Richard Peto’s Paradox, first described in 1975 from an epidemiological perspective, established an inverse correlation between the probability of developing cancer in multicellular organisms and the number of cells. Larger animals exhibit fewer tumors compared to smaller ones, though exceptions exist. Mice are more susceptible to cancer than humans, while elephants and whales demonstrate significantly lower cancer prevalence rates than humans. How nature and evolution have addressed the issue of cancer in the animal kingdom remains largely unexplored. In the field of medicine, much attention has been devoted to cancer predisposing genes, as they offer avenues for intervention, including blocking, downregulating, early diagnosis, and targeted treatment. Predisposing genes also tend to manifest clinically earlier and more aggressively, making them easier to identify. However, despite significant strides in modern medicine, the role of protective genes lags behind. Identifying genes with a mild predisposing effect poses a significant challenge. Consequently, comprehending the protective function conferred by genes becomes even more elusive, and their very existence is subject to questioning. While the role of variable expressivity and penetrance defects of the same variant in a family is well-documented for many hereditary cancer syndromes, attempts to delineate the function of protective/modifier alleles have been restricted to a few instances. In this review, we endeavor to elucidate the role of protective genes observed in the animal kingdom and within certain genetic syndromes that appear to act as cancer-resistant/repressor alleles. The ultimate goal is to discern why individuals, like Winston Churchill, managed to live up to 91 years of age, despite engaging in minimal physical activity, consuming large quantities of alcohol daily, and not abstaining from smoking.

Treacher Collins syndrome (TCS) is a rare congenital disorder characterized by craniofacial abnormalities due to underdeveloped facial bones. In addition to physical deformities, TCS also presents with several neurological disorders resulting from facial defects and brain malformations. This paper reviews the neurological manifestations of TCS with a focus on facial nerve paralysis, neurodevelopmental delay, intellectual disability, and autism spectrum disorder. Facial nerve hypoplasia leads to an inability to control facial muscles and expressions. Neurodevelopmental delays in motor function and language acquisition are commonly reported in infants with TCS due to hearing loss, facial impairments, poor nutrition, infections, and structural brain changes. Intellectual disability with below average IQ is also more prevalent in TCS, affecting about one third of patients. Brain imaging reveals abnormalities like white matter hypoplasia, cortical atrophy, and reduced grey matter volume which likely contribute to cognitive deficits. Additionally, the rate of autism spectrum disorder is significantly higher in TCS compared to the general population. The reasons are unclear but may involve hearing loss, facial dysmorphisms, and socio-emotional processing centers in the brain. Management is multidisciplinary, focusing on early interventions like speech, physical, feeding, and behavioral therapy to maximize developmental and functional outcomes. Further research on the neurological pathophysiology of TCS is needed to better elucidate the mechanisms linking craniofacial defects with adverse neurodevelopmental consequences.

Objectives: Multicentric Osteolysis, Nodulosis, and Arthropathy (MONA) syndrome is a rare genetic skeletal dysplasia. Its diagnosis can be deceptively similar to childhood-onset genetic skeletal dysplasias and juvenile idiopathic arthritis. We aimed to report the syndrome’s clinical and radiologic features with emphasis on skeletal manifestations. And establish relevant phenotype-genotype correlations. Methods: We evaluated two boys, 4-and-7-years-old with MONA syndrome. Both patients had consanguineous parents. We verified the diagnosis by correlating the outcomes of clinical, radiologic and molecular analysis. We specifically evaluated the craniofacial morphology and clinical and radiographic skeletal abnormalities. We contextualized the resultant phenotype-genotype correlations to publications on MONA and its differential diagnosis. Results: Skeletal manifestations were the presenting symptoms and mostly restricted to hands and feet in terms of fixed extension deformity of the metacarpophalangeal and flexion deformity of the interphalangeal joints with extension deformity of big toes. There were arthritic symptoms in the older patient especially of the wrists and minute pathologic fractures. The skeletal radiographs showed osteopenia/dysplastic changes of hands and feet. Both patients had variants in the matrix metalloproteinase2 gene which conformed to phenotype of previously reported literature in one patient while the other had a novel variant which conformed to MONA phenotype. Craniofacial abnormalities were present. However, minimal extra-skeletal manifestations. Conclusion: Overall, there is an emerging distinctive skeletal pattern of involvement in terms of both clinical and radiographic features. This includes age of onset and location of presenting skeletal manifestations, chronological order of joint affection, longitudinal disease progression, specifics of skeletal radiographic pathology and craniofacial features. Nevertheless, physicians are cautioned against differential diagnosis of similar genetic skeletal dysplasias and juvenile idiopathic arthritis.

21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH), is associated with pathogenic variants in CYP21A2 gene. The clinical form of the disease ranges from classic or severe to non-classic (NC) or mild late onset. The CYP21A2 gene is located on the long arm of chromosome 6, within the RCCX region, one of the most complex loci in the human genome. The 3’untranslated sequence of CYP21A2 exon 10 overlap the last exon of TNXB gene (these genes lie on the opposite strands of DNA and have the opposite transcriptional direction) that encodes an extracellular matrix glycoprotein tenascin-X (TNX). A recombination event between TNXB and its pseudogene TNXA causes a 30-kb deletion producing a chimeric TNXA/TNXB gene (CAH-X chimera) where both CYP21A2 and TNXB genes are impaired. This genetic condition characterizes a subset of patients with 21OHD who display the hypermobility phenotype of Ehlers Danlos Syndrome (hEDS) (CAH-X Syndrome). The aim of this study was to assess the prevalence of CAH-X syndrome in an Italian cohort of patients with 21OHD. At this purpose, 196 probands were recruited. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were used to identify the CAH-X genotype. Twenty-one individuals showed the heterozygous continuous deletion involving the CYP21A2 and part of the TNXB gene. EDS-related clinical manifestations were identified in most patients carrying the CAH-X chimera. A CAH-X prevalence of 10.7% was estimated in our population.

Miller Fisher Syndrome (MFS) is a rare variant of Guillain-Barré Syndrome (GBS). It is largely a clinical diagnosis based on the classical features of ataxia, areflexia, and opthalmoplegia. Its clinical evolution is most often favorable. However, other neurological signs and symptoms may also be present. Supportive laboratory studies (positivity of antibodies, CSF albumin-cytological dissociation and nerve conduction studies) are useful especially in uncommon presentations. We report a case of a 74-year-old patient who exhibited dysphonia and difficulty to swallowing previously to the classic triad of ataxia, areflexia, and opthalmoplegia, characteristic of MFS. CSF analysis demonstrates an albumin-cytological dissociation but anti-GQ1b antibody were negative. The patient has spontaneously and completely recovered after several weeks.

Gardasil 4, a human papilloma virus vaccine, has been shown to protect against various cancers, including cervical cancer. Common side effects include injection site pain, fever, headaches, and muscle aches. In some individuals, the severe side effect of postural orthostatic tachycardia syndrome (POTS) has been reported. POTS is characterized by the abnormal response of lightheadedness, blurry vision, and dizziness while transitioning to an upright posture. POTS predominately affects women, with more than eighty-five (85) percent of POTS patients being female. POTS on average, takes five years and eleven months to receive the diagnosis. Additionally, ​A strong association between POTS and Ehlers Danlos Syndrome Type III (EDS) exists. Eighty (80) percent of patients with EDS have POTS. This severe side effect dictates that providers need to be aware of this strong association of HPV vaccinations and POTS. ​In this report we will present a case of a young women with a past medical history significant for EDS type III who was diagnosed with POTS after receiving Gardasil 4 vaccination. This case demonstrates the need for physicians to be aware of the association of POTS with EDS type III and HPV vaccination. Physician awareness of the associations, signs and symptoms of POTS and earlier testing at the first presentation of signs and symptoms will limit the negative impact on patient’s quality of life.

The Kounis syndrome (KS) is an acute coronary syndrome triggered by allergic or hypersensitiv-ity reactions. Incidence rates vary, with studies reporting 19.4 per 100.000 among all admissions and 3.4% among allergy patients. This review explores the expanding understanding of KS, en-compassing various manifestations, and focusing on both clinical data and forensic findings useful in performing the diagnosis. The pathophysiology of this syndrome involves a complex in-terplay between allergic reactions and the cardiovascular system. Mast cell activation, histamine release, leukotrienes, cytokines, and platelet activation can contribute to the coronary events. A classification system with three types (Allergic Angina, Allergic Myocardial Infarction, Allergic Stent Thrombosis) aids in categorizing presentations. The diagnosis of KS relies on clinical presentation, laboratory findings and imaging. Post mortem assessment of KS is based on the in-tegration of circumstantial data, autopsy and histological findings. Biochemical and immuno-histochemical analyses also contribute to post-mortem diagnosis. In conclusion, a combined, multidisciplinary approach, should be gained to ease diagnostic pro-cess which is crucial for forensic practitioners in confirming KS occurrence.

Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.

Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under neuronal control. However, this vision has recently evolved into a more integrative conception, in which astroglia, rather than just acting as metabolic supply and structural anchoring for neurons, interact at distinct levels modulating neuronal communication and possibly also cognitive processes. Recently, genetic tools have made it possible to specifically manipulate astrocyte activity unraveling novel functions that involve astrocytes in memory function in the healthy brain. However, astrocyte manipulation has also underscored potential mechanisms by which dysfunctional astrocytes could contribute to memory deficits in several neurodevelopmental disorders revealing new pathogenic mechanisms in intellectual disability. Here, we review the current knowledge about astrocyte dysfunction that might contribute to learning and memory impairment in neurodevelopmental disorders, with special focus on Fragile X syndrome and Down syndrome.

Balínt Syndrome is an acquired disorder manifesting in the inability to recognize several objects at once (simultagnosia), inaccurate visually guided limb movements despite intact motor function (optic ataxia) and the inability to make accurate voluntary saccades to visual targets despite demonstrating unrestricted range of eye movements (ocular motor apraxia). Here we report the first case of a patient presenting with Balínt Syndrome caused by a platelet-derived growth factor receptor A mutation (PDGFRA)-induced Hypereosinophilic Syndrome (HES).

Down Syndrome (DS) is a chromosomal disorder due to the presence of an additional chromosome 21 that causes intellectual deficit and physical anomalies and predisposes patients to develop infections throughout their lives. Pneumonias are more serious in patients with DS, requiring hospitalization, and represent an important cause of mortality in this population. Cytomegalovirus (CMV) causes widespread and serious infections in immunocompromised individuals, affecting the respiratory tract and, causing interstitial pneumonia, is associated with a high mortality rate. However, CMV-induced pneumonia is not reported in DS patients. The prevalence and severity of CMV respiratory infections in subjects with DS is unknown. This case describes a 50-year-old female patient suffering from DS who developed extensive bilateral pneumonia with severe respiratory failure which required hospitalization in intensive care, intubation and mechanical ventilation after approximately 10 days of empiric antibiotic and anitimycotic therapy for fever, cough and dyspnea. The patient was diagnosed with CMV pneumonia and recovered after treatment with Ganciclovir. To the best of our knowledge, this is the first reported case of CMV pneumonia in a patient with DS. This case aims to highlight that CMV pneumonia in individuals with DS can be a life-threatening condition. It also clarifies the importance of early diagnosis of infections from opportunistic pathogens such as CMV to ensure timely and efficient treatment.

Classifications of AAFD/PCFD have evolved with an increased understanding of the pathology involved. A review of classification systems helps identify deficiencies and respective contributions to the evolution in understanding the classification of AAFD. Using multiple electronic database searches (Medline, PubMed) and Google search, original papers classifying AAFD were identified. Nine original articles were identified that met the inclusion criteria. Johnson's original classification and multiple variants provided a significant leap in understanding and communicating the pathology but remained tibialis posterior tendon focussed. Drawbacks of these classifications include the implication of causality, linearity of progression through stages, an over-simplification of stage 2 deformity and a failure to understand multiple tendons react, not just tibialis posterior. Later classifications, such as the PCFD classification, are deformity-centric. Early instability in non-cavus feet and all stages of cavus feet can present pain and instability with minor/no deformity. These may not be captured in deformity-based classifications biased to planus feet.' The authors developed the 'Triple Classification' (TC) understanding that primary pathology is a progressive ligament failure/instability that presents as tendon reactivity, deformity, and painful impingement. There is a variable manifestation dependent on starting foot morphology. This review has identified deficiencies within classification systems used in AAFD/PCFD and, as a result, was used to help develop a more comprehensive 'Triple classification'. Advantages of the TC include representing foot types with no deformity, defining complex secondary instabilities, delinking of foot types, tendon reactivity/ligament instability and deformity to represent these independently in a more comprehensive classification system.

Brugada Syndrome is a cardiac channelopathy closely related to lethal arrhythmias and sudden death in people without underlying structural pathology. The diagnosis is usually assumed with electrocardiographic patterns strictly limited to the right precordial leads, V1 or V2; but this is not so at all. In our article, we describe the clinical case of a patient with a novel and different electrocardiographic presentation: the typical diagnostic pattern was presented in a lower lead of the electrocardiogram, and next to it, another pattern was presented in a contiguous lead. In addition, we propose the possible association of a structural pathology (non-compaction cardiomyopathy) with Brugada Syndrome, since both share a possible common genetic origin in the SCN5A gene.

Rett syndrome (RTT) is a rare disease and one of the most abundant causes for intellectual disa-bilities in females. Single mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2), are responsible for the disease. MeCP2 regulates gene expression as a transcriptional regulator as well as through epigenetic imprinting and chromatin condensation. Consequently, numerous biological pathways on multiple levels are influenced however, the exact molecular pathways from genotype to phenotype are currently not fully elucidated. Treatment of RTT is purely symptomatic where no curative options for RTT have yet to reach the clinic. The paucity of this is mainly due to an incomplete understanding of the underlying pathophysiology of the dis-order with no clinically useful common disease drivers, biomarkers or therapeutic targets being identified. With the premise of identifying universal and robust disease drivers and therapeutic targets, here we interrogated a range of RTT transcriptomic studies spanning different species, models and MECP2 mutations. A meta-analysis using RNA sequencing data from brains of RTT mouse models human post-mortem brain tissue and patient-derived induced pluripotent stem cells (iPSC) neurons was performed using Weighted Gene Correlation Network Analysis (WGC-NA). This study identified a module of genes common to all datasets with the following ten hub genes driving the expression ATRX, ADCY7, ADCY9, SOD1, CACNA1A, PLCG1, CCT5, RPS9, BDNF and MECP2. Here we discuss the potential benefits of these genes as therapeutic targets.

A Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology under growing interest now in view of the increasingly recognized post-COVID syndrome as a new entity with similar clinical presentation. We performed the first cross-sectional study of ME/CFS in community population in Russia and then described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders. Of the cohort of 76 individuals who suggested themselves suffering from ME/CFS 56 subsequently were confirmed as having CFS/ME according to ≥1 of the 4 most commonly used case definition. Of the cohort of 14 individuals with post-COVID-19 syndrome 14 met diagnostic criteria for ME/CFS. The prevalence of clinically expressed and subclinical anxiety and depression in ME / CFS and post-COVID ME/CFS did not differ significantly from that in healthy individuals. Severity of anxiety / depressive symptoms did not correlate with the severity of fatigue neigther in ME / CFS nor in post-COVID ME/CFS, but the positive correlation was found between the severity of fatigue and 20 other symptoms of ME / CFS related to the domains of “post-exertional exhaustion”, “immune dysfunction”, “sleep disturbances”, "dysfunction of the autonomic nervous system", "neurological sensory / motor disorders" and "pain syndromes". Immunological abnormalities were identified in 12/12 patients with ME / CFS according to the results of laboratory testing. The prevalence of postural orthostatic tachycardia assessed by the active standing test was 37.5% in ME / CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02) There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group. Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls. The identified pattern corresponded to the hyperemic form of microcirculation disorders, usually observed in acute inflammatory processes or in deficiency of systemic vasoconstriction influences.

Meier–Gorlin syndrome (MGS) is a rare genetic developmental disorder that causes primordial proportional dwarfism, microtia, absent or hypoplastic patellae and other skeletal anomalies. Overlapping skeletal symptoms make MGS difficult to diagnose clinically. We describe a 3-year-old boy with short stature, recurrent respiratory infections, short-rib dysplasia, tower head and facial dysmorphisms who was admitted to the Tomsk Genetic Clinic to verify a clinical diagnosis of Jeune syndrome. Clinical Exome sequencing revealed two variants (compound heterozygosity) in the ORC6 gene: c.2T>C(p.Met1Thr) and c.449+5G>A. In silico analysis showed the pathogenicity of these two mutations and predicted a decrease in donor splicing site strength for c.449+5G>A. An in vitro minigene assay demonstrated that variant c.449+5G>A causes a complete skipping of exon 4 in ORC6 gene. The parents asked for urgent prenatal testing for MGS for the next pregnancy, but it ended in a miscarriage. Thus, this case report may help to prevent MGS misdiagnosis in the future. We also performed in silico and functional analyses of ORC6 mutations and developed a restriction fragment length polymorphism and haplotype-based short-tandem-repeat assay for prenatal genetic testing for MGS. These findings should elucidate MGS aetiology and improve the quality of genetic counselling for affected families.

Hantavirus cardiopulmonary syndrome (HCPS) is characterized by capillary leak, pulmonary edema (PE) and shock that leads to death in up to 40% of patients. Treatment is supportive, including mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO). Hemodynamic monitoring is critical to titrate therapy and to decide ECMO support. Transpulmonary thermodilution (TPTD) provides hemodynamic and PE data that has not been systematically used to understand HCPS pathophysiology. We identified 11 HCPS patients monitored with TPTD; 5 on MV, 3 on ECMO. We analyzed 133 measurements to describe the hemodynamic pattern and its association to PE. The main findings were reduced stroke volume, global ejection fraction (GEF) and preload parameters associated to increased extravascular lung water and pulmonary vascular permeability compatible with hypovolemia, myocardial dysfunction and increased permeability PE. Lung water correlated positively with heart rate (HR, r=0.20) and negatively with mean arterial pressure (r=-0.27) and GEF (r=-0.36), suggesting that PE is linked to hemodynamic impairment. Pulmonary vascular permeability correlated positively with HR (r=0.31) and negatively with cardiac index (r=-0.49), end-diastolic volume (r=-0.48) and GEF (r=-0.40), suggesting that capillary leak contributes to hypovolemia and systolic dysfunction. In conclusion, TPTD data suggests that in HCPS patients, increased permeability leads to PE, hypovolemia and circulatory impairment.

Background: Auriculotherapy is a widely used approach for alleviating discomfort in patients experiencing pain, itchiness, sleep disturbances, and heightened anxiety. This method is also applicable to patients dealing with significant burn scars, who often encounter similar symptoms. Employed as an adjuvant therapy, auriculotherapy demonstrates potential in mitigating these clinical manifestations among individuals with major burn scars. These symptoms are known to be influenced by the autonomic nervous system. Objectives: Despite the absence of current data elucidating the impact of auriculotherapy on the autonomic nervous system, we embarked on an analysis of our heart rate variability (HRV) data to evaluate autonomic system functionality before and after the administration of auriculotherapy. Methods: Paired-samples t-tests and linear regression analysis of HRV variables and correlations with TBSA before and after auriculotherapy of a cohort of 31 survivors from 2016 Formosa Color Dust Explosion was carried out. Results: Significant change of specific HRV variables were found before and after auriculotherapy, and significantly negative correlations was revealed between TBSA and pre-SD prior to auriculotherapy. Conclusion: Our study showed that auriculotherapy may, at least in part, restore the equilibrium of autonomic nervous system and improve HRV parameters.

(1) Background: Metabolic syndrome is a strong predictor of cardiovascular disease thus the objective of the study was to verify the prevalence of metabolic syndrome in farmers, as well as to verify the association with sociodemographic, work and lifestyle factors. (2) Methods: Cross-sectional, observational study, carried out with 790 individuals. For the diagnosis of metabolic syndrome, the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) and International Diabetes Federation (IDF) criteria were used. Pearson's chi-square test and binary logistic regression were used to verify factors associated with metabolic syndrome (3) Results: The prevalence of MS according to the IDF criteria was 16.3% overall, with 9.7% of women (95% CI: 6.66–16.16) and 6.6% of men (95% CI: 5.17–11.97). According to the NCEP/ATP III criterion, it was 12.3% overall, with 7.5% corresponding to women (95% CI: 6.62 – 13.13) and 4.8% to men (95% CI: 3.5 – 8.70). With regard to the conditions that make up metabolic syndrome, it was found that high density lipoprotein, high blood pressure and high waist circumference were the most prevalent. (4) Conclusions: The prevalence of metabolic syndrome is considerable in the population when compared to other regions, both rural and urban, in Brazil.

Osmotic demyelination syndrome (ODS) is an acute demyelinating disorder characterized by the loss of myelin in the center of the basis pons which is defined as central pontine myelinolysis (CPM) and demyelination process in locations outside the pons which is defined as extrapontine myelinolysis (EPM). ODS including CPM and EPM is mainly caused by the rapid correction of hyponatremia. However, there are several reports of ODS in medical condition such as malnutrition, alcoholism, liver transplantation, malignancy, sepsis, electrolyte imbalance including hypernatremia, hypokalemia, hypophosphatemia, and chronic illness. Rarely, ODS was reported in patients with hyperammonemia or hyperbilirubinemia without sodium fluctuations. The symptoms usually correspond to the lesion site and EPM precedes CPM. Because ODS may be irreversible, prevention is more important. Here, we report a case of ODS secondary to the hyperammonemia and hyperbilirubinemia, as it can have unfavorable prognosis.

It is important to be familiar with the presentation of Turner syndrome and to understand the common causes of death associated with the disease. Using the autopsy case as an example, this case report will outline the classic presentation of Turner syndrome, go over its physiology, epidemiology, pathogenesis and explain the cause of death in this particular case while also highlighting other common causes of death/risk factors within Turner syndrome. Differential diagnosis and mimicking disease processes will also be discussed. This report will also highlight the molecular tests used for the diagnosis of Turner syndrome, discuss developments using in situ hybridization, and discuss why this method is best for the determination of Turner syndrome over conventional karyotyping.

Introduction: VULTO-VAN SILFHOUT-DE VRIES SYNDROME (VSVS;OMIM#615828) is an extremely rare hereditary disease associated with impaired intellectual development and speech, delayed psychomotor development and behavioral anomalies, including autistic behavioral traits and poor eye contact. To date, 27 patients with VSVS have been reported in the world literature. Materials and Methods: We describe a 23y.o. male patient with autism spectrum disorder (ASD) who was admitted to the gastroenterological hospital with signs of pseudomembranous colitis. ASD was first noted in the patient at the age of 2.5y.o. Later he developed epileptic seizers and prominent growth retardation. Prior to the hospitalization he was excluded chromosomal aberrations, Martin-Bell syndrome, aminoacidopathies/aminoacidurias associated with ASD. Whole genome sequencing was prescribed to the patient at 23y.o. Results: The patient appeared to be a heterozygous carrier of “de novo” variant c.662C>T (p.S221L) in ex 4 of the DEAF1 gene. c.662C> T had not been previously described in genomic databases. According to the ACMG criteria this missense variant was considered to be pathogenic. VSVS was diagnosed in the patient. Conclusions: The phenotype of the patient is very similar to the data presented in the world literature. However, growth retardation and cachexia, not previously described in the articles, are of interest.

Gilbert Syndrome, is a benign condition characterized by persistent indirect hyperbilirubinemia due to reduced UDP-glucuronyltransferase enzyme activity. Its coexistence with other clinical disorders has important clinical and pharmacological implications. GS is known to coexist with many hemolytic conditions and may lead to diagnostic difficulty and also increased incidence of gallstones. UGT1A1 gene has been shown to be involved in the conjugation of various physiologically important endogenous and exogenous compounds, so individuals with Gilbert mutation (the variant allele UGT1A1*28) have an increased risk of toxicity of various drugs and endogenous compounds like irinotecan, steroid hormones, implicated in various human carcinoma like colorectal and breast carcinoma. Deferiprone (DFP) is an orally available chelator used in the management of iron overload in patients with Transfusion Dependent Thalassemia (TDT). In this study, fifteen out of 275 patients with TDT, had a deferiprone-induced joint deformity. Among these fifteen patients with joint deformity, eleven patients (four patients were homozygous for TA 7 repeats and seven were heterozygous for TA7 repeats) had associated gilbert mutation. Therefore, we hypothesize that patients of TDT who had underlying Gilbert mutation might have decreased enzymatic activity of UGTIA6, which metabolizes the DFP, leading to more prominent adverse effects related to DFP.

Inflammation is known to be risk factors for metabolic diseases. The purpose of this study was to develop a Food-based Index of Dietary Inflammatory Potential (FBDI) and conduct its validation assessment. This study analyzed raw data from Korean Genome and Epidemiology Study 2012–2014 data of 17,771 people. We carried out the correlation analysis between 51 food groups and hs-CRP. The FBDI was developed by multiple regression method with hs-CRP and selected 17 food group. For the validation of FBDI, 7795 people in the 6th Korea National Health and Nutrition Examination Survey (KNHAES) was used. Binary logistic regression analysis was used for risk analysis of metabolic syndrome and FBDI. The FBDI model included that 7 were composed of anti-inflammatory food groups and 3 of inflammatory food groups. The FBDI was calculated by multiplying the intake of food group by β coefficients. KNHAES were included in the validation of FBDI. The risk of metabolic syndrome was found to be 2.152 times higher in the group with the highest FBDI than in the group with the lowest one (95% Cl:1.458–3.178, p for trend = 0.000). This study developed FBDI reflecting food intake for Koreans, which showed a significant relationship with the risk of metabolic syndrome.

Proposed fundamental laws of biology and a model of health and disease underscore the importance of the lymphatic system. The lymphatics are responsible for two of the laws of biology and the fulcrum of health and disease balancing proliferation with regeneration through the immune system. It is responsible for protection from the environment and repair of senile and damaged tissue. Life is constantly bombarded by forces that increase entropy. Lymphatics provide negative entropy to maintain health. Lymphatics help maintain cellular homeostasis removing products of metabolism. Using these principles, the role of lymphatics is investigated in salt sensitivity hypertension, cardiorenal system, the new pillar of heart failure and kidney disease - Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors, and brain diseases. The realization of organ lymphatics in maintenance of health and disease opens the avenue to new therapeutics. This is the unrealized potential of lymphatic study.

Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signalling pathways and transcription programs. Forkhead Box G1 (FOXG1) is one of the master regulators that plays fundamental roles in forebrain development, from the timing of neurogenesis to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as increased yield of information from high throughput omics opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems to highlight prospects of research and possible clinical interventions.

Furthermore, the nasal congestion typical of rhinitis can contribute to upper airway obstruction and sleep-disordered breathing. A vicious circle is created between asthma and sleep-disordered breathing: uncontrolled asthma and sleep-disordered breathing can worsen each other. In children with genetic obesity, despite alterations in the immune system, fewer allergies are found compared to the general population. The causes of this reduced allergenicity are unclear but probably involve genetic, immunological, and environmental factors. Further studies are needed to understand the mechanisms. The study emphasizes the importance of jointly evaluating and managing allergies, obesity, and sleep-disordered breathing in children, considering their close interconnection.

(1) Background: Sudden Infant Death Syndrome (SIDS) represents unexplained and sudden deaths during the sleep of infants under one year of age, despite thorough investigation. Screening for prolonged QTc or Long QT Syndrome (LQTS) should be conducted on all newborns to reduce the incidence of SIDS. Neonatal electrocardiogram (ECG) could identify congenital heart defects (CHD) early, especially those not detected at birth. Infants with prolonged QT intervals typically undergo genetic analysis for Long QT Syndrome; (2) Methods: The study involved infants aged 20-40 days, born clinically healthy, with initial ECG screening. Infants with prenatal diagnoses or signs/symptoms of CHD identified immediately after birth, as well as those who underwent ECG or echocardiogram for other clinical or historical indications, were excluded from the study. The data were analyzed using SPSS version 22.0; (3) Results: Of the 42,200 infants involved, 2,245 were enrolled, with 39.9% being males. Subsequently, 164 children (37.8% males) with prolonged QT intervals underwent further diagnostic investigations. Genetic mutations were identified in 11 out of 18 tested children. The most common mutations were LQT1 (54.5%), LQT2 (36.4%), and LQT3 (1 patient). Medications used included propranolol (39.8%), nadolol (22.2%), inderal (11.1%), metoprolol (11.1%), and no treatment (16.7%). The most common abnormalities were focal right bundle branch block (54.5%), left axis deviation (9.2%), and nonspecific ventricular repolarization abnormalities (7.1%). Multiple anomalies were found in 0.47% of children with focal right bundle branch block. Structural abnormalities were associated with specific features in 267 patients (11.9%), primarily isolated patent foramen ovale (PFO) at 61.4%; (4) Conclusions: The screening has proven effective in early diagnosing Long QT Syndrome and other cardiac rhythm anomalies, with additional benefits in detecting mutations and/or QTc prolongations in family members. Identifying other ECG abnormalities and congenital heart malformations further enhances the benefits of the screening.

(1) Background: The stylohyoid syndrome, known as classical Eagle Syndrome (cES), is characterized by calcificatication of the stylohyoid chain with numerous nonspecific symptoms, mainly pain. This study introduces Minimally Invasive Cervical Styloidectomy (MICS). (2) Methods: MICS was performed on sixty-five patients diagnosed with classical Eagle syndrome. Patients underwent meticulous differential diagnosis. Surgical plans were established based on the findings from neck angioCT. (3) Results: The healing process was uneventful without significant complications. The overall success rate was 97.0%, with a follow-up of a minimum of six months. In one case, the surgery did not yield the desired improvement. In one case, a partial relapse of symptoms was observed. (4) Conclusions: MICS is a straightforward and efficient surgical treatment technique for stylohyoid syndrome.

A multisystem chronic autoimmune disorder, Sjogren syndrome, is characterized by lymphocytic infiltrates in the exocrine glands. Keratoconjunctivitis sicca and xerostomia are the two pathognomic findings in Sjogren syndrome. Here, we present a case of a 30-year-oldan old Indian woman presenting with primary Sjogren syndrome. The clinical features, diagnostic modalities, treatment options, and management of complications have been discussed.

Background: The purpose of this review is to clarify the natural course of Benign Paroxysmal Torticollis (BPT) and to update the relationship of this disorder with migraine. BPT belongs to a group of “episodic syndromes that may be associated with migraine” and is diagnosed when according to diagnostic criteria of the International Classification of Headache Disorders, 3rd edition. It is present in infants and young children and it is an underdiagnosed manifestation, because it is not well recognized and in most cases with a benign evolution, but requires careful differential diagnosis. It was first described by Snyder in 1969 as a movement disorder, a cervical dystonia consequent to labyrinthic disorder.Materials and methods: The PubMed and Web of Science databases were consulted from 1968 to 2024, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines ,2020.( PRISMA)Results: 113 articles were identified, 86 selected and 20 considered for the purpose of this review. The clinical studies were considered in relation to evolution, cognitive and motor development, to genetic and not genetic etiology, to the relationship with migraine with and without aura, vestibular migraine, hemiplegic migraine, and paroxysmal vertigo.

Background Although the management of the majority of patients with IBS is dealt with by General Practitioners, randomized clinical trials and treatment guidelines are developed mostly in academic settings. Probiotics are one of the most investigated treatment modality for this condition. Scarce information is available as regards GPs attitude in this regard. Methods A literature search was performed to identify papers specifically dealing with probiotic treatment of IBS in the general practice setting. Moreover, the preliminary results of a survey on this topic conducted by the authors among general practitioners in a province in northern Italy are reported. Results Five papers specifically addressing probiotic treatment of IBS in general practice were found. The response rate varied from 4 to 100%. The prescription rate of probiotics by GPs in IBS varied from <10 to 46%, regardless of the patients’ bowel habits. Physicians’ satisfaction with this treatment varied from 20 to 93%. The variability of these results probably depends on factors such as differences in the interpretation of the available data on probiotics use in IBS and traditional/ cultural differences. Moreover, compliance with patient satisfaction, may play a role. Conclusions The reported data on the treatment of IBS with probiotics in general practice is scarce and inhomogeneous, thus it does not allow firm conclusions. It is suggested that the involvement in research on the use of probiotics in IBS of physicians working in general practice would be useful in order to pursue more reliable and useful results, since the majority of the IBS population is followed in general practice and may differ from the one represented in academic clinical trials.

Research on microglia in Down syndrome (DS) has shown that microglial activation, increased inflammatory gene expression, and oxidative stress occur at different ages in DS brains. However, most studies resulted in simplistic definitions of microglia as quiescent or active, ignoring potential intermediate states. However, a recent work on microglial cells in young DS brains indicated that those evolve through different intermediate activation phenotypes before reaching a full activated state. Here we used single nucleus RNA sequencing, to examine how trisomy affects microglial states in the Ts65Dn mouse model of DS. Despite no substantial changes in the proportion of glial populations, differential expression analysis revealed cell type-specific gene expression changes, most notably in astroglia, microglia, and oligodendroglia. Focusing on microglia, we identified differential expression of genes associated with different microglial states, including disease-associated microglia (DAMs), activated response microglia (ARMs), and human Alzheimer’s disease microglia (HAMs), in trisomic microglia. Furthermore, pseudotime analysis reveals a unique reactivity profile in Ts65Dn microglia, with fewer in a homeostatic state and more in an intermediate aberrantly reactive state than in euploid microglia. This comprehensive understanding of microglial transcriptional dynamics sheds light on potential pathogenetic mechanisms but also possible avenues for therapy for neurodevelopmental disorders.

Acute peritonitis is a severe complication of abdominal surgery with a high mortality rate. Intes-tinal insufficiency syndrome (IIS) is a key factor in the progression of peritonitis, contributing significantly to morbidity and mortality. The most characteristic and rapid manifestation of IIS is the development of intestinal paresis. Intestinal paresis is a condition characterized by inhibi-tion of intestinal motility, with the inability to evacuate intestinal contents. Intestinal paresis is caused by a cascade of neuroreflex and humoral reactions that lead to severe microcirculatory and metabolic disturbances. In the absence of adequate treatment, IIS can progress to enteritis, a state of complete intestinal insufficiency, with the inability to absorb nutrients and water.

Background Late-onset hypogonadism (LOH) is a condition caused by the decline of testosterone with aging, and is associated with various symptoms, including lower urinary tract symptoms (LUTS). Although some reports have shown that testosterone replacement treatment for LOH improved LUTS, no large study has revealed a correlation between LUTS and LOH. This study investigated the correlation between the severity of LOH and LUTS in Asian Japanese males of >40 years of age using a web-based questionnaire. Methods We asked a total of 2,000 Japanese male individuals to answer both the AMS and IPSS/QOL questionnaires using a web-based survey. Among these 2,000 individuals, 500 individuals were assigned to each of the following age groups: 40-49, 50-59, 60-69, and ≥70 years. LOH symptoms were assessed by AMS score as no/little (17-26 points), mild (27-36 points), moderate (37-49 points), and severe (≥50 points). To compare the risk of voiding and storage dysfunction according to the severity of AMS, voiding dysfunction was assessed by the sum of IPSS Q1, Q3, Q5, and Q6, while storage dysfunction was assessed by the sum of IPSS Q2, Q4, and Q7. Results The IPSS total score was positively correlated with the severity of AMS (shown as median [mean±SD]): no/little group, 2 (3.67±5.36); mild group, 6 (7.98±6.91); moderate group, 11 (12.49±8.63); and severe group, 16 (14.83±9.24) (p<0.0001). The prevalence of an IPSS total score of ≥8 in the AMS severity groups was as follows: no/little group, 13.3% (111 of 834); mild group, 38.3% (225 of 587); moderate group, 64.2% (244 of 380); severe group, 72.4% (144/199). The prevalence of nocturia in the AMS severity groups was as follows: no/little group, 19.8% (165 of 834); mild group, 31.5% (185 of 587); moderate group, 43.9% (167 of 380); and severe group, 50.8% (101 of 199). Conclusions Individuals with higher AMS values, which represents severe LOH symptoms, showed a higher risk of nocturia and LUTS.

Background and Objectives: A 62-year-old patient presented with significant visual reduction in the last three months. Best corrected visual acuity (BCVA) of the right eye (RE) dropped from 20/20 on both eyes to 20/200 on the RE and counting fingers (CF) on the left eye (LE); respectfully. She was diagnosed with stage 4 ovarian cancer 1 month ago. Materials and Methods: Examination revealed significant progression of cataracts and subretinal fluid on the posterior pole with choroidal thickening. Multifocal, orange-pigmented elevated choroidal lesions were observed in the RE, while the view of the left eye fundus was obstructed by cataracts. OCT revealed bilateral choroidal thickening with overlying folds and subretinal fluid and ultrasound of the choroidal lesions showed moderate homogenous internal reflectivity. Results: The patient was diagnosed with BDUMP (bilateral diffuse uveal melanocytic proliferation), a paraneoplastic syndrome characterised by simultaneous, bilateral, painless vision loss and rapidly acquired bilateral cataracts with serous retinal detachments. Cataract extraction had not obtained the expected visual recovery (RE: CF; LE 2/200, respectfully). Plasmapheresis demonstrated some success by stabilizing vision loss obtained by serous retinal detachments. Conclusion: The focus of treating BDUMP is aimed at the underlying malignancy. Vision typically deteriorates to near blindness within a year from presentation. Overall prognosis is generally poor and mean survival is reported at 12-15.7 months from the time of ocular diagnosis.

Methotrexate (MTX) is commonly used in intrathecal chemotherapy for patients with acute lymphocytic leukemia (ALL) to prevent central nervous system (CNS) involvement. However, the use of MTX-based chemotherapy can lead to rare yet severe complications, such as MTX-induced myelopathy. Here we report the case of MTX-induced myelopathy initially misdiagnosed as Guillain-Barre syndrome, leading to a delay in diagnosis and treatment. We present a case of a 39-year-old male with a history of B-cell acute lymphoblastic leukemia (B-ALL) who experienced bilateral foot paresthesia and progressive lower extremity weakness after intrathecal methotrexate (MTX) treatment. Initially suspected as Guillain-Barre syndrome (GBS) due to similar clinical features and nerve conduction studies. The patient received intravenous immunoglobulin (IVIG) treatment, but his condition worsened. A subsequent spine MRI revealed MTX-induced myelopathy. This case highlights the diagnostic challenge posed by the similarity in clinical presentation between MTX-induced myelopathy and GBS. Differentiating between these conditions is critical for appropriate management. Prompt recognition and treatment with folate metabolism compounds may mitigate neurological sequelae.

The aim of this systematic review was to describe clinical and genetic features of syndromes showing oligodontia as a sign. The review was performed according to the PRISMA 2020 checklist guidelines, and the search was conducted using PubMed, Scopus, Lilacs, Web of science, Livivo and EMBASE and supplemented by a gray literature search on Google Scholar and ProQuest, applying key terms relevant to the research questions. The systematic review identified 49 types of syndromes in 91 studies, and the most common was hypohidrotic ectodermal dysplasia, which was reported in 24 patients in 22 studies. Other commonest syndromes that reported oligodontia included Axenfeld-Rieger syndrome, Witkop’s syndrome, Ellis-van Creveld syndrome, blepharocheilodontic syndrome and oculo-facio-cardio-dental syndrome. The X-linked mode of inheritance was the most reported (n=14 studies), followed by the autosomal dominant (n=11 studies). The review describes the main syndromes that may have oligodontia as a clinical sign and reinforce the need of oro-dental-facial examining for adequate diagnosis and treatment of the affected patients. Molecular analysis in order to better understand the occurrence of oligodontia is imperative.

Aortic dissection is a clinicopathological entity caused by rupture of the intima leading to a high mortality if not treated. Over time, diagnostic and investigative methods, antihypertensive therapy, and early referrals have resulted in improving outcomes according to registry data. Some data has also emerged from recent studies suggesting a link between Human Cytomegalovirus (HCMV) infection and aortic dissection. Furthermore, the use of microRNAs have also become increasingly widespread in the literature. These have been noted to play a role in aortic dissections with elevated levels noted in studies as early as 2017. This review aims to provide a broad and holistic overview of the role of miRNAs, while studying the role of HCMV infection in the context of aortic dissections. The role of long non-coding RNAs, circular RNAs and microRNAs are explored to identify changes in expression during aortic dissections. The use of such biomarkers may one day be translated into clinical practice to allow early detection and prognostication of outcomes and drive preventative and therapeutic options in the future.

Abstract: Down Syndrome (DS) is a common genetic disorder characterized by an extra copy of chromosome 21, leading to dysregulation of various metabolic pathways. Oxidative stress in DS is associated with neurodevelopmental defects, neuronal dysfunction, and the onset of dementia re-sembling Alzheimer's disease. Additionally, chronic oxidative stress contributes to cardiovascular diseases and certain cancers prevalent in DS individuals. This study investigates the impact of ageing on oxidative stress and liver fibrosis using a DS murine model (Ts2Cje mice). The liver in DS mice shows increased oxidative stress and impaired antioxidant defenses, as evidenced by reduced glutathione levels and increased lipid peroxidation. Furthermore, DS liver exhibits an altered in-flammatory response as measured by the expression of cytokines and heat shock proteins. DS liver also displays dysregulated lipid metabolism, indicated by altered expression of peroxisome prolif-erator-activated receptors and fatty acid transport proteins. Consistently, these changes might contribute to non-alcoholic fatty liver disease development, a condition characterized by liver fat accumulation. Finally, histological analysis of DS liver reveals increased fibrosis and steatosis, in-dicative of potential progression to liver cirrhosis. This finding highlights the increased risk of liver pathologies in DS individuals, particularly when combined with the higher prevalence of obesity and metabolic dysfunctions in DS patients. These results shed light on the liver's role in DS-associated pathologies and suggest potential therapeutic strategies targeting oxidative stress and lipid metabolism to prevent or mitigate liver-related complications in DS individuals.

The concept of “hyperferritinemic syndrome” defines a complex pathophysiological and clinical entity, characterized by a systemic hyperinflammatory state, generally associated with elevated levels of proinflammatory cytokines (hypercytokinemia) and high serum levels of ferritin (hyperferritinemia), traditionally recognized as an iron-binding plasma protein involved in the storage of iron in a biologically available form for different physiological cellular processes. Recent studies have shown that ferritin has other important functions as well, operating both as a proinflammatory mediator and as a immunosupressive agent, its elevated levels in the serum being detected in various conditions associated with inflammatory states, such as infectious diseases, autoimmune and autoinflammatory disorders and, in some cases, in malignancies. Catastrophic antiphospholipid syndrome (cAPS), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD) and acquired forms of hemophagocytic lymphohistiocytosis (HLH), which includes macrophage activation syndrome (MAS), have been associated with hyperinflammatory states and dramatic elevations of serum ferritin, generating hyperferritinemic syndromes. Severe forms of coronavirus disease-2019 (COVID-19), in which MAS may frequently develop, has also been linked to the development of a hyperferritinemic syndrome. This review offers several insights into the physiological and pathophysiological roles of ferritin in several (hyper-)inflammatory diseases, but also into the causal entities, the underlying pathophysiological mechanisms, clinical manifestations and diagnostic features of somewhat obscure, yet potentially fatal pathological conditions, reunited under the concept of hyperferritinemic syndromes.

(1) Background: Metabolic syndrome is associated with cardiovascular complications. Therefore, this study aims to establish cut points for the conicity index based on the components of the metabolic syndrome and to associate it with characteristics sociodemographic, food consumption and occupational factors in Brazilian rural workers; (2) Methods: Cross-sectional study carried out with farmers. The receiver operating characteristic curve was calculated and the cutoff points for the conicity index were identified by the area under the curve, sensitivity and specificity. The variables included in the binary logistic regression analysis were selected by considering p &lt; 0.20 in the bivariate test; (3) Results: The cut points were similar in females according to both criteria, resulting in a single cut-off of 1.269. In males, the cut points showed differences, resulting in 1.272 according to the NCEP-ATP III and 1.252 according to the IDF. We have shown that younger people, those who work more than 40 hours a week and the lowest contribution of culinary ingredients are associated with increased odds of abdominal obesity. While the consumption of the products they sell or produce decreases these chances; (4) Conclusions: The conicity index showed high discriminatory power for the identification of abdominal obesity in rural workers.

Background: Metabolic syndrome (MS) is associated with a greater risk of morbimortality. Ob-jective: To estimate the prevalence of Metabolic Syndrome (MS) and associated factors in patients of a Psychosocial Care Center (CAPS) in the city of Salvador, state of Bahia, Brazil. Method: Cross-sectional study set at CAPS in the city of Salvador-Bahia, between August 2019 and February 2020. MS was evaluated according to the National Cholesterol Education Program's Adult Treatment Panel III. In addition to descriptive statistics, gross and adjusted prevalence ratios were described. Results: MS was found in 100 (35.2%) individuals, 116 (40.9%) were obese and 165 (58.1%) had increased waist circumference. Polypharmacy was identified in 63 (22.3%) patients and 243 (85.9%) used antipsychotics. In the gross evaluation, the female (PR = 1.88; 95% CI: 1.35-2.63) and the use of antidepressants (PR = 1.41; 95%CI: 1.05-1.88) were associated with MS. After logistic re-gression, depression (PR = 1.86; 95%CI: 1.38-2.51), acanthosis (PR = 1.50; 95%CI: 1.18 - 1.90), use of antipsychotics (PR = 1.88; 95%CI: 1.13 - 2.75) and the hypertriglyceremic waist (PR = 3.33; 95%CI: 2.48- 4.46) were associated with MS. Conclusion: The prevalence of MS alerts to multimorbidity among individuals with mental disorders and the need for clinical screening.

Lynch syndrome (LS) is an autosomal dominant genetic condition caused by mutations in the DNA mismatch repair (MMR) genes in the germline. Colorectal cancer and/or LS-associated cancer are more likely in people who carry pathogenic mutations in these genes. Cancers of the endometrium, small intestine, stomach, pancreas, and biliary tract, ovarian, brain, upper urinary tract, and skin are among the cancer types linked to LS. The criteria for a clinical diagnosis of LS, as well as the processes for genetic testing to identify carriers of pathogenetic mutations in MMR genes, have been known for a long time. The precise description of the pathogenicity associated with MMR genetic variants is critical in the mutation detection analysis, especially in order to enroll mutation carriers in endoscopic surveillance programs that are more suited to them. As a result, this may aid in the improvement of LS-related cancer prevention efforts. In this review, we discuss recent advances in the molecular genetics of LS.

1) Background. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, characterized by extensive necrosis and detachment of the epidermis. 2) Case presentation. We present a case of a 46-year-old patient with late-stage high-grade serous ovarian cancer who was primarily treated with neoadjuvant chemotherapy and interval debulking which was followed by adjuvant chemotherapy. At first recurrence, she was again treated with chemotherapy and due to severe abdominal pain, an elastomeric pump containing analgesics, anti-inflammatories and ondansetron was administered. In the same month, she was admitted to the hospital due to severe dysphagia and in the following days, she developed haemorrhagic vesiculobullous lesions on facial skin and trunk. Stevens-Johnson syndrome was confirmed and ondansetron as a leading cause was discontinued. Despite multimodal treatment, her condition deteriorated, and she died. 3) Discussion and conclusion. Although gynaecologists rarely encounter Stevens-Johnson syndrome, high mortality of the disease should ensure a low threshold for diagnosing and treating this disease.

Depression and metabolic diseases often coexist having several features in common, e.g., chronic low-grade inflammation and intestinal dysbiosis. Different microbiota interventions have been proposed to be used as a treatment for these disorders. In the paper we review the efficacy of probiotics in depressive disorders, obesity, metabolic syndrome and its liver equivalent based on the published experimental studies, clinical trials and meta-analyses. Probiotics seem to be effective in reducing depressive symptoms when administered in addition to antidepressants. Additionally, probiotics intake may ameliorate some of the clinical components of metabolic diseases. However, standardized methodology regarding probiotics clinical trials has not been established yet. In this narrative review we discuss current knowledge on the recently used methodology with its strengths and limitations and propose criteria that may be implemented to create a new study of the effectiveness of probiotics in depressive disorders comorbid with metabolic abnormalities. We put across our choice on type of study population, probiotics genus, strains, dosages and formulations, intervention period, as well as primary and secondary outcome measures.

Sjogren syndrome (SS) is an autoimmune disease that involves salivary and lacrimal glands. There are rare articles describing hypohidrosis or anhidrosis in SS patients. Little is known about the histologic findings seen in patients with SS who do not report decreased sweating. We analyzed skin samples from 31 patients with SS who had undergone skin biopsies for reasons not related to SS. We assessed the number, distribution and pathologic changes within and around the eccrine ducts, glands and acrosyringia. The composition of the inflammatory infiltrate was additionally accessed utilizing immunohistochemical stains. Overall, in 60% of cases we observed some degree of inflammation. In virtually all cases the inflammatory infiltrate was located around the eccrine ducts at a distance from the non-SS pathology. It was mainly composed of CD3+ T cells with increasing number of B and plasma cells as periductal inflammation intensified. This study is the first histologic analysis of asymptomatic skin in patients with SS. It demonstrates the presence of skin involvement in the majority of SS patients. Our results emphasize the importance of systematic skin evaluation in this category of patients as well as counseling, early preventive measurements and timely treatment when indicated.

Burning Mouth Syndrome (BMS) is an idiopathic condition that manifests itself primarily with the onset of burning sensation. The aim of the research was to perform Photobiomodulation Therapy (PBM) using a diode laser on the oral mucosa of BMS patients, followed by an objective evaluation of the morphological changes in the vascular bed underlying the mucosa using polarized light videocapillaroscopy. A group of 40 patients were included in the study. The patients were randomly divided into two groups (using simple randomization): 20 patients were assigned to the laser group and 20 patients were assigned to the placebo group. Each patient of the laser group received 8 irradiations (with 4 Watt of power, wavelength 800nm, energy 1200 Joules, irradiation time for 300 seconds of time, energy density 50J/cm2 , 60 mW continuous wave laser, irradiance 180mW/cm2 ), twice a week, blinded to the type of irradiation administered, for four consecutive weeks. The patients in the placebo group underwent the same sessions as the others, the only difference being the non-emission of the laser. An initial check of the vascular bed was performed with a polarized light videocapillaroscope. This was followed by treatment with a therapeutic diode laser and a subsequent check with a videocapillaroscope. It was possible to observe that in the group of patients that underwent laser therapy, there was a lasting improvement in symptoms. The capillary oral bed in the placebo groups did not show any statistically significant difference (P>0.05). In the laser group we observed: in the buccal mucosa the diameter of the capillary had a reduction of 3μm; in the upper lip mucosa a reduction of 3μm; in the lower lip mucosa, there was a reduction of 3μm; in the dorsal lingual surface, there was a reduction of 2 μm. An increase in capillary length was also obtained in all irradiated regions in the laser group patients (P < 0.05). PBM induces microcirculatory changes that are still present at a distance of time, such as an improvement in the clinical picture. The improvement in the symptoms has been correlated to the reduction of the capillary diameter. Placebo effect only leads to a temporary improvement in symptoms that are unrelated to changes in the microcirculatory pattern.

Aims: Clinical evidence indicates that innate immune cells may contribute to the onset and outcome of acute coronary syndrome (ACS). Our prospective study aimed at analysing neutrophil phenotypes in ACS and their role in predicting 1-year major cardiovascular events. Methods: Blood neutrophil phenotypes were analysed by flow cytometry. Differential blood cell count and plasma levels of soluble markers were recorded at admission and at 6-month follow-up. Results: 108 patients categorized in chronic stable coronary artery disease (n=37), unstable angina (UA) (n=19), Non-ST-Elevation Myocardial Infarction (NSTEMI) (n=25), and ST-Elevation Myocardial Infarction (STEMI) (n=27) were included. STEMI and NSTEMI patients displayed higher neutrophil count and neutrophil-to-lymphocyte ratio (NLR) than stable and UA patients (P<0.0001), which normalized at 6-month after MI. STEMI patients were characterized by elevated percentages of band cells in low-density neutrophils (P=0.007) and in high-density neutrophils (P=0.019) compared to the other patients. Multivariable logistic regression analysis revealed that plasma levels of total MPO was associated with STEMI when compared to stable (OR: 1.434; 95% CI: 1.119-1.837; P<0.0001), UA (1.47; 1.146-1.886; P=0.002), and NSTEMI (1.213; 1.1-1.134; P=0.0001) patients, while increased neutrophil SSC signal intensity was associated with NSTEMI compared to stable patients (3.828; 1.033-14.184; P=0.045). Based on multivariable Cox regression analysis, elevated plasma levels of PCSK9 and low-density neutrophil percentage predicted 1-year outcome independently of cardiovascular risk factors (c-index: 0.915; IQR: 0.908-0.929). Conclusions: Changes in neutrophil phenotype are concomitant to ACS. These changes may differ between STEMI and NSTEMI. They may also contribute to ACS risk and patient outcome.

People with Down syndrome present cognitive difficulties that affect their reading skills. In this study we present results about the use of gestural interaction with Kinect sensor to improve the reading skills of students with Down syndrome. Following a case of study method for small samples with disabilities, measuring different variables related to reading skills in an experimental group and in a control group. We found improvements in the visual association, visual comprehension, sequential memory, and visual integration after this stimulation in the experimental group compared to the control group. Also, we found that the number of error and delay time of interaction decrease between sessions in the experimental group.

For decades, neurologic and other extra glandular manifestations have been described in Sjögren’s syndrome (SS). More recently, neuropathic, psychological and cognitive alterations are being considered part of the disease. The lacrimal glands (LG), the ocular surface (OS), salivary glands (SG) and the central nervous system (CNS) are integrated to modulate the autonomic functions and, not just those organs, but also the hippocampus, which is linked to the autonomic nervous system, and modulate behavior responses appears to be compromised in the SS. Recent studies confirm that the tryptophan/kynurenine pathway (TKP) can be stimulated by interferon-γ (IFN-γ) and other cytokines, activating the indoleamine-pyrrole 2,3-dioxygenase (IDO) in SS. This pathway interferes on serotonergic and glutamatergic neurotransmission, mostly in the hippocampus, and other structures of the CNS. Although not demonstrated, it is plausible that this constant interference induces clinical signs of SS, and contributes to the discrepancy between symptoms and signs, towards manifestations of hyperalgesia and depression in patients with SS. Therapeutic strategies are being reexamined and new options designed and tested to regulate the involved steps of the TKP. In the future, the application of this concept may offer a clue to the mosaic of manifestations of SS.

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown cause characterized by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and more recently post-COVID-19 condition (Long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders. Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. Accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and Long COVID. To address this issue, this article aimed to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.

A patient in her early 20s presented with constant and progressive lower abdominal and back pain, mainly on the right side of the abdomen, purulent vaginal discharge and pyrexia. Radio-logical assessment revealed a possible tuboovarian abscess and incidental diagnosis of ipsilateral renal agenesis. The patient was treated for pelvic inflammatory disease (PID), however after antibiotic administration and since the symptoms were not resolving, an abdominal MRI was requested which revealed a uterus didelphys with two cervices, an obstructed haemivagina and evidence of haematocolpos. The diagnosis of OHVIRA syndrome was confirmed and the patient underwent an excision of the vaginal septum, drainage of the haematopyocolpos and laparoscopic drainage of the tuboovarian abscess. She achieved a good recovery.

Background: Hantavirus cardiopulmonary syndrome (HCPS) has a high lethality. About two-thirds of the severe cases may be rescued by extracorporeal membrane oxygenation (ECMO). However, about half of the patients supported by ECMO suffer major complications. High volume hemofiltration (HVHF) is a depurative extracorporeal support that provides homeostatic balance allowing hemodynamic stabilization in some critically ill patients. Methods: We implemented HVHF prior to ECMO consideration in the last five severe HCPS patients requiring mechanical ventilation and vasoactive drugs admitted to our intensive care unit. Patients were considered HVHF-responders if ECMO was avoided and nonresponders if ECMO support was needed. Results: The first two patients required ECMO, while the last three did not. Patients had a maximum serum lactate of 8.4 [4.3-14] mMol/L and a lowest cardiac index of 1.76 [1.45-2.9] L/min/m2. Nonresponders were connected later to HVHF, displayed progressive tachycardia and decreasing stroke volume. The opposite was true for HVHF-responders who also received targeted-HVHF compounded by aggressive hyperoncotic albumin, sodium bicarbonate and calcium supplementation plus ultrafiltration to avoid fluid overload. All patients survived, but one of the ECMO patients suffered a vascular complication. Conclusion: HVHF may contribute to support severe HCPS patients avoiding the need for ECMO in some of them. Early connection and targeted-HVHF may increase the chance of success.

The 22q11.2 deletion syndrome is a multisystemic disorder characterized by a marked variability of phenotypic features making the diagnosis challenging for clinicians. The wide spectrum of clinical manifestations includes congenital heart defects, most frequently conotruncal cardiac anomalies, thymic hypoplasia and predominating cellular immune deficiency, laryngeal developmental defects, midline anomalies with cleft palate and velar insufficiency, structural airway defects, facial dysmorphism, parathyroid and thyroid gland hormonal dysfunctions, speech delay, developmental delay, neurocognitive and psychiatric disorders. Significant progress has been made in understanding the complex molecular genetic etiology of the 22q11.2 deletion syndrome underpinning the heterogeneity of clinical manifestations. The deletion is caused by chromosomal rearrangements in meiosis and is mediated by non-allelic homologous recombination events between low copy repeats or segmental duplications in the 22q11.2 region. A range of genetic modifiers, environmental factors as well as the impact of hemizygosity on the remaining allele contribute to the intricate genotype-phenotype relationships. This comprehensive review has been aimed at highlighting the molecular genetic background of 22q11.2 deletion syndrome in correlation with a clinical multidisciplinary approach.

A short review of the important studies was conducted to evaluate the potential of aerosol transmission of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The minimum size of droplets potentially carrying the SARS-CoV-2 was newly estimated and discussed in this review.

Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.

GCTs are developmental tumors and likely to reflect ontogenetic and teratogenetic determinants. The objective was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were used. According to Teilum's holistic concept malignant and benign teratomas were registered. We used a case control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher’s exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 17 isolated cases of eGCT with a wide range of syndromes, however not significantly associated following Bonferroni correction. All these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

Hamman’s syndrome is a rare condition that mostly affects young males, often with a predisposition of asthma. It includes the presence of free air in the mediastinum and subcutaneous emfysema with no other underlying cause such as trauma or infection. It occurs spontanously and often in association with prolonged valsalva manouvre. This might explain why there are some cases of Hamman syndrome among young females giving birth. Here we present a case report of a 24-year- old primigravida with Hamman’s syndrome. She presented with symptoms a few hours after an uncomplicated vaginal delivery at 40+1 pregnancy week. The symptoms resolved spontanously after a few days of observation. We also give a systemic review of reported cases since 2000 to provide overview on pathomechanism, symptoms, diagnostics, treatment and management of this condition. Hamman’s syndrome is a rare, usually benign, but potentially serious complication that can occur during the second stage of labour. Diagnostics include inquiring about typical symptoms, clinical examination and chest x-ray or CT scan. Treatment is usually conservative with oxygen, bronchodilators and pain relief. The reccurence rate is low and there is no contraindication to vaginal delivery in future pregnancies. However, it is suggested that physicians and midwives be cautious and consider low threshold for instrumental delivery or caesarean section to avoid excessive valsalva manoeuvre.

This study aimed to investigate the efficacy of manual therapy and exercise versus synchronized telerehabilitation with self-manual therapy and exercise in treating Subacromial Pain Syndrome (SPS). Sixty individuals diagnosed with SPS, aged 18-50 years, were randomly assigned to home exercise (HE), manual therapy (MT), and telerehabilitation (TR) groups. Treatment protocols were administered over 8 weeks and included specific exercises and therapy interventions. Out-come measures included Visual Pain Scale (VAS), shoulder range of motion (ROM) via gonio-metric measurements, Quick Disability Arm-Shoulder-Hand Problems Survey (Q-DASH), and patient satisfaction. Results revealed that both MT and TR groups exhibited reduced pain, in-creased ROM, lower Q-DASH scores, and higher patient satisfaction compared to the HE group. However, no significant differences were found between MT and TR groups in pain levels, ROM, Q-DASH scores, or patient satisfaction. The study concludes that both telerehabilitation and manual therapy effectively alleviate pain and are well-received by patients with SPS. Addition-ally, manual therapy demonstrates superiority in enhancing functional levels compared to exer-cise-based interventions. (Registration: NCT05200130)

Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 (MECP2). Most often, the disease causing MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI) resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on MECP2 genotype with a correlation between XCI and severity observed only in individuals with MECP2 variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects.

Mosquitoes are a family of the order Diptera, which includes more than 3500 species. Two groups able to suck human blood and transmit diseases: the anophelines and the culicines comprise several genera such as Culex, Aedes and Aedes communis (Ac). Previous study has demonstrated a significant relationship between Ac sensitization and either extract or single bee venom components suggesting a “bee-mosquito syndrome” occurrence. It is well known that CCD can interference with the measurement of quantitative IgE results. Hence, it has been hypnotized that the presence of sIgE to CCD could have a role in the Bee-Mosquito syndrome. Method Serum from 21 different Mosquito and Ape melifera allergic individuals were combined with extracts of Mosquito (in house) and Apis melifera. SDS-PAGE and Immunoblot (IB) were carried out without and with with CCD-Inhibitor. Results The data would suggest IgE binding to common bands between Culex male, Culex female and Aedes species mosquitos of approximate molecular weight ~21kDa, ~35kDa, ~40kDa and ~55kDa. Whilst IgE binding has been observed to protein bands from the Apis melifera extract, these bands do not align with any present in the mosquito extracts. The use of a CCD-Inhibitor results in differences in IgE binding. Specifically, bands that were previously observed in the Apis melifera venom sample without use of CCD-Inhibitor at 40kDa and 90kDa are no longer observed when CCD-Inhibitor is used. Two bands of the Apis melifera venom remain present between 15-20kDa. No major differences in banding pattern were observed for the mosquito samples with or without CCD-Inhibitor, although the blot appears cleaner with less background when CCD-Inhibitor is used. Conclusion Further experiments have to be done to determine whether the reactive bands from Apis melifera are unrelated proteins or whether the proteins are related homologues of varying molecular weight.

Previous investigations have illuminated the significant association between the gut microbiome and a broad spectrum of health conditions, including obesity, diabetes, cardiovascular diseases, and psychiatric disorders. Evidence from certain studies suggests that dysbiosis of the gut microbiota may play a role in the etiology of obesity and diabetes. Moreover, it is acknowledged that dietary habits, pharmacological interventions, psychological stress, and other exogenous factors can substantially influence the gut microbial composition. For instance, a diet rich in fiber has been demonstrated to increase the population of beneficial bacteria, whereas the consumption of antibiotics can reduce these advantageous microbial communities. In light of the established correlation between the gut microbiome and various pathologies, strategically altering the gut microbial profile represents an emerging therapeutic approach. This can be accomplished through the administration of probiotics or prebiotics, which aim to refine the gut microbiota and, consequently, mitigate the manifestations of associated diseases. The present manuscript evaluates recent literature on the relationship between gut microbiota and metabolic syndrome published over the past three years and anticipates future directions in this evolving field.

Intellectual disability with speech delay and behavioural abnormalities as well as hypotonia, seizures, feeding difficulties and cra-niofacial dysmorphism are the main symptoms associated with pathogenic variants of ZMYND11 gene. The range of clinical mani-festations of ZMYND phenotype is constantly being expanded by new cases described in the literature. Here, we present 2 previ-ously unreported paediatric patients with neurodevelopmental features diagnosed with missense variants in ZMYND11 gene. It should be noted that one of the individuals manifested with hyperinsulinemic hypoglycaemia (HH), a symptom that was not de-scribed before in published works. Although the reason for the occurrence of HH in our proband is not clear, it is likely that it broadens the spectrum of symptoms characteristic of ZMYND11 syndrome. Thus, this paper contributes to extending the range of possible manifestations of ZMYND disease and further supports its association with neurodevelopmental challenges.

Study design : Technical note. Objectives: To present a new spinal shortening technique for tethered cord syndrome. Background : Tethered cord syndrome (TCS) is a debilitating condition of progressive neurological decline. Surgical detethering for TCS is a gold standard. However, symptomatic retethering of TCS has been reported in 5%–50% of patients after initial release. To solve this problem, posterior spinal shortening osteotomy has been reported. This technique has risks of massive blood loss and neurological deterioration. The authors hereby report a new safe spinal shortening technique for tethered cord syndrome. Materials and Methods : A 31-year-old man with gait disturbance was referred to our hospital. After the delivery, he underwent surgical untethering of spinal cord in another hospital. He had hyperreflexia of Achilles tendon reflex and muscle weakness of bilateral legs (MMT 3-4). He also had urinary and bowel incontinence, and total sensory loss below L5.Anteroposterior lumbar radiogram indicates partial laminectomy of L3 and L4. Lumbar MRI showed retethering of spinal cord. Results: He underwent new spinal shortening technique for tethered cord syndrome under the guidance of O-arm navigation. First, from anterior approach disectomy from T12 to L3 was performed. Second, from posterior Ponte osteotomy was done from T12 to L3, shorten the spinal column 15 mm. The patient was successfully treated surgically. Postoperative lumbar MRI showed the tension of spinal cord was released. Manual muscle testing results and sensory function of the left leg had recovered almost fully on final follow-up at one year. Conclusions/Level of Evidence: Retethered spinal cord after initial untethering was difficult to treat. This new spinal shortening technique was effective and very safe technique to release the tension of spinal cord. Level V.

Abstract: Background: Vasoplegic shock syndrome(VSS) after an off-pump coronary artery bypass graft (OPCABG) is an extremely rare condition. Inotropic support is usually the first-line therapy though it can precipitate several complications or be ineffective. We report the first case of severe refractory VSS after OPCABG successfully treated with hydroxycobalamin. Methods: A 77-year-old gentleman underwent OPCABG for three vessels coronary artery disease. Preoperative LV ejection fraction was 28%, and the patient before surgery started sacubi-tril/valsartan titrated, then, to the highest dose. Surgery was uneventful and, by the end of the procedure, TEE showed improved biventricular contractility. Results: The patient was transferred to the ICU without inotropic support but he developed soon hypotension. TEE ruled out pericardial tamponade and confirmed fair contractility. Norepineph-rine was titrated to a medium-high dose, vasopressin was started and a Swan-Ganz catheter was placed. SVR was 480 dyn·s·cm−5. Despite aggressive pharmacologic treatment (including Methylprednisolone and Methylene blue), no improvements were noticed. 10 g of hydroxycobalamin were administered. One hour later hemodynamic status re-assessment showed SVR > 800 dyn·s·cm−5. Afterward, vasopressors were gradually reduced. Conclusions: Our case demonstrated the importance of adequate early treatment in VSS after OPCABG. For the first time, hydroxycobalamin was effectively used to restore homeostasis.

Abstract Background: Massive resection of the small intestine leading to short bowel syndrome (SBS) deprives organism of many immunocompetent cells concentrated in gut associated lymphoid tissue- the largest immune organ in humans. We have aimed to access the influence of bowel resection on adaptive immunity in children, basing on peripheral lymphocyte subsets and serum immunoglobulins. Methods: 15 children, who underwent bowel resection in the first month of life and required further home parenteral nutrition were enrolled into the study.. Based on flow cytometry the following subsets of lymphocytes were evaluated: T, B, NK, CD4+, C8+and activated T cells. Results: Significantly statistical differences were found for the rates of lymphocytes B, T, CD8 + and NK cells. Absolute count of NK cells was lower in SBS group than in the control group. Absolute counts of lymphocytes, lymphocytes B, T, CD4+ and percentages of lymphocytes CD4+, and activated T cells inversely correlated with the time after resection. Conclusions: Children with SBS do not present with clinical signs of immunodeficiency as well as deficits in peripheral lymphocyte subsets and serum immunoglobulins. The tendency of the lymphocyte subpopulations to decrease over time after resection points out the necessity for longer follow- up.

Background: Polycystic ovary syndrome (PCOS) is a common reproductive and endocrinological disease characterized by ovulatory dysfunction, polycystic ovaries, and hyperandrogenism. Adipokines are believed to contribute to developing PCOS and its accompanying metabolic complications such as dyslipidemia, insulin resistance, and cardiovascular diseases. Oncostatin M (OSM), a novel adipokine, plays a role in oogenesis, lipogenesis, and inflammation and may contribute to PCOS pathogenesis and its related metabolic problems. Methods: In this case-control study, the patients were grouped in a 1:1 ratio into either the PCOS (n = 32) or the control group (n = 32). Blood samples were obtained between the 3rd and 5th days of the menstrual cycle. Serum levels of fasting glucose, insulin, C-reactive protein (CRP), low-density lipoprotein, high-density lipoprotein, triglyceride, white blood cell count, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, total testosterone, prolactin estradiol, and OSM were analyzed. Results: OSM levels were significantly lower, but CRP levels were substantially higher in the PCOS group than in the control group (p = .002, p = .001, respectively). OSM was inversely correlated with total cholesterol, non-high-density lipoprotein cholesterol, fasting glucose, and the luteinizing hormone/follicle-stimulating hormone ratio (ρ = .329, p = .017; ρ = .386, p = .005; ρ = .440, p = .001; ρ = .316, p = .023, respectively). Conversely, there was no correlation between OSM and total testosterone level (ρ = .220; p = .118). In the context of inflammation and metabolic parameters, OSM was inversely correlated with CRP, Homeostatic Model Assessment for Insulin Resistance score (HOMA-IR), and low-density lipoprotein cholesterol (LDL) (ρ = .353, p = .019; ρ = .275, p = .048; ρ = .470, p &lt; .001, respectively). The performance of Oncostatin M for diagnosing PCOS showed 50% sensitivity, 75% specificity, and 63% accuracy (p = .009) in ROC curve analysis. Conclusions: Plasma OSM levels were considerably lower in patients with PCOS than in the control group, and this was inversely correlated with the hormonal and metabolic parameters of PCOS. Thus, OSM may be a novel therapeutic target for PCOS and metabolic complications.

Perceptual and statistical evidence has underlined voice characteristics of individuals affected by genetic syndromes different from that of normophonic subjects. In this paper we propose a procedure for the systematic collection of such pathological voices and the development of AI-based automatic tools to support differential diagnosis. Guidelines are provided concerning most suitable recording devices, vocal tasks and acoustical parameters, in order to simplify, speed up and make the whole procedure homogenous and replicable. The proposed procedure was applied to a set of 56 subjects, affected by Costello syndrome (CS), Down syndrome (DS), Noonan syndrome (NS) and Smith-Magenis syndrome (SMS). The whole database has been divided into three groups, respectively called: paediatric subjects (PS, individuals &lt; 12 years of age), female adults (FA) and male adults (MA) subjects. In line with literature results, the Kruskal-Wallis test and post-hoc analysis with Dunn-Bonferroni test highlighted several significant differences in acoustical features not only between healthy subjects and patients, but also across syndromes within PS, FA and MA groups. Machine learning provided for the PS group a k-nearest neighbour classifier with 75% accuracy, for the FA group a support vector machine (SVM) model with 84% accuracy and for the MA group a SVM model with 97% accuracy. These preliminary results suggest that the proposed procedure, based on acoustical analysis and AI, might be helpful for an effective non-invasive automatic characterization of genetic syndromes.

This study assessed the associations between host genetic variants and subgingival microbiota in patients with metabolic syndrome (MetS); 103 patients with MetS underwent medical and periodontal examinations and had blood and subgingival plaque samples taken. DNA was extracted and processed (assessing a panel of selected single nucleotide polymorphisms (SNPs) first (hypothesis-testing), and then expanding to a discovery phase. The subgingival plaque microbiome from these patients was profiled. Analysis of associations between host genetic and microbial factors was performed, stratified for periodontal diagnosis. Specific SNPs within RUNX2, CAMTA1 and VDR genes were associated with diversity metrics, with no genome-wide associations detected for periodontitis severity or Mets components at p&lt;10-7. Severe periodontitis was associated with pathogenetic genera and species. Some SNPs correlated with specific bacterial genera, as well as with microbial taxa, notably VDR (rs12717991) with Streptococcus mutans and RUNX2 (rs3749863) with Porphyromonas gingivalis. This is the first study exploring the role of host genotype variation in subgingival microbial dysbiosis in patients with MetS and periodontitis. In conclusion, variation in host genotypes may play a role in the dysregulated immune responses characterizing periodontitis and thus the oral microbiome, suggesting that systemic health-associated host traits further interact with oral health and microbiome.

The term "Osmotic Demyelination Syndrome" (ODS) is synonymous with central pontine myelinolysis (CPM), denoting a condition characterized by brain damage, particularly affecting the white matter tracts of the pontine region. This damage arises due to rapid correction of metabolic imbalances, primarily cases of hyponatremia. Noteworthy triggers encompass severe burns, liver transplantations, anorexia nervosa, hyperemesis gravidarum, and hyperglycaemia, all linked to the development of CPM. Clinical manifestations encompass a spectrum of signs and symptoms, including dysphagia, dysarthria, spastic quadriparesis, pseudobulbar paralysis, ataxia, lethargy, tremors, disorientation, catatonia, and, in severe instances, locked-in syndrome and coma. A recent case involving a 45-year-old woman illustrates these complexities. Upon admission to the Medicine Intensive Care Unit, she presented with symptoms indicative of diminished responsiveness and bilateral weakness in upper and lower limbs. Of significance, the patient had a pre-existing medical history of hyperthyroidism. Extensive diagnostic investigations were undertaken, revealing compelling evidence of profound hyponatremia through blood analyses. Furthermore, magnetic resonance imaging (MRI) was performed, unveiling conspicuous areas of abnormal hyperintensity located in the central pons, intriguingly accompanied by spared peripheral regions. These radiological findings align with the characteristic pattern associated with osmotic demyelination syndrome, illuminating the underlying pathology.

Hutchison-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of LMNA gene. HGPS affects systemic levels, except cognition or brain development in children, showing that cellular aging can occur in the short term. However, the causes of aging that humanity is working to overcome remain poorly understood. Studying progeria could be useful for unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear cause of HGPS or the development of a therapeutic medicine will provide inconceivable comfort for young patients and enable them to live a normal life. This review aimed to: i) briefly describe how progerin was discovered as the causative agent of HGPS, ii) elucidate the puzzling observation of the absence of primary neurological disease in HGPS, iii) present several studies showing the deleterious effects of progerin and the beneficial effects of its inhibition, and iv) summarize research to develop a therapy for HGPS, and introduce clinical trials for its treatment.

Introduction: This study aimed to identify factors associated with late diagnosis and clinically monitor newly diagnosed HIV/AIDS patients. Method: Retrospective longitudinal study, based on secondary data from a specialized unit at a tertiary hospital. Data collection included sociodemographic, behavioral, clinical, and laboratory data of newly diagnosed HIV patients between 2015-2019. Data analysis adopted inferential statistical tests using the SPSS program, considering α ≤ 0.05. Results: 314 individuals were newly diagnosed with HIV/AIDS. 70.3% (208) had a late diagnosis, and 57.1% (169) were diagnosed very late. There was an association of the very late diagnosis with the variables sex and education and with origin, entry, occurrence of opportunistic diseases, use of ARV therapy, and death, associated with late and very late diagnosis, respectively. The results of the regression model indicate that males had 2.28 [95% CI 1.11 - 4.46] higher chances of having a late diagnosis compared to females. Conclusions: This study evidenced a high prevalence of late and very late diagnoses in newly diagnosed male HIV patients who presented with opportunistic diseases, requiring hospitalization, and having a significant risk of progressing to death.

Crohn's disease (CD) is a chronic, relapsing disorder belonging to inflammatory bowel diseases (IBD). It is manifested by relapsing transmural inflammation found in any segment of the gastrointestinal tract. Chronic fatigue is a common and underrecognized symptom of CD, which prevalence is much higher in the population of CD patients as compared to healthy population. It stems from an intricate web of interactions between various risk factors, and its pathophysiology is still not fully understood. Implementation of routine screening and holistic, multidisciplinary approach involving psychological support may be crucial in management of CD patients with chronic fatigue. There is currently no single intervention aimed at decreasing fatigue alone, and its treatment is especially difficult in patients with fatigue persisting despite clinical and endoscopic remission. Extensive research is still needed in order to be able to predict, prevent, identify and ultimately treat fatigue associated with CD. The aim of this review is to summarize the knowledge on the etiology, diagnosis, and treatment of chronic fatigue in CD patients.

The etiology of autism spectrum disorder (ASD) has not yet been completely elucidated. Through time, multiple attempts have been made to uncover the causes of ASD. Different theories have been proposed, such as that it is caused by “Gods Wrath,” alternations in the gut–brain axis with an emphasis on gut dysbiosis, post vaccine complications, and genetic or even autoimmune causes. In this review we present data covering over 170 000 participants at age ranging from 2 to 14 years focusing on human cell changes rather than using animal models found in previous studies. The male/female ratio was 4:1. Data collection occurred in many countries covering ethnically diversified subjects. Moreover, we aim to show how the progress in genetic techniques influence the explanation found in medical White Papers based on the human genetic samples we have observed from our studies

Atypical hemolytic uremic syndrome (aHUS) is a rare and life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, necessitating differentiation from other thrombotic microangiopathy disorders. Definitive biomarkers for disease diagnosis and activity are currently lacking, and identifying molecular markers is essential. We conducted single-cell sequencing on peripheral blood mononuclear cells from 13 aHUS patients, 3 aHUS family members, and 4 healthy controls. Analysis included clustering, cell type annotation, pseudotime estimation, and cell-cell communication. Immune cell populations differ among aHUS, aHUS families, and healthy controls. Disease activity and treatment influence T, NK, B, and monocyte subpopulations, with increased intermediate monocyte levels distinguishing aHUS from controls and aHUS groups with varying disease activity. Subclustering revealed differential gene expression in patients compared to controls; higher expression of mitochondria-related genes suggests cell metabolism may influence clinical course. Pseudotime trajectory analysis demonstrated unique immune cell differentiation, and cell-cell interaction analysis identified distinct signaling pathways among patients, family members, and controls. This single-cell sequencing study is the first to confirm immune cell dysregulation in aHUS pathogenesis, offering valuable insights into molecular mechanisms and potential new diagnostic and disease activity markers.

The aim of this study was to determine the association of metabolic syndrome (MetS) with kidney cancer and the impact of age and gender on such association. Using Korean National Health Insurance Service database, 9,932,670 subjects who had check-up in 2009 were followed up until the diagnosis of kidney cancer or death or until 2019. Kidney cancer was significantly associated with MetS (HR 1.56). This association was higher in the younger age group (HR: 1.82, 1.5, and 1.37 in 20-39 years, 40-64 years, and ≥65 years, respectively). In terms of the association of kidney cancer with obesity and central obesity, young-aged males showed higher HR for kidney cancer than old-aged ones (HR of obesity: 1.96, 1.52, and 1.25; HR of central obesity: 1.94, 1.53, and 1.3 in 20-39 years, 40-64 years, ≥65 years, respectively), while young-aged females showed lower HR. Kidney cancer was associated with obesity and MetS. The association was higher in younger aged population than in older ones. Regarding gender, MetS, obesity, and central obesity showed higher associations with kidney cancer in younger aged male population, while there was no significant difference in such association according to age in females.

The metabolic syndrome, first introduced by Hermann Haller in 1975, was sometimes also known as insulin resistance syndrome, syndrome X, and plurimetabolic syndrome. In 1989 it was rechristened by Kaplan as "Deadly Quartet" based on a consolidation of central obesity, impaired glucose tolerance, dyslipidemia, and systemic hypertension. Metabolic syndrome is positively associated with a pro-inflammatory and pro-thrombotic state, attributed to increased pro-thrombotic and inflammatory markers activity. Moreover, Metabolic syndrome is frequently associated with increased atherosclerotic cardiovascular disease, impaired glucose tolerance, hyperuricemia, obstructive sleep apnea, and chronic kidney disease. Despite concerted endeavors worldwide, the complexity of the pathophysiology of metabolic syndrome is still not clearly understood. Currently, therapeutic possibilities are confined to individual therapy of hyperglycemia, hypertension, hypertriglyceridemia, hyperuricemia, regular physical exercise, and a restricted diet.

In South Sudan, three case-control studies found a positive association between Nodding Syn-drome (NS) and a Mansonella perstans infection. To investigate whether M. perstans could play the primary and sole causal role in the development of NS, we examined blood films of persons with and without epilepsy in rural villages affected by NS in Mahenge, Tanzania, to identify M. perstans infections. Study participants were also examined for onchocercal nodules and skin lesions and tested for the presence of anti-O. volvulus antibodies (Ov16 ELISA). One hundred and thirteen epilepsy cases and 132 controls were enrolled, with a mean age of 28.3 years (interquartile range 22 – 34 years); 125 (51%) were females. Of the persons with epilepsy, 43 (38.1%) met the probable NS criteria. M. perstans infection was absent in all participants, but Ov16 prevalence and oncho-cerciasis-associated skin manifestations were positively associated with epilepsy, including probable NS. Onchocercal nodules in the mothers of cases were also positively associated with epilepsy. In conclusion, in contrast with O. volvulus, M. perstans is likely not endemic in Mahenge and therefore cannot be a co-factor for NS in the area. Hence, this filaria cannot be the primary and sole causal factor in the development of NS.

Introduction: Acute compartment syndrome (ACS) is a surgical emergency that requires urgent intervention in order to prevent permanent structural damage and irreversible functional disability. The diagnosis of ACS depends on a high index of suspicion, relying on the following diagnostic criteria commonly known as the 5 Ps; Pain, Paresthesia, Paralysis, Pallor, and Pulse-lessness. When the diagnosis is uncertain, intracompartmental pressure greater than 30 mmHg is suggestive of ACS. Case Presentation: We report a case of an underdiagnosed ACS, with a lack of classical presentation in a thirty-seven-years-old male patient with a history of myopathy. The patient was admitted to the emergency room due to direct trauma to his right hip, without a significant Visual Analogue Score. On his hip radiograph a subtrochanteric fracture of the right femur was demonstrated. An additional masked ipsilateral subcapital fracture was detected during the operation. The diagnosis of ACS was made during the operation while relying on the clinical appearance of the thigh and the clinical findings during surgery. Fasciotomies were performed, and open reduction with internal fixation via Proximal Femoral Nail was done. The diagnosis of ACS was confirmed later on, by the biopsy results. Conclusion: This case suggests that myopathy can mask the classical presentation of ACS. Furthermore, the extent of pain complaints and accompanying paresthesia cannot be relied on in this regard and other clinical features should be considered in order to diagnose ACS.

Transarterial chemoembolization (TACE) has been used to treat hepatocellular carcinoma (HCC) for more than 4 decades. So far, there is no consensus on which substances and which method should be used for the most effective treatment. A publication commissioned by CIRSE 2021 attempted to formulate recommendations. However, only the spectrum of currently implemented procedures is outlined. No recommendation was made as to how the various patients should be treated. In this article, therefore, basic considerations regarding the technique of chemoembolization are presented. Additionally, the authors discuss fundamental considerations about the embolism materials used, the cytostatic drugs and their dosage, as well as about pain therapy during treatment. Then, a technique is presented which used degradable starch microspheres (DSM) as an embolic agent. This technique allows multiple treatments over a longer period. The aim is to provide interventionalists with a decision-making aid for the TACE technique. A major problem when evaluating publications from different working groups is that the technology used is not adequately described and the individual studies are therefore not comparable. Therefore, a classification is presented that systematizes the possible different techniques. Future randomized trials should use this classification. Hopefully, if they are carried out on a sufficient number of patients, it will finally be possible to identify what is the best TACE procedure for individual patients. Until then the technique proposed by the authors can be applied.

Introduction: Established predictors for COVID-19 related mortalities are diverse, with cytokine release syndrome (CRS), a key intermediator to the case fatalities being dominant and multi-faceted. The impact of these several risk factors on coronavirus mortality have been previously reported in several meta‐analyses limited by small sample sizes and premature data, and CRS not fully being accounted for. The objective of this systematic review and meta-analysis was to evaluate the evidence on the risk of COVID-19 related CRS and mortality with HIV serostatus using published data, and a meta-regression to account for possible covariates. Method: Electronic databases including Google Scholar, Cochrane Library, Web of Sciences (WOS), EMBASE, Medline/PubMed, COVID-19 Research Database, and Scopus, were systematically searched till 30th February, 2022. All human studies were included irrespective of publication date or region. Twenty-two studies with a total of 19,783,097 patients detailing COVID-related mortality and eleven with a total of 2,005,274 were included. To pool the estimate, a random-effects model with risk ration as the effect measure was used. Moreover, publication bias and sensitivity analysis were evaluated followed by meta-regression. The trial was registered (CRD42021264761) on the PROSPERO register. Results: The findings were consistent in stating the contribution of HIV infection for COVID-19 related CRS and mortality. The cumulative COVID-19 related mortality and CRS was 110270 (0.6%) and 48863 (2.4%) with total events of 2010 (3.6%), 108260 (0.5%) and 837(4.6%), 48026 (2.4%) among HIV-positive and negative persons respectively. HIV infection showed an increased risk of COVID-19 related CRS and mortality [RR= 1.48, 95% CI (1.16, 1.88) (P=0.002)] and [RR =1.19, 95% CI (1.02 -1.39) (P=0.00001)] respectively, both with substantial heterogeneity (I² > 80%). The true effects size in 95% of all the comparable populations fell between 0.64 to 2.22 and 0.67 to 3.29 for mortality and CRS respectively. MC studies and COVID-19 mortality with HIV infection showed a significant association [RR = 1.305, 95% CI (1.092 -1.559) (P = 0.003)], similar to studies conducted in America (RR = 1.422, 95% CI 1.233–1.639) and South Africa (RR = 1.123, 95% CI 1.052–1.198). HIV infection showed a risk for ICU admission [(P=0.00001) (I² = 0%)] and mechanical ventilation [(P=0.04) (I² = 0%)] as parameters of CRS. Furthermore, risk of COVID-19 related CRS is influenced by the year a study was conducted (R² = 0.55) and the region (R² = 0.11) same for mortality (R² = 0.60). The variance proportion explained by covariates was significant for CRS (I² = 86.5%, Q = 73.99, df = 10, P = 0.0000) (R² = 0.78) and mortality (I² = 87.5%, Q = 168.02, df = 21, p = 0.0000) (R² = 0.67). Conclusion: Our updated meta-analysis indicated that HIV infection was significantly associated with an increased risk for both COVID-19 – CRS and mortality, which might be modulated by regions, study setting and year. Risk for ICU admission and mechanical ventilation are the key indicators of CRS. We believe the updated data further anchoring CRS will contribute to more substantiation of the findings reported by similar earlier studies (Dong et al., 2021; K. W. Lee et al., 2021; Massarvva, 2021; Mellor et al., 2021; Ssentongo et al., 2021)

Purpose: To investigate the molecular basis of congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome. Methods: We report ocular features of 3 girls with GAPO syndrome born of consanguineous marriage in a multi- generation consanguineous family. The proband (4year old girl) and her younger sibling (1 year old girl) were operated for bilateral congenital glaucoma in both eyes. The elder sibling (10year old female) had features of GAPO syndrome but did not manifest features of glaucoma. Results: A genetic evaluation using whole exome sequencing revealed a homozygous ANTXR1 mutation in all 3 affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense mutation in TGFBI gene was shared in the two siblings with congenital glaucoma and GAPO syndrome.Conclusions: Mutations in TGFBI gene could have a role in the pathogenesis of congenital glaucoma.

A two phase survey of epilepsy was conducted in selected villages in Mundri West and East Counties (26 June−8 July, 2021), an onchocerciasis-endemic area in Western Equatoria State in South Sudan. In the first phase, households were visited by a trained research team to identify persons suspected to have epilepsy. In the second phase, persons suspected to have epilepsy were interviewed and examined by a clinician to confirm the diagnosis. A total of 364 households agreed to participate in the survey, amounting to 2,588 individuals. The epilepsy screening questionnaire identified 91 (3.5%) persons suspected to have epilepsy, of whom in 86 (94.5%) the diagnosis of epilepsy was confirmed by a clinician. The overall prevalence of confirmed epilepsy was 3.3% (95% CI: 2.7-4.1%), and of nodding syndrome 0.9% (95% CI: 0.6-1.4%). In 61 (16.8%) households there was at least one person with epilepsy. Only 1,212 (46.9%) of 2,583 people took ivermectin during the last distribution round in 2021. The annual epilepsy incidence was 77.3/100.000 (95% CI: 9.4-278.9/100,000) and the annual epilepsy mortality 251.2/100,000 (95% CI: 133.8-428.7/100,000). In conclusion, a high prevalence and incidence of epilepsy was observed in villages in Mundri. Urgent action is needed to prevent children from developing onchocerciasis-associated epilepsy by strengthening the local onchocerciasis elimination programme.

Background: Cytokine storm in COVID-19 is heterogenous. There are at least three subtypes: cytokine release syndrome (CRS), macrophage activation syndrome (MAS), and sepsis. Methods: A retrospective study comprising 276 patients with SARS-CoV-2 pneumonia. All patients were tested for ferritin, interleukin-6, D-Dimer, fibrinogen, calcitonin, and C-reactive protein. According to the diagnostic criteria, three groups of patients with different subtypes of cytokine storm syndrome were identified: MAS, CRS or sepsis. In each group, treatment results were assessed depending on whether or not tocilizumab was used. Results: MAS was diagnosed in 9.1% of the patients examined, CRS in 81.8%, and sepsis in 9.1%. Median serum ferritin in patients with MAS was significantly higher (5894 vs. 984 vs. 957 ng/ml, p &lt;0.001) than in those with CRS or sepsis. Hypofibrinogenemia and pancytopenia were also observed in MAS patients. In CRS patients, a higher mortality rate was observed among those who received tocilizumab, 21 vs. 10 patients (p=0.043), RR = 2.1 (95% CI 1.0-4.3). In MAS patients, tocilizumab decreased the mortality, 13 vs. 6 patients (p=0.013), RR = 0.50 (95% CI 0.25-0.99). Сonclusions: Tocilizumab therapy in patients with COVID-19 and CRS was associated with increased mortality, while in MAS patients it contributed to reduced mortality.

Objective: To examine associations between chemokines and menstrual cycle associated symptoms (MCAS). Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days of the menstrual cycle. MCAS is diagnosed when the total daily DRSP score during the menstrual cycle is > 0.666 percentile. We assayed plasma CCL2, CCL5, CCL11, CXCL8, CXCL10, EGF, IGF-1, and PAI-1 at days 7, 14, 21 and 28 of the menstrual cycle. Results: CCL2, CCL5, CCL11 and EGF are significantly higher in women with MCAS than in those without. Increased CCL2, CXCL10, CXCL8, CCL11 and CCL5 levels are significantly associated with DRSP scores while CCL2 is the most significant predictor explaining 39.6% of the variance. The sum of the neurotoxic chemokines CCL2, CCL11 and CCL5 is significantly associated with the DRSP score and depression, physiosomatic, breast-craving and anxiety symptoms. The impact of chemokines on MCAS symptoms may differ between consecutive weeks of the menstrual cycle with CCL2 being the most important predictor of increased DRSP levels during the first two weeks, and CXCL10 or a combination of CCL2, CCL11 and CCL5 being the best predictors during week 3 and 4, respectively. Discussion: The novel case definition “MCAS” is externally validated by increased levels of uterus-associated chemokines and EGF. Those chemokines are involved in MCAS and are regulated by sex hormones and modulate endometrium functions and brain neuro-immune responses, which may underpin MCAS symptoms. As such, uterine-related chemokines may link the uterus with brain functions via a putative uterine-chemokine-brain axis.

Introduction and objectives: a close association between metabolic syndrome among subjects with erectile dysfunction has been addressed, since mechanisms underlying metabolic syndrome compromise the blood flow to the penis in numerous ways. This study aims to analyze the relationship between erectile dysfunction and metabolic syndrome in a group of Mexican patients, to study the influence of other morbidity factors on erectile dysfunction, and to define the specific metabolic syndrome components most associated with erectile dysfunction severity. Methods: a descriptive and cross-sectional study was completed in a group of 86 adult Mexican patients with previous diagnosis of erectile dysfunction. Participants were classified as with or without metabolic syndrome. Erectile dysfunction severity, alcohol or tobacco consumption, and depressive behavior were identified through validated questionnaires and compared between both groups, as well as anthropometric, biochemical, and clinical parameters. Results: anthropometric measures, laboratory values, clinical characteristics and the Beck Depression Inventory score were significantly different among both groups. Additionally, more patients affected by severe and moderate erectile dysfunction were identified in the group with metabolic syndrome. Among the metabolic syndrome components, HbA1c >5.7% and fasting glucose >110 mg/dl were significantly associated to the development of erectile dysfunction (p = 0.004 and 0.04, respectively). Conclusions: metabolic syndrome components aggravate erectile dysfunction, particularly the lack of glycemic control manifested by Hb1Ac >5.7% and/or fasting glucose >110 mg/dL. The inclusion of fasting glucose and HbA1c as a complementary biochemical screening among patients with erectile dysfunction should be assessed.

Systemic amyloidosis is a multisystem illness characterized by fibrillary protein deposition, which causes dysfunction in the afflicted organ systems. Its diagnosis is frequently delayed since the disease's symptoms are unpredictable and non-specific. Its two main variants are light chain (AL) amyloidosis and transthyretin-related ATTR amyloidosis, which has both a sporadic (wildtype, ATTRwt) and hereditary (mutated, ATTRv) subtype. We discuss a case of Amyloidosis emerging in the kidneys and heart as a result of chronic inflammation caused by failure to treat TB, as well as its typical radiological characteristics, clinical presentation, imaging and instrumental evaluations, and therapeutic plan. This case report serves as a good reminder to medical personnel to ensure thorough patient follow-up in order to avoid extremely unusual and late complications resulting from treatment default.

The human gastrointestinal gut contains about 100 trillion of microorganisms including up to 5000 different types of bacteria called the "gut microbiome". Alterations in the composition of gut microorganisms (dysbiosis) can cause threatening for life diseases. This present seeks to evaluate if finally diet and more specifically functional foods affect the intestinal microbiome, and if obesity and the metabolic syndrome (Mets) are associated with the intestinal microbiome. This systematic review was accomplished according to PRISMA guidelines mostly using the key words functional foods, microbiome, obesity, Mets, Mediterranean diet. The search was carried out of recent scien-tific articles from the databases Pubmed, Scopus, and Google Scholar. The most studies discussed in this review showed a potential therapeutic effect of the Mediterranean diet rich in beneficial nutrients, on body weight, fat deposition, in correlation with modulation of the synthesis of gut microbiome. This literature review demonstrates a possible relationship between the metabolites of the microflora, the endotoxemia, obesity and Mets. The role of probiotics, prebiotics, and polyphe-nols in the prevention of obesity and Mets is of high importance in promoting healthy aging. The future challenge is to understand how different dietary patterns can regulate the composition of the gut microflora and whether these changes could be long-term.

Background: People with Down syndrome (DS) have a trisomy of chromosome 21 and marked deficits in verbal memory but relatively preserved visuospatial perception. Verbal memories are related to semantic knowledge. Little is known about the organization of semantic knowledge in people with DS, which was the aim of this study. Aims: The extent of false memory in people with DS was examined. Possible differences in the number of false memories induced by nominal and verbal themes were examined. Methods and Procedures: In the study phase, ten word lists with semantically related associates were presented. In the recognition phase, participants made judgments on whether each word had been represented previously as semantically related lures, old words, and semantically unrelated new words. Outcomes and Results: Differences in the processing of nominal and verbal theme-related lures were observed among people with DS. When processing nominal theme-related lures, people with DS showed delayed false positives. When processing verbal theme-related lures, people with DS showed no differences compared to controls. Similar patterns have been observed in people with DS when processing nominal theme-related associates and verbal theme-related associates. People with DS have delayed recognition of associates. When processing unrelated words, they showed significantly higher false positives than controls for both nominal and verbal eliciting themes. Further analyses of the themes revealed differences in false positives across syntactic categories among groups. Conclusions and Implications: People with DS showed a delayed recognition of associates and deviance in recognizing unrelated words in the nominal and verbal theme categories. People with DS were delayed in terms of nouns, but deviated with verbs in associated and unrelated words. Additionally, people with DS showed distinct patterns in processing five nominal lures and three verbal lures, suggesting that they formed false memories differently based on distinct syntactic categories. Thus, it was concluded that people with DS develop a deviant semantic structure. Category-based interventions for people with DS should be implemented in order to improve their semantic knowledge through lexical connections.

Infection with human immunodeficiency virus (HIV) and induced acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst the HAART regimens, darunavir and atazanavir in terms of protease inhibitors, tenofovir disoproxil fumarate, nevirapine or rilpivirine in terms of nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors respectively, and especially integrase inhibitors, have demonstrated the most favorable lipid profile emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.

Objectives: Metabolic interactions amongst mutated genes in myelodysplastic syndrome (MDS) offer promising avenues for novel anticancer treatments. Our comprehensive study delves into these mutational and transcriptomic landscapes, pinpointing hallmark gene mutations and deregulated gene expression that could influence MDS patients’ metabolomes. Methods: The study utilized a retrospective, cross-sectional approach, employing mutational data on the cBio Cancer Genomics Portal conducted and reported by the University of Tokyo in 2011 and multi-center MDS cohorts regulated by Wellcome Trust Sanger Institute, United Kingdom, all in 2020. For transcriptomic data, we selected three publicly accessible independent cohorts on the Gene Expression Omnibus (GEO) database (GSE114922 in Wellcome Trust Centre for Human Genetics, United Kingdome, GSE63569 in University of Oxford, United Kingdome, and GSE183328 in CIMA, Spain) held in 2015, 2018, and 2022, respectively. To compile clinical, mutational, and transcriptomic data on MDS patients from multiple datasets and studies. This meta-analysis included genomic data derived from cellular genomics sources to assess mutations in specific genes, alongside an examination of transcriptomic data from three separate datasets that have been previously published. Results: DNMT3A presented a 20% mutation frequency, playing a pivotal role in MDS metabolomics. The DNMT3A gene mutations displayed significant mutual exclusivity with the SRSF2, ASXL1, JAK2, and TP53 genes. The mutational analysis also showed that the gene expression landscape in MDS is associated with alterations to DNA methylation pathways. Conclusion: This analysis suggests a potential therapeutic niche. Identifying signature genes in MDS that have metabolic and methylation affiliations could illuminate the disease's intricate biology and inspire novel treatments.

Burning mouth syndrome (BMS) is a chronic oral pain disorder. There is a theory that BMS is nociplastic pain. Standard treatment for BMS has not yet been established. Kampo medicine is a traditional oriental medicine. The purpose of this study is to evaluate the effectiveness of rikkosan—a traditional Japanese herbal medicine (Kampo)—in the treatment of BMS. A single-center retrospective study was conducted in 20 patients who were diagnosed with BMS and treated with rikkosan alone (7.5 g) three times daily for approximately 4 weeks. They were treated with rikkosan alone approximately 4 weeks (29.5 ± 6.5 days) for the initial treatment. They had an average age of 63 years and 90% were being treated for other illnesses, but their medication status was the same during this study period, except for rikkosan. No side effects were observed in patients. Numerical rating scale (NRS) or visual analogue scale (VAS)/10 scores decreased significantly between the time of the initiation of rikkosan and the one-month after (-2.1 ± 1.2, p < 0.05). Rikkosan has a short-term effect of reducing NRS by two levels in BMS patients.

Serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome with growth deficit, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP-loss leads to longevity. CLPP substrates are selected by CLPX, an AAA+ unfoldase. CLPX is known to target delta-amino-levulinic-acid synthase (ALAS) to promote pyridoxal-phosphate (PLP) binding. CLPX may influence cofactor association with other enzymes. Here, the evaluation of P. anserina metabolomics highlighted arginine/histidine reduction. In Mus musculus cerebellum, reductions of Arginine/Histidine and Citrulline occurred with concomitant accumulation of heme-precursor protoporphyrin-IX. This suggests that increased biosynthesis of 5-carbon (C5) chain deltaALA consumes not only C4 succinyl-CoA with C1 glycine but also specific C5 delta amino-acids. As responsible enzymes for these converse effects, elevated abundance of CLPX and ALAS is paralleled by elevation of OAT (PLP-dependent, ornithine-delta-aminotransferase). Possibly as consequence of altered C1 metabolism, CLPP-null cells in P. anserina proteome profiles showed strong accumulation of a methyltransferase and two mitoribosomal large subunit factors. Reduced Histidine levels may explain previously observed metal interaction problems. As main nitrogen-storing metabolite, deficient Arginine would affect the urea cycle and polyamine synthesis. Supplementation of Arginine and Histidine might rescue growth deficits of CLPP-mutant patients.

Hepatic vein outflow obstruction causes congestion of the liver, leading to necrosis, fibrosis, and portal hypertension (PH). Transjugular intrahepatic portosystemic shunt (TIPS) reduces congestion and PH by providing artificial outflow. The aim of the study was to investigate fibrosis progression in patients with Budd-Chiari syndrome (BCS) and TIPS using transient elastography (TE). From 2010 to 2022, 25 patients received 80 TEs using FibroScan® (3.2±2.1 per patient). TIPS function was assessed using Doppler ultrasound or radiological intervention. At the time of TE examination, 21 patients had patent shunts. Four patients had occluded shunts but normal pressure gradients during the intervention. The first TE measurement performed 9.8±6.8 years after the BCS diagnosis showed stiffness values of 24.6±11.5 kPa. A second or last measurement performed 7.0±2.9 years after the first measurement showed similar stiffness values of 24.1±15.7 kPa (p=0.943). Except for three patients, the liver stiffness was always >12 kPa, indicating advanced fibrosis. Stiffness values obtained <5 years (n=8, 23,8±9,2 kPa) or >5 years after the BCS diagnosis (24,9±12,7 kPa) did not differ (p=0.907). In addition, stiffness was not related to the interval between BCS and TIPS implantation (p=0.999). One patient received liver transplantation, and two patients died from non-hepatic causes. Most patients develop mild to moderate cirrhosis, possibly during the early phase of the disease. Timing of TIPS did not influence fibrosis progression. This and the release of portal hypertension may argue in favor of a generous TIPS implantation practice in patients with BCS.

In the contest of childhood epilepsies, the concept of continuous spike-waves during slow sleep (CSWS) includes several childhood-onset heterogeneous conditions, sharing an electroencephalogram (EEG) characterized by a high frequency of paroxysmal abnormalities during sleep which are attributed negative effects on the cognitive development and behavior of the child. These negative effects may have the characteristics of a clear regression or of a slowdown in development. Seizures are very often present, but not constantly. The above makes it clear why CSWS have been included in epileptic encephalopathies, in which by definition the frequent EEG paroxysmal abnormalities have an unfavorable impact on the cognitive functions, including socio-communicative skills causing autistic features, even regardless of the presence of clinically overt seizures. Although several decades have passed since the original descriptions of the electroclinical condition of CSWS, there are still many areas that are little known and deserve to be further studied, including the EEG diagnostic criteria, the most effective electrophysiological parameter for monitoring the evolution, the role of the thalamus in the CSWS pathogenesis, the long-term evolution, the nosographic location of Landau-Kleffner syndrome, the standardized neuropsychological and behavioral assessment, the pharmacological and non-pharmacological therapies.

Abstract Background Pentraxin 3 (PTX3), an acute-phase protein associated with innate immunity, serves as a promising biomarker with diagnostic and prognostic value in preterm newborns. We aimed to investigate the relationship between PTX3 levels in neonates diagnosed with FIRS and early postnatal outcomes. Material and methods The study was designed as a prospective study. A total of 62 infants, 28–36 weeks of gestational age, were enrolled. During their neonatal intensive care unit (NICU) stay, the patients' mortality and morbidity outcomes were recorded and monitored. PTX3 concentrations were studied in plasma in the maternal peripheral blood and umbilical/peripheral veins of neonates. The relationship between PTX3 concentrations and neonatal outcomes was investigated using non-parametric tests, regression analysis, and receiver operating characteristic (ROC) analysis. Results PTX3 levels in cord blood and peripheral blood samples of neonates were significantly associated with clinical conditions such as respiratory distress syndrome (RDS) (p = 0.022), sepsis (p = 0.001), neonatal pneumonia (p = 0.016), and FIRS (p = 0.001). In infants with FIRS, the increase in PTX3 was statistically significant (p = 0.013), with an OR of 1.131 (95% CI 1.026–1.246). The PTX3 level had a cutoff value >4.45 (p<0.001) for predicting FIRS with an AUC of 0.759, 76.9% sensitivity (95% CI 56.4–91), and 63.9% specificity (95% CI 46.2–79.2). Conclusions This study demonstrates that PTX3 shows potential as a sensitive and specific biomarker for the early diagnosis of FIRS in preterm newborns. PTX3 levels were significantly associated with clinical outcomes such as RDS, sepsis, neonatal pneumonia, and FIRS.

In advanced Parkinson’s disease (PD), and especially in PD related dementia (PDD), psychotic symptoms are common. One of the manifestations of psychosis in PD is delusional misidentification syndrome, a phenomenon in which the patient believes the identity of a person, object or location has been duplicated or altered. Our patient, a 75-year-old female, was diagnosed with idiopathic Parkinson’s disease at the age of 68. Recently, her cognition deteriorated and she developed the believe that she lived in a replica of her real home. The delusion resolved completely with rivastigmine patches. Also visual hallucinations improved on treatment. This suggests that the dysfunctional connections were likely to be cholinergic.

Fibromyalgia syndrome (FMS) is a nonarticular rheumatic syndrome which presents as chronic musculoskeletal pain, stiffness and body aches. FMS affects approximately 2.5% of the population, mostly women. FMS causes physical and psychological problems and reduces quality of life. The objective of this study is to identify qualitative evidence about experiences of women diagnosed with FMS about their sexuality. Methods: Metasynthesis of qualitative studies. The search included articles published between 2000 and June 2023 on the PubMed, WOS, CINAHL, SCOPUS, and SCIELO databases. Results: 450 articles were found through the initial search, of which, only 9 fulfilled the criteria and were included in the thematic synthesis. From this analysis, three main themes emerged: (1) “I want to, but I can’t”: FMS causes a shift in feminine sexuality. (2) Resetting sex life and intimacy. (3) Taking charge of a “new sexuality.” Conclusions: Women with FMS suffer from limitations of their sexuality that affect their partner. Pain, stiffness and a loss of desire make sexual encounters difficult. Becoming aware of this and striving not to lose their sexuality is key to coping with this problem. Women and their sexual partners can change roles and encourage communication, games, foreplay or touching. The use of lubricants, physical exercise and complementary therapies, along with social, professional and partner support, are key to coping with FMS.

Intestinal microbiota attracts daily attention of a growing number of study which have attempted to link gut dysbiosIs with a variety of disease states: irritable bowel syndrome (IBS), inflamed bowel disease (IBD), Crohn's disease (CD), leaky gut syndrome (LGS), food intolerance, diabetes, metabolic syndrome, cancer, etc.. In our study we analyzed how intestinal dysbiosis may be related to chronic fatigue syndrome (CFS) and depression through the exchange of information through the gut-brain axis (GBA). We studied 33 subjects, 13 males and 20 females, who reported CFS or/and depression: we investigated their salivary cortisol levels, blood serotonin, omega 3/6 ratio, intestinal dysbiosis (calculated on the urinary levels of indoxyl sulfate and skatole), and we looked for the presence of Candida a. or mycetes in the stool; the data accumulated with this research show a correlation between the presence of Candida a./miceti, indoxyl sulfate urine values beyond the physiological and low serotonin levels. In addition, data analysis showed that the EPA/DHA values also show pro-inflammatory levels in case of dysbiosis and low serotonina levels. The relationship, however, with cortisol levels requires further research although this study showed a statistically significant positive correlation between these values, measured at specific times, and serotonin levels. Aims its connections with We investigated the relationship between stress (evaluated through the measurement of salivary cortisol levels) and gastrointestinal efficiency measured as a function of intestinal fermentative and putrefactive dysbiosis, evaluating the levels of urinary indoxyl sulfate in the first case (a possible correlation with the presence of Candida spp or Mycetes in the subjects feces was investigated), urinary skatole levels in the second one, in patients with chronic fatigue syndrome (SFC) and depression. In these patients we also have studied omega 3/6 ratio, and finally we have analized the impact that the alteration of these parameters can have on the serotonin levels. This research attemps to highlight the contact points, in some cases not so obvious, among these topics, contact points that, although they give us interesting indications, show the need to be further deepened by analyzing a larger amount of data.