Role of Vitamin D in Cognitive Dysfunction: New Molecular Concepts and Discrepancies between Animal and Human Findings

Purpose of review: increasing evidence suggests that besides the several metabolic, endocrine, and immune functions of 1alpha,25-dihydroxyvitamin D (1,25(OH)2D), the neuronal effects of 1,25(OH)2D should also be considered an essential contributor to the development of cognition in the early years and its maintenance in aging. The developmental disabilities induced by vitamin D deficiency (VDD) include neurological disorders (e.g., attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia) characterized by cognitive dysfunction. On the other hand, VDD has frequently been associated with dementia of aging and neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s disease). Recent findings: various cells (i.e., neurons, astrocytes, and microglia) within the central nervous system (CNS) express vitamin D receptors (VDR). Moreover, some of them are capable of synthesizing and catabolizing 1,25(OH)2D via 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1) and 25-hydroxyvitamin D 24-hydroxylase (CYP24A1) enzymes, respectively. Both 1,25(OH)2D and 25-hydroxyvitamin D were determined from different areas of the brain and their uneven distribution suggests that vitamin D signaling might have a paracrine or autocrine nature in the CNS. Although both cholecalciferol and 25-hydroxyvitamin D pass the blood–brain barrier, the influence of supplementation has not yet demonstrated to have a direct impact on neuronal functions. So, this review summarizes the existing evidence for the action of vitamin D on cognitive function in animal models and humans and discusses the possible pitfalls of therapeutic clinical translation.     

Molecular pathways and pathomorphology of colorectal cancers

Colorectal carcinomas (CRCs) evolve through multiple pathways. These pathways may be defined based on two molecular features: (1) chromosomal instability and (2) chromosomal stability. Tumors showing chromosomal stability evolve through the so-called microsatellite instability pathway. These types of tumors show different clinico-pathological features and need different therapy so very important to separate them. As Hematoxylin-Eosin (HE) based histology is influenced by the different genetic alterations of a tumor, it is reasonable that different gene expression profiles result in different HE morphology. Our aim was to find specific histomorphological features specific for colorectal tumors showing different molecular features. We analyzed the clinicopathological parameters of 324 colorectal carcinomas, 26 hereditary non-polyposis colorectal cancers, 32 sporadic high-level microsatellite-instable (MSI-H) cancers and 266 microsatellite-stable or low-level microsatellite-instable (MSI-L) cancers among them. Our results showed that we could recognize different genetic types of tumors on the base of clinicopathological features like patient's age, tumor localization and histological characteristics of CRCs. Main histological parameters help in differentiation are inflammatory background, nuclear features and pattern of infiltration. Clinical parameters like clinical stage and localization and careful histological analysis helps to select molecular method to define molecular features and to select the most appropriate therapy of a given tumor.     

Structure and biological activity of pathogen-like synthetic nanomedicines

Here we characterize the structure, stability and intracellular mode of action of DermaVir nanomedicine that is under clinical development for the treatment of HIV/AIDS. This nanomedicine comprises pathogen-like pDNA/PEIm nanoparticles (NPs) having the structure and function resembling spherical viruses that naturally evolved to deliver nucleic acids to the cells. Atomic force microscopy demonstrated spherical 100 - 200 nm NPs with a smooth polymer surface protecting the pDNA in the core. Optical absorption determined both the NP structural stability and biological activity relevant to their ability to escape from the endosome and release the pDNA at the nucleus. Salt, pH and temperature influence nanomedicine shelf-life and intracellular stability. This approach facilitates the development of diverse polyplex nanomedicines where the delivered pDNA-expressed antigens induce immune responses to kill infected cells. FROM THE CLINICAL EDITOR: The authors investigated DermaVir nanomedicine comprised of pathogen-like pDNA/PEIm nanoparticles with structure and function resembling spherical viruses. DermaVir delivery of pDNA expresses antigens that induce immune responses to kill HIV infected cells.     

Comparative assessment of vascular function in autoimmune rheumatic diseases: considerations of prevention and treatment

Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to increased cardio- and cerebrovascular disease risk. Traditional risk factors, as well as the role of systemic inflammation including cytokines, chemokines, proteases, autoantibodies, adhesion receptors and others have been implicated in the development of these vascular pathologies. The characteristics of vasculopathies may significantly differ depending on the underlying disease. While classical accelerated atherosclerosis has been associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or spondyloarthropathies (SpA), obliterative vasculopathy may rather be characteristic for systemic sclerosis (SSc) or mixed connective tissue disease (MCTD). Antiphospholipid antibodies have been implicated in vasculopathies underlying SLE, antiphospholipid syndrome (APS), RA and MCTD. There is also heterogeneity with respect to inflammatory risk factors. Cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin 6 (IL-6) and immune complexes are primarily involved in arthritides, such as RA, SpA, as well as in SLE. On the other hand, autoantibodies including anti-oxLDL anti-cardiolipin and anti-β2GPI are rather involved in SLE- and APS-associated vasculopathies. Regarding the non-invasive assessment of vascular function, endothelial dysfunction, overt atherosclerosis and vascular stiffness may be indicated by brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and aortic pulse-wave velocity (PWV), respectively. These abnormalities have been described in most inflammatory rheumatic diseases. While ccIMT and stiffness are relatively stable, FMD may be influenced by many confounding factors. In addition to traditional vasculoprotection, immunosuppressive agents including corticosteroids, traditional and biologic DMARDs may have significant vascular and metabolic effects. The official EULAR recommendations on the assessment and management of cardiovascular disease in arthritides have just been published, and similar recommendations in connective tissue diseases are to be developed soon.     

Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics

Purpose  

This review summarizes protein biomarkers in mild and severe traumatic brain injury in adults and children and presents a strategy for conducting rationally designed clinical studies on biomarkers in head trauma.     

Mortality and major morbidity in premature infants less than 31 weeks gestational age in the decade after introduction of surfactant

OBJECTIVE: Population- but also center-based mortality and major morbidity rates of premature infants are essential for prenatal counseling and quality control. METHODS: Records of all infants <30 + 6 weeks (n=674) admitted (1991-2000) to a single neonatal intensive care unit were reviewed and compared to the state-wide mortality. RESULTS: Six hundred and ninety-one infants were born in or transferred to the hospital and 600 infants (89%) survived. The mean (SD) birth weight was 1018 g (+/-314) and the mean gestational age 27+5 weeks (+/-2.0). Mortalityand morbidity did not change significantly over the 10-year period but correlated inversely with gestational age from 45% at 23(0/7) weeks to 5% at 30(6/7) weeks. Study center mortality rate for extremely low birth weight infants with birth weight <750 g was significantly lower than reported for the entire state (local 25%; Bavaria 36% p = 0.0003). Thirty-four per cent (251/600) of the survivors had one or more major complications: intracranial hemorrhage III-IV 8% (88/600), periventricular leucomalacia 6% (41/600), bronchopulmonary dysplasia with oxygen requirement at 36 weeks 20% (128/600), necrotizing enterocolitis 6% (43/600), and retinopathy of prematurity grade III-IV 9% (55/600). Survival without major morbidity increased from 32% at 23 weeks to 92% at 30 weeks. CONCLUSIONS: Despite changes in obstetric and neonatal care during the 1990s, mortality and major morbidity rates did not change significantly after the introduction of surfactant in 1991. Comparison of local, regional, national, and international mortality and morbidity rates are becoming more important in allocating resources and in decision-making at the limits of viability.     

mRNA expression analysis and classification of colonic biopsy samples using oligonucleotide and cDNA microarray techniques

Despite tremendous progress in the past few decades, certain important aspects regarding the diagnosis, therapy, and follow-up of colorectal cancer still remain unsolved. In our work we searched for biomarkers of the development of colorectal carcinoma, and performed gene expression analysis for colorectal disease classification. We have established that the oligonucleotide microarray analyses of biopsy samples wholly fulfil the Affymetrix quality requirements, are highly standard and reproducible and the Taqman microfluidic card system is suitable for high-throughput, quick and cost efficient real-time-PCR validation of gene expression changes. We have shown that the sequential overexpression of osteopontin and osteonectin mRNAs and proteins significantly correlates with the progression of the colorectal adenoma-dysplasia-carcinoma sequence. We have identified and validated ten novel markers with continuously increasing mRNA expression in line with the adenoma-dysplasia-carcinoma transition. We have identified the top 27, 13 and 10 genes associated with adenoma, colorectal cancer, and inflammatory bowel diseases.