the recent trials have fallen.

Blood-based Amyloid and Tau Biomarker Tests For Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is the most seen cause of dementia. Biomarker tests will be essential to improve the early diagnosis of AD, as treatment is more effective in the early stage. The biomarkers of AD are divided into two main classes: amyloid β-peptide (Aβ) accumulation, and tau-related neuronal degeneration. Peripheral blood represents an alternative sample for reflecting pathological events occurring in the body. Blood samples are a possible alternative for cerebrovascular fluid samples. The potential advantages of blood biomarkers are obvious: less invasive; simple to perform, convenient to use, and not harmful to the patient.

Methods: Review publications about peripheral blood amyloid and tau biomarker tests by ELISA for AD stages; analyze and interpret data in comparison with cerebrovascular fluid results. Also review publications about peripheral messenger RNA biomarkers tests for AD diagnosis; analyze feasibility of diagnostic tests using blood messenger RNA biomarkers for AD.

Results: With sensitive and specific ELISA, extensive studies of plasma Aβ42 level and Aβ42/Aβ40 ratio were reported during the development of blood-based protein biomarkers. High level of plasma Aβ42 increased risk of AD or cognitive decline. The majority of the studies also indicated that increased plasma Aβ42 level was present prior to or at the start of the development of AD, and Aβ42 level decreased as disease progressed; the lowest Aβ42/Aβ40 ratio reported was associated with developing dementia. However, some studies showed inconsistent results. Reliable methods to determine levels of tau and phosphorylated tau in blood of AD patients are still being explored.

Conclusion: The effort to discover and develop diagnostic protein biomarkers in blood has not led to feasible candidate markers close to CSF. It may be helpful for each laboratory to set its own normal value or cut-offs due to different ELISA kits used. Improving clinical diagnostic criteria may be another valuable option. Development of additional biomarkers may also increase diagnostic accuracy. Compared with other technologies used in routine diagnostic tests, real time reverse transcription polymerase chain reaction (RT-qPCR) is sensitive, specific, scalable, and cost-effective. There is relatively less evidence of blood mRNAs acting as biomarkers in AD. The scientific merit and feasibility of diagnostic tests for monitoring AD progress using blood mRNAs biomarker quantification need to be established.

Nursing Assessment, Education, and Care of Extremely Premature Neonates with Patent Ductus Arteriosus

The care of extremely premature neonates with suspected or confirmed diagnosis of patent ductus arteriosus (PDA) is a frequent challenge for pediatric nurses. It is important for nurses to have adequate knowledge of the normal postnatal changes in cardiovascular and pulmonary function to recognize any adverse symptoms. Nurses caring for these vulnerable neonates must have a thorough understanding of the pathophysiology of a PDA in order to assess, plan, and implement patient-centered care. Recognition of characteristic symptoms of PDA in a timely manner is essential for optimal management and outcomes. Understanding the science behind treatment options is also imperative for pediatric nurses to provide the best care and effectively educate parents. Pediatric nurses are a significant resource in managing extremely premature neonates through comprehensive assessment, effective parent education, and high-quality patient-centered care.

Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches

Background: Prader-Willi syndrome (PWS) is a neuro-developmental genetic disorder due to lack of expression of genes inherited from the paternal chromosome 15q11-q13 region with three main genetic subtypes. These include paternal 15q11-q13 deletion (about 70% of cases), maternal uniparental disomy 15 or both 15s from the mother (20-30% of cases), and defects in the imprinting center (1-3%) which controls the expression of imprinted genes in this chromosome region. Clinical manifestations include infantile hypotonia with a poor suck resulting in failure to thrive, short stature, small hands/feet and hypogonadism/hypogenitalism due to growth and other hormone deficiencies, hyperphagia and excessive weight gain with obesity and cognitive and behavioral problems including obsessive compulsions, tantrums and self-injury. The phenotype is likely related to hypothalamic dysfunction.

Objective: Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS requiring accurate diagnosis, appropriate medical management and treatment; the major objective of our report.

Methods and Results: An extensive review of the literature was undertaken including genetics, clinical and behavioral aspects, and updated health-related information addressing the importance of early diagnosis and treatment of individuals with Prader-Willi syndrome. A searchable, bulleted and formatted list of topics related to this obesity syndrome was provided utilizing a Table of Contents approach for the clinical practitioner.

Conclusions: Physicians and other health care providers can use this review with clinical, genetic and treatment summaries divided into sections that are pertinent in the context of clinical practice. Finally, frequently asked questions by clinicians, families and other interested participants will be addressed.

Maintenance Therapy in Multiple Myeloma: Novel Concepts in Clinical Practice from Recent Clinical Trials

The introduction of novel drugs in multiple myeloma therapy has changed disease survivals in last 15 years. Besides to be more effective in this disease new agents have been utilized in novel strategies such as consolidation and maintenance therapy. Lenalidomide has been one of the favourite in clinical trials because of its oral administration, and bortezomib has been utilized too after the drug has been proved to be effective subcutaneously. Advances in the understanding of disease biology and genetics could give a risk stratification to identify those patients who can benefit more and to better drive maintenance therapy in the future.

Pharmacotherpy and Alzheimer’s Disease: The M-Drugs (Melatonin, Minocycline, Modafinil, and Memantine) Approach

Despite advances in understanding the pathophysiology of Alzheimer’s disease (AD), its therapy remains largely symptomatic and supportive. Acetylcholinesterase inhibitors - the first-line drugs used today do not prevent and treat AD. So far, over 90 Phase 3 trials of AD have been unsuccessful with 99.0% failure rate. There is, therefore, an urgent need to find effective new therapies for AD. Owing to the multifactorial nature of AD pathogenesis, polypharmacy with drugs that target heterogeneous pathophysiological pathways, needs to be considered. Fortunately, several drugs used currently in clinical use as monotherapies can be exploited in AD. This article, therefore, presents a novel pharmacological treatment paradigm and recommends the use of valuable diseasemodifying approved drugs, viz. melatonin, minocycline, modafinil, and memantine (the “M” Drugs). Melatonin - a neuroprotector is an antioxidant and anti-inflammatory. Minocycline is also neuroprotective, it reduces neuroinflammation and CNS pathology and prevents cell death. Sleep deprivation leads to decreased hippocampal neurogenesis, increased amyloid beta generation, and causes memory dysfunction. Modafinil - a wake-promoting agent is approved for use in narcolepsy and obstructive sleep apnea. It improves global mental status, hippocampal neurogenesis, attention, and cognition. Memantine is an uncompetitive N-methyl-d-aspartic acid receptor antagonist and is approved for the management of moderate-to-severe AD. The paramount possible beneficial effects of the M-drugs may include significant memory and cognitive enhancement in aging, mild cognitive impairment, and AD. The M drugs-centric pharmacotherapy strategy is comprehensive and pragmatic and is meant to combat multiple pathological targets and ameliorate cognitive dysfunction/AD.

A Link Between Nerve Growth Factor Metabolic Deregulation and Amyloid-β-Driven Inflammation in Down Syndrome

In Alzheimer's disease and Down syndrome, cholinergic neurons of the basal forebrain progressively degenerate. This neurotransmitter system is the main source of acetylcholine to the cortex and hippocampus. In the mature and fully differentiated central nervous system, the phenotype of forebrain cholinergic neurons and their nerve terminals in cortex and hippocampus depend on the continuous endogenous supply of nerve growth factor (NGF). It has been recently demonstrated that NGF is secreted from cortical neurons in an activity-dependent manner as a precursor molecule, proNGF. Individuals with Alzheimer’s disease and Down syndrome exhibit proNGF accumulation in cortex, yet cholinergic neurons become atrophic in both diseases, despite the apparent abundance of the NGF precursor. This review illustrates the recent evidence that NGF metabolism is affected both in Alzheimer’s disease and in Down syndrome brains and also discusses a role for amyloid-β peptides and central nervous system inflammation in unleashing such deficits. It further considers the potential of the NGF metabolic pathway as a new pharmacological target to slow down the neurodegenerative process both in Alzheimer’s disease and in individuals with Down syndrome.

Anesthesia Issues in Central Nervous System Disorders

Every year, millions of people affected by disorders of the central nervous system (CNS) undergo various diagnostic, therapeutic and surgical procedures requiring administration of anesthetic agents. Anesthetics exert their anesthetic, amnesic and analgesic effects by acting on multiple neuronal membrane proteins in the CNS. While some of the causal anesthetic targets have been identified, a large number of anesthetic targets remain unknown. The consequent longterm effect of anesthetic agents on expression of these various molecular targets has been implicated in mediating potentially long-lasting adverse effects. Recent work suggested that the effects of general anesthetics may not be entirely reversible, with animal studies demonstrating persistent changes in CNS protein expression post recovery from anesthesia. Age-associated or disease-induced alterations in the CNS can profoundly alter multiple aspects of brain structure, biochemistry, and function. Such maladaptive changes in the brain can render it increasingly vulnerable to the effects of various anesthetics. The selection of appropriate anesthesia drugs and protocol is mandatory, especially in individuals with pre-existing CNS disorders, so as to maximize anesthesia efficiency, avoid occurrence of adverse events, and ensure patient safety. This review aims to summarize and consider the effects and potential risks of commonly used anesthetic agents in patients with compromised CNS function. We provide a comprehensive review of the established as well as the implicated effects of anesthetic agents on the elderly as well as on the pathology and progression of common neurological conditions.

Novel Methods of Genetic Modification of Human Pluripotent Stem Cells

Genomic engineering has enormous potential along basic research, drug discovery and cell therapeutics. Many existing methods for targeted gene knockout mutagenesis or integration rely on homologous recombination. The low rate of spontaneous recombination in nearly all mammalian cell types, as well as the scale of screening, effort and time required to isolate the targeted events during genome modification, have hindered progress in this field. The present review has the objective to present latest improvements of technology to develop genetic modification to a clinical grade level so it can be used in human therapy.

Calcium Signalling Toolkits in Astrocytes and Spatio-Temporal Progression of Alzheimer's Disease

Pathological remodelling of astroglia represents an important component of the pathogenesis of Alzheimer's disease (AD). In AD astrocytes undergo both atrophy and reactivity; which may be specific for different stages of the disease evolution. Astroglial reactivity represents the generic defensive mechanism, and inhibition of astrogliotic response exacerbates b-amyloid pathology associated with AD. In animal models of AD astroglial reactivity is different in different brain regions, and the deficits of reactive response observed in entorhinal and prefrontal cortices may be linked to their vulnerability to AD progression. Reactive astrogliosis is linked to astroglial Ca²⁺ signalling, this latter being widely regarded as a mechanism of astroglial excitability. The AD pathology evolving in animal models as well as acute or chronic exposure to β-amyloid induce pathological remodelling of Ca²⁺ signalling toolkit in astrocytes. This remodelling modifies astroglial Ca²⁺ signalling and may be linked to cellular mechanisms of AD pathogenesis.

PERK-opathies: An Endoplasmic Reticulum Stress Mechanism Underlying Neurodegeneration

The unfolded protein response (UPR) plays a vital role in maintaining cell homeostasis as a consequence of endoplasmic reticulum (ER) stress. However, prolonged UPR activity leads to cell death. This time-dependent dual functionality of the UPR represents the adaptive and cytotoxic pathways that result from ER stress. Chronic UPR activation in systemic and neurodegenerative diseases has been identified as an early sign of cellular dyshomeostasis.

The Protein Kinase R-like ER Kinase (PERK) pathway is one of three major branches in the UPR, and it is the only one to modulate protein synthesis as an adaptive response. The specific identification of prolonged PERK activity has been correlated with the progression of disorders such as diabetes, Alzheimer’s disease, and cancer, suggesting that PERK plays a role in the pathology of these disorders. For the first time, the term “PERK-opathies” is used to group these diseases in which PERK mediates detriment to the cell culminating in chronic disorders. This article reviews the literature documenting links between systemic disorders with the UPR, but with a specific emphasis on the PERK pathway. Then, articles reporting links between the UPR, and more specifically PERK, and neurodegenerative disorders are presented. Finally, a therapeutic perspective is discussed, where PERK interventions could be potential remedies for cellular dysfunction in chronic neurodegenerative disorders.

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

Down syndrome (DS) is the most common non-lethal genetic condition that affects approximately 1 in 700 births in the United States of America. DS is characterized by complete or segmental chromosome 21 trisomy, which leads to variable intellectual disabilities, progressive memory loss, and accelerated neurodegeneration with age. During the last three decades, people with DS have experienced a doubling of life expectancy due to progress in treatment of medical comorbidities, which has allowed this population to reach the age when they develop early onset Alzheimer’s disease (AD). Individuals with DS develop cognitive and pathological hallmarks of AD in their fourth or fifth decade, and are currently lacking successful prevention or treatment options for dementia. The profound memory deficits associated with DS-related AD (DS-AD) have been associated with degeneration of several neuronal populations, but mechanisms of neurodegeneration are largely unexplored. The most successful animal model for DS is the Ts65Dn mouse, but several new models have also been developed. In the current review, we discuss recent findings and potential treatment options for the management of memory loss and AD neuropathology in DS mouse models. We also review agerelated neuropathology, and recent findings from neuroimaging studies. The validation of appropriate DS mouse models that mimic neurodegeneration and memory loss in humans with DS can be valuable in the study of novel preventative and treatment interventions, and may be helpful in pinpointing gene-gene interactions as well as specific gene segments involved in neurodegeneration.

Clinical Assessment of Cognitive Decline in Adults with Down Syndrome

Down syndrome is an intellectual disability requiring periodic monitoring of cognition given the near universal presence of Alzheimer’s Disease related neuropathology and high rates of dementia in middle adulthood. We review current approaches to detecting decline in this population, including informant-based measures, dementia screening tools, and neuroimaging techniques. The challenges for detecting decline in this group are discussed, including the need to take into account premorbid cognitive function as well as medical comorbidity.

Noradrenergic System in Down Syndrome and Alzheimer’s Disease A Target for Therapy

Locus coeruleus (LC) neurons in the brainstem send extensive noradrenergic (NE)-ergic terminals to the majority of brain regions, particularly those involved in cognitive function. Both Alzheimer’s disease (AD) and Down syndrome (DS) are characterized by similar pathology including significant LC degeneration and dysfunction of the NE-ergic system. Extensive loss of NE-ergic terminals has been linked to alterations in brain regions vital for cognition, mood, and executive function. While the mechanisms by which NE-ergic abnormalities contribute to cognitive dysfunction are not fully understood, emergent evidence suggests that rescue of NE-ergic system can attenuate neuropathology and cognitive decline in both AD and DS. Therapeutic strategies to enhance NE neurotransmission have undergone limited testing. Among those deployed to date are NE reuptake inhibitors, presynaptic α-adrenergic receptor antagonists, NE prodrugs, and β-adrenergic agonists. Here we examine alterations in the NE-ergic system in AD and DS and suggest that NE-ergic system rescue is a plausible treatment strategy for targeting cognitive decline in both disorders.

The NGF Metabolic Pathway in the CNS and its Dysregulation in Down Syndrome and Alzheimer’s Disease

It is well established that individuals with Down syndrome develop Alzheimer’s disease neuropathology by middle age. Both in Alzheimer’s disease and Down syndrome, this is accompanied by the atrophy of NGF-dependent cholinergic neurons of the basal forebrain. An NGF trophic compromise in Alzheimer’s disease had been early suspected. This hypothesis was discarded with the finding of unaltered NGF mRNA synthesis and of increased NGF precursor levels (proNGF) in postmortem Alzheimer’s disease brains. The possibility of an NGF trophic disconnection has been recently revisited at the light of a newly discovered extracellular NGF metabolic pathway; where proNGF is released in an activity-dependent manner and converted by plasmin to mature NGF in the extracellular space. Mature NGF is ultimately degraded by the metalloprotease MMP-9. This pathway has been shown to be compromised in Alzheimer’s disease and Down syndrome brains, thus reviving the trophic factor hypothesis to explain the atrophy of basal forebrain cholinergic neurons in these disorders. This chapter will discuss the physiological role of NGF and its biological significance to cholinergic neurons of the CNS, and present the evidence for a dysregulation of the NGF metabolism in Alzheimer’s disease and Down syndrome.

Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer’s Disease

Although Down syndrome (DS) can be diagnosed prenatally, currently there are no effective treatments to lessen the intellectual disability (ID) which is a hallmark of this disorder. Furthermore, starting as early as the third decade of life, DS individuals exhibit the neuropathological hallmarks of Alzheimer’s disease (AD) with subsequent dementia, adding substantial emotional and financial burden to their families and society at large. A potential therapeutic strategy emerging from the study of trisomic mouse models of DS is to supplement the maternal diet with additional choline during pregnancy and lactation. Studies demonstrate that maternal choline supplementation (MCS) markedly improves spatial cognition and attentional function, as well as normalizes adult hippocampal neurogenesis and offers protection to basal forebrain cholinergic neurons (BFCNs) in the Ts65Dn mouse model of DS. These effects on neurogenesis and BFCNs correlate significantly with spatial cognition, suggesting functional relationships. In this review, we highlight some of these provocative findings, which suggest that supplementing the maternal diet with additional choline may serve as an effective and safe prenatal strategy for improving cognitive, affective, and neural functioning in DS. In light of growing evidence that all pregnancies would benefit from increased maternal choline intake, this type of recommendation could be given to all pregnant women, thereby providing a very early intervention for individuals with DS, and include babies born to mothers unaware that they are carrying a fetus with DS.

Effects of Maternal Choline Supplementation on the Septohippocampal Cholinergic System in the Ts65Dn Mouse Model of Down Syndrome

Down syndrome (DS), caused by trisomy of chromosome 21, is marked by intellectual disability (ID) and early onset of Alzheimer’s disease (AD) neuropathology including hippocampal cholinergic projection system degeneration. Here we determined the effects of age and maternal choline supplementation (MCS) on hippocampal cholinergic deficits in Ts65Dn mice compared to 2N mice sacrificed at 6-8 and 14-18 months of age. Ts65Dn mice and disomic (2N) littermates sacrificed at ages 6-8 and 14-18 mos were used for an aging study and Ts65Dn and 2N mice derived from Ts65Dn dams were maintained on either a choline-supplemented or a choline-controlled diet (conception to weaning) and examined at 14-18 mos for MCS studies. In the latter, mice were behaviorally tested on the radial arm Morris water maze (RAWM) and hippocampal tissue was examined for intensity of choline acetyltransferase (ChAT) immunoreactivity. Hippocampal ChAT activity was evaluated in a separate cohort. ChAT-positive fiber innervation was significantly higher in the hippocampus and dentate gyrus in Ts65Dn mice compared with 2N mice, independent of age or maternal diet. Similarly, hippocampal ChAT activity was significantly elevated in Ts65Dn mice compared to 2N mice, independent of maternal diet. A significant increase with age was seen in hippocampal cholinergic innervation of 2N mice, but not Ts65Dn mice. Degree of ChAT intensity correlated negatively with spatial memory ability in unsupplemented 2N and Ts65Dn mice, but positively in MCS 2N mice. The increased innervation produced by MCS appears to improve hippocampal function, making this a therapy that may be exploited for future translational approaches in human DS.

Aging in Down Syndrome and the Development of Alzheimer’s Disease Neuropathology

Chromosome 21, triplicated in Down Syndrome, contains several genes that are thought to play a critical role in the development of AD neuropathology. The overexpression of the gene for the amyloid precursor protein (APP), on chromosome 21, leads to early onset beta-amyloid (Aβ) plaques in DS. In addition to Aβ accumulation, middle-aged people with DS develop neurofibrillary tangles, cerebrovascular pathology, white matter pathology, oxidative damage, neuroinflammation and neuron loss. There is also evidence of potential compensatory responses in DS that benefit the brain and delay the onset of dementia after there is sufficient neuropathology for a diagnosis of AD. This review describes some of the existing literature and also highlights gaps in our knowledge regarding AD neuropathology in DS. It will be critical in the future to develop networked brain banks with standardized collection procedures to fully characterize the regional and temporal pathological events associated with aging in DS. As more information is acquired regarding AD evolution in DS, there will be opportunities to develop interventions that are age-appropriate to delay AD in DS.

Editorial (Thematic Issue: The Link between Alzheimer’s Disease and Down Syndrome. A Historical Perspective)

Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer’s Disease

Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer’s disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.

Editorial (Thematic Issue: Immunophilins, Protein Chemistry and Cell Biology of a Promising New Class of Drug Targets – Part II)

Novel Therapeutic Approach for Autism Spectrum Disorder: Focus on SHANK3

SHANK3 is a synaptic scaffolding protein and plays an important role in neuronal development. SHANK3 interacts with various synaptic molecules, including post-synaptic density-95 (PSD-95), homer and GluR1 AMPA receptor. SHANK3 gene is a causable gene of the Phelan- McDermid syndrome (also known as the 22q13.3 deletion syndrome), whose manifestation is global developmental delay and autistic behavior, especially shows severe speech and language deficit. Additionally since cumulative gene analysis in autistic subjects identified several mutations in SHANK3 gene, including deletion and duplication in a particular region, abnormality of SHANK3 gene is thought the be related with the neuropathology of autism spectrum disorder (ASD). We here review the recent findings in regard to the roles of SHANK3 in higher brain functions, molecular-biologic studies of the complex expression of Shank3 transcripts and production of SHANK3 isoforms, and behavioral studies of Shank3-mutant mice, including our recent findings, and discuss a novel therapeutic approach for ASD.

Alterations of the X Chromosome in Lymphocytes of Alzheimer’s Disease Patients

Chromosomal alterations as a sign of genetic instability are a feature of Alzheimer’s disease (AD). Assessment of the genetic instability of non-neuronal cells of AD patients may provide a method to diagnose or monitor prognosis of the disease. Considering the importance of X chromosome alterations in the possible etiology of AD females, we used fluorescent in situ hybridization (FISH) for the centromere region of the X chromosome to determine aneuploidy, for a possible correlation with premature centromere division (PCD, X) in lymphocytes of AD females and age-matched controls. In AD patients, our results showed a marked and significant increase in the frequency of the X chromosome aneuploidy comparing with age matched controls (p<0.001). Also, a significant difference was detected in the PCD, X frequency between AD females when compared with age matched controls (p<0.001). In addition, a strong (R2=0.97, n=20) and significant (p<0.001) correlation was found between the frequency of aneuploidy and PCD, X in the AD group. Our results support the view that AD is a generalized systematic disease where PCD is to be considered as a stable sign of disease leading to aneuploidy.

Genetics of Bladder Malignant Tumors in Childhood

Bladder masses are represented by either benign or malignant entities. Malignant bladder tumors are frequent causes of disease and death in western countries. However, in children they are less common. Additionally, different features are found in childhood, in which non epithelial tumors are more common than epithelial ones. Rhabdomyosarcoma is the most common pediatric bladder tumor, but many other types of lesions may be found, such as malignant rhabdoid tumor (MRT), inflammatory myofibroblastic tumor and neuroblastoma. Other rarer tumors described in literature include urothelial carcinoma and other epithelial neoplasms. Rhabdomyosarcoma is associated to a variety of genetic syndromes and many genes are involved in tumor development. PAX3-FKHR and PAX7-FKHR (P-F) fusion state has important implications in the pathogenesis and biology of RMS, and different genes alterations are involved in the pathogenesis of P-F negative and embryonal RMS, which are the subsets of tumors most frequently affecting the bladder. These genes include p53, MEF2, MYOG, Ptch1, Gli1, Gli3, Myf5, MyoD1, NF1, NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, IGF1R, PDGFRA, ERBB2/4, MET, BCOR. Malignant rhabdoid tumor (MRT) usually shows SMARCB1/INI1 alterations. Anaplastic lymphoma kinase (ALK) gene translocations are the most frequently associated alterations in inflammatory myofibroblastic tumor (IMT). Few genes alterations in urothelial neoplasms have been reported in the paediatric population, which are mainly related to deletion of p16/lnk4, overexpression of CK20 and overexpression of p53. Here, we reviewed available literature to identify genes associated to bladder malignancies in children and discussed their possible relationships with these tumors.

Genetic Predisposition to Neonatal Tumors

The development of tumors within the first month of life is extremely rare and this very young age at presentation should raise concern for an underlying cancer predisposition syndrome. This chapter discusses genetic predisposition to neonatal solid tumors, specifically those involving the eyes, kidneys, liver, adrenal glands and lungs. For each tumor type, we discuss the most common associated predisposition syndromes and for eye and lung tumors, we also review the approach to diagnosis and management. The reader is referred to the other chapters of this volume for an overview of management details for the other tumor types. The management of neonates with cancer predisposing syndromes is challenging, with many patients demonstrating multisystem involvement. Accordingly, it is critical to use a team approach, where providers with expertise in neonatology, oncology, genetics, surgery and other pediatric subspecialties can appropriately tailor management of the patient and coordinate genetic evaluation of the family.

Current Management of Neonatal Liver Tumors

This review is focused on the special issues and challenges confronting physicians and surgeons caring for an unborn child, or a newborn with a liver tumor. Liver tumors at this age are very rare and they make it difficult for pediatric surgeons to gain experience necessary to obtain good results. On the other hand, adult hepatobiliary surgeons faced with a fetus or infant with a liver mass are ill equipped to care for the patient even if they have done a high volume of adult liver surgery and are expert in the field. Often a team approach is the best solution.

Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans

Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans.

Cord Blood as Diagnostic Window for Preeclampsia

Preeclampsia is a multisystem disorder, pathophysiology of which is still not clear. It is one of the leading causes of maternal and fetal morbidity and mortality. Epigenetic programing is altered during fetal life and postnatal period and after birth, this sceniaro is changed to metabolic disorders of metabolic syndrome complex and this may contribute to future risk of hypertension, DM2, and cardiovascular disease. During (normal and abnormal) gestations, complex physiological changes occur in maternal blood. For studying next generation diagnostic biomarkers for maternal-fetal interface, it is essential to explore the protein changes in maternal serum during healthy gestation. Umbilical cord blood (UCB) is in contact with all the fetal tissues and can reflect both normal physiological as well as pathological states of the fetus. UCB can be compared with adult blood and the diagnostic potential of UCB still remains to be tapped. UCB will be a potential diagnostic medium in future in assessing infant health. Also, UCB can aid in detection and identification of candidate biomarkers for various disease pathways and it can be of help in assessing the existing or future adverse effects. Patents are available for biomarkers in preeclampsia and fewer patents are reported in UCB. Future studies will further uncover the diagnostic value of the umbilical cord blood in human physiology and pathology.

Ocular Biomarkers of Alzheimer’s Disease

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterised clinically by a progressive decline in executive functions, memory and cognition. Classic neuropathological hallmarks of AD include intracellular hyper-phosphorylated tau protein which forms neurofibrillary tangles (NFT), and extracellular deposits of amyloid β (Aβ) protein, the primary constituent of senile plaques (SP). The gradual process of pathogenic amyloid accumulation is thought to occur 10-20 years prior to symptomatic manifestation. Advance detection of these deposits therefore offers a highly promising avenue for prodromal AD diagnosis. Currently, the most sophisticated method of ‘probable AD’ diagnosis is via neuroimaging or cerebral spinal fluid (CSF) biomarker analysis. Whilst these methods have reported a high degree of diagnostic specificity and accuracy, they fall significantly short in terms of practicality; they are often highly invasive, expensive or unsuitable for large-scale population screening. In recent years, ocular screening has received substantial attention from the scientific community due to its potential for non-invasive and inexpensive central nervous system (CNS) imaging. In this appraisal we build upon our previous reviews detailing ocular structural and functional changes in AD (Retinal manifestations of Alzheimer’s disease, Alzheimer’s disease and Retinal Neurodegeneration) and consider their use as biomarkers. In addition, we present an overview of current advances in the use of fluorescent reporters to detect AD pathology through non-invasive retinal imaging.

Epidemiology, Clinical Presentation and Treatment of Uveal Melanoma

Uveal melanoma represents the most common primary intraocular tumor in adults. However, it remains a relatively infrequent malignancy where large clinical trials are difficult to accomplish. However, during the last couple of years we have witnessed an unprecedented expansion of our understanding of this disease. New genetic and molecular pathways were found to play key roles in the development of uveal melanoma and they represent potential targets for future therapies. At the same time there were some improvements in the delineation of prognostic features as well as treatment options for metastatic disease, with both liver-directed strategies as well as targeted agents. In this review we will try to summarize and update the reader with the most relevant information in terms of its pathogenesis, clinical presentation, prognostic factors– cytogenetic and genetic profiling –, state of the art management of liver only as well as systemic metastatic disease. Finally we will also discuss current ongoing clinical trials as well as future directions in terms of research and clinical investigation.

Management of Incidental Findings in the Era of Next-generation Sequencing

Next-generation sequencing (NGS) technologies allow for the generation of whole exome or whole genome sequencing data, which can be used to identify novel genetic alterations associated with defined phenotypes or to expedite discovery of functional variants for improved patient care. Because this robust technology has the ability to identify all mutations within a genome, incidental findings (IF)- genetic alterations associated with conditions or diseases unrelated to the patient’s present condition for which current tests are being performed- may have important clinical ramifications. The current debate among genetic scientists and clinicians focuses on the following questions: 1) should any IF be disclosed to patients, and 2) which IF should be disclosed – actionable mutations, variants of unknown significance, or all IF? Policies for disclosure of IF are being developed for when and how to convey these findings and whether adults, minors, or individuals unable to provide consent have the right to refuse receipt of IF. In this review, we detail current NGS technology platforms, discuss pressing issues regarding disclosure of IF, and how IF are currently being handled in prenatal, pediatric, and adult patients.

Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS.

Genomic and Epigenetic Complexity of the FOXF1 Locus in 16q24.1: Implications for Development and Disease

The FOXF1 (Forkhead box F1) gene, located on chromosome 16q24.1 encodes a member of the FOX family of transcription factors characterized by a distinct forkhead DNA binding domain. FOXF1 plays an important role in epithelium-mesenchyme signaling, as a downstream target of Sonic hedgehog pathway. Heterozygous point mutations and genomic deletions involving FOXF1 have been reported in newborns with a lethal lung developmental disorder, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV). In addition, genomic deletions upstream to FOXF1 identified in ACDMPV patients have revealed that FOXF1 expression is tightly regulated by distal tissue-specific enhancers. Interestingly, FOXF1 has been found to be incompletely paternally imprinted in human lungs; characterized genomic deletions arose de novo exclusively on maternal chromosome 16, with most of them being Alu-Alu mediated. Regulation of FOXF1 expression likely utilizes a combination of chromosomal looping, differential methylation of an upstream CpG island overlapping GLI transcription factor binding sites, and the function of lung-specific long non-coding RNAs (lncRNAs). Foxf1 knock-out mouse models demonstrated its critical role in mesoderm differentiation and in the development of pulmonary vasculature. Additionally, epigenetic inactivation of FOXF1 has been reported in breast and colorectal cancers, whereas overexpression of FOXF1 has been associated with a number of other human cancers, e.g. medulloblastoma and rhabdomyosarcoma. Constitutional duplications of FOXF1 have recently been reported in congenital intestinal malformations. Thus, understanding the genomic and epigenetic complexity at the FOXF1 locus will improve diagnosis, prognosis, and treatment of ACDMPV and other human disorders associated with FOXF1 alterations.

Navigating the Sea Changes in Patent Law to Successfully Build Value

Major changes in U.S. patent law are having an impact on the value of patents. The Leahy-Smith America Invents Act (AIA) introduced numerous changes to U.S. patent law including the switch to a first to file patent system from a first to invent patent system. New proceedings at the U.S. Patent and Trademark Office to challenge the grant of issued patents have produced quick results and emerging trends. Recent U.S. Supreme Court decisions have changed the threshold determination of patentability under 35 U.S.C. § 101, altering the patentability standards for biotech/pharma inventions, as well as computer/business method inventions. In Europe, the framework for an emerging unitary patent system, expected to be implemented by mid-2016, will add complexity to strategic patent planning for that region. This article will review these changes, discuss trends and provide strategies to build a patent portfolio with valid and enforceable patent claims as a foundation to withstand patentability and validity challenges.

Clinical, Genetic, and Neuroimaging Features of Early Onset Alzheimer Disease: The Challenges of Diagnosis and Treatment

Early Onset Alzheimer Disease (EOAD) is a rare condition, frequently associated with genetic causes. The dissemination of genetic testing along with biomarker determinations have prompted a wider recognition of EOAD in experienced clinical settings. However, despite the great efforts in establishing the contribution of causative genes to EOAD, atypical disease presentation and clinical features still makes its diagnosis and treatment a challenge for the clinicians. This review aims to provide an extensive evaluation of literature data on EOAD, in order to improve understanding and knowledge of EOAD, underscore its significant impact on patients and their caregivers and influence public policies. This would be crucial to define the urgency of evidence-based treatment approaches.

Composite Lymphomas: A Challenging Entity

Composite lymphomas (CLs) are characterized by the rare occurrence of two or more morphologically and/or immunophenotypically different lymphomas in the same anatomic tissue site. Many different combinations of lymphoma have been reported including multiple B-cell lymphomas, B-cell and T-cell non Hodgkin lymphomas, non Hodgkin lymphomas and Hodgkin lymphoma and complex B-cell, T-cell and Hodgkin lymphoma cases. The two lymphoma components usually are not clonally related but the use of thorough molecular techniques revealed that in some cases the two components are clonally related suggesting origin from a common progenitor cell. Pathogenesis of these lymphomas remains not well defined and the etiology differs according to the types of lymphomas involved. Composite B-cell lymphomas with two distinct low grade components are rare and usually are characterized by the existence of two different unrelated progenitors. CLs consisting of two types of non Hodgkin lymphomas of the same lineage, mostly B-cells, represent in most of the cases tumor progression and transformation from an indolent B-cell lymphoma to diffuse large B-cell lymphoma (DLBCL) and the low grade and high grade components in this type of CL are often clonally related while a clonal link has also been reported in cases of CLs containing Hodgkin lymphoma with various non Hodgkin lymphomas. CLs must be carefully diagnosed because the containing disease entities may not only have different natural course but also may differ in prognosis and treatment.

The Emerging Role of Bcr-Abl-Induced Cystoskeletal Remodeling in Systemic Persistence of Leukemic Stem Cells

Abl kinase plays a critical role in development and homeostasis of hematopoietic system. The importance of this kinase becomes apparent from the consequences of a specific, reciprocal translocation between chromosome 9 and chromosome 22 that yields a chimeric fusion protein, Bcr-Abl, in which the function of auto-regulatory mechanisms are inactivated. The resultant constitutively active kinase is responsible for development of a systemic leukemogenic phenotype. Studies employing currently available highly specific inhibitors, with high potency to block kinase activity, uncovered unanticipated characteristics of Bcr-Abl fusion protein. It became apparent that the kinase domain, with its primary significance for development and progression of leukemia, is not solely responsible for leukemogenic features of the Bcr-Abl transformed leukemic stem cells. In this review we summarize current understanding of non-enzymatic characteristics of Bcr-Abl, its effect on actin cytoskeleton, and its potential contribution to drug resistance and systemic persistence of leukemic stem cells.