Harnessing the Stem Cell Niche in Regenerative Medicine: Innovative Avenue to Combat Neurodegenerative Diseases.

Regenerative medicine harnesses the body's innate capacity for self-repair to restore malfunctioning tissues and organs. Stem cell therapies represent a key regenerative strategy, but to effectively harness their potential necessitates a nuanced understanding of the stem cell niche. This specialized microenvironment regulates critical stem cell behaviors including quiescence, activation, differentiation, and homing. Emerging research reveals that dysfunction within endogenous neural stem cell niches contributes to neurodegenerative pathologies and impedes regeneration. Strategies such as modifying signaling pathways, or epigenetic interventions to restore niche homeostasis and signaling, hold promise for revitalizing neurogenesis and neural repair in diseases like Alzheimer's and Parkinson's. Comparative studies of highly regenerative species provide evolutionary clues into niche-mediated renewal mechanisms. Leveraging endogenous bioelectric cues and crosstalk between gut, brain, and vascular niches further illuminates promising therapeutic opportunities. Emerging techniques like single-cell transcriptomics, organoids, microfluidics, artificial intelligence, in silico modeling, and transdifferentiation will continue to unravel niche complexity. By providing a comprehensive synthesis integrating diverse views on niche components, developmental transitions, and dynamics, this review unveils new layers of complexity integral to niche behavior and function, which unveil novel prospects to modulate niche function and provide revolutionary treatments for neurodegenerative diseases.

Clinical Efficacy of Extracellular Vesicle Therapy in Periodontitis: Reduced Inflammation and Enhanced Regeneration.

Periodontitis, a prevalent inflammatory condition, affects the supporting structures of teeth, leading to significant oral health challenges. Traditional treatments have primarily focused on mechanical debridement, antimicrobial therapy, and surgery, which often fail to restore lost periodontal structures. Emerging as a novel approach in regenerative medicine, extracellular vesicle (EV) therapy, including exosomes, leverages nano-sized vesicles known for facilitating intercellular communication and modulating physiological and pathological processes. This study is a proof-of-concept type that evaluates the clinical efficacy of EV therapy as a non-surgical treatment for stage I-III periodontitis, focusing on its anti-inflammatory and regenerative potential. The research involved seven patients undergoing the therapy, and seven healthy individuals. Clinical parameters, including the plaque index, bleeding on probing, probing depth, and attachment level, were assessed alongside cytokine levels in the gingival crevicular fluid. The study found significant improvements in clinical parameters, and a marked reduction in pro-inflammatory cytokines post-treatment, matching the levels of healthy subjects, underscoring the therapy's ability to not only attenuate inflammation and enhance tissue regeneration, but also highlighting its potential in restoring periodontal health. This investigation illuminates the promising role of EV therapy in periodontal treatment, advocating for a shift towards therapies that halt disease progression and promote structural and functional restoration of periodontal tissues.

Cytokine Dynamics in Autism: Analysis of BMAC Therapy Outcomes.

Autism spectrum disorder (ASD) has recently been linked to neuroinflammation and an aberrant immune response within the central nervous system. The intricate relationship between immune response and ASD remains elusive, with a gap in understanding the connection between specific immune mechanisms and neural manifestations in autism. In this study, we employed a comprehensive statistical approach, fusing both overarching and granular methods to examine the concentration of 16 cytokines in the cerebrospinal fluid (CSF) across each autologous bone marrow aspirate concentrate (BMAC) intrathecal administration in 63 male and 17 female autism patients. Following a six-month period post the third administration, patients were stratified into three categories based on clinical improvement: Group 1- no/mild (28 subjects), Group 2-moderate (16 subjects), and Group 3-major improvement (15 subjects). Our integrated analysis revealed pronounced disparities in CSF cytokine patterns and clinical outcomes in autism subjects pre- and post-BMAC transplantation. Crucially, our results suggest that these cytokine profiles hold promise as predictive markers, pinpointing ASD individuals who might not exhibit notable clinical amelioration post-BMAC therapy.

Stem Cell Homing in Intrathecal Applications and Inspirations for Improvement Paths.

A transplanted stem cell homing is a directed migration from the application site to the targeted tissue. Intrathecal application of stem cells is their direct delivery to cerebrospinal fluid, which defines the homing path from the point of injection to the brain. In the case of neurodegenerative diseases, this application method has the advantage of no blood-brain barrier restriction. However, the homing efficiency still needs improvement and homing mechanisms elucidation. Analysis of current research results on homing mechanisms in the light of intrathecal administration revealed a discrepancy between in vivo and in vitro results and a gap between preclinical and clinical research. Combining the existing research with novel insights from cutting-edge biochips, nano, and other technologies and computational models may bridge this gap faster.

Mathematical modeling of the neuron morphology using two dimensional images.

In this study mathematical analyses such as the analysis of area and length, fractal analysis and modified Sholl analysis were applied on two dimensional (2D) images of neurons from adult human dentate nucleus (DN). Using mathematical analyses main morphological properties were obtained including the size of neuron and soma, the length of all dendrites, the density of dendritic arborization, the position of the maximum density and the irregularity of dendrites. Response surface methodology (RSM) was used for modeling the size of neurons and the length of all dendrites. However, the RSM model based on the second-order polynomial equation was only possible to apply to correlate changes in the size of the neuron with other properties of its morphology. Modeling data provided evidence that the size of DN neurons statistically depended on the size of the soma, the density of dendritic arborization and the irregularity of dendrites. The low value of mean relative percent deviation (MRPD) between the experimental data and the predicted neuron size obtained by RSM model showed that model was suitable for modeling the size of DN neurons. Therefore, RSM can be generally used for modeling neuron size from 2D images.

Neurons from the adult human dentate nucleus: neural networks in the neuron classification.

OBJECTIVES: Topological (central vs. border neuron type) and morphological classification of adult human dentate nucleus neurons according to their quantified histomorphological properties using neural networks on real and virtual neuron samples. RESULTS: In the real sample 53.1% and 14.1% of central and border neurons, respectively, are classified correctly with total of 32.8% of misclassified neurons. The most important result present 62.2% of misclassified neurons in border neurons group which is even greater than number of correctly classified neurons (37.8%) in that group, showing obvious failure of network to classify neurons correctly based on computational parameters used in our study. On the virtual sample 97.3% of misclassified neurons in border neurons group which is much greater than number of correctly classified neurons (2.7%) in that group, again confirms obvious failure of network to classify neurons correctly. Statistical analysis shows that there is no statistically significant difference in between central and border neurons for each measured parameter (p>0.05). Total of 96.74% neurons are morphologically classified correctly by neural networks and each one belongs to one of the four histomorphological types: (a) neurons with small soma and short dendrites, (b) neurons with small soma and long dendrites, (c) neuron with large soma and short dendrites, (d) neurons with large soma and long dendrites. Statistical analysis supports these results (p<0.05). CONCLUSION: Human dentate nucleus neurons can be classified in four neuron types according to their quantitative histomorphological properties. These neuron types consist of two neuron sets, small and large ones with respect to their perykarions with subtypes differing in dendrite length i.e. neurons with short vs. long dendrites. Besides confirmation of neuron classification on small and large ones, already shown in literature, we found two new subtypes i.e. neurons with small soma and long dendrites and with large soma and short dendrites. These neurons are most probably equally distributed throughout the dentate nucleus as no significant difference in their topological distribution is observed.

An anatomical study of the lumbar external foraminal ligaments: appearance at MR imaging.

PURPOSE: The purpose of this study was to examine the MRI appearance of the ligaments within the external space of the lumbar intervertebral foramen by correlating MR images with the corresponding anatomic dissection of the cadaver lumbar spine. METHODS: This was a two part study. Part I of the anatomic study consisted of the dissection of lumbar specimens from one embalmed adult male cadaver. At each lumbar level the external ligamentous structures were identified and their origin, insertion and position were determined. Part II of the study consisted of the anatomical analysis of the external transforaminal ligaments in the 180 lumbar intervertebral foramina on the MR images (1.5 T) in the sagittal plane. The diagnostic procedure was performed on 18 individuals from 18 to 25 years of age. RESULTS: The external transforaminal ligaments were observed at all levels and from both sides in the lumbar intervertebral foramen. The presence of the superior corporotransverse ligament was found in 45.56% intervertebral foramina, while the inferior corporotransverse ligament was found in 61.67% intervertebral foramina in the MRI. CONCLUSION: Our results confirm that external transforaminal ligaments are common structures in the intervertebral foramen. The results of this study show that the external transforaminal ligaments can be clearly visualized in MR images. It is crucial to have previous knowledge of the cadaveric specimens to recognize the transforaminal ligaments in MR images. The presence of these ligaments is clinically important because the ligaments could be the cause of nerve root compression or the low back pain syndrome.

Ectopic adrenocortical tissue: an incidental finding during inguinal surgery in children.

Adrenal rests are usually unrecognized during operation, and the incidence of ectopic adrenal cortical tissue in pediatric patients during inguinal surgery procedures is unknown. We performed 3028 groin surgical explorations in 2680 patients aged 1 month to 17 years. Ectopic adrenal tissue was found in 69 inguinal operations (2.2%): 37 during 1.524 orchiopexy (2.4%), 23 during 1.115 herniectomy (2.0%), and 9 during 389 hydrocoela operation (2.3%). Statistically there were no significant differences among those three groups. No adrenal rests were detected in females. Although a few reported cases with hormonal activity of ectopic adrenocortical tissue (EACT), the recommendation is to remove them if found.

Potential Impact of Polymorphisms in Toll-like Receptors 2, 3, 4, 7, 9, miR-146a, miR-155, and miR-196a Genes on Osteoarthritis Susceptibility.

Osteoarthritis (OA) is a progressive inflammatory disease of synovial joints and a leading cause of disability among adults. Inflammation-related genes, including genes for Toll-like receptors (TLRs), are tightly controlled by several microRNAs that, in addition to their pivotal role in the epigenetic regulation of target genes, are ligands for TLR activation and downstream signaling. Thus, we evaluated the association between OA risk and genetic variants in TLR2, TLR3, TLR4, TLR7, TLR9, and microRNAs that regulate TLRs signaling miR146a, miR155, and miR196a2. Our study group consisted of 95 surgically treated OA patients and a control group of 104 healthy individuals. Genetic polymorphisms were determined using TaqMan real-time PCR assays (Applied Biosystems). Adjusted logistic regression analysis demonstrated that polymorphisms in TLR4 rs4986790 (OR = 2.964, p = 0.006), TLR4 rs4986791 (OR = 8.766, p = 0.00001), and TLR7 rs385389 (OR = 1.579, p = 0.012) increased OA risk, while miR-196a2 rs11614913 (OR = 0.619, p = 0.034) was significantly associated with decreased OA risk. Our findings indicate that polymorphisms in the TLR4 and TLR7 genes might increase OA risk and suggest a novel association of miR-196a2 polymorphism with decreased OA susceptibility. The modulation of TLRs and miRNAs and their cross-talk might be an attractive target for a personalized approach to OA management.

On the classification of normally distributed neurons: an application to human dentate nucleus.

One of the major goals in cellular neurobiology is the meaningful cell classification. However, in cell classification there are many unresolved issues that need to be addressed. Neuronal classification usually starts with grouping cells into classes according to their main morphological features. If one tries to test quantitatively such a qualitative classification, a considerable overlap in cell types often appears. There is little published information on it. In order to remove the above-mentioned shortcoming, we undertook the present study with the aim to offer a novel method for solving the class overlapping problem. To illustrate our method, we analyzed a sample of 124 neurons from adult human dentate nucleus. Among them we qualitatively selected 55 neurons with small dendritic fields (the small neurons), and 69 asymmetrical neurons with large dendritic fields (the large neurons). We showed that these two samples are normally and independently distributed. By measuring the neuronal soma areas of both samples, we observed that the corresponding normal curves cut each other. We proved that the abscissa of the point of intersection of the curves could represent the boundary between the two adjacent overlapping neuronal classes, since the error done by such division is minimal. Statistical evaluation of the division was also performed.

Classification by morphology of multipolar neurons of the human principal olivary nucleus.

The principal olivary nucleus is the largest part of the inferior olivary complex and is involved in the spatial and temporal organization of movement and motor learning. Nearly all neurons in this nucleus is multipolar along with having a highly complex dendritic tree and significant asymmetry in shape. In this study, we updated the current classification scheme, examined morphological differences between the proposed groups, and investigated age-related morphological changes. Histological preparations were digitized by a light microscope and a sample of 259 images of neurons was analyzed by 17 computationally generated parameters of morphology. These were reduced to the four variables of principal component analysis and the sample was classified by k-means method of clustering into three clusters. The differences between clusters were documented and for medium-sized neurons the relationship between four morphological parameters and age were investigated. Finally, for two of the age groups the changes in the morphology were explored. This study includes a detailed and robust classification of the PON neurons and the findings improve upon past qualitative work.

Quantitative analysis of spiny neurons in the adult human caudate nucleus: can it confirm the current qualitative cell classification?

The caudate nucleus, as a part of the striatum (neostriatum or dorsal striatum), is involved in the control of cognitive, motor and limbic functions. The majority of the caudate nucleus cells are projection spiny neurons, whose activity is determined by excitatory inputs from the cortex, thalamus, globus pallidus and brainstem. A qualitative analysis of human caudate nucleus neurons involves the description of the structure and features of cells, and accordingly, their classification into an appropriate type. The aim of this study is to determine the justification of the current qualitative classification of spiny neurons in the precommissural head of the human caudate nucleus by quantifying morphological properties of neurons. After the qualitative analysis of microscopic images of the Golgi-impregnated caudate nucleus neurons, five morphological properties of cells were measured/quantified. In terms of the dendritic field area, caudate nucleus neurons were divided into two subgroups: small and large neurons. In our sample of 251 projection nerve cells, 58.17 % (146) were small and 41.83 % (105) were large neurons. These data show that suggested groups of spiny neurons in the human caudate nucleus differ in their morphology. Since the structure and function of cells are closely correlated, it is possible that these morphologically different types of neurons may represent different functional groups.

A painful symphony: the presence of overuse syndrome in professional classical musicians / Una sinfonía dolorosa: la presencia del síndrome de uso excesivo en músicos clásicos profesionales

Musculoskeletal problems are common in instrumental musicians. Little is known about the factors that place musicians at risk, and the ways in which musicians can prevent these problems. Overuse syndrome is the most reported diagnosis among instrumental musicians suffering from playing related musculoskeletal injuries. The study group comprised 50 musicians employed in Symphony Orchestra of the Serbian National Theatre of Novi Sad. Out of the 50 musicians, 30 (60 %) are male and 20 (40 %) female. Higher frequencies of the presence of musculoskeletal symptoms were neck, region of trapezius, back, shoulder, wrist, hand and arm. A larger number of musicians (81.8 %) had perception of high demand of the profession. This investigation with professional classical musicians should show the music-medical interest.

Los problemas musculo-esqueléticos son comunes en los músicos instrumentales. Poco se sabe sobre los factores que ponen en riesgo a los músicos y las formas en que los ellos pueden prevenir estos problemas. El síndrome de uso excesivo es el diagnóstico más informado entre los músicos instrumentales que sufren lesiones musculo-esqueléticas relacionadas al uso de instrumentos musicales. El grupo de estudio estuvo compuesto por 50 músicos de la Orquesta Sinfónica del Teatro Nacional Serbio de Novi Sad. De los 50 músicos, 30 (60 %) eran hombres y 20 (40 %) mujeres. La frecuencia más alta de presencia de síntomas musculoesqueléticos se produjo en el cuello, músculo trapecio, espalda, hombro, muñeca, mano y brazo. Un mayor número de músicos (81,8 %) tuvo una percepción de alta demanda de la profesión. Esta investigación con músicos clásicos profesionales debería ser de interés médico-musical.

Prevalence of third coronary artery: variation or constant coronary artery? / Prevalencia de la tercera arteria coronaria: ¿variación o arteria coronaria constante?

Third coronary artery or supernumerary coronary artery is a direct branch from right aortic sinus and it supplies pulmonary conus and upper part of right ventricle. Third coronary artery is an important bridge for collateral circulation between right and left coronary system. The aim of this study was to determine the number of arteries that origin from right aortic sinus, their frequency and position. The study included 55 adult human hearts collected from Department of Anatomy. The hearts were morphologically studied by gross dissection for the prevalence and topographical anatomy of supernumerary coronary arteries. Out of 55 hearts, 26 (47.3 %) had one right coronary artery, 23 (41.8 %) had two right coronary arteries, and 6 (10.9 %) had three coronary arteries. The supernumerary arteries arises from the right aortic sinus. Right supernumerary coronary arteries may be present in about 52.7 % of the Serbian population. Interpretation of signs and symptoms of coronary occlusion should therefore consider possible contribution of this blood vessels.

La tercera arteria coronaria o arteria coronaria supernumeraria es una rama directa del seno aórtico derecho y su ministra el cono pulmonar y la parte superior del ventrículo derecho. La tercera arteria coronaria es importante para la circulación colateral entre el sistema coronario derecho e izquierdo. El objetivo de este estudio fue determinar el número de arterias de origen del seno aórtico derecho, su frecuencia y posición. El estudio incluyó 55 corazones humanos adultos pertenecientes al Departamento de Anatomía. Los corazones se estudiaron morfológicamente mediante disección macroscópica para determinar la prevalencia y la anatomía topográfica de las arterias coronarias supernumerarias. De 55 corazones, 26 (47,3 %) tenían una arteria coronaria derecha, 23 (41,8 %) tenían dos arterias coronarias derechas, y 6 (10,9 %) tenían tres arterias coronarias. Las arterias supernumerarias surgen del seno aórtico derecho. Las arterias coronarias supernumerarias derechas pueden estar presentes en aproximadamente el 52,7 % de la población serbia. La interpretación de los signos y síntomas de la oclusión coronaria debería considerar la posible contribución de estos vasos sanguíneos.

Neuronal images of the putamen in the adult human neostriatum: a revised classification supported by a qualitative and quantitative analysis.

A qualitative analysis of the morphology of human putamen nerve cells involves a detailed description of the structure and features of neurons and, accordingly, their classification into already defined classes and types. In our sample of 301 neurons, 64.78 % (195) were spiny and 35.22 % (106) aspiny cells. By analyzing cell bodies and dendritic trees, we subdivided spiny cells into two types (I and II) and aspiny cells into three types (III, IV and V). Our sample of neurons, classified according to the previously described scheme, consisted of 80 type I, 115 type II, 16 type III, 42 type IV and 48 type V nerve cells. In the present study, after qualitative analysis of microscopic images of the Golgi impregnated neurons of the putamen, we measured/quantified five morphological properties, i.e., the sizes of the soma and dendritic field, shape of the neuron, straightness of individual dendrites and the branching complexity of the dendritic tree, using eight morphometric parameters. Hence, we identify five types of nerve cells in the human putamen: type I-small spiny neurons; type II-large spiny neurons; type III-large aspiny neurons; type IV-neurons with a large soma and a medium dendritic field; and type V-small aspiny neurons. By performing an adequate statistical analysis on these parameters, we point out that the proposed types differ enough in their morphology to warrant our qualitative classification.

[Quantitative analysis of the change in neuronal numerical density of the human nucleus dentatus within development].

BACKGROUND/AIM: The role of the dentate nucleus is to coordinate input information coming from the lower olivary complex and various parts of the brainstem of the spinal marrow with the output information from the cerebellar cortex. To better understand functions and relations of the dentate nucleus it is highly important to study its development process. The aim of this study was to determine a possible mathematical model of decrease in neuronal numerical density of the human nucleus dentatus at different stages of development. METHODS: This study included 25 fetal brains of different age (12.5-31 weeks of gestational age and one brain of a 6-day-old newborn). The brains were fixed in 10% formalin-alcohol solution and embedded in paraffin. Sections were cut at a thickness of 6, 15, and 30 microm and stained with cresyl violet. Each fifth section was analyzed using a light microscope, and numerical density of dentate nucleus neurons was established using the M42 Weibel's grid system. RESULTS: The obtained results revealed a constant decrease in numerical density value. The changes of numerical densities at different stages of development correspond with Boltzmann function principles. The first, almost perpendicular part of Boltzmann function corresponds with the development of the dorsomedial lamina and the appearance of ventrolateral lamina primordium. The second, more or less horizontal part of Boltzmann function corresponds with the development of both laminae. CONCLUSION. The obtained results indicate that Boltzmann function can be considered a mathematical model of change in neuronal numerical density of dentate nucleus at different stage of development.

Morphology and cell classification of large neurons in the adult human dentate nucleus: a quantitative study.

The dentate nucleus represents the most lateral of the four cerebellar nuclei that serve as a major relay centres for fibres coming from the cerebellar cortex. Although many relevant findings regarding to the three-dimensional structure, the neuronal morphology and the cytoarchitectural development of the dentate nucleus have been presented so far, very little quantitative information has been collected to further explain several types of large neurons in the dentate nucleus. In this study we quantified the morphology of the large dentate neurons in the adult human taking, into account seven morphometric parameters that describe the main properties of the cell soma, the dendritic field and the dendritic branching pattern. Since the lateral cerebellar nucleus in the cat and other lower mammals is homologous to the dentate nucleus in primates and man, we have classified our sample of large neurons in accordance with the shape of the cell body, the dendritic arborization and their location within the dentate nucleus. By performing the appropriate statistical analysis, we have proved that our sample of human dentate neurons can be classified into four distinct types. In that sense, our quantitative analysis verifies the validity of previous qualitative conclusions concerning the large neurons in the developing human dentate nucleus. Furthermore, the present study represents the first attempt to perform a quantitative analysis and cell classification of the large projection neurons in the adult human dentate nucleus.

[Quantitative analysis of dendritic branching pattern of large neurons in human cerebellum].

BACKGROUND/AIM: Dentate nucleus (nucleus dentatus) is the most distant of the cerebellar nuclei and the major system for information transfer in the cerebellum. So far, dendritic branches of four different kinds of large neurons of dentate nucleus, have been considered mainly qualitatively with no quantification of their morphological features. The aim of the study was to test the qualitative hypothesis that the human dentate nucleus is composed of various types of the large neurons by quantitative analysis of their dendritic branching patterns. METHODS: Series of horizontal sections of the dentate nuclei were taken from 15 adult human brains, free of diagnosed neurological disorders. The 189 Golgi-impregnated images of large neurons were recorded by a digital camera connected to a light microscope. Dendritic branching patterns of digitized neuronal images were analyzed by modified Sholl and fractal analyses. RESULTS: The number of intersections (N(m)), critical radius (r(c)) and fractal dimension (D) of dendritic branching pattern for four types of the large neurons were calculated, statistically evaluated and analyzed. The results show that there is a significant difference between four neuronal types in one morphometric parameter at least. CONCLUSION: The present study is the first attempt to analyze quantitatively the dendritic branching pattern of neurons from the dentate nucleus in the human. The hypothesis that the four types of the large neurons exist in this part of human cerebellum is successfully supported.

Morphology and classification of large neurons in the adult human dentate nucleus: a qualitative and quantitative analysis of 2D images.

The dentate nucleus represents the most lateral of the four cerebellar nuclei that serve as major relay centres for fibres coming from the cerebellar cortex. Although many relevant findings regarding to the structure, neuronal morphology and cytoarchitectural development of the dentate nucleus have been presented so far, very little quantitative information has been collected on the types of large neurons in the human dentate nucleus. In the present study we qualitatively analyze our sample of large neurons according to their morphology and topology, and classify these cells into four types. Then, we quantify the morphology of such cell types taking into account seven morphometric parameters which describe the main properties of the cell soma, dendritic field and dendrite arborization. By performing appropriate statistics we prove out our classification of the large dentate neurons in the adult human. To the best of our knowledge, this study represents the first attempt of quantitative analysis of morphology and classification of the large neurons in the adult human dentate nucleus.