Clinical and Genetic Correlation in Neurocristopathies: Bridging a Precision Medicine Gap.

Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo epithelial-mesenchymal transition (EMT) and upon key developmental gene deregulation, fetuses and neonates are prone to exhibit diverse manifestations depending on the affected area. These conditions are generally rare and often have a genetic basis, with many following Mendelian inheritance patterns, thus making them perfect candidates for precision medicine. Examples include cranial NCPs, like Goldenhar syndrome and Axenfeld-Rieger syndrome; cardiac-vagal NCPs, such as DiGeorge syndrome; truncal NCPs, like congenital central hypoventilation syndrome and Waardenburg syndrome; and enteric NCPs, such as Hirschsprung disease. Additionally, NCCs' migratory and differentiating nature makes their derivatives prone to tumors, with various cancer types categorized based on their NCC origin. Representative examples include schwannomas and pheochromocytomas. This review summarizes current knowledge of diseases arising from defects in NCCs' specification and highlights the potential of precision medicine to remedy a clinical phenotype by targeting the genotype, particularly important given that those affected are primarily infants and young children.

Anthropometric measurements of the foot cannot predict the screw diameter for fifth metatarsal fractures intramedullary fixation.

PURPOSE: The present study aimed to evaluate the accuracy of anthropometric foot measurements in predicting the diameter of the intramedullary screw for fifth metatarsal fracture fixation. Secondary aim was to identify whether the fifth metatarsal intramedullary canal diameter is correlated to the fifth metatarsal length and the foot dimensions. METHODS: In 29 cadaveric feet, the maximum length of the plantar surface of the foot (PL) and the perimeter of the foot at the level of the fifth metatarsal base (PBFM) were measured using a measuring tape. Subsequently, the fifth metatarsal was excised. Using Computed Tomography scan, the metatarsal length (FML), and the horizontal (HDI) and vertical diameter (VDI) at the isthmus level were measured. The HDI values were grouped in 5 mm increments to correspond to the recommended screw diameter (RSD) for intramedullary fixation. A univariate linear regression analysis considered RSD and HDI as the dependent variables and FML, PL, PBFM as the independent variables. A multivariate regression analysis was performed to examine the predictive value of the two anthropometric measurements. A p-value < 0.05 was considered statistically significant. RESULTS: All six univariate analyses revealed that the dependent variable was significantly correlated with the independent variable. However, the multivariate regression models showed that the anthropometric measurements were not significantly correlated with the RSD and HDI. CONCLUSION: The current study found an association between the fifth metatarsal intramedullary canal diameter and the fifth metatarsal length and foot anthropometric dimensions. However, the anthropometric measurements of the foot presented a low predictive value for the decision of an intramedullary screw diameter in the treatment of fractures of the base of the fifth metatarsal.

Histological Alterations in Hashimoto's Disease: A Case-Series Ultrastructural Study.

BACKGROUND: Hashimoto's thyroiditis (HT) is an autoimmune disease exhibiting stromal fibrosis and follicular cell destruction due to lymphoplasmacytic infiltration. Besides deprecated analyses, histopathological approaches have not employed the use of electron microscopy adequately toward delineating subcellular-level interactions. METHODS: Biopsies for ultrastructural investigations were obtained from the thyroids of five patients with HT after a thyroidectomy. Transmission electron microscopy (TEM) was utilized to study representative tissue specimens. RESULTS: Examination indicated interstitial extravasated blood cells and a plethora of plasma cells, based on their subcellular identity landmarks. These antibody-secreting cells were profoundly spotted near follicular cells, fibroblasts, and cell debris entrenched in collagenous areas. Pathological changes persistently affected subcellular components of the thyrocytes, including the nucleus, endoplasmic reticulum (ER), Golgi apparatus, mitochondria, lysosomes, and other intracellular vesicles. Interestingly, significant endothelial destruction was observed, specifically in the larger blood vessels, while the smaller vessels appeared comparatively unaffected. CONCLUSIONS: Our TEM findings highlight the immune-related alterations occurring within the thyroid stroma. The impaired vasculature component and remodeling have not been described ultrastructurally before; thus, further exploration is needed with regards to angiogenesis in HT in order to achieve successful prognostic, diagnostic, and treatment-monitoring strategies.

CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease.

Being immune privileged, the central nervous system (CNS) is constituted by unique parenchymal and non-parenchymal tissue-resident macrophages, namely, microglia and border-associated macrophages (BAMs), respectively. BAMs are found in the choroid plexus, meningeal and perivascular spaces, playing critical roles in maintaining CNS homeostasis while being phenotypically and functionally distinct from microglial cells. Although the ontogeny of microglia has been largely determined, BAMs need comparable scrutiny as they have been recently discovered and have not been thoroughly explored. Newly developed techniques have transformed our understanding of BAMs, revealing their cellular heterogeneity and diversity. Recent data showed that BAMs also originate from yolk sac progenitors instead of bone marrow-derived monocytes, highlighting the absolute need to further investigate their repopulation pattern in adult CNS. Shedding light on the molecular cues and drivers orchestrating BAM generation is essential for delineating their cellular identity. BAMs are receiving more attention since they are gradually incorporated into neurodegenerative and neuroinflammatory disease evaluations. The present review provides insights towards the current understanding regarding the ontogeny of BAMs and their involvement in CNS diseases, paving their way into targeted therapeutic strategies and precision medicine.

Variant-Related Differences in Laboratory Biomarkers among Patients Affected with Alpha, Delta and Omicron: A Retrospective Whole Viral Genome Sequencing and Hospital-Setting Cohort Study.

During the COVID-19 pandemic, different SARS-CoV-2 variants of concern (VOC) with specific characteristics have emerged and spread worldwide. At the same time, clinicians routinely evaluate the results of certain blood tests upon patient admission as well as during hospitalization to assess disease severity and the overall patient status. In the present study, we searched for significant cell blood count and biomarker differences among patients affected with the Alpha, Delta and Omicron VOCs at admission. Data from 330 patients were retrieved regarding age, gender, VOC, cell blood count results (WBC, Neut%, Lymph%, Ig%, PLT), common biomarkers (D-dimers, urea, creatinine, SGOT, SGPT, CRP, IL-6, suPAR), ICU admission and death. Statistical analyses were performed using ANOVA, the Kruskal-Wallis test, two-way ANOVA, Chi-square, T-test, the Mann-Whitney test and logistic regression was performed where appropriate using SPSS v.28 and STATA 14. Age and VOC were significantly associated with hospitalization, whereas significant differences among VOC groups were found for WBC, PLT, Neut%, IL-6, creatinine, CRP, D-dimers and suPAR. Our analyses showed that throughout the current pandemic, not only the SARS-CoV-2 VOCs but also the laboratory parameters that are used to evaluate the patient's status at admission are subject to changes.

Origin and Emergence of Microglia in the CNS-An Interesting (Hi)story of an Eccentric Cell.

Microglia belong to tissue-resident macrophages of the central nervous system (CNS), representing the primary innate immune cells. This cell type constitutes ~7% of non-neuronal cells in the mammalian brain and has a variety of biological roles integral to homeostasis and pathophysiology from the late embryonic to adult brain. Its unique identity that distinguishes its "glial" features from tissue-resident macrophages resides in the fact that once entering the CNS, it is perennially exposed to a unique environment following the formation of the blood-brain barrier. Additionally, tissue-resident macrophage progenies derive from various peripheral sites that exhibit hematopoietic potential, and this has resulted in interpretation issues surrounding their origin. Intensive research endeavors have intended to track microglial progenitors during development and disease. The current review provides a corpus of recent evidence in an attempt to disentangle the birthplace of microglia from the progenitor state and underlies the molecular elements that drive microgliogenesis. Furthermore, it caters towards tracking the lineage spatiotemporally during embryonic development and outlining microglial repopulation in the mature CNS. This collection of data can potentially shed light on the therapeutic potential of microglia for CNS perturbations across various levels of severity.

Valproic acid induced selective apoptosis of ocular fibrous tunic in mice fetuses.

BACKGROUND: Valproic acid (VPA), a prescribed drug commonly used for various neurological perturbations, has been implicated in teratogenic inflictions on developing fetuses during pregnancy. The purpose of this research was to delineate the gross morphological and histological effects of VPA in the developing eye tunics and lens. METHODS: A time-dependent administration of 500 mg/kg VPA to BALB/c groups of female mice was coordinated during organogenesis (gestational days 7, 8, and 9) and compared to controls that received normal saline. Seized fetuses were checked for macroscopic eye anomalies, histological malformations with Azan trichrome staining, and levels of apoptotic activity with the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. RESULTS: Histochemical analysis showed that VPA-treated groups exhibited collagen deficiency (2.5-50% decrease in aniline blue intensity) and a marked increase in TUNEL-positive cells (p < .05) in corneal stroma and sclera/choroid layers while less was detected in retina and lens, when compared to controls. CONCLUSIONS: Since the evaluation of the inner structures did not manifest major differences, we conclude that VPA teratogenic influence display eclectic toxicity, as seen by increased apoptosis to eye layers with high degree fibrous context, particularly the outer tunics.

A rare bifurcation of the external iliac artery into femoral and deep femoral arteries.

PURPOSE: The current cadaveric report describes a quite rare unilateral bifurcation of the external iliac artery (EIA) into two femoral arteries (FAs) of almost equal diameter and parallel course, at the level of the inguinal ligament (IL). METHODS: The variant FAs were identified on a 75-year-old formalin-embalmed female cadaver, derived from a body donation program after a signed informed consent. RESULTS: The EIA bifurcated into a FA and a deep femoral artery (DFA). The DFA extremely high origin was identified at the IL level. Both lateral and medial circumflex femoral arteries originated from the DFA. CONCLUSION: The in-depth knowledge of the FA variant origin is of paramount importance to vascular surgeons and interventional radiologists during vessel catheterization and attempts to interpret the angiographic findings. In particular, the DFA's high origin from the EIA and the coexistence of two FAs in a parallel course may pose problems to clinicians during angiographic procedures leading to diagnostic errors. The DFA high origin may also complicate femoral arterial and venous puncture and femoral nerve blocks, due to the close neurovascular relationship. There is a possibility for the FA to be mistaken for a vein leading to accidental intra-arterial injection and consequently thrombosis. Thus, variable arterial pattern is important to be identified preoperatively using Doppler ultrasound imaging.

Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin.

The mammalian central nervous system (CNS) coordinates its communication through saltatory conduction, facilitated by myelin-forming oligodendrocytes (OLs). Despite the fact that neurogenesis from stem cell niches has caught the majority of attention in recent years, oligodendrogenesis and, more specifically, the molecular underpinnings behind OL-dependent myelinogenesis, remain largely unknown. In this comprehensive review, we determine the developmental cues and molecular drivers which regulate normal myelination both at the prenatal and postnatal periods. We have indexed the individual stages of myelinogenesis sequentially; from the initiation of oligodendrocyte precursor cells, including migration and proliferation, to first contact with the axon that enlists positive and negative regulators for myelination, until the ultimate maintenance of the axon ensheathment and myelin growth. Here, we highlight multiple developmental pathways that are key to successful myelin formation and define the molecular pathways that can potentially be targets for pharmacological interventions in a variety of neurological disorders that exhibit demyelination.

The Polygenic Nature and Complex Genetic Architecture of Specific Learning Disorder.

Specific Learning Disorder (SLD) is a multifactorial, neurodevelopmental disorder which may involve persistent difficulties in reading (dyslexia), written expression and/or mathematics. Dyslexia is characterized by difficulties with speed and accuracy of word reading, deficient decoding abilities, and poor spelling. Several studies from different, but complementary, scientific disciplines have investigated possible causal/risk factors for SLD. Biological, neurological, hereditary, cognitive, linguistic-phonological, developmental and environmental factors have been incriminated. Despite worldwide agreement that SLD is highly heritable, its exact biological basis remains elusive. We herein present: (a) an update of studies that have shaped our current knowledge on the disorder's genetic architecture; (b) a discussion on whether this genetic architecture is 'unique' to SLD or, alternatively, whether there is an underlying common genetic background with other neurodevelopmental disorders; and, (c) a brief discussion on whether we are at a position of generating meaningful correlations between genetic findings and anatomical data from neuroimaging studies or specific molecular/cellular pathways. We conclude with open research questions that could drive future research directions.