Cause Of Pathology Research Articles

An Integrated Multi-Channel Deep Neural Network for Mesial Temporal Lobe Epilepsy Identification Using Multi-Modal Medical Data.

Epilepsy is a chronic brain disease with recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is the most common pathological cause of epilepsy. With the development of computer-aided diagnosis technology, there are many auxiliary diagnostic approaches based on deep learning algorithms. However, the causes of epilepsy are complex, and distinguishing different types of epilepsy accurately is challenging with a single mode of examination. In this study, our aim is to assess the combination of multi-modal epilepsy medical information from structural MRI, PET image, typical clinical symptoms and personal demographic and cognitive data (PDC) by adopting a multi-channel 3D deep convolutional neural network and pre-training PET images. The results show better diagnosis accuracy than using one single type of medical data alone. These findings reveal the potential of a deep neural network in multi-modal medical data fusion.

Preclinical assessment of IL-1β primed human umbilical cord mesenchymal stem cells for tendon functional repair through TGF-β/IL-10 signaling

BackgroundInadequate repair capacity and disturbed immune compartments are the main pathological causes of tendinopathy. Transplantation of mesenchymal stem cells (MSCs) become an effective clinic option to alleviate tendinopathy. Interleukin-1β (IL-1β) could confer on MSCs enhanced immunoregulatory capability to remodel the repair microenvironment favoring tissue repair. Therefore, IL-1β activated UC-MSCs (1βUC-MSCs) may exert favorable efficacy in promoting tendon repair in a preclinical tendinopathy rat model. MethodsTendon-derived stem cells (TDSCs) were isolated and characterized. In vitro, the levels of immunoregulatory-related cytokines such as IL-1β, IL-6, IL-10, and TGF-β secreted by 1βUC-MSCs and unprimed UC-MSCs was measured. And tendon-specific markers expressed by TDSCs cultured with primed cultured medium (CM) or unprimed CM were detected. In vivo, Achilles tendinopathy was induced by 30 μL collagenase I injection in Sprague Dawley rats. One week later, the rats were randomly injected with UC-MSCs primed with IL-1β (106 cells per tendon), UC-MSCs, or PBS. After rats were sacrificed, histological evaluation, electron microscopy, biomechanical tests, gait performance were conducted to evaluate the structural and functional recovery of Achilles tendons. The inflammation and metabolic state of the extracellular matrix, and the potential mechanism were assessed by immunohistochemical staining and Western blot. ResultsUC-MSCs were activated by IL-1β to secrete higher levels of IL-10 and TGF-β while the secretion levels of IL-6 and IL-1β were not changed significantly, promoting a higher expression level of COL I and TNMD in TDSCs under proinflammatory environment. In vivo, the transplanted 1βUC-MSCs could survive up to 5 weeks after injection with tenogenic differentiation and improved tendon healing histologically semi-quantified by modified Bonar scores. This structural regeneration was further confirmed by observation of ultrastructural morphology, and led to good functional recovery including improved biomechanical properties and gait performance. During this process, the inflammatory response and metabolism of the extracellular matrix was improved through TGF-β/IL-10 pathway. ConclusionThis study demonstrated that the transplantation of UC-MSCs activated by IL-1β exhibited satisfactory ability for promoting tendon functional repair in a tendinopathy rat model. During this process, the balance of inflammatory response and extracellular matrix metabolism was remodeled, and the TGF-β/Smad2/3 and IL-10 signaling pathways were activated simultaneously. We cautiously conclude that the IL-1β primed UC-MSCs could be a promising strategy for enhancing the ability of MSCs to treat tendinopathy.

Allergy to fungi: Advances in the understanding of fungal allergens

Allergic diseases are a major health problem due to their increasing incidence and high prevalence worldwide. Asthma has several aetiologies, and allergy plays an important role in its development in approximately 60% of adults and 80% of children and adolescents. Although the link between aeroallergen sensitization and asthma exacerbations has been long recognized, the investigations of the triggering allergens may be superficial in many asthma cases. The main allergenic sources related to asthma, and other allergic diseases, are pollens, mites, fungi, and animal epithelia. Fungi are considered the third most frequent cause of respiratory pathologies. Asthma caused by several fungi species may have a bad prognosis in some cases due to its severity and difficulty in avoidance methods. Despite the recognised relevance of fungi in respiratory allergies, the knowledge about fungal allergens seems to be scarce, with few descriptions of new allergens, compared to other allergenic sources. The study of major, minor, and cross-reactive fungal allergens, and their relevance in the allergic disease, might be crucial, not only to accurately diagnose these allergies, but also to predict exacerbations and responses to therapies, as well as for the development of personalized treatment plans in a fast-changing climate scenario.

Conservative Management of Dentigerous Cysts Associated With Mixed Dentition: A Retrospective Cohort Study.

Objectives Thepediatric dentigerous cysts might vary by region and population group.Large cystic lesions are typically treated with marsupialization before enucleation in order to decompress the lesion and reduce its volume; however, in pediatric cystic lesions, conservative marsupialization and decompression can be used to manage the condition without additional enucleation. The current study's objectives were to present a case series of pediatric dentigerous cysts and discuss the conservative management of these cystic lesions associated with mixed dentition. Methods A retrospective cohort analysis of patientsdiagnosed with cystic lesions between 2016 and 2023 was identified. Data on clinical, radiological, pathological, and odontogenic causes were collected. The marsupialization approach was performed in all cases.Patient demographic information was also examined, and a literature review was carried out to identify comparable cases. Results Sixteen young patients were diagnosed with dentigerous cysts, and this was confirmed by clinical, radiological, and pathological examinations. Females comprised 56.2% of the cases, with the right side predominating (62.5%).Deciduous teeth related to the lesion could be extracted normally in all cases. All associated permanent teeth erupted rapidly after the intervention. Conclusion The marsupialization technique used in the current cases of dentigerous cysts associated with mixed dentition was highly successful, and all permanentimpacted teeth erupted without any cystic recurrence.

THU168 PRMT7 Gene Mutation—A Rare Genetic Syndrome With Novel Endocrine Associations

Abstract Disclosure: K. Nutakki: None. S. Nalla: None. P. Deb: None. A. Vulpala: None. Background: Causes of short stature in children include pathologic causes (genetic diseases, underlying systemic disease, or growth hormone deficiency) and non-pathological variants such as familial and constitutional short stature. Genetic causes include Turner’s syndrome, SHOX mutations, Noonan’s syndrome and Silver- Russel syndrome besides others. Homozygous/compound heterozygous mutations in Protein Arginine Methyltransferase 7 (PRMT7) can result in Short Stature, Brachydactyly, Intellectual Developmental Disability and Seizures syndrome (SBIDDS) . Here, we report a child with SBIDDS syndrome who has associated endocrine manifestations of growth hormone deficiency and primary hypothyroidism. Case report: A 9-year-old male child, twin A of dichorionic diamniotic gestation, presented to the Endocrine OPD with short stature. There was a history of developmental delay, seizure disorder and mild intellectual deficit. Excessive weight gain was observed since 4 years of age. On examination, he was short with abdominal obesity, brachydactyly, simian crease and macroglossia. Height was below 3rd centile and weight at the 97th percentile. SMR was pre-pubertal. Investigations confirmed primary hypothyroidism.GH deficiency (peak GH after clonidine stimulation was less than 4 microgram/L) and reduced IGF-I levels were also found. Twin B was noted to have a normal height percentile. In both, skeletal maturation was consistent with chronological age. Twin A was treated with rGH and levothyroxine and responded well to rGH treatment. Whole exome sequencing revealed homozygosity for PRMT7 mutation in twin A with both parents heterozygous for the same gene mutation. His twin sibling, twin B was also found to be homozygous for the mutation, but he did not display any characteristics of the syndrome. Discussion: To the best of our knowledge, this is only the second reported case of SBIDDS syndrome (PRMT7 mutation) with documented growth hormone deficiency and only case with documented primary hypothyroidism. Height gain observed over the period of rGH treatment is suggestive of a possible role of GH/IGF-I axis alterations as contributors of growth impairment in these children. PRMT7 encodes for an arginine methyltransferase, involved in several biological processes, such as DNA transcription and repairing, RNA splicing, cell differentiation. We would like to propose that children with SBIDDS syndrome may be tested for GH deficiency as part of their overall assessment. Likewise, it should be further explored if PRMT7 gene mutation testing should be recommended in a child presenting with short stature and one or more manifestations of SBIDDS syndrome. Presentation: Thursday, June 15, 2023

FRI315 Hyperprolactinemia In The Presence Of Severe Calorie Restriction And Stress

Abstract Disclosure: T. Alrasheed: None. M. Alanazi: None. L. Albishi: None. H. Mirghani: None. Abstract: The effects of obesity and calorie restriction on prolactin levels (PL) are controversial. Here, we have an unusual case of physiological hyperprolactinemia in the presence of severe calorie restriction and emotional stressors. Case Presentation A 31-year-old security guard with obesity (31.5 kg/m2) started dieting by adopting severe calorie restrictions at 900 calories a day. He lost about 15 kg in two months, but even with weight loss, he was in poor health. He felt fatigued and unable to work. On testing, he had an elevated PL of 78.93 ng/ml. The remaining tests were normal, however, with the elevated PL, he was referred to our endocrinology clinic. He had a negative medical, surgical, and family history. He had a normal physical exam. We increased his calorie intake gradually to ∼2000 calories/day. With these changes, his energy improved, and his symptoms were resolved. The repeated PL was normalized (14.70 ng/ml). Discussion In clinical practice, hyperprolactinemia can result from physiological, pharmacological, or pathological causes due to the widespread effect of prolactin on the body. One of the physiological causes is stress, which could raise PL to 100 ng/ml, although the exact mechanism needs further study. It has been suggested that physiological stress affects the neuroendocrine by inducing changes in dopamine and serotonin levels, contributing to the increase in PL. However, the relationship between PL and obesity is controversial. While there was no direct association between the two even after significant weight loss, (similarly, changes in calories did not show a direct effect on PL) there was a study that showed enhancement of prolactin release in obese women in proportion to the size of their visceral fat, and severe weight loss was associated with a reduction in PL. In our case, calorie restriction was the start of this cascade of symptoms and elevated PL. Decreased calorie intake affected his daily function, which led to his emotional stress, which in turn led to hyperprolactinemia. After increasing calorie consumption and resolving his physical stressors, his symptoms improved, and his PL was normalized. Conclusion A combination of low-calorie diets and stress could cause hyperprolactinemia. Further study is required to understand the clinical significance of elevated PL and its physiological functions. Knowing the widespread effect and relationship of prolactin in the body will help to avoid misdiagnoses and unnecessary treatments.

FRI674 Association Between Metabolic Syndrome And The Presence Of Enthesophytes On Musculoskeletal Ultrasound Compared To Joint X-ray

Abstract Disclosure: S. Brown: None. J. Hardin: None. S.N. Mahmood: None. Background: Enthesophytes consist of calcium deposition on tendons or ligaments that are proposed to form in response to localized inflammation of the enthesis, either idiopathic or in response to repetitive strain. The exact etiology of these deposits is unknown, but it has been proposed that they form as a result of tendon degeneration or a cell-mediated reactive process, and one working theory postulates that enthesophyte formation could be correlated with metabolic disorders. It is suggested that metabolic syndromes contribute to enthesopathy through tendon degeneration, aging and overuse. While joint X-ray is known to identify enthesophytes, musculoskeletal ultrasound (MSUS) offers dynamic testing due to its non-invasive nature, decreased radiation burden, affordability and versatility. There is limited research that focuses on ultrasound identification of enthesophytes in relation to metabolic syndrome and compared to other imaging modalities. Methods: This pilot study compared the prevalence of metabolic syndrome, (characterized as hypertension, hyperlipidemia, diabetes mellitus, elevated Body Mass Index (BMI)) and enthesophytes identified on imaging between MSUS examinations and joint X-rays. The patients were identified through retrospective data collection taken from General Rheumatology Clinic and Rheumatology MSUS Clinic. 49 joints evaluated for joint pain by X-ray demonstrated enthesophytes and 5 joints evaluated for joint pain by MSUS demonstrated enthesophytes. We aimed to evaluate how many patients with joint pain found to have enthesophytes also had comorbid metabolic syndrome. Results: Of the 49 joints demonstrating enthesophytes on X-ray, this population showed a prevalence of comorbid metabolic syndrome per joint as follows: pelvis - 17/18, knee - 9/10, and ankle - 21/21. The joint X-ray population showed evidence of enthesophytes according to age range per joint as follows: pelvis - <40yo: 0/8, 40-70yo: 15/71, and >70yo: 3/11, knee - <40yo: 0/8, 40-70yo: 6/71, >70yo: 4/11, and ankle - <40yo: 0/8, 40-70yo: 16/71, and >70yo: 5/11. Of the 5 joints demonstrating enthesophytes with MSUS, this population showed a similar prevalence of comorbid metabolic syndrome in isolated studies of the hip/pelvis (n=1), ankle (n=3). Discussion: As a pilot study, we found that X-ray is useful in detecting enthesophytes as a pathologic cause of pain in patients with metabolic syndrome. This highlights the need to investigate further the mechanism that drives this force. Joint X-ray showed a correlation of metabolic syndrome and age with the presence of enthesophytes. In our early MSUS evaluations, detection is achievable as well and demonstrates the high prevalence metabolic syndrome and the presence of enthesophytes, which indicates that there may be a safer, faster, more affordable way to evaluate for this underlying comorbid condition. Presentation: Friday, June 16, 2023

Smoking in French prisons: Factors associated with consumption and cessation

For the past twenty years, researchers have emphasized the importance of producing data on tobacco use among incarcerated people. With a prevalence rate that can reach 97% in some countries, smoking is much more frequent in that population compared to the general population and this constitutes one of the main causes of chronic pathologies and mortality in prisons. In France, more than 80% of inmates use tobacco while the prevalence of smoking is 31.9% in the general population in 2021. In a global context of decreasing smoking rates, tobacco use in prison contributes to the persistence of social inequalities in health. This article presents the results of a sociological study which was part of the diagnostic phase of an interventional study whose overreaching goal was to construct, implement and evaluate an intervention aiming to reduce tobacco use in prisons. The objective of this paper is to identify the factors associated with tobacco use among inmates as well as the factors that hinder or facilitate the cessation process. Qualitative interviews with 21 inmates and 30 professionals were conducted and analysed thematically, using an inductive approach and Nvivo software. In light of our findings, we discuss the importance of behavioral awareness and the community-based approach that are essential to the construction and implementation of a relevant and acceptable public health program.

Evaluation of maxillary sinus volumes and pathologies in children with and without cleft lip and palate using cone beam computed tomography.

The aim of this study is to evaluate the maxillary sinus (MS) volume and pathologies, nasal septum (NS) deviation, and MS septa formation in children with and without cleft lip and palate (CLP); also to investigate the possible causes of MS pathologies. Cone Beam Computed Tomography (CBCT) images of 200 (100 CLP, 100 control) children (5-18 years old) were evaluated from the computer database of Marmara University Faculty of Dentistry. Children with a history of maxillofacial trauma, diseases that affect bone metabolism, orthognathic surgery, extrinsic pathologies of the MS, and accompanying syndromes were excluded. NS deviation, MS septa formation, volume, and pathologies evaluated using Mimics® software. In statistical evaluations; Student t test, paired sample t test, Chi-Square test, Fisher's Exact Chi-Square test, Continuity Correction, Chi-square analysis in one-eyed layout, McNemar test, and logistic regression analysis were used. Total MS volume was smaller in the CLP group (21 232 mm3) than in control children (23 763 mm3) (P:0.026). NS deviation and MS pathology were more frequent in the CLP. In logistic regression analysis, there was no significant relation between the presence of NS deviation and pathology in MS. The presence of CLP increased the risk of MS pathology by 2.6 times. We found that children with CLP have less MS volume and an increased rate of NS deviation and MS pathology compared to the control group. Further radiological and clinical studies are needed to explain the predisposing factors of MS pathology in children with CLP.

Systemic Lupus Erythematosus Initially Presenting as Acute Motor andSensory Axonal Neuropathy Variant ofGuillain-Barre Syndrome ina Healthy Active Duty Female.

Guillain-Barre syndrome (GBS) is an acute monophasic immune-mediated polyradiculoneuropathy characterized by rapidly evolving ascending weakness, mild sensory loss, and hypo- or areflexia, typically progressing to peak symptoms over the course of 4 weeks. The precise mechanism is unclear but is proposed to be an immune-mediated reaction with the generation of antibodies against peripheral nerves triggered by a preceding viral infection. Acute motor and sensory axonal neuropathy (AMSAN) is a rare and severe variant of Guillain-Barre syndrome with limited published literature. Discussion of risk factors for this subtype has not been done in a systematic way. This case report involves a 34-year-old, active duty, West African female, who immigrated to the United States in 2019. She presented with worsening diplopia, bilateral distal upper and lower extremity paresthesias as well as progressively worsening bilateral upper extremity weakness. Her clinical picture was complicated by constitutional symptoms, diffuse lymphadenopathy, no preceding viral illness, and marked clinical deterioration. Ultimately, she was diagnosed with acute motor and sensory axonal neuropathy in the setting of a new diagnosis of systemic lupus erythematosus, a rarely described association emphasizing the importance of a thorough evaluation for underlying causes of acute neurologic pathologies.

PCSK9 Inhibitor Therapy as an Alternative for Statin Intolerance

Scientific relevance. The main cause of cardiovascular pathologies is atherosclerosis, which is secondary to lipid metabolism disorders, in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. Dyslipidaemia treatment with the largest evidence base predominantly includes statins in combination therapy, but their use is limited by into lerance in some patients. Alternatively, the treatment may include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.Aim. The study aimed to analyse the applicability of PCSK9 inhibitors in patients with statin intolerance.Discussion. According to the literature analysis, the most common presentation of statin intolerance is statin-associated muscle symptoms. The pathogenesis of statin-associated adverse events is mainly mediated by HMGCoA reductase inhibition, treatment effects on cellular and subcellular processes and skeletal muscles, and patients’ genetic makeup. The mechanism of action of PCSK9 inhibitors is entirely different and involves binding and inactivation of the PCSK9 protein, which lowers blood LDL cholesterol levels. PCSK9 inhibitors have been associated with some adverse drug reactions, most notably immunogenicity; however, PCSK9 inhibitors effectively reduce LDL levels even if patients develop antibodies.Conclusions. Therefore, PCSK9 inhibitors are a safe, well-tolerated, and effec tive therapeutic strategy for hyperlipidaemia in patients with statin intolerance.

Wilson’s Disease and Autoimmune Hepatitis Coexistence: A Cause of Diagnostic Delay

This case report describes a 27-year-old housewife who presented with a progressive and insidious onset of abdominal distension, loss of appetite, and fatigue which started 3 months before her presentation. The physical assessment showed moderate ascites and small liver size, and no other peripheral evidence of chronic liver disease was observed. A diagnosis of liver cirrhosis and was confirmed by investigations and imaging, where ascites responded well to therapy with diuretics. Investigations for the cause of cirrhosis was established through the diagnosis of autoimmune hepatitis, and she was started on steroids and azathioprine with partial improvement in liver biochemistry. She presented 8 months later with neuropsychiatric symptoms in the form of slurred speech and difficulty walking. Accordingly, Wilson’s disease was suspected to be the cause and further investigations confirmed this. A chelating agent, D penicillamine, was added to her immunosuppressive treatment. Nine months later she showed slow improvement in her neurological symptoms and was referred for assessment for liver transplantation. Wilson’s disease, although rare, should be suspected in patients with decompensated liver disease. The dominance of clinical and epidemiological features of autoimmune hepatitis as a common causative pathology for chronic liver disease in young and middle-aged ladies may hide the presence of other serious different pathologies such as Wilson’s disease.

Обструкция пиелоуретерального сегмента: этиология, патогенез, морфологические особенности.

Introduction. Congenital anomalies of the kidneys and urinary tract cause chronic kidney disease in 7% of cases. The zone of the pyeloureteral segment (PUS) is affected most often. The kidney and ureter originate from two different rudiments, the violation of their connection under the influence of teratogenic or genetically determined causes determines the obstruction of the pelvic-ureteral junction. Materials and methods. The search, analysis and systematization of publications in PubMed databases and eL ibrary.ru using the keywords «hydronephrosis», «etiology», «pathogenesis». As a result, 27 publications were selected, on the basis of which this narrative literature review was prepared. Results and discussion. Among the many causes of pathology of the PUS, there is a violation of the recanalization of this zone, a vicious interaction of the ureteral rudiment and mesanephros, from which the pelvis is differentiated. Genetic studies provide new data for understanding pathogenesis. Pathology of angiotensin receptors, bone morphogenetic protein, TSHZ3, SHH, TBX18, calceneurin genes can lead to PUS stenosis. In the future, genetic discoveries may be the key to preventing the disease. Of all the existing mechanisms for the formation of an obstruction of the PUS, the conflict with the aberrant vessel is proven. Diagnosis, observation, and the timing of surgical treatment are left to the discretion of the specialist. Timely plastic surgery of the PUS zone prevents the formation of nephrosclerosis and chronic kidney disease. Along with the lesion of vascular structures, nephrons in the pathology of PUS, changes occur in the walls of the abdominal system. Retention of urine leads to ulceration, atrophy of the transitional epithelium, hypertrophy of muscle fibers, hyalinosis and overgrowth of connective tissue, which inhibits the contractility of the upper urinary tract and may worsen the result of surgery. Conclusion. Currently, the mechanisms of PUS obstruction formation are not fully disclosed. Information about embryogenesis, the course of pathological processes allows the clinician to optimally approach the treatment of pathology

A new perspective on Alzheimer's disease: microRNAs and circular RNAs.

microRNAs (miRNAs) play a multifaceted role in the pathogenesis of Alzheimer's disease (AD). miRNAs regulate several aspects of the disease, such as Aβ metabolism, tau phosphorylation, neuroinflammation, and synaptic function. The dynamic interaction between miRNAs and their target genes depends upon various factors, including the subcellular localization of miRNAs, the relative abundance of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions. The miRNAs are released into extracellular fluids and subsequently conveyed to specific target cells through various modes of transportation, such as exosomes. In comparison, circular RNAs (circRNAs) are non-coding RNA (ncRNA) characterized by their covalently closed continuous loops. In contrast to linear RNA, RNA molecules are circularized by forming covalent bonds between the 3'and 5'ends. CircRNA regulates gene expression through interaction with miRNAs at either the transcriptional or post-transcriptional level, even though their precise functions and mechanisms of gene regulation remain to be elucidated. The current stage of research on miRNA expression profiles for diagnostic purposes in complex disorders such as Alzheimer's disease is still in its early phase, primarily due to the intricate nature of the underlying pathological causes, which encompass a diverse range of pathways and targets. Hence, this review comprehensively addressed the alteration of miRNA expression across diverse sources such as peripheral blood, exosome, cerebrospinal fluid, and brain in AD patients. This review also addresses the nascent involvement of circRNAs in the pathogenesis of AD and their prospective utility as biomarkers and therapeutic targets for these conditions in future research.

The Effect of Helicobacter pylori Density on Serum Vitamin B12 and Folate Levels in Patients With Non-atrophic Gastritis.

Introduction Chronic infection with Helicobacter pylori (Hp) is an essential cause of gastrointestinal pathologies in adults. Despite being a microorganism proven to play a role in vitamin B12 deficiency by causing gastric atrophy, Hp's role in patients with non-atrophic gastritis has not been fully explained. Our study investigated whether the presence and density of Hp is related to vitamin B12 and folate deficiencies in patients with non-atrophic gastritis. Methods This retrospective cohort study analyzed the following parameters, vitamin B12, folate, and mean red blood cell volume (MCV) in the hemogram; these were measured simultaneously in patients diagnosed with non-atrophic gastritiswho had undergone gastroscopy to investigate Hp levels. Patients with conditionsthat could have caused vitamin B12 and folate deficiencieswere excluded from the study. The study included 244 patientswho met the criteria. The Sydney classification was used for histopathologic grading and staging of gastric biopsies of patients with gastritis. Results There was no relationship between the presence and density of Hp with vitamin B12 levels. However, folate levels were significantly lower in Hp-positive patients than in Hp-negative patients (p = 0.017). Folate levels were substantially lower in patients with chronic pan-mucosal gastritis than in patients with chronic inactive gastritis (p = 0.034). Statistically, a significant difference was found between folate levels on the basis of neutrophil activity and inflammation score (p = 0.011 and p <0.001, respectively). Conclusions Although there was no statistically significant relationship between the presence and density of Hp and vitamin B12, our study found an association between folate levels and Hp density. This may be associated with the time for the depletion of vitamin B12 and folate stores and the relatively early stage of gastritis. In cases with vitamin B12 and folate deficiencies, appropriate studies should be performed for specific epidemiological reasons in respective fields.

Elucidation of the Role of Lipids in Late Endosomes on the Aggregation of Insulin.

Abrupt aggregation of misfolded proteins is the underlying molecular cause of numerous pathologies including diabetes type 2 and injection amyloidosis. Although the exact cause of this process is unclear, a growing body of evidence suggests that protein aggregation is linked to a high protein concentration and the presence of lipid membranes. Endosomes are cell organelles that often possess high concentrations of proteins due to their uptake from the extracellular space. However, the role of endosomes in amyloid pathologies remains unclear. In this study, we used a set of biophysical methods to determine the role of bis(monoacylglycero)phosphate (BMP), the major lipid constituent of late endosomes on the aggregation properties of insulin. We found that both saturated and unsaturated BMP accelerated protein aggregation. However, very little if any changes in the secondary structure of insulin fibrils grown in the presence of BMP were observed. Therefore, no changes in the toxicity of these aggregates compared to the fibrils formed in the lipid-free environment were observed. We also found that the toxicity of insulin oligomers formed in the presence of a 77:23 mol/mol ratio of BMP/PC, which represents the lipid composition of late endosomes, was slightly higher than the toxicity of insulin oligomers formed in the lipid-free environment. However, the toxicity of mature insulin fibrils formed in the presence of BMP/PC mixture was found to be lower or similar to the toxicity of insulin fibrils formed in the lipid-free environment. These results suggest that late endosomes are unlikely to be the source of highly toxic protein aggregates if amyloid proteins aggregate in them.

Signaling Mechanisms of Stem Cell Therapy for Intervertebral Disc Degeneration.

Low back pain is the leading cause of disability worldwide. Intervertebral disc degeneration (IDD) is the primary clinical risk factor for low back pain and the pathological cause of disc herniation, spinal stenosis, and spinal deformity. A possible approach to improve the clinical practice of IDD-related diseases is to incorporate biomarkers in diagnosis, therapeutic intervention, and prognosis prediction. IDD pathology is still unclear. Regarding molecular mechanisms, cellular signaling pathways constitute a complex network of signaling pathways that coordinate cell survival, proliferation, differentiation, and metabolism. Recently, stem cells have shown great potential in clinical applications for IDD. In this review, the roles of multiple signaling pathways and related stem cell treatment in IDD are summarized and described. This review seeks to investigate the mechanisms and potential therapeutic effects of stem cells in IDD and identify new therapeutic treatments for IDD-related disorders.

Overweight and obesity in children and adolescents with endocrine disorders.

Obesity has become a serious medical condition where many factors can contribute to excess weight gain. The most common type of childhood obesity is simple obesity, which is due to gene-obesogenic environment interaction. Only a minority are due to pathological causes. Secondary causes of obesity, while less common, include these: genetic syndromes, drug-related obesity, as well as endocrine disorders (hypothyroidism, Cushing's syndrome, growth hormone deficiency, hypogonadism, pseudohypoparathyroidism type Ia, insulinoma, hypothalamic obesity and polycystic ovary syndrome). Given that some conditions may be treatable, physicians must be aware of obesity due to endocrinopathies and distinguish them from simple obesity, and treat them properly. Although rare among children, early detection of the endocrine cause of obesity leads to reduced morbidity and, in some cases, reduced mortality in these individuals. The aim of this review is to summarize the current findings on obesity-related endocrinopathies in children (illustrated by clinical examples), highlighting aspects of pathogenetic mechanisms, genetics, the clinical diagnosis, growth, body mass index and possible therapeutic approaches. Early detection and correction of endocrine obesity is of paramount importance for obese children who could benefit from timely diagnosis and an improved management of obesity as many disturbances related to obesity can be reversed at the early stage, if weight loss is achieved.

RNA-RNA competitive interactions: a molecular civil war ruling cell physiology and diseases

The idea that proteins are the main determining factors in the functioning of cells and organisms, and their dysfunctions are the first cause of pathologies, has been predominant in biology and biomedicine until recently. This protein-centered view was too simplistic and failed to explain the physiological and pathological complexity of the cell. About 80% of the human genome is dynamically and pervasively transcribed, mostly as non-protein-coding RNAs (ncRNAs), which competitively interact with each other and with coding RNAs generating a complex RNA network regulating RNA processing, stability, and translation and, accordingly, fine-tuning the gene expression of the cells. Qualitative and quantitative dysregulations of RNA-RNA interaction networks are strongly involved in the onset and progression of many pathologies, including cancers and degenerative diseases. This review will summarize the RNA species involved in the competitive endogenous RNA network, their mechanisms of action, and involvement in pathological phenotypes. Moreover, it will give an overview of the most advanced experimental and computational methods to dissect and rebuild RNA networks.

Design, synthesis, metal chelation potential and biological evaluation of pyridine chalcones as multi-target-directed ligands against Alzheimer's disease

Two sets of 1-phenyl-3-(pyridinyl) prop‑2-en-1-one analogs, 7a-d and 8a-d were designed by the incorporation of pyridine and chalcone privileged scaffolds with the objective of developing multifunctional molecules for Alzheimer's disease (AD). The structure-based approach was used to evaluate the binding potential of the designed pyridine chalcone series in acetylcholinesterase, prior to synthesis. The hybrid molecules designed from the amalgamation of two privileged scaffolds demonstrated excellent potential for simultaneous inhibition of acetylcholinesterase (AChE) and amyloid beta (Aβ1–42) aggregation in addition to promising radical scavenging activities, metal-chelating properties and inhibitory potential for attenuation of advanced glycation products. The compounds showed mixed inhibition of AChE in enzyme kinetic studies with the most potent compound 8c showing an IC50 value of 0.1 ± 0.01 μM. Compounds of both series exhibited good potential of inhibiting Aβ1–42 aggregation, with compound 8c exhibiting an inhibitory potential of 83.58% after 48 h. The molecules demonstrated moderate to good radical scavenging activity in both DPPH and H2O2 radical scavenging assays, moderate inclination for metal chelation and significant potential to inhibit formation of advanced glycation products. The mechanistic basis of these actions has been probed by experimental and computational techniques that leads to greater understanding of the underlying structural basis for the activities of these promising molecules for holistic treatment of AD. Taken together, this work reveals the multifaceted pleiotropy of the designed molecules, especially the 4-pyridine analogs, with the compounds 8b and 8c demonstrating excellent potential as multi-target directed ligands to address most of the causative pathologies of AD.