1) Introduction: Negative pressure wound therapy (NPWT) is a frequently applied open abdomen (OA) treatment. There are only a few experimental data supporting this method and describing the optimal settings and pressure distribution in the abdominal cavity during this procedure. The aim of our study was to evaluate pressure values at different points of the abdominal cavity during NPWT in experimental abdominal compartment syndrome (ACS) animal model. 2) Methods: In this study (permission Nr. 13/2014/UDCAR) 27 Hungahib pigs (15.4- 20.2 kg) were operated. ACS was generated by implanting a plastic bag in the abdomen through mini-laparotomy and filled with 2100- 3300 ml saline solution (37 C°) to an intraabdominal pressure (IAP) of 30 mmHg. After 3 hours, NPWT (Vivano Med ® Abdominal Kit, Paul Hartmann AG, Germany) or Bogota bag was applied. NPWT group was divided into -50, -100 and 150 mmHg suction group. Pressure distribution to the abdominal cavity was monitored at 6 different points of the abdomen via a multichannel pressure monitoring system. 3) Results: The absolute pressure levels were significantly higher above than below the layer. The values of the pressure were similar in the midline than laterally. Amongst the bowels, the pressure values changed periodically between 0 and -12 mmHg which might be caused by the peristaltic movements. 4) Conclusions: The porcine model of the present study seems to be well applicable for investigating ACS and NPWT. It was possible to provide valuable for clinicians. The pressure was well distributed by the protective layer to the lateral parts of the abdomen and this phenomenon did not change considerably during the therapy.

A number of epidemiological studies have implicated elevated iron levels with higher risks of cardiometabolic diseases, including the metabolic syndrome (MetS). MetS is a pathologic clustering of metabolic derangements characterized by central obesity, insulin resistance, hypertension, and dyslipidemia, which can all lead to increased cardiovascular disease morbidity and mortality. However, it remains unclear whether a causal association exists between higher iron status and MetS and its associated risk components. Using the data from the Taiwan Biobank (TWB) (19,012 males; 42,340 females) and of the European Whites from the UK Biobank (UKB) (128,549 males; 142,817 females), we first constructed ethnic- and sex-specific hemoglobin-polygenic risk scores (Hb-PRS) as instrumental variable (IV) for iron status with the Hb-associated SNPs we previously identified from genome-wide association studies (GWAS). We then conducted Mendelian randomization (MR) analyses to elucidate the causal role of elevated iron (either Hb-PRS quintiles or continuous Hb-PRS) on various metabolic components. MR-Egger regressions determined the potential pleiotropic effects of the constructed Hb-PRSs, while the causal relationship of Hb-PRS with anemia served as a control in the analyses. The mean Hb concentration range corresponding to the Hb-PRS quintiles is relatively narrow in both UKB (14.91-15.21 g/dL for males and 13.39-13.71 g/dL for females) and TWB (14.79-15.28 g/dL for males and 12.78-13.21 g/dL for females). In these windows of Hb-PRSs, we found differential associations of Hb-PRS with diabetes (T2D) or hyperglycemia (HGY) as compared to other MetS components. The highest quintiles of Hb-PRSs were causally associated with greater risks of hypertension (HTN) and hypertriglyceridemia (DLP) (i.e., [Taiwanese HC males: Q5 vs. Q1 ORHTN = 1.10 (1.00–1.21), p = 0.0473, Q4 vs. Q1 ORDLP = 1.10 (1.00–1.22), p = 0.0485; European White males: ORHTN = 1.05 (1.01–1.09), p = 0.0194, ORDLP = 1.04 (1.00–1.08), p = 0.0468]). Interestingly, we obtained a consistent negative causal association between increasing Hb-PRS quintiles and T2D or HGY risk across all sex subgroups (i.e., [Taiwanese HC females: ORHGY = 0.89 (0.84–0.95), 0.88 (0.83–0.94), 0.87 (0.82–0.93), 0.86 (0.81–0.92) from Q2 to Q5; European White females: ORHGY = 0.92 (0.87–0.98), 0.91 (0.86–0.97), 0.93 (0.87–0.98), 0.87 (0.82–0.93) from Q2 to Q5; all p < 0.05]. The positive causal relationships between Hb-PRSs and diastolic blood pressure (DBP) and triglycerides (TG) but inverse causal association with glucose (GLU) and glycated hemoglobin (HbA1c) further corroborated such findings. There is, however, a lack of causal association with central obesity (CO), while a U-shaped type of causality was observed for gout (GT) or hyperuricemia (HUA). Sensitivity analyses, which excluded subjects based on self-reports of health conditions or medications and hospital episode statistics data, revealed similar results. Our MR studies confirm a modest causal relationship between propensity of elevated iron status and increased risk of HTN and DLP. We have further observed that modestly lower iron levels causally contribute to the development of T2D. Further validation and elucidation of the underlying biological mechanisms are highly warranted.

The enteric nervous system is affected by inflammatory bowel diseases (IBD). Gut microbiota ferment dietary fibers and produce short-chain fatty acids, such as Butyrate, which bind to G protein-coupled receptors, such as GPR41, and contribute to maintaining intestinal health. This work aimed to study the GPR41 in myenteric neurons and analyze the effect of Butyrate in mice submitted to experimental ulcerative colitis. The 2, 4, 6 trinitrobenzene sulfonic acid (TNBS) was injected intrarectally in C57BL/6 mice (Colitis). Sham group received ethanol (vehicle). One group was treated with 100mg/kg of Sodium Butyrate (Butyrate), and the other groups received saline. Animals were euthanized 7 days after colitis induction. Analyzes demonstrated colocalization of GPR41 with neurons immunoreactive (-ir) to nNOS and ChAT-ir, and absence of colocalization of the GPR41 with GFAP-ir glia. Quantitative results demonstrated losses of nNOS-ir, ChAT-ir, and GPR41-ir neurons in Colitis group, and Butyrate treatment attenuated neuronal loss. The number of GFAP-ir glia increased in Colitis group, whereas Butyrate reduced the number of these cells. In addition, morphological alterations observed in Colitis group were attenuated in Butyrate group. The presence of GPR41 in myenteric neurons was identified and the treatment with Butyrate attenuated the damage caused by experimental ulcerative colitis.

Protein glycation is usually referred to as an array of non-enzymatic post-translational modifications, formed by reducing sugars and carbonyl products of their degradation. Resulting advanced glycation end products (AGEs) represent a heterogeneous group of covalent adducts, known for their pro-inflammatory effects in mammals, and impacting on pathogenesis of metabolic diseases and ageing. In plants, AGEs are the markers of tissue ageing and response to environmental stressors, the most prominent of which is drought. Although water deficit enhances protein glycation in leaves, its effect on seed glycation profiles is still unknown. Moreover, the effect of drought on biological activities of seed protein in mammalian systems is still unstudied in respect of glycation. Therefore, here we address the effects of a short-term drought on the patterns of seed protein-bound AGEs and accompanying alterations in pro-inflammatory properties of seed protein in the context of seed metabolome dynamics. A short-term drought, simulated as polyethylene glycol-induced osmotic stress and applied at the stage of seed filling, resulted in dramatic suppression of primary seed metabolism, although secondary metabolome was minimally affected. This was accompanied with significant suppression of NF-kB activation in human SH-SY5Y neuroblastoma cells after a treatment with protein hydrolyzates, isolated from the mature seeds of drought-treated plants. This effect could not be attributed to formation of known AGEs. Most likely, the prospective anti-inflammatory effect of short-term drought is related to antioxidant effect of unknown secondary metabolite protein adducts, or down-regulation of unknown plant-specific AGEs due to suppression of energy metabolism during seed filling.

As Chronic Non-Communicable Diseases (CNCD) increase, preventive approaches become more crucial. In this review, Calorie Restriction (CR) effects on human beings were evaluated, comparing benefits and risks of different CR diets: classic CR vs ketosis-inducing diets, including Intermittent Fasting (IF), Classic Ketogenic Diet (CKD), Fasting Mimicking Diet (FMD), Very-Low-Calorie Ketogenic Diet (VLCKD) and Spanish Ketogenic Mediterranean Diet (SKMD). Special emphasis on Insulin Resistance (IR) was placed, as it mediates Metabolic Syndrome (MS), a risk factor for CNCD, and predicts MS diagnosis. CR is the most robust intervention known to increase lifespan and health span, with high evidence and known biochemical mechanisms. CR improves cardiometabolic risk parameters, boosts exercise insulin sensitivity response, and there may be benefits of implementing moderate CR on healthy young and middle-aged individuals. However, there is insufficient evidence to support long-term CR. CKD is effective for weight and MS management, and may have additional benefits such as prevention of muscle loss and appetite control. SKMD has extreme significance benefits for all the metabolic parameters studied. Studies show inconsistent benefits of IF compared to classic CR. More studies are required to study biochemical parameters, reinforce evidence, identify risks, and seek effective and safe nutritional CR approaches.

Abstract: The brain endothelial cell (BEC) glycocalyx (ecGCx) is a BEC surface coating consisting of a complex interwoven polysaccharide (sweet husk) mesh-like network of membrane-bound proteoglycans, glycoproteins, and glycosaminoglycans (GAGs) covering the apical luminal layer of the brain endothelial cells. The ecGCx may considered as the 1st barrier of a tripartite blood-brain barrier (BBB) consisting of 1) ecGCx; 2) BECs; (3) extravascular compartment of pericytes, extracellular matrix, and perivascular astrocytes, Perturbations of this barrier allow for increased permeability in the postcapillary venule that will be permissive to both fluids, solutes, and proinflammatory peripherally-derived leukocytes into the perivascular spaces (PVS) to result in enlargement as well as increased neuroinflammation. The ecGCx is known to have multiple functions, which include its physical and charge barrier, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation functions. This review discusses each of the listed functions in detail and utilizes multiple transmission electron micrographs and illustrations to allow for a better understanding of the ecGCx structural and functional roles as it relates to enlarged perivascular spaces (EPVS). This is the 5th review of a series quintet that discuss the importance of EPVS from the perspective of the cells of brain barriers. Attenuation and/or loss of the ecGCx results in brain barrier disruption with increased permeability to proinflammatory leukocytes, fluids and solutes, which accumulate in the postcapillary venule perivascular spaces. This accumulation results in obstruction and results in EPVS with impaired waste removal of the recently recognized glymphatic system. Importantly, EPVS are progressively being regarded as a marker of cerebrovascular and neurodegenerative pathology.

Functional gastro-intestinal disorders (FGID) including irritable bowel syndrome (IBS) are frequently handled by self-management with over the counter (OTC) products such as hyoscine butylbromide (HBB), alone or in combination with paracetamol, and natural products such as peppermint oil. To obtain real-world information, we have performed an anonymous pharmacy-based patient survey among 1686 users of HBB, HBB + paracetamol and peppermint oil. Based on the distinct but overlapping indications for the three OTC products, multiple logistic regression was applied to compare them in users reporting gastrointestinal cramps and pain, bloating, flatulence, or IBS as cardinal symptom. All three treatments reduced symptoms and associated impairments of work/daily chores, leisure activities, and sleep by approximately 50%. Based on the four cardinal symptoms and the four dependent continuous variables of interest (change of intensity of symptoms and of the three impairment domains) a total of 16 logistic regression models were applied. HBB, HBB + paracetamol, and peppermint oil had similar reported overall effectiveness in those models. Gender, age, baseline symptom severity and impairment in one of three domains had small and inconsistent effects on perceived treatment success. We provide evidence that HBB, HBB + paracetamol, and peppermint oil have comparable effectiveness in their approved indications under real-world conditions in an OTC setting.

Patients with sAID are a population at high risk of severe COVID outcomes but evidence on the efficacy of SARS-CoV-2 vaccination in this group of patients is scarce. To investigate the efficacy of SARS-CoV-2 vaccination in patients with systemic autoinflammatory diseases (sAID) receiving interleukin-1 inhibition is important. Vaccination responses from 100 sAID patients most of whom were treated with IL-1inhibitors (N=96) and 100 healthy controls (HC) were ana-lyzed. After 2nd SARS-CoV-2 vaccination, sAID patients showed similar anti-SARS-CoV-2 anti-body responses (mean (SD): 6.7 (2.7)) compared to HC (5.7 (2.4)) as well as similar neutralizing antibodies (85.1 ±22.9% vs. 82.5 ±19.7%). Anti-SARS-CoV-2 antibody responses and neutralizing antibodies were similar in sAID patients after SARS-CoV-2 infection and double vaccination. Furthermore, while antibodies increased after 1st and 2nd vaccination in sAID patients they did not further increase after 3rd and 4th vaccination. No difference was found in antibody responses between anakinra and anti-IL-1 antibody treatments and also the additional use of colchicine or other drugs did not impair vaccination responses. Primary and booster SARS-CoV-2 vaccination lead to protective antibody responses in sAID patients, which are at the same level of vaccination responses in HC and in sAID patients after SARS-CoV-2 infection. Immunomodulatory treatments used in sAID do not seem to affect antibody responses to the SARS-CoV-2 vaccine.

Abstract: Astrocytes (ACs) are the most abundant human cell in the brain and importantly, are the master connecting and communicating cells that provide structural and functional support of brain cells at all levels of organization. Further, they are recognized to be the guardians and housekeepers of the brain. Protoplasmic perivascular astrocyte endfeet and their basal lamina form the delimiting outermost barrier (glia limitans) of the perivascular spaces in postcapillary venules and are important for the clearance of metabolic waste and comprise the glymphatic system, which is critically dependent on the proper waste removal by the pvACef polarized aquaporin 4 water channels. Also, the protoplasmic perisynaptic astrocyte endfeet (psACef) are important in cradling the neuronal synapses that serve to maintain homeostasis and serve a functional and supportive role for synaptic transmission. Enlarged perivascular spaces (EPVS) are emerging as important aberrant findings on magnetic resonance imaging (MRI) and associate with white matter hyperintensities, lacunes, aging, accepted to be biomarkers for cerebral small vessel disease, increased in obesity, metabolic syndrome, and type 2 diabetes. Knowledge is exponentially expanding regarding EPVS along with the glymphatic system, since EPVS are closely associated with impaired glymphatic function and waste removal from the brain to the cerebrospinal fluid and systemic circulation. This review intends to focus on how the pvACef play a crucial role in the development of EPVS.

Enzyme replacement therapy (ERT) improves the somatic manifestations in mucopolysaccharidoses (MPS))．However, because intravenously administered enzymes cannot cross the blood brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT intend to achieve CNS effects, but the burdens on patients are inimical to long-term multiple administrations. However, after pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in mice model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the hitherto obtained preclinical and clinical evidence associated with this drug, and discusses the preclinical, translational and clinical challenges of evaluating, ameliorating and preventing the neurodegeneration in patients with MPS-II.

We document for the first time epsilon waves on the electrocardiogram of a patient with Dravet syndrome (DS) who does not exhibit structural cardiac pathology. DS, a severe form of pediatric epilepsy, involves mutations in the SCN1A gene, which disrupt sodium ion flow and increase the risk of sudden unexpected death in epilepsy. The epsilon waves, typically associated with arrhythmogenic right ventricular dysplasia, may also suggest a link between neuronal and cardiac dysfunctions. In our case, the epsilon waves appear to originate from abnormalities in sodium channels rather than structural changes in the myocardium. This finding underscores the importance of assessing both neurological and cardiac manifestations in patients with severe epilepsy, opening new avenues for the research and treatment of these interactions in DS.

Abstract: Infertility affects around 1 in 5 couples in the world. Congenital absence of the uterus results in absolute infertility in females. Mullerian agenesis(MA) is the nondevelopment of the uterus. Mayer-Rokitansky-Küster-Hauser(MRKH) syndrome is a condition of uterovaginal agenesis in the presence of normal ovaries and 46 XX Karyotype. With the advancement of re-productive techniques, having a biological offspring in women with MA is possible. The exact etiology of MA is unknown although several genes and mechanisms affect the development of Mullerian ducts. Through this systematic review of the available literature, we searched for the genetic basis of MA. The aims included identification of the genes, chromosomal locations, changes responsible for MA, and fertility options, in order to offer proper management and counseling to these women with MA. A total of 85 studies were identified through searches. Most of the studies identified multiple genes at various locations although the commonest in-volved chromosomes 1, 17, and 22. There is also conflicting evidence of the involvement of var-ious candidate genes in the studies. The etiology of MA seems to be multifactorial and complex involving multiple genes, and mechanisms including various mutations and mosaicism.

Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries [1]. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease [1], all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under transcriptional regulation of both the nuclear and the mitochondrial genome, to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, to dynamics which regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function to cause disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs including the ovary (oocyte and granulosa cell), uterus, placenta, and circulation to cause reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in transgenerational transmission of PCOS and metabolic disorders.

A 36-year-old professional marathon runner reported sudden heart palpitations occurring during competitions, with heart rates (HR) of 230 bpm recorded on sports HR monitor (HRM) over 4 years. These episodes subsided upon the cessation of exercise. Electrocardiograms, echocardiography, and cardiac magnetic resonance imaging results were borderline for athlete's heart. Because an electrophysiology study and standard exercise tests provoked no arrhythmia, doctors suspected Munchhausen syndrome. Ultimately, an exercise test that simulated the physical effort during a competition provoked tachyarrhythmia consistent with the HRM readings. This case demonstrates the diagnostic difficulties related to exercise-induced arrhythmia and the diagnostic usefulness of sports HRMs.

Abstract: Cherubism is a rare genetic disorder characterized by painless bilateral expansion of the mandible and maxilla. We present an unusual case of a 50-year-old female patient with Ramon syndrome, a rare variant of cherubism, accompanied by gingival fibromatosis. The patient exhibited symptoms of short stature, mental retardation, rheumatoid arthritis, epilepsy, hirsutism, and gingival enlargement. Clinical examination revealed generalized gingival inflammation with plaque and attachment loss. Radiographically, bilateral defined multilocular radiolucencies were observed in the mandibular body and ramus. The patient underwent a non-surgical phase, including oral hygiene motivation and periodontal debridement, followed by a surgical phase involving gingivoplasty and internal bevel gingivectomy with open flap debridement. Histopathological analysis confirmed the presence of fibroblasts, multinucleated giant cells, and fibrous connective tissue. The patient's son also presented with bilateral facial swelling and similar radiographic findings, indicating familial inheritance of cherubism. The case demonstrates the clinical, radiographic, and histopathological features of cherubism associated with gingival fibromatosis and highlights the challenges in diagnosis and management. Regular follow-up and maintenance are essential for long-term stability and prevention of recurrence. This report contributes to the limited literature on cherubism in older patients and emphasizes the importance of early identification and intervention in affected individuals.

Background: The aim of this study was to demonstrate involvement of whole-body compensatory alignment in different conditions of spinopelvic sagittal balance (compensated/decompensated). Methods: We enrolled 330 healthy subjects and divided them according to sagittal vertical axis (SVA): the compensated group, < 4 cm, (group C) and the decompensated group, ≥ 4 cm, (group D). The correlation between lack of ideal lumbar lordosis (iLL), which is calculated by using the Schwab formula, and the compensatory radiographic parameters in each group were analyzed. The threshold value of KF angle that indicates a spinopelvic sagittal imbalance (SVA ≥ 4) was determined by ROC curve analysis. Results: Correlation analysis of lack of iLL and each com-pensatory parameter showed a strong correlation for pelvic tilt (PT) (r = -.723), and a weak cor-relation for thoracic kyphosis (TK) (r = 275) in Group C. In Group D, the correlations were strong for PT (r = -.796), moderate for TK (r = .462), and KF (r = -.415). The optimal cutoff value for KF angle was determined to be 8.4 degrees (sensitivity 89%, specificity 46%). Conclusions: The pre-sent study showed differences between compensated/decompensated spinopelvic sagittal balance in the correlation strength between lack of iLL and whole-body compensatory parameters.

The main aim of the present study was to explore health professionals’ reported experiences and approaches to managing children who receive a designation of cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive inconclusive diagnosis following a positive NBS result for cystic fibrosis. An online questionnaire was distributed via Qualtrics Survey Software and circulated to a purposive, international sample of health professionals involved in managing children with this designation. In total, 101 clinicians completed the online survey; 39 from the US, six from Canada and 56 from Europe (including the UK). Results indicated that while respondents reported minor deviations in practice, they were cognizant of recommendations in the updated guidance and for the most part, attempted to implement these into practice consistently internationally. Where variation was reported, the purpose of this appeared to be to enable clinicians to respond to either clinical assessments or parental anxiety in order to improve outcomes for the child and family. Further research is needed to determine if these findings are reflective of both a wider audience of clinicians and actual (rather than reported) practice.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood monocytic cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase TORC1. These differences were correlated with disease severity, as measured by the Richardson and Lidbury Weighted Standing Test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and Receiver Operating Characteristic (ROC) curve analysis. We found that results from three different tests, lymphocyte death rate, mitochondrial respiratory function and TORC1 activity could each individually serve as biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.

Celiac disease is a gluten-sensitive immune-mediated enteropathy of the small intestine that occurs in genetically predisposed individuals. Abnormal immune response results in mucosal inflammation, villous atrophy, and crypt hyperplasia. This study was a proof-of-concept exercise that used a convolutional neural network to classify hematoxylin and eosin (H&E) histological images of celiac disease, normal small intestine control, and non-specified duodenal inflammation; 7294, 11,642, and 5966 images, respectively. The trained network classified celiac disease images with high performance (accuracy 99.7%, precision 99.6%, recall 99.3%, F1-score 99.5%, and specificity 99.8%). Interestingly, when the same network (already trained for the 3 class images), analyzed duodenal adenocarcinoma (3723 images), the new images were classified as duodenal inflammation in 63.65%, small intestine control in 34.73%, and celiac disease in 1.61% of the cases. Finally, when the network was retrained using the 4 histological subtypes of images, all performance parameters were above 99% for celiac disease. In conclusion, the convolutional neural network (CNN)-based deep neural system was able to classify medical histological images with high performance. Narrow artificial intelligence (AI) is designed to perform tasks that typically require human intelligence, but it operates within limited constraints and is task specific.

Malassezia are lipid-dependent basidiomycetous yeast of the normal skin microbiome, although Malassezia DNA has been recently detected in other body sites and has been associated with cer-tain chronic human diseases. This new perspective raises many questions. Are these yeasts truly present in the investigated body site or were they contaminated by other body sites, adjacent or not? Does this DNA contamination come from living or dead yeast? If these yeasts are alive, do they belong to the resident mycobiota or are they transient colonizers which are not permanently established within these niches? And, finally, are these yeasts associated with certain chronic diseases or not? In an attempt to shed light on this knowledge gap, we critically re-viewed the 31 published studies focusing on the association of Malassezia spp. with chronic human diseases, including psoriasis, atopic dermatitis (AD), chronic rhinosinusitis (CRS), asthma, cystic fibrosis (CF), HIV infection, inflammatory bowel disease (IBD), colorectal cancer (CRC), and neurodegenerative diseases.

Nutrition support is increasingly recognized as a clinically relevant aspect of the intensive care treatment of cardiac surgery patients. However, evidence from adequate large-scale studies evaluating its clinical significance for patients’ mid- to long-term outcome remains sparse. Considering nutrition support as a key component in the perioperative treatment of these critically ill patients, led us to review and discuss our understanding of the metabolic response to the inflammatory burst induced by cardiac surgery. In addition, we discuss how to identify patients who may benefit from nutrition therapy, when to start nutritional interventions, present evidence about the use of enteral and parenteral nutrition and the potential role of pharmaconutrition in cardiac surgery patients. Although the clinical setting of cardiac surgery provides advantages due to its scheduled insult and predictable inflammatory response, researchers and clinicians face lack of evidence and several limitations in the clinical routine, which are critically considered and discussed in this paper.

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which alter the functions of domains to either bind to methylated DNA or interact with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We tried to elucidate RTT through evolution and structure assessment of MeCP2, CDKL5, and FOXG1, by focusing on their binding partners and disordered structures. Here, we provide insight into the similarities of the FOXG1 and MECP2 binding partners evolution and function. On the other hand, we suggest that CDKL5 could be a potential candidate for a classical RTT treatment, particularly based on its disordered structure that spans after the catalytic domain to the C-terminus, which shows abundant linear motifs that can bind to molecules with divergent structures of similar affinity. Additionally, we provide insight into the relationship between disordered structure and disease.

Background: Symptomatic Pelvic Congestion Syndrome (PCS) is often underdiagnosed and undertreated. We investigate a symptoms-based screening algorithm and treatment algorithm focused on position and location of pain for each type of PCS. Methods: This study is a retrospective, single-institution, multi-site review of 343 female patients who presented with pelvic pain. Results: Following a symptoms-based algorithm, 302 patients fulfilled criteria for inclusion; 299 patients had positional symptoms with a positive predictive value (PPV) of 97.99%, sensitivity of 98.99% and Odds Ratio (OR) of 48.83 (p=0.0003) while duplex ultrasonography (DUS) had a PPV of 98.84%, sensitivity of 86.49%, and OR of 6.4 (p=0.0396) confirmed by contrast venography. Patients with Type I PCS were treated with embolization and 87.5% reported total relief of anterior symptoms. Patients with Type II PCS were treated with embolization and/or vascular stenting based on their associated lesion, May-Thurner syndrome or Nutcracker syndrome, and 88.54% reported ≥50% symptom relief and 59.03% reported ≥80% symptom relief. Full treatment resulted in a mean “overall satisfaction” score of 96.07%. Conclusions: Algorithmic approaches are essential for PCS evaluation, diagnosis, and treatment. Patients with positional pelvic symptoms consistent with PCS should undergo diagnostic venography. Distinguishing between the types of PCS and using symptoms as a guide may be beneficial over a “one-size-fits-all” approach.

Inflammatory processes play major roles in carcinogenesis and progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But there are no therapies for NASH related HCC, especially focusing on these critical steps. Previous studies reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed expression of phosphorylated nuclear factor-κB and transforming growth factor-β. Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.

In Sub-Saharan African Countries such as Nigeria with high prevalence rate, Child HIV/AIDs acquired through Mother-to-Child transmission (MTCT) can be largely prevented by using a well-established prevention programme and scheme. This study examined factors that can enhanced Prevention of Mother-to-Child transmission (PMTCT) in Nasarawa State. To achieve this, structured questionnaire were used to collect data from one hundred and sixteen (116) women attending two (2) primary facilities and two (2) secondary facilities in the State. This study utilized methods of Poisson Regression, Negative Binomial Regression and Logistic Regression Analyses. Results revealed that women with at least a secondary school education, women with husband in military and women with perceived confidentiality of their HIV status significantly enhanced PMTCT of HIV in Nasarawa State while significant proportion of the women attest to the fact that drugs are available in the facilities (p-value=0.0000<0.05) . Other factors include mother income level, willingness to continue with PMTCT programme and women in support group can also enhanced PMTCT though they are not significant. This study recommends that the factors identified should be explored by NGOs, Ministry of Health and, Support groups and other relevant agencies since they have the capacity to enhanced PMTCT of HIV in Nasarawa State, Nigeria.

Macrophages serve as vital defenders, protecting the body by exhibiting remarkable cellular adaptability in response to invading pathogens and various stimuli. These cells express nicotinic acetylcholine receptors, with the α7-nAChR being extensively studied due to its involvement in activating the cholinergic anti-inflammatory pathway. Activation of this pathway plays a crucial role in suppressing macrophages' production of proinflammatory cytokines, thus mitigating excessive inflammation and maintaining host homeostasis. Macrophage polarization, which occurs in response to specific pathogens or insults, is a process that has received limited attention concerning the activation of the cholinergic anti-inflammatory pathway and the contributions of the α7-nAChR in this context. This review aims to present evidence highlighting how the cholinergic machinery in macrophages, led by the α7-nAChR, facilitates the polarization of macrophages towards anti-inflammatory phenotypes. Additionally, we explore the influence of viral infections on macrophage inflammatory phenotypes, taking into account cholinergic mechanisms. We also review the current understanding of macrophage polarization in response to these infections. Finally, we provide insights into the relatively unexplored partial duplication of the α7-nAChR, known as dup α7, which is emerging as a significant factor in macrophage polarization and inflammation scenarios.

A 70-year-old female with a significant medical history of hypertension, hypothyroidism, chronic back pain, and a left hip prosthetic joint infection experienced complications following a total hip replacement. After multiple revisions and eventual discharge to a rehabilitation facility, she developed surgical site bleeding and a femoral head dislocation extending into the pelvis. At our hospital, imaging revealed a failed hip arthroplasty with extensive damage and infection, necessitating complex revision surgery and an antibiotic regimen. During her treatment, she developed a diffuse rash diagnosed as vancomycin-induced hypersensitivity reaction (DRESS), prompting a switch to oral linezolid and systemic corticosteroids. Despite transient eosinophilia and elevated inflammatory markers, her condition stabilized, and she was discharged with instructions for follow-up. This case underscores the importance of vigilant monitoring and timely intervention in managing complex postoperative infections and drug reactions.

Brain imaging studies have recently provided some evidence in favour of covert cognitive processes ongoing in patients with disorders of consciousness (DoC) (e.g., minimally consciousness states, vegetative state/unresponsive wakefulness syndrome) engaged in passive sensory stimulation or active tasks such as motor imagery. In this exploratory study, we used transcranial magnetic stimulation (TMS) of the motor cortex to assess modulations of corticospinal excitability induced by action observation in eleven patients with DoC. Action observation is known to facilitate corticospinal excitability in healthy subjects, unveiling how the observer’s motor system maps others’ actions onto her/his motor repertoire. Additional stimuli were non-biological motion and acoustic startle stimuli, provided that sudden and loud acoustic stimulation is known to lower corticospinal excitability in healthy subjects. Results indicate that some form of motor resonance is spared in a subset of patients with DoC with some significant difference between biological and non-biological motion stimuli. However, there was no covariation between corticospinal excitability and the type of DoC diagnosis (i.e., whether VS/UWS or MCS). Similarly, no covariation was detected with clinical changes between admission and discharge in clinical outcome measures. Both motor resonance and biological/non-biological motion discrimination correlated with the amplitude of the N20 somatosensory evoked potentials following the stimulation of the median nerve at the wrist (i.e., the temporal marker signalling the activation of the contralateral primary somatosensory cortex). Moreover, the startle-evoking stimulus produced an anomalous increase in corticospinal excitability, suggesting a functional dissociation between cortical and subcortical circuits in patients with DoC. Further work is needed to better comprehend the conditions in which corticospinal facilitation occurs and whether and how they may relate to individual clinical parameters.

Device-mediated, non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive techniques and devices have been proposed or investigated to enhance drug delivery across the BBB. This paper presents the current state of the art and case studies that address the pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women characterized by hyperandrogenism, oligo-anovulation and insulin resistance closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter-gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutional model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are now affected by today’s contemporary environment through epigenetic events that predispose to lipotoxicity with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today’s obesogenic environment.

Polycystic ovary syndrome (PCOS) is increasingly being characterized as an evolutionary mismatch disorder that presents with a complex mixture of metabolic and endocrine symptoms. The Evolutionary Model proposes that PCOS arises from a collection of inherited polymorphisms that have been consistently demonstrated in a variety of ethnic groups and races. In-utero developmental programming of susceptible genomic variants are thought to predispose the offspring to develop PCOS. Postnatal exposure to lifestyle and environmental risk factors results in epigenetic activation of developmentally programmed genes and disturbance of the hallmarks of health. The resulting pathophysiological changes represent the consequences of poor-quality diet, sedentary behaviour, endocrine disrupting chemicals, stress, circadian disruption, and other lifestyle factors. Emerging evidence suggests that lifestyle-induced gastrointestinal dysbiosis plays a central role in the pathogenesis of PCOS. Lifestyle and environmental exposures initiate changes that result in disturbance of the gastrointestinal microbiome (dysbiosis), immune dysregulation (chronic inflammation), altered metabolism (insulin resistance), endocrine and reproductive imbalance (hyperandrogenism), and central nervous system dysfunction (neuroendocrine, autonomic nervous system). PCOS can be a progressive metabolic condition that leads to obesity, gestational diabetes, type 2 diabetes, metabolic-associated fatty liver disease, metabolic syndrome, cardiovascular disease, and cancer. This review explores the mechanisms that underpin the evolutionary mismatch between ancient survival pathways and contemporary lifestyle factors involved in the pathogenesis and pathophysiology of PCOS.

Metabolic disorders, metabolic syndrome and non-alcoholic fatty liver disease, and depression are those of the most common and debilitating disorders worldwide that often coexist further increasing mortality risks. Although the exact mechanisms underlying this association are poorly known, several hypotheses have been proposed: antipsychotic medication and antidepressants use, diet and physical activity or any other lifestyle factors. However, the high co-occurrence rate of depression and metabolic disorders suggests a possible pathophysiological overlap. In this paper I review several raised mechanisms for this overlap which are the hypothalamic-pituitary-adrenal axis dysregulation, immune alterations with chronic inflammation, as well as oxidative stress. In my view, there is one common thread running through all the aforementioned areas of pathophysiology which is microbiota alteration. So far, several possible interventions in our microbiota have been introduced into clinical practice - dietary and other lifestyle changes, supplementation with prebiotics or probiotics, fecal microbiota transplantation – but with vague indications. A better characterization of the above associations may represent a critical step at phenotyping, and a more targeted approach to the treatment of both depressive and metabolic disorders. At the end of the paper, I give several practical applications for future studies.

Next Generation Sequencing based cancer risk screening with multigene panels has become the most successful method for programming cancer prevention strategies. ATM germ-line heterozygosity has been described as able to increase tumor susceptibility. In particular, families that carry heterozygous germ-line variants of ATM gene show a 5- to 9-fold risk of developing breast cancer. Recent studies identified ATM as the second most mutated gene after CHEK2 in BRCA-negative patients. Nowadays, more than 170 potential missense variants and several truncating mutations have been identified in ATM gene. Here we present the molecular characterization a new ATM deletion, identified thanks to the CNV algorithm implemented in the NGS analysis pipeline. An automated workflow implementing the SOPHiA Genetics’ Hereditary Cancer Solution (HCS) protocol was used to generate NGS libraries that were sequenced on Illumina MiSeq Platform. NGS data analysis allowed to identify a new inactivating deletion of exons 19-27 of ATM gene. DNA breakpoint was characterized both at DNA and RNA level

Objectives: This study was undertaken to reveal therapeutic effects and the preliminary mechanism of Chinese medicine formula Qianlie Tongli decoction (QTD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods: A total of 50 male C57BL/6 mice were randomly divided into five groups. All groups except the control group were injected subcutaneously T2 peptide emulsion, which induced the CP/CPPS model. After the induction of CP/CPPS, the model group was given 0.9% NaCl by oral gavage while low-dose, medium-dose, and high-dose groups were treated with Chinese medicine formula. Micturition habits and pain behavior of mice were analyzed for each group. Hematoxylin and eosin staining were used to investigate prostate inflammation. The serum level of tumor necrosis factor-α (TNF-α) was measured by enzyme-linked immunosorbent assay (ELISA) kit. Key findings: Chinese medicine formula significantly reduced the number of urine spots and improved pain response frequency in the medium-dose and high-dose group. The high-dose group showed reduced considerably inflammatory lesion and inflammatory cell infiltration than the low-dose and medium-dose groups. Serum levels of TNF-α in the high-dose group were significantly reduced compared with the model group. Conclusions: The results demonstrated the therapeutic effects of Qianlie Tongli decoction in CP/CPPS mice by analyzing clinically relevant symptoms (urinary tract system, pelvic pain, and prostate inflammation), and preliminary explored the inflammatory-related treatment mechanisms by measuring TNF-α.

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems. Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

Compelling epidemiologic data support the critical role of dietary fructose in the epidemic of obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). The metabolic effects of fructose on the development of metabolic syndrome and NAFLD are not completely understood. High fructose intake impairs copper status, and copper-fructose interactions have been well documented in rats. Altered copper-fructose metabolism leads to exacerbated experimental metabolic syndrome and NAFLD. A growing body of evidence has demonstrated that copper levels are low in NAFLD patients. Moreover, hepatic and serum copper levels are inversely correlated with the severity of NAFLD. Thus, high fructose consumption and low copper availability are considered two important risk factors in NAFLD. However, the causal effect of copper-fructose interactions as well as the effects of fructose intake on copper status remain to be evaluated in humans. The aim of this review is to summarize the role of copper-fructose interactions in the pathogenesis of the metabolic syndrome and discuss the potential underlying mechanisms. This review will shed light on the role of copper homeostasis and high fructose intake and point to copper-fructose interactions as novel mechanisms in the fructose induced NAFLD.

Purpose: To investigate the effect of pigment dispersion on trabecular meshwork (TM) cells. Methods: Porcine TM cells from ab interno trabeculectomy specimens were exposed to pigment dispersion, then analyzed for changes in morphology, immunostaining, and ultrastructure. Their abilities to phagocytose, migrate, and contract were quantified. An expression microarray, using 23,937 probes, and a pathway analysis were performed. Results: TM cells readily phagocytosed pigment granules. Pigment induced stress fiber formation (pigment (P): 60.1 ± 0.3%, n = 10, control (C): 38.4 ± 2.5%, n = 11, P < 0.001) and contraction at 24 hours onward (P < 0.01). Phagocytosis declined (P: 68.7 ± 1.3%, C: 37.0 ± 1.1%, n = 3, P < 0.001) and migration was reduced after 6 hours (P: 28.0.1 ± 2.3, n = 12, C: 40.6 ± 3.3, n = 13, P < 0.01). Microarray analysis revealed that Rho, IGF-1, and TGFβ signaling cascades were central to these responses. Conclusions: TM cell exposure to pigment dispersion resulted in reduced phagocytosis and migration, as well as increased stress fiber formation and cell contraction. The Rho signaling pathway played a central and early role, suggesting that its inhibitors could be used as a specific intervention in treatment of pigmentary glaucoma.

The research work examined the trend of HIV/AIDS, Tuberculosis, and Hepatitis diseases in Plateau state. Annual data from 2003 to 2018 was collected from the department of biostatistics at Plateau State Specialist Hospital (PSSH), Jos. The methods of analysis used are the Poisson Autoregressive Model (PAR(1)) and the Poisson Exponentially Weighted Moving Average Model (PEWMA). The results revealed a significant annual decrease of 23.9% and 4% in Tuberculosis and HIV/AIDS respectively. Furthermore, the results showed a significant annual increase of 46% in Hepatitis. The PEWMA model used revealed that TB increased by 0.02% when there is an increase in HIV but not significant, while Hepatitis significantly aggravates TB by at least 0.24%. Also, there is a significant rise in HIV by 0.85% when TB increases but Hepatitis has no such effect on HIV. Lastly, PEWMA model indicated a rise of 0.5% in Hepatitis cases when there is an increase in TB, but a surge in HIV has no such effect on Hepatitis cases in Jos. The study recommended that fight against TB should be intensified since TB cases significantly affect both HIV and Hepatitis in Jos, Nigeria.

Background and Objectives: The relevance of red flags in serious spinal pathology (SSP) evolved throughout the last years. Recently, new considerations have been proposed to expand the consideration of red flags. The purpose of this study was to determine, approve and test a model for the triage and manage-ment process of SSP based on the latest data available in the literature. Materials and Methods: The SSP model was initially built on the basis of a literature re-view. The model was further determined and approved by an expert panel us-ing a Delphi process. Finally, clinical scenario were used to test the applicabil-ity of the model. Results: After three rounds of Delphi process, panellists reached a consensus on a final version of the model. The use of clinical scenari-os by experts bring about reflexive elements both on the determined model and on the evocative SSP of the clinical cases. Conclusions: The validation of the model and its implementation in the clinical field could help assess the skills of first-line practitioners managing spinal painful patients. To this end, the devel-opment of additional clinical scenarios fitting with the determined model should be further considered.

Systemic lupus erythematosus (SLE) is a prevalent autoimmune condition, yet its alignment with a specific host immunological pathway remains unclear. The THαβ host immunological pathway, recognized for its defense against viruses and prions, has recently emerged as a response to DNA, RNA, and protein pathogens. SLE patients often produce anti-double strand DNA antibodies and anti-nuclear antibodies, suggesting a potential association with the THαβ host immune reaction. Throughout the course of SLE, elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 are commonly observed. These cytokines and antibody isotypes are indicative of the THαβ host immunological pathway. Similarly, Myasthenia gravis, Grave’s disease, Graft versus host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjogren’s syndrome are also linked to THαβ-related type 2 hypersensitivities. Considering the potential association of these diseases with dysregulated THαβ immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferons α/β could be explored to manage these disorders effectively.

Rett syndrome (RTT) is mainly caused by mutations in methyl CpG-binding protein 2, cyclin-dependent kinase-like 5, or forkhead box protein G1. These RTT-causing proteins harbor an intrinsically disordered region (IDR) whose conformation exhibits spatiotemporal heterogeneity, which not only confer versatility to the protein, but also implicates them in diseases. The IDR generally evolves more rapidly than an ordered structure. In this study, we examined the relationship between pathogenic RTT-associated point mutations in RTT-causing proteins and the evolutionary dynamics of sequence features including structural order–disorder, phosphorylation sites, and evolutionary rates. We also analyzed the molecular properties and evolution of proteins that interact with RTT-causing proteins in terms of phylogenetic profiles, tissue specificity, subcellular localization, expression level, and functions. The results indicate that constrained IDRs may function by forming contacts with other regions in the protein sequence causing pathogenic missense mutations likely to arise in the rapidly evolving IDR and affect molecular networks, leading to disease. The results also provide novel insights into the genetic basis for RTT and the evolution of the neocortex in higher vertebrates.

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal diseases in humans. It is characterized by visceral pain and/or discomfort, hypersensitivity and abnormal motor responses along with change in gut habits. Although the etio-pathogenesis of IBS is only partially understood, a main role has been attributed to psychosocial stress of different origin. Animals models such as neonatal maternal separation, water avoidance stress and wrap restraint stress have been developed as psychosocial stressors in the attempt to reproduce the IBS symptomatology and identify the cellular mechanisms responsible for the disease. The study of these models has led to the production of drugs potentially useful for IBS treatment. This review intends to give an overview on the results obtained with the animal models; to emphasize the role of the enteric nervous system in IBS appearance and evolution and as a possible target of drug therapies.

Background: Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS), Gulf War Ill-ness (GWI) and control subjects had fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction Methods: Activated midbrain nuclei were inferred by re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI had greater activation during cognition than ME/CFS in left pedunculotegmental nucleus. Postexercise ME/CFS had greater activation than GWI for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI indicating reciprocal patterns of activation. Controls had no changes. Conclusions: Exercise caused opposite effects with increased activation in ME/CFS but decreased activation in GWI indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.

We present here a case of complex uterine anomaly – Obstructed HemiVagina with Ipsilateral Renal Agenesis (OHVIRA), also known as Herlyn-Werner-Wunderlich syndrome in a 13-year-old girl with the history of recurrent urinary tract infections (rUTI). In emergency room, trans-abdominal sonography revealed ovarian cyst and renal agenesis, without any suspicion of vaginal obstruction. This led to delay in the diagnosis of this uncommon anomaly. Finally, MRI findings confirmed the presence of OHVIRA syndrome. As the congenital anomalies of kidney and urinary tract (CAKUT) are in almost one third of cases associated with genital malformations, urologist should carefully search for patients with rUTI. The patient underwent simultaneous laparoscopy and vaginoscopy, what was in our opinion the most appropriate therapeutic decision. In this article we are also going to discuss the role of laparoscopy in the management of OHVIRA syndrome as well as other surgical techniques described in the literature.

Background/Objectives: Hematopoietic stem cell transplantation (HSCT) in pediatric and young adult (YA) patients can lead to endotheliopathy, such as thrombotic microangiopathy (TMA), sinusoidal obstruction syndrome (SOS), and diffuse alveolar hemorrhage (DAH). Natriuretic peptides have been studied as markers of endotheliopathy and critical illness. We hypothesized that elevation in NT-proBNP was associated with development of endotheliopathy (DAH, SOS, or TMA) in the first 100 days following HSCT in pediatric and YA patients. Methods: IRB exempt status was obtained. This retrospective case-control study reviewed HSCT at our institution from 2016-2020. Cases were selected based on an endotheliopathy diagnosis in the first 100 days after HSCT. Cases were matched with controls. Baseline and near-event NT-proBNP levels were compared between cases and matched controls. Effect of NT-proBNP levels on developing endotheliopathy was estimated using conditional logistic regression. Results: Sixty-two patients were included (31 cases, 31 controls). Near-event NT-proBNP was significantly higher in cases compared to controls (Median: 473 vs. 187 pg/mL, p = 0.03, Wilcoxon rank-sum test), in contrast to comparison in baseline NT-proBNP (Median: 86 vs. 86 pg/mL, p = 0.51). After adjusting for co-variates, association between near-event NT-proBNP and odds of developing endotheliopathy did not achieve statistical significance. However, trends from most common transplant indications suggested an association between elevated near-event NT-proBNP level and endotheliopathy, particularly in acute lymphoblastic leukemia (ALL) patients. Conclusions: NT-proBNP should be studied further as a biomarker for endotheliopathy in pediatric and YA patients undergoing HSCT. This may be particularly relevant for patients undergoing HSCT for ALL.

Objective: The current study aimed to delineate the relationship of furin with inflammation while cervical intraepithelial neoplasia progresses to cancer. Study Design:This cross-sectional study included 81 women who required colposcopic examinations. The study groups were formed based on pathological results: Group I included women with cervical intraepithelial neoplasia (CIN) I (n=30); Group II included women with CIN II-III (n=28); and Group III included women with cervical cancer (CC) (n=23). Furin, ki-67, and p16 levels were evaluated based on immunostaining intensity. The inflammatory indices were calculated parallel with the literature from routine blood samples retrieved within one week before the procedure. Results:Furin expression gradually increased from CIN I to CIN II-III and from CIN II-III to CC, respectively (p < .001, p = .005). The NLR, MLR, PLR, and SII were significantly higher in the CC group (p < .001). ROC curve analysis unveiled that NLR, MLR, PLR and SII predicted the presence of CC with a cutoff value of 2.39 for NLR (sensitivity: 91.3%, specificity: 63.8%, AUROC: 0.79, p < .001); a cutoff value of 0.27 for MLR (sensitivity: 78.3%, specificity: 72.4%, AUROC: 0.77, p = .009); a cutoff value of 123 for PLR (sensitivity: 100%, specificity: 41.4%, AUROC: 0.70, p = .04); and a cutoff value of 747 for SII (sensitivity: 69.6%, specificity: 90.7%, AUROC: 0.71, p = .014). Conclusion:Furin expression increased gradually in parallel to the severity of cervical intraepithelial neoplasia. The inflammatory indices were higher in the presence of CC and denoted good discrimination ability for predicting cervical cancer.

Alzheimer’s disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in AD’s brain. A filtrate of Helicobacter pylori’s culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood brain barrier and directly induce tau’s phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed HPU (50-300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1β and TNF-α, expressed Iba1 and showed reduced viability, consistent with a neurotoxic effect of HPU. Rats received daily i.p. HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Thr205, Ser199 and Ser396 sites was seen in hippocampal homogenates of treated rats, with no alterations in total tau or GSK-3b levels. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease.

Fibromyalgia (FM) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are diseases of unknown etiology presenting complex and often overlapping symptomatology. Despite promising advances on the study of miRNomes of these diseases, no validated molecular diagnostic biomarker yet exists. Since FM and ME/CFS patient treatments commonly include polypharmacy it is of concern that biomarker miRNAs are masked by drug interactions. Aiming at discriminating between drug-effects and true disease-associated differential miRNA expression, we evaluated the potential impact of commonly prescribed drugs on disease miRNomes, as reported by the literature. By using the web search tools SM2miR, Pharmaco-miR and repoDB, we found a list of commonly prescribed drugs that impact on FM and ME/CFS miRNomes and therefore could be interfering in the process of biomarker discovery. On another end, disease-associated miRNomes may incline patient´s response to treatment and toxicity. Here, we explored treatments for diseases in general that could be affected by FM and ME/CFS miRNomes finding a long list of them, including treatments for lymphoma, a type of cancer affecting ME/CFS patients at a higher rate than healthy population. We conclude that FM and ME/CFS miRNomes could help refine pharmacogenomic/pharmacoepigenomic analysis to elevate future personalized medicine and precision medicine programs in the clinic.

Prolylcarboxypeptidase (PRCP, PCP, Lysosomal Pro-X-carboxypeptidase, Angiotensinase C) controls angiotensin - and kinin- induced cell signaling. Elevation of PRCP appear to be activated in chronic inflammatory diseases (cardiovascular disease (CVD), diabetes) in proportion to severity. Vascular endothelial cell senescence and mitochondrial dysfunction have consistently been shown in models of CVD in aging. The cellular senescence, a driver of age-related dysfunction, can differentially alter the expression of lysosomal enzymes due to lysosomal membrane permeability. There is a lack of data demostrating the effect of age-related dysfunction on the expression and function of PRCP. To explore the changes in PRCP, PRCP-dependent prekallikrein (PK) pathway was charcterized in early – and late-passage human pulmonary artery endothelial cells (HPAECs). Detailed kinetic analysis of cells treated with high molecular weight kininogen (HK), a precursor of bradykinin (BK), and PK revealed a mechansim by which senescent HPAECs activate the generation of kallikrein upon the assembly of the HK-PK complex on HPAECs in parallel with an upregulation of PRCP and endothelial nitric oxide (NO) synthase (eNOS) and NO formation. The NO production and expression of both PRCP and eNOS increased in early-passage HPAECs while decreased in late-passage HPAECs. Low activity of PRCP in late passage HPAECs was associated with rapid decreased telomerase reverse transcriptase mRNA levels. We also found that, with an increase in the passage number of HPAECs, reduced PRCP altered respiration rate. These results indicated that aging dysregulates PRCP protein expression, and further studies will shed light into the complexity of PRCP-dependent signling pathway in aging.

Copper (Cu) is an essential micronutrient for the correct development of eukaryotic organisms. This metal plays a key role in many cellular and physiological activities, including enzymatic activity, oxygen transport, and cell signaling. Although the redox activity of Cu is crucial for enzymatic reactions, this property also makes it potentially toxic when found at high levels. Due to this dual action of Cu, highly regulated mechanisms are necessary to prevent both the deficiency and the accumulation of this metal since its dyshomeostasis may favor the development of multiple diseases, such as Menkes’ and Wilson’s diseases, neurodegenerative diseases, diabetes mellitus, and cancer. As the relationship between Cu and cancer has been the most studied, we analyze how this metal can affect three fundamental processes for tumor progression: cell proliferation, angiogenesis, and metastasis. Gynecological diseases are characterized by high prevalence, morbidity, and mortality, depending on the case, and mainly include benign and malignant tumors. The cellular processes that promote their progression are affected by Cu, and the mechanisms that occur may be similar. We analyze the crosstalk between Cu deregulation and gynecological diseases, focusing on therapeutic strategies derived from this metal.

Keywords: Interspecific competition; Character displacements, Behavioral syndrome; Foraging; Pecking; Probing; Sweeping; Ballistic transport, Surface tension transport; Lingual transport

Infection with the porcine reproductive and respiratory syndrome virus type 1 (PRRSV-1) has serious economic consequences for the pig industry. Swine practitioners and other agricultural advisors often describe an increase in antibiotic use when PRRSV-1 is circulating. Our objective was to assess the impact of PRRSV-1 stabilization programmes on reducing antibiotic use. The study was carried out on 19 French farrow-to-finish farms that successfully implemented a PRRSV-1 stabilization protocol between 2007 and 2019. For each farm, antibiotic consumption (expressed in mg/PCU and ALEA) were compared one year before (P1) and one year after (P2) the implementation of such a protocol and the change between P1 and P2 were calculated in percentages. Data were then analysed by level of consumption. Antibiotic use decreased significantly between P1 and P2 if expressed in mg/PCU and showed a decreased tendency in terms of exposure (ALEA). Concerning the change from P1 to P2, our results showed that the higher consumption levels in P1, the greater antibiotic reduction in P2. This study highlights the ability of a stabilization protocol against PRRSV-1 to reduce antibiotic use, especially on farms that have high consumption. These hopeful results show that further investigations about the relationship between PRRSV-1 and antibiotic usage could be beneficial.

Lynch syndrome (LS) is an inherited disorder in which affected individuals have a significantly higher-than-average risk of developing colorectal and non-colorectal cancers, often before the age of 50 years. In LS, mutations in DNA repair genes lead to a dysfunctional post-replication repair system. As a result, the unrepaired errors in coding regions of the genome produce novel proteins, called neoantigens. Neoantigens are recognised by the immune system as foreign and trigger an immune response. Due to the invasive nature of cancer screening tests, universal cancer screening guidelines unique for LS (including colonoscopy) are poorly adhered to by LS variant heterozygotes (LSVH). Currently, it is unclear whether immunogenomic components produced as a result of neoantigen formation can be used as novel biomarkers in LS. We hypothesize that: (i) LSVH produce measurable and dynamic immunogenomic components in blood, and (ii) these quantifiable immunogenomic components correlate with cancer onset and stage. Here, we discuss feasibility and propose the potential to: (a) identify personalised novel immunogenomic biomarkers, (b) reduce invasive cancer screening tests and thus increase non-invasive cancer surveillance, (c) improve compliance and adherence to recommended cancer screening guidelines in LSVH.

Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally ab-normal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.

Retinal findings may change in patients with obstructive sleep apnea syndrome (OSAS). The present study aims to evaluate several retinal findings such as macula layer thickness, peripapillary retinal nerve fiber layer, and the optic nerve head in patients with OSAS using optical coherence tomography (OCT) and monitor the result of several types of treatment of OSAS with OCT. A prospective comparative study was designed. Patients were recruited at a Sleep Unit of a University Hospital and underwent comprehensive ophthalmological examinations. Following exclusion criteria, fifty-two patients with OSAS were finally included. Patients were examined by OCT twice: first, before treatment; secondly, after six months of treatment. In mild-moderate patients, where retinal swelling has been demonstrated, retinal thicknesses decreased [fovea (p=0.026), as well as inner ring macula (p=0.007), outer ring macula (p=0.015), and macular volume (p=0.015)]. In severe patients, where retinal atrophy had been observed, retinal thickness increased [fovea (p&lt;0.001)]. No statistically significant differences in efficacy between treatments were demonstrated. In conclusion, OCT can evaluate the retina in patients with OSAS and help monitor results after treatment. In severe OSAS, retinal thickness increased six months after treatment.

Proper treatment of infectious air could potentially mitigate the spread of airborne viruses such as porcine reproductive and respiratory syndrome virus (PRRSV). The objective of this research is to test the effectiveness of ultraviolet (UV) in inactivating aerosolized PRRSV, specifically, four UV lamps, UV-A (365 nm, both fluorescent and LED-based), "excimer" UV-C (222 nm), and germicidal UV-C (254 nm), were tested. The two UV-C lamps effectively irradiated fast-moving PRRSV aerosols with short treatment times (<2 s). One-stage and two-stage UV inactivation models estimated the UV doses needed for target percentage (%) reductions on PRRSV titer. UV-C (254 nm) dose needed for 3-log (99.9%) reduction was 0.521 and 0.0943 mJ/cm2, respectively, based on one-stage and two-stage models. An order of magnitude lower UV-C (222 nm) doses were needed for a 3-log reduction, i.e., 0.0882 and 0.048 mJ/cm2, based on one-stage and two-stage models, respectively. However, the cost of 222-nm excimer lamps is still economically prohibitive for scaling-up trials. The UV-A (365 nm) lamps could not reduce PRRSV titers for tested doses up to 4.11 mJ/cm2. Pilot-scale or farm-scale testing of UV-C on PRRSV aerosols simulating barn ventilation rates are recommended based on its effectiveness and reasonable costs comparable to HEPA filtration.

Post-concussion syndrome, recently recognized as a complication of mild traumatic brain injury, is considered a consequence of the summative effect of multiple concussions received over lifetime. In elderlies, the main mild brain trauma mechanism is fall (low impact force). Many falls are often not reported or noticed but may generate serious medical and medico-legal consequences. Our research question was to find if a single, very mild brain trauma can induce neuro-behavioral consequences in elderlies. One database was queried (PubMed – MeSH terminology) looking for histopathological, neuro-cognitive and behavioral changes that can be generated by sub-concussional trauma in senescent rodents, in comparison with young animals. 41 published research articles were selected. 17 of them used very mild brain trauma in young and senescent animals, in the same experiment (6 rats and 11 mice). 24 articles evaluated the effect of sub-threshold brain trauma in adult animals (no control group). Five trauma models were used (blast models were excluded). Neuro-inflammatory changes were detected immediate after very mild primary impact. In young animals, observed pathology disappeared fast (after 3 to 7 days). Increased apoptosis, mild axonal injury in white matter tracts plus maladaptive astrogliosis and microglial activation was stronger in aged animals, persisted over time (8 months) and significantly altered animals’ cognition and behavior. Associated preexisting pathology (hypertension, tau protein deposits, microbleeds, reactive inflammation) was often responsible for amplification of the primary impact results. As translation of observation is the weak spot of pathology and behavior animal research, further investigation is needed before to conclude that even a single, very mild brain trauma may have medical consequences on human senescent brain.

Previously we have shown that the combination of radiotherapy with human-umbilical-cord-derived mesenchymal stem-cell therapy significantly reduces the size of the xenotumours in mice, both in the directly irradiated tumour and in the distant non-irradiated tumour or in its metastasis. We have also shown that exosomes secreted from mesenchymal stem-cells pre-irradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from non-irradiated mesenchymal cells and also that proteins, exosomes and microvesicles secreted by mesenchymal cells suffer a dramatic change when cells are activated or non-activated, with the amount of protein present in the exosomes of the pre-irradiated cells being 1.5-fold times greater compared to those from non-irradiated cells. This finding correlates with a dramatic increase in the anti-tumour activity of the exosomes secreted by pre-irradiated mesenchymal-cells. After the proteomic analysis of the load of the exosomes released from both irradiated and non-irradiated cells, we conclude that annexin A1 is the most important and significant difference between the exosomes released by the cells in either status. Knowing the role of annexin A1 in the control of hypoxia and inflammation which is characteristic of acute-distress-respiratory syndrome, we have designed a hypothetical therapeutic strategy, based on the transplantation of mesenchymal stem cells stimulated with radiation, to alleviate the symptoms of patients who, due to pneumonia caused by COVID-19, require the care of an intensive care unit for patients with life-threatening conditions. With this hypothesis, we would seek to improve the patients’ respiratory capacity and increase the expectations of their cure.

The aggregate aftermath of persistent inflammation in patients with inflammatory bowel disease (IBD) places them at increased risk for the advancement to colitis-associated colorectal cancer (CACRC). CACRC is preceded by IBD, the highly heterogenous, pharmacologically incurable, pertinacious, reverting/worsening, and immune-mediated inflammatory pathologies of the colon and rectum. The molecular and immunological basis of CACRC is highly correlated with the length/duration and stringency/severity of colon inflammation predisposed by the exogenous/free hemoglobin alpha chain (HbαC) the byproduct of infiltrating immune cells, extravasated erythrocytes, and macrophage erythrophagocytosis. The exogenous free HbαC prompts oxygen-free radical-arbitrated DNA damage (DNAD) through increased cellular reactive oxygen species (ROS) exacerbated by decreased tissue antioxidant defenses. Mitigation of Fenton reaction via pharmaceutical therapy would attenuate the ROS, promote apoptosis, DNAD repair, and subsequent prevent the incidence of CACRC. Three pharmaceutical options that attenuate hemoglobin toxicity include haptoglobin, deferoxamine, and flavonoids (vitamins C/E). Haptoglobin’s clearance rare from plasma is inversely correlated with its size; the smaller the size, the faster the clearance. Thus, the administration of Hp1-1 may prove to be beneficial. Furthermore, deferoxamine’s hydrophilic structure limits its ability to cross cell membranes. Thus, it may be beneficial if administered intracellularly to avoid the higher plasma concentrations and longer incubation periods associated with extracellular administration. Finally, the effectiveness of flavonoids and natural herb antioxidants is associated with high reactivity of hydroxyl substituents. Multiple analyses are currently underway to assess the clinical context of CACRC and outline the molecular basis of HbαC-induced ROS pathogenesis by exposing colonocytes and/or colonoids to HbαC. These cells are then treated with haptoglobin, deferoxamine (DFO), and flavonoids in order to separate free HbαC and measure their impact on hydroxyl radical formation therapies. The molecular pathogenesis of sporadic colorectal cancer (SCRC) i.e., “inflammation-dysplasia-carcinoma” progression sequence is well described, but the immunopathogenesis of CACRC herein reviewed is broadly still in prodromal stage/phase to be validated and understood. Therefore this timely review outlines the molecular and immunological basis of disease pathogenesis and the pharmaceutical intervention as a protective measure for CACRC.

Cerebellar ataxia, neuronopathy, and vestibular areflexia syndrome (CANVAS) is caused by biallelic pathogenic expansions, or compound heterozygosity with other pathogenic variants in the RFC1 gene. CANVAS is estimated to be underdiagnosed, both because of the lack of formal diagnostic criteria and molecular challenges that translate to lesser access and high cost of routine testing. Our aim was to address the need for making CANVAS genetic testing routine, by designing a streamlined two-step PCR consisting of a short-allele screening PCR and a confirmatory PCR with fragment capillary electrophoresis detection. Exome sequencing of RFC1 was additionally foreseen to resolve potential compound heterozygosity cases. Specificity of our approach was evaluated using ataxia patients with known non-CANVAS diagnoses, and optimized using Southern blot confirmed CANVAS patients. We evaluated our approach by testing patients consecutively referred for clinically suspected CANVAS using first the two-step PCR, followed by exome sequencing. Our approach was able to accurately identify negative and confirm positive cases in prospectively collected suspected CANVAS patients presenting with at least three typical clinical signs. The proposed testing approach provides an alternative method able to clearly distinguish between CANVAS negative and positive cases and can be easily incorporated into the genetic diagnostic laboratory workflow.

Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

We report a small footprint cost-effective isothermal rapid DNA amplification system, with integrated microfluidics for automated sample analysis and detection of SARS-CoV-2 in human and environmental samples. Our system measures low-level fluorescent signal in real-time during amplification, while maintaining the desired assay temperature, on a low power, portable system footprint. A unique soft microfluidic chip design was implemented to mitigate thermocapillary effects and facilitate optical alignment for automated image capture and signal analysis. The system-on-board prototype coupled with the LAMP primers designed by BioCoS, is sensitive enough to detect viral loads of SARS-CoV-2 in a broad concentration range corresponding to a threshold cycle range of 16 to 39. Clinical specimens were tested at Kingston Health Sciences using a clinically validated PCR assay and variants were determined using whole genome sequencing.

Three patients with multi-year histories of relapsing and remitting Lyme disease and associated co-infections despite extended antibiotic therapy were each given double dose dapsone combination therapy (DDD CT) for a total of 7-8 weeks. At the completion of therapy, all three patients major Lyme symptoms remained in remission for a period of 25-30 months. In conclusion, Double dose dapsone therapy could represent a novel and effective anti-infective strategy in chronic Lyme disease/PTLDS, especially in those individuals who have failed regular dose dapsone combination therapy (DDS CT) or standard antibiotic protocols. A randomized, blinded, placebo-controlled trial is warranted to evaluate the efficacy of DDD CT in those individuals with chronic Lyme disease/PTLDS.

A novel approach for the long-term medical treatment of the inner ear is the diffusion of drugs through the round window membrane from a patient-individualized, drug-eluting implant, which is inserted in the middle ear. In this study, drug-loaded (10 wt% Dexamethasone) guinea pig round window niche implants (GP-RNIs, ~1.30 mm x 0.95 mm x 0.60 mm) were manufactured with high precision via micro injection molding (µIM, Tmold = 160 °C, crosslinking time of 120 s). The medical grade silicone elastomer MED-4244 (NuSil Technology LLC, Radnor, PA, USA) was used. Molds for µIM were 3D printed from a commercially available resin PlasGRAY V2 (Asiga, Alexandria, Australia, TG = 84 °C) via a high-resolution DLP process (xy-resolution of 32 µm, z-resolution of 10 µm, 3D printing time of about 6 h). Drug release, biocompatibility, and bio-efficacy of the GP-RNIs were investigated in vitro. GP-RNIs could be successfully produced. Wear of the molds due to thermal stress was observed. However, the molds are suitable for single use in the µIM process. About 10% of the drug load (8.2 ± 0.6 µg) was released after 6 weeks (medium: isotonic saline). The implants showed high biocompatibility over a time of 28 days (lowest cell viability ~80%). Moreover, we found anti-inflammatory effects over a time of 28 days in a TNF-α-reduction test. These results are promising for the development of long-term drug-releasing implants for human inner ear therapy.

Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of about 10,000 different soluble and membrane proteins in humans. It involves co- or post-translational targeting of precursor polypeptides to the ER and their subsequent membrane insertion or translocation. So far, three pathways for ER targeting of precursor polypeptides plus four pathways for ER targeting of mRNAs were described. Typically, these pathways deliver their substrates to the Sec61 polypeptide-conducting channel in the ER membrane. Next, the precursor polypeptides are inserted into the ER membrane or translocated into the ER lumen, which may involve auxiliary translocation components, such as the TRAP and Sec62/Sec63 complexes, or auxiliary membrane protein insertases, such as EMC and the TMCO1 complex. Recently, the PEX19/PEX3-dependent pathway, which has a well-known function in targeting and inserting various peroxisomal membrane proteins into pre-existent peroxisomal membranes, was also found to act in targeting and, putatively, inserting monotopic hairpin proteins into the ER. These either remain in the ER as resident ER membrane proteins or are pinched off from the ER as components of new lipid droplets. Therefore, the question arose if this pathway may play a more general role in ER protein targeting, i.e. represents a fourth pathway for ER targeting of precursor polypeptides. Thus, we addressed the client spectrum of the PEX19/PEX3-dependent pathway in both PEX3-depleted HeLa cells and PEX3-deficient Zellweger patient fibroblasts by an established approach, which involves label-free quantitative mass spectrometry of the total proteome of depleted or deficient cells and differential protein abundance analysis. The negatively affected proteins included twelve peroxisomal proteins and two hairpin proteins of the ER, thus confirming two previously identified classes of putative PEX19/PEX3-clients in human cells. Interestingly, fourteen collagen-related proteins with signal peptides or N-terminal transmembrane helices and belonging to the secretory pathway were also negatively affected by PEX3-deficiency, which may suggest compromised collagen biogenesis as a hitherto unknown contributor to organ failures in the respective Zellweger patients.

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder which impair ovarian function. The adherence to healthy dietary patterns and physical exercise are the first line of recommended treatment for PCOS patients, but it is no clear what type of diet is more adequate. In this case-control study, we explore the association between the adherence to five dietary quality indices widely used and PCOS. We enrolled 126 cases of PCOS and 159 controls (Murcia, Spain). Diagnostic of PCOS and its phenotypes were established following the Rotterdam criteria [hyperandrogenism (H), oligoanovulation (O), polycystic ovaries morphology (POM)]. We used a validated food frequency questionnaires to calculate the scores for five dietary indices: alternate Healthy Eating index (AHEI), AHEI-2010, relative Mediterranean Dietary Score (rMED), alternate Mediterranean Dietary Score (aMED) and Dietary Approaches to Stop Hypertension (DASH). We used multivariable logistic regression to estimate adjusted odds ratios and confidence intervals. In the multivariable analysis, AHEI-2010 index was inversely associated with “H+O” PCOS’ phenotype (ORQ3 VS Q1= 0.1; 95% CI :(0.0; 0.9); P for trend= 0.02). In conclusion, we did not find any statistical significative association between dietary indices and total, anovulatory and ovulatory PCOS, but it seems interesting explore these association among the diverse phenotypes of PCOS in studies with higher sample size.

Neuromyelitis optica spectrum disorder (NMOSD), previously known as Devic disease or neuromyelitis optica (NMO), represents inflammatory conditions affecting the central nervous system. These disorders are characterized by severe immune-mediated demyelination and axonal damage, with a predilection for targeting optic nerves and the spinal cord. Key clinical features of NMOSD encompass acute episodes of bilateral or rapid sequential optic neuritis and transverse myelitis, typically exhibiting a relapsing course. These attacks endure for several days, and recovery varies, spanning from weeks to months. In this report, we present the case of a 35-year-old individual who initially complained of urinary retention, followed by decreasing vision in the left eye and subsequently in the right eye. These visual symptoms were succeeded by weakness in the right upper and lower limbs.

The study aimed to assess the prevalence of the frailty syndrome in older patients hospitalized in the geriatric ward depending on the diagnostic criteria used, the feasibility of particular diagnostic scales in hospitalized patients, and their compatibility. Material and methods: Patients admitted to the Department of Geriatrics of Hospital of the Ministry of the Interior and Administration in Bialystok within eight months were included in the study. Four diagnostic scales were used to identify the frailty syndrome: Fried criteria, 7-point Clinical Frailty Scale (CFS), 40-item Frailty Index (FI), and FRAIL Scale. The compatibility of the scales was determined using Cohen's Kappa statistics. Results: 416 patients (mean age 81.2 ± 6.91 years, 77.4% women) were included in the study. Depending on the scale, the prevalence of frailty syndrome varied from 26.8% ( FRAIL Scale), 52.3% (Clinical Frailty Scale), and 58.1% (Fried criteria) up to 62.9% (Frailty Index). We observed the highest feasibility for CFS (100%), intermediate for Frailty Index (95.2%), FRAIL Scale (89.7%), and the lowest for Fried scale (79.8%). The highest level of agreement was found between the CFS and Fried scale, with 70.2% consistent ratings (Cohen Kappa 0.49). Conclusions: Patients in the geriatric ward are characterized by a high prevalence of frailty, although it differs depending on the criteria. The Frailty Index found the highest prevalence and the lowest in the case of the FRAIL scale. The feasibility of scales and their comparability differed; the most difficult to use in daily practice was the Fried scale, while the Clinical Frailty Scale was determined feasible in all patients. The highest agreement was observed between the Fried criteria and the Clinical Frailty Scale and the lowest between the FRAIL scale and the remaining ones.

A Pediatric Sleep Questionnaire (PSQ) and a recording of the respiratory parameters with a noc-turnal home cardiorespiratory polygraphy (PG) are necessary to diagnose OSAS. Few researchers have studied how obesity could influence the respiratory parameters in OSAS children. The aim of the study was to investigate how obesity can influence sleep respiratory parameters in OSAS children. Methods: The study analyzes 56 Caucasian children and adolescents aged 11 ± 2.79 years with a BMI> 5th percentiles and PSQ value of 0.33. Children were divided into the Obesity Group (OG) with a BMI of  95th and the Control Group (CG) with a 5th<BMI> 95th percentile. All selected children underwent PG. Respiratory parameters were extracted to divide into levels of severity OSAS: snoring, mild, moderate, and severe. Results: The comparison analysis of AHI, SaO2, and Nadir between the OG and CG showed a statistical significance only for ODI (p = 0.02). The comparison analysis of PSQ between the OG and CG and of PSQ and respiratory parameters showed no significant result. A statistically significant correlation between BMI and AHI (r2=0.01), SaO2 (r2=0.09), and Nadir O2 (r2=0.00) was found. Conclusion: There was no strong correlation between Obesity and OSAS, but it was found between BMI increasing and AHI severity

Sudden unexpected death (SUD) is a fatal event that occurs in an apparently healthy subject so that such an abrupt outcome could have not been predicted. SUD - including sudden intrauterine unexplained death (SIUD), sudden neonatal unexpected death (SNUD), sudden infant death syndrome (SIDS), sudden unexpected death of the young (SUDY), sudden unexpected death in the adult (SUDA) - occurs as the first manifestation of an unknown underlying disease or within a few hours of presentation of a disease. SUD is a major unsolved, shocking form of death that occurs frequently and can happen at any time without warning. For each case of SUD, a review of clinical history data and performance of a complete autopsy, particularly focused on the study of the cardiac conduction system were carried out according to the necropsy protocol devised by the Lino Rossi Research Center, Università degli Studi di Milano, Italy. Research cases are represented by 75 SUD victims, subdivided into 15 SIUD, 15 SNUD, 15 SUDY, and 15 SUDA victims, collected and selected for this study. After the routine autopsy and clinical history analysis, the death remained unexplained and hence a diagnosis of SUD was assigned to the 75. subjects, which included45 females (60%) and 30 (40%) males, ranging in age from 27 gestational weeks to 76 years. Serial sections of the cardiac conduction system disclosed frequent congenital alterations, of the cardiac conduction system in fetuses and infants. An age-related significant difference in distribution among the 5 age-related groups was detected for the following anomalies of the conduction system: central fibrous body (CFB) islands of conduction tissue, fetal dispersion, resorptive degeneration, Mahaim fiber, CFB cartilaginous meta-hyperplasia, His bundle septation, sino-atrial node (SAN) artery fibromuscular thickening, atrio-ventricular junction hypoplasia, intramural right bundle branch, and SAN hypoplasia. The results data are useful to understand the cause of death for all SUD cases that were unexpected and would have otherwise remained unexplained, so to motivate medical examiners and pathologists to perform more in-depth studies.

In golden retriever dogs, a 1 bp deletion in the canine TTC8 gene has been shown to cause progressive retinal atrophy (PRA), the canine equivalent of retinitis pigmentosa. In humans, TTC8 is also implicated in Bardet-Biedl syndrome (BBS). To investigate if the affected dogs only exhibit a non-syndromic PRA or develop a syndromic ciliopathy similar to human BBS, we recruited ten affected dogs to the study. The progression of PRA for two of the dogs was followed for two years, and a rigorous clinical characterization allowed a careful comparison with primary and secondary characteristics of human BBS. In addition to PRA, the dogs showed a spectrum of clinical and morphological signs similar to primary and secondary characteristics of human BBS patients, such as obesity, renal anomalies, sperm defects, and anosmia. We used Oxford Nanopore long-read cDNA sequencing to characterize retinal full-length TTC8 transcripts in affected and non-affected dogs, the results of which suggest that three isoforms are transcribed in the retina, and the 1 bp deletion is a loss-of-function mutation, resulting in a canine form of Bardet-Biedl syndrome with heterogeneous clinical signs.

Background. Chronic kidney disease (CKD) is a progressive condition with limited treatment options that often lead to significant morbidity. Recent studies suggest that oxyhydrogen nanobubbles (HHOnb) may offer therapeutic benefits due to their antioxidative and anti-inflammatory properties. This case series examines the effects of intravenous HHOnb therapy on three patients with varying stages of CKD.Methods. Three patients with CKD underwent a series of ten HHOnb infusions over a period of two to three months. The patients, aged 43 to 70, presented with additional comorbidities including hypertension, diabetes mellitus, and polycystic kidney disease. Clinical parameters, including glomerular filtration rate (GFR), serum creatinine, blood pressure, and uric acid levels, were monitored alongside subjective health improvements.Results. Patient A. A 70-year-old woman with CKD grade 3a experienced a reduction in serum creatinine from 0.98 mg/dL to 0.82 mg/dL and an improvement in GFR from 59 mL/min/1.73 m² to 73.2 mL/min/1.73 m². She reported reduced leg swelling and increased vitality. Patient B. A 52-year-old man with CKD grade 4 and class III obesity showed a decrease in serum creatinine from 3.0 mg/dL to 2.86 mg/dL, an increase in GFR from 23 mL/min/1.73 m² to 24.4 mL/min/1.73 m², and improved sleep quality. Blood pressure reduced from 167/82 mmHg to 145/85 mmHg. Patient C. A 43-year-old man with CKD grade 4 and massive polycystic kidney disease reported reduced fatigue and normalized urination. His serum creatinine decreased from 3.26 mg/dL to 3.09 mg/dL, and his GFR improved from 22 mL/min/1.73 m² to 23.6 mL/min/1.73 m².Conclusion. Intravenous HHOnb therapy demonstrated potential benefits in improving renal function and overall health in CKD patients. These findings suggest that HHOnb could be a promising complementary treatment for CKD, though larger, controlled studies are needed to confirm its efficacy and safety.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and as such provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may results in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in the epigenetic regulation primarily via modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extra nuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases and we will discuss the potential of their inhibitors for lung injury prevention.

Methylglyoxal (MGO) is the major compound belonging to reactive carbonyl species (RCS) responsible for the generation of advanced glycation end products (AGEs). Its upregulation followed by deleterious effects at the cellular and systemic level is associated with metabolic disturbances (hyperglycemia/hyperinsulinemia/insulin resistance/hyperlipidemia/inflammatory processes/carbonyl stress/oxidative stress/hypoxia). Therefore, it is implicated in a variety of disorders including metabolic syndrome, diabetes mellitus and cardiovascular diseases. In this review an interplay between pathways leading to MGO generation and scavenging is addressed, in regard to this system’s impairment in pathology. The issues associated with mechanistic MGO involvement in pathological processes, as well as the discussion on its possible causative role in cardiometabolic diseases are enclosed. Finally, the main strategies aimed at MGO and its AGEs downregulation with respect to cardiometabolic disorders treatment are addressed. Potential glycation inhibitors and MGO scavengers are discussed, as well as the mechanisms of their action.

The COVID-19 pandemic first observed in December 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has influenced every individual on the planet. The virus has influenced our lifestyle, education, economy and the environment. Though the vaccines against COVID-19 have provided protection against the disease; new strains of the virus have lowered the efficiency of the vaccines. There is still no effective therapy for the treatment of the disease. Understanding the protein structure of the virus may lead to the development of effective therapies for the disease. We recently mapped the structural proteins and non-structural proteins of SARS-CoV-2. The accessory proteins (Open reading frames, Orfs) of SARS-CoV-2 modulate the host environment to favor virus replication. This paper reports mapping the accessory proteins (Orfs) of SARS-CoV-2.

Background: Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2. In Colombia, many commercial methods are now available to perform the RT-qPCR assays, and the laboratories must evaluate its diagnostic accuracy to ensure reliable results to suspected COVID-19 patients. The purpose of the study was to compare four commercial RT-qPCR assays for detection of SARS-CoV2 virus, from nasopharyngeal swab samples referred to Laboratorio Carvajal IPS, SAS of Tunja, Boyacá - Colombia. Methods: This prospective study was conducted on 152 samples of respiratory tract samples (Nasopharyngeal Swab) from patients with suspected SARS-CoV-2 infection. Diagnostic accuracy of GeneFinderTM COVID-19 Plus RealAmp (In Vitro diagnostic), One-Step Real-Time RT-PCR (Vitro Master diagnostica), Berlin modified protocol and gold standard Berlin protocol (Berlin Charite Probe One-Step RT-qPCR Kit, New England Biolabs) as reference was assessed. Operational characteristics were estimated in terms of sensitivity, specificity, agreement, and predictive values. Results: Using Berlin Charite Probe One-Step RT-qPCR Kit as reference, the sensitivity/specificity for the diagnostic tests were found to be GeneFinderTM COVID-19 Plus RealAmp Kit 100%/92.7%, One-Step Real-Time RT-PCR, One-Step Real-Time RT-PCR 92.75%/67.47%, and Berlin modified protocol 100%/96.39%. The results of four commercially available methods were found to be consistent with those obtained from Berlin Modified protocol analysis for % of the samples and showed good agreement (κ= 0.96). Concordant SARS-CoV2 negative and positive RT-qPCR results were reported for xxx and xxx samples, respectively. Summarize something about the Ct. Conclusion: Our data demonstrate that all commercially available methods are rapid and reliable for the identification of SARS-CoV-2 virus associated with COVID-19. One-Step RT-qPCR Kit and GeneFinderTM COVID-19 Plus RealAmp assay show optimal sensitivity compared with Belin modified protocol. In addition, there is no significant correlation between xxxxx

Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a novel immunotherapy that has shown remarkable success in the treatment of adult relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma, adult R/R mantle cell lymphoma, and R/R acute paediatric lymphoblastic leukaemia. One barrier to the widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) with a variable grade of severity. The main manifestations of CRS are fever, hypotension, cytopenia, organ dysfunction among others. Neurological toxicities vary widely and range from headaches to encephalopathy. In addition, anti-CD19 CAR T-cell therapy provokes an array of less frequent events, such as coagulopathies, delayed cytopenia, and cardiovascular toxicities. In general, toxicities are usually reversible and resolve on their own in most cases, though severe cases may require intensive care and immunosuppressive therapy. Deaths due to CRS, neurologic toxicity and infectious complications have been reported, which highlights the gravity of these syndromes and the critical nature of appropriate intervention. In this paper, we look at all available FDA- and EMA-approved information about the pathophysiology, clinical manifestations, risk factor reviews of existing toxicity grading systems, current management strategies, and guidelines for anti-CD19 CAR T-cell toxicities. We also present new approaches, which are under investigation, to mitigate these adverse events.

The epidemic transmission of Zika virus (ZIKV) in Brazil has been identified as a cause of microcephaly and other neurological malformations in babies of ZIKV-infected women. This study provides a descriptive analysis, since the onset of symptoms to the delivery, of a cohort who were registered as having ZIKV infection in pregnancy, from November 2015 to December 2016. Suspected cases were registered at a referral center for infectious and tropical diseases in Manaus, in the Brazilian Amazonian region. A total of 834 women with suspected ZIKV in pregnancy were included, of whom 91.4% had confirmed pregnancy. Reverse-transcriptase polymerase chain reaction (RT-PCR) confirmed ZIKV infection in 42.2% of the cohort. In 35.2% of the cohort, ZIKV was the sole infection identified. Severe adverse pregnancy outcomes (abortion, stillbirth, or microcephaly) were observed in both RT-PCR ZIKV-positive (4.96%) and ZIKV-negative (2.15%) cases. Women with suspected ZIKV infection were much more likely to have adverse pregnancy outcomes if they were symptomatic during the first trimester of pregnancy (odds ratio 10.5; 95% confidence interval 4.0–27.0; p<0.001). Among pregnant women with suspected ZIKV infection, the occurrence of symptoms in the first trimester is associated with an especially high risk of severe adverse pregnancy outcomes.

Urethral pain syndrome (UPS) is still a pathology in which the diagnosis is formulated as a "diagnosis of exclusion". The exact pathogenetic mechanisms are not yet fully understood and clear recommendations for the prevention and treatment of UPS are absent. The goal of the study was to assess the condition of the tissues in the female urethra in UPS, by using transvaginal ultrasound (TVUS) and cross-polarization optical tomography (CP OCT). TVUS showed an expansion in the diameter of the internal lumen of the urethra, especially in the proximal region compared with the norm. Compression elastography revealed areas with increased stiffness (presence of fibrosis) in urethral and surrounding tissues. When studied with CP OCT it was shown that with UPS, the structure of the tissues in most cases was changed: trophic alterations in the epithelium (hypertrophy or atrophy) and fibrosis of underlying connective tissue were observed. The proximal fragment of the urethra with UPS underwent changes identical to those of the bladder neck. This paper showed that the introduction of new technology — CP OCT — in conjunction with TVUS will allow verification of structural changes in tissues of the lower urinary tract at the level of their architectonics and will help doctors understand better the basics of the UPS pathogenesis.

Although phylogenetic analysis shows coronaviruses (CoV) share similar genome sequences, CoVs encode different number of proteins (5 to 14), which has implication on viral pathogenicity and infection. Here, we aimed to identify (in-silico) the similarities between different members of coronavirus family. The analysis included 50 coronavirus proteomes, including SARS-CoV-2 (COVID-19), to find the variation of the number of protein functional motifs and domain in each coronavirus. For this role, we used the experimentally validated domain (motif) that known to be crucial for viral infection. Although human CoVs are classified within one genus, we found variations among them. SARS-CoV-1, SARS-CoV-2 and MERS-CoV encode different type of domains, which has implications on the molecular interactions triggered by each virus within human cells. Secondly, we used functional motifs to reconstruct the potential molecular pathways or interactions triggered by SARS-CoV-2 proteins within human cell.

Aim: This study aims to analyze the collaborative structure of Intestinal Behçet’s Disease (IBD) research by examining co-authorship networks in publications indexed in the Web of Science (WoS) Core Collection from 2000 to 2023. The goal is to identify key researchers, institutions, and collaboration patterns that have shaped the field over the past two decades. Method: This study utilized network analysis techniques to evaluate 484 publications related to IBD research indexed in the WoS Core Collection between 2000 and 2023. The analysis was conducted using Python (Version 3.10.5) in the PyCharm development environment (Software Version 2022.1.3). The co-authorship networks were assessed using macro-level indicators such as network density (the ratio of actual to possible connections), clustering coefficient (degree of node clustering), number of components (distinct connected subgroups), and average path length (average distance between nodes). Micro-level indicators including degree centrality (importance based on the number of connections), closeness centrality (proximity to other nodes), and betweenness centrality (frequency of a node on the shortest paths between others) were also analyzed.Result: From 2000 to 2009, the co-authorship network was highly fragmented with a low network density of 0.0114 and 84 distinct components, indicating limited collaboration. Key contributors during this period included Kim, Won Ho, and Cheon, Jae Hee (South Korea), who played central roles in connecting disparate research clusters. In the following decade (2010-2019), network density decreased slightly to 0.0086, and the number of components increased to 113, reflecting continued fragmentation despite growing research output. However, from 2020 to 2023, network density increased to 0.0171, and the number of components decreased to 73, indicating a trend towards greater integration and collaboration. Notable researchers in this period included Emmi, Giacomo (Italy), and Hatemi, Gulen (Turkey), who emerged as central figures, highlighting a shift in research leadership from Asia to Europe..Conclusion: The co-authorship network analysis of IBD research reveals an evolving collaborative landscape with increasing network density and decreasing fragmentation over time, particularly in the most recent period. From 2000 to 2019, Japanese and Korean researchers were prominent contributors, highlighting the significance of Asia in the global research arena. However, since 2020, researchers from Italy and Turkey have gained significant international prominence, suggesting a shift in the research focus from Asia to Europe. This transition may be attributed to changes in the incidence rates of IBD, where rapid increases were observed in Asian countries like Japan, Korea, and China until 2020, followed by stabilization or decline, while incidence rates have been increasing in European countries such as Italy and Turkey. These findings underscore the importance of expanding international collaborations to enhance the understanding of IBD. Fostering global partnerships could further advance the field, promoting more integrated and innovative research efforts, and addressing the shifting dynamics of IBD prevalence across regions.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by profound fatigue, post-exertional malaise (PEM), and neurocognitive dysfunction. Immune dysregulation and gastrointestinal symptoms are commonly observed in ME/CFS patients. Despite affecting approximately 0.89% of the general population, the underlying pathophysiological mechanisms remain poorly understood. This study aimed to elucidate the relationship between immunological characteristics and intestinal barrier function in ME/CFS patients. ME/CFS patients were stratified into two groups based on their immune competence. After documentation of detailed medical records, serum and plasma samples were collected for assessment of inflammatory immune mediators and biomarkers for intestinal barrier integrity by ELISA. We found reduced complement protein C4a levels in immunodeficient ME/CFS patients suggesting a sub-group specific innate immune dysregulation. ME/CFS patients without immunodeficiencies exhibit a mucosal barrier leakage, as indicated by elevated levels of Lipopolysaccharide-binding protein (LBP). Stratifying ME/CFS patients based on immune competence enabled the distinction of two subgroups with different pathophysiological patterns. The study highlights the importance of emphasizing precise patient stratification in ME/CFS, particularly in the context of defining suitable treatment strategies. Given the substantial health and socioeconomic burden associated with ME/CFS, urgent attention and research efforts are needed to define causative treatment approaches.

Background: This study aimed to compile and analyze an assortment of research findings concerning potential therapeutic strategies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The understanding of the multifaceted nature of ME/CFS and the need for varied and personalized therapeutic approaches were central to this investigation.Methods: A comprehensive review and analysis of various studies conducted on ME/CFS was undertaken. These studies covered a wide array of interventions, including pharmacological treatments, nutritional supplements, dietary changes, physical therapies, and lifestyle modifications. The analysis pertained to the effectiveness of these interventions, potential physiological and biochemical markers, and the response of ME/CFS patients to different treatment strategies.Results: The 22 selected papers investigated demonstrated varied responses to the multitude of interventions. While some interventions showed significant improvement in fatigue and biochemical parameters, others found no significant differences between the treated and control groups. Potential physiological and biochemical markers for ME/CFS, such as impaired T cell metabolism, reduced flow-mediated dilation, and decreased work rate at the ventilatory threshold, were highlighted.Conclusion: The findings underscored the complexity of ME/CFS and the need for personalized treatment strategies. Despite mixed results and several limitations, these studies collectively contributed to understanding ME/CFS's complex pathophysiology and treatment, laying the groundwork for future research towards more effective therapeutic strategies for this debilitating disease.

The microbiota–gut–brain axis has garnered increasing attention in recent years for its role in various health conditions, including neuroinflammatory disorders like complex regional pain syndrome (CRPS). CRPS is a debilitating condition characterized by chronic neuropathic pain, and its etiology and pathophysiology remain elusive. Emerging research suggests that alterations in the gut microbiota composition and function could play a significant role in CRPS development and progression. Our paper explores the implications of microbiota in CRPS and the potential therapeutic role of boron (B). Studies have demonstrated that individuals with CRPS often exhibit dysbiosis, with imbalances in beneficial and pathogenic gut bacteria. Dysbiosis can lead to increased gut permeability and systemic inflammation, contributing to the chronic pain experienced in CRPS. B, an essential trace element, has shown promise in modulating the gut microbiome positively and exerting anti-inflammatory effects. Recent preclinical and clinical studies suggest that B supplementation may alleviate neuropathic pain and improve CRPS symptoms by restoring microbiota balance and reducing inflammation. Our review highlights the complex interplay between microbiota, inflammation, and neuropathic pain in CRPS and underscores the potential of B as a novel therapeutic approach to target the microbiota–gut–brain axis, offering hope for improved management of this challenging condition.

Xylella fastidiosa (Xf) is classified as a quarantine pest due to its consequences on economically significant crops. Its main form of transmission in Europe is through the insect Philaenus spumarius. Due to climate change, populations of insect vectors became more extensive, resulting in the dissemination of the bacteria through longer periods, but destruction of these insects raises issues, due to their role in nature. Upon infection, Xf causes the occlusion of xylem vessels by bacterial aggregates, and tylosis production by the plant as a response to infection. Although symptomatic manifestations of Xf are often linked to water stress, a variety of plant species have been found to carry the pathogen without symptoms, making it all too easy to evade detection when relying on visual inspections. Beyond water stress, other conditions (individual plant resistance/tolerance, bacterial concentrations, transpiration rates, and interactions between subspecies) may be implicated in symptom development. A thorough understanding of how this disease develops, especially its capacity to spread from the initial focus and establish a systemic infection, is imperative. This review focuses on the Xf infection process, the development of symptoms, its spread within Portugal, and the actions that have been taken to counter it.

The coronavirus disease 2019 (COVID-19) was officially declared a pandemic on the 11^th March 2020. It is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), impacting the lower respiratory tract. International travel to Australia during the early stages of the pandemic prior to border closure provided avenues for this virus to spread into Australia. There is little understanding of the clonality of SARS-CoV-2 isolates in Australia, and where they originated. This study aimed to investigate the clonality and ancestral sources of SARS-CoV-2 isolates in Australia using in silico methods. We retrieved 1,346 complete genomes from Australia along with 153 genomes from other countries from the NCBI nucleotide database and Global Initiative On Sharing All Influenza Data (GISAID). We then constructed a representative population of 270 sequences for downstream phylogenetic analysis and ancestral area reconstruction. Overall, two major clusters, one stemming from Europe and another from Asia, especially East Asia, were observed, implying at least two major transmission events with subsequent clades confirming the multiclonality of Australian isolates. We also identified three potential dissemination routes of SARS-CoV-2 into Australia. This study supports the hypothesis of multiple clonality and dispersals of SARS-CoV-2 isolates into Australia.

Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine expansion in Ataxin-2 (ATXN2). This factor binds RNA/proteins to modify metabolism after stress, and to control calcium (Ca2+) homeostasis after stimuli, thus exerting crucial neuroprotection for cerebellar ataxias and corticospinal motor neuron degeneration. Our Atxn2-CAG100-Knock-In mouse faithfully models features observed in patients at pre-onset, early and terminal stages. Here, its cerebellar global RNA profiling revealed downregulation of signaling cascades to precede motor deficits. Validation work at mRNA/protein level defined alterations that were independent of constant physiological ATXN2 functions, but specific for RNA/aggregation toxicity, and progressive across the short lifespan. Earliest changes were detected at 3 months among Ca2+ channels/transporters (Itpr1, Ryr3, Atp2a2, Atp2a3, Trpc3), IP3 metabolism (Plcg1, Inpp5a, Itpka), and Ca2+-Calmodulin dependent kinases (Camk2a, Camk4). CaMKIV–Sam68 control over alternative splicing of Nrxn1, an adhesion component of glutamatergic synapses between granule and Purkinje neurons, was found affected. Systematic screening of pre/post-synapse components, with dendrite morphology assessment, suggested early impairment of CamKIIα abundance together with weakening of parallel fiber connectivity. These data reveal molecular changes due to ATXN2 pathology, impacting communication and excitability of cerebellar neurons. Discovery of such risk versus progression markers improves the assessment of pre-symptomatic treatments in SCA2 and related disorders.

Electrical storm (ES) is defined as the presence of at least three episodes of sustained ventricular tachycardia or ventricular fibrillation within 24 hours. This patient had a previously known arterial hypertension, type II diabetes mellitus, and chronic kidney disease and has presented to the Emergency Department (ED) with symptoms of retrosternal chest pain lasting for several hours prior. The initial 12-lead electrocardiogram revealed ST segment elevation in the anterior leads (V1-V6). Emergent coronary angiography revealed an acute occlusion of the proximal left anterior descending artery (pLAD) and percutaneous coronary intervention was performed with successful implantation of one drug-eluting stent in the pLAD. On the day 8 of hospitalization, patient developed a refractory ES for which he received 50 DC shocks and did not respond to multiple lines of antiarrhythmic medications. Due to a failure of medical therapy, we decided to implant a temporary pacemaker and initiate ventricular overdrive pacing (VOP) that was successful in terminating ES. Following electrical stabilization, the patient underwent a successful ICD implantation. This case demonstrates that VOP can contribute to hemodynamic and electrical stabilization of a patient that suffers from refractory ES and this treatment modality might serve as a temporary bridge to ICD implantation.

The number of individuals meeting criteria for genetic counseling and testing for hereditary cancer syndromes (HCS) is far less than the number that actually receive it. To facilitate identification of patients at risk for HCS, Counsyl developed a digital identification tool (digital ID tool) to match personal and family cancer history to National Comprehensive Cancer Network (NCCN) BRCA-related Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome, and polyposis testing criteria in one-to-one, automated fashion. The purpose of this study was to validate the ability of the digital ID tool to accurately identify histories that do and do not meet NCCN testing criteria. Methods: Third-party recorded three-generation pedigrees were retrospectively reviewed by a certified genetic counselor (CGC) to determine if independent events included in pedigree histories met NCCN guidelines, and were then sorted into groups: high risk events (meets criteria) and low risk events (does not meet criteria). Events were entered into the digital ID tool to determine the extent of its concordance with events sorted by CGC review. Statistical tests of accuracy were calculated at a 95% confidence interval (CI). Results: 197 pedigrees were reviewed consecutively representing 765 independent events for analysis across groups. 382/382 (100%) high risk events identified by the digital ID tool and 381/383 (99.47%) low risk events identified by the digital ID tool were concordant with CGC sorting. The digital ID tool had a sensitivity of 100% (99.04-100% CI) and specificity of 99.48% (98.13-99.94% CI). The overall accuracy of the digital ID tool was estimated to be 99.74% (99.06-99.97% CI), reflecting the rate at which the digital ID tool reached the same conclusion as that of CGC review of pedigree events for the recommendation of genetic testing for individuals at risk for HCS. Conclusions: The digital ID tool accurately matches NCCN criteria in one-to-one fashion to identify at-risk individuals for HCS and may be useful in clinical practice, specifically for BRCA-related HBOC and Lynch Syndrome.

Clinical and histological similarities between sarcoidosis and tuberculosis have driven repeated investigations looking for a mycobacterial cause of sarcoidosis. Over 50 years ago “anonymous mycobacteria” were suggested to have a role in the etiology of sarcoidosis. Both tuberculosis and sarcoidosis have a predilection for lung involvement though each can be found in any area of the body. A key histopathologic feature of both sarcoidosis and tuberculosis is the granuloma – while the tuberculous caseating granuloma has an area of caseous necrosis with a cheesy consistency; the non-caseating granuloma of sarcoidosis does not have this feature. This article reviews and reiterates the complicity of the infectious agent, Mycobacterium avium ss. paratuberculosis (MAP) as a cause of sarcoidosis. MAP is involved in a parallel story as the putative cause of Crohn’s disease, another disease featuring noncaseating granulomas. MAP is a zoonotic agent infecting ruminant animals and is found in dairy products and in environmental contamination of water and air. Despite increasing evidence tying MAP to several human diseases, there is a continued resistance to embracing its pleiotropic roles. "Who Moved My Cheese" is a simple yet powerful book that explores the ways in which individuals react to change. Extending the metaphor, the “non-cheesy” granuloma of sarcoidosis actually contains the difficult-to-detect “cheese”, MAP; MAP did not move, it was there all along.

Activation of the NLRP3 inflammasome plays a crucial role in innate immune response. During cell division, the NLRP3 inflammasome activation must be strictly controlled. Here, we discovered the anaphase promoting complex subunit 10 (Anapc10, APC10), a substrate recognition protein of the anaphase promoting complex/cyclosome (APC/C), is a critical mediator of the NLRP3 inflammasome activation. APC10 protein interacts with NLRP3, and co-localizes with NLRP3 protein in the cytoplasm. During interphase, APC10 interacts with NLRP3 to promote the NLRP3 inflammasome activation. During mitosis, APC10 disassociates from the NLRP3 inflammasome to inhibit the inflammatory responses. This study reveals a distinct mechanism by which APC10 serves as a switch of the NLRP3 inflammasome activation during cell cycle.

The use of chimeric antigen receptors (CAR-T cells) for the treatment of patients with malignant haematological diseases has become a well-established application, for conditions such as refractory or relapsed B cell acute lymphoblastic leukaemia (B-ALL), B cell lymphomas (BCL), and multiple myeloma (MM). Nearly 35,000 patients have received autologous CAR-T cells for the treatment of these conditions only in the USA. Since their approval by the Food and Drug Administration (FDA) in 2017, over 1200 clinical trials have been initiated globally and there are at least 10 different CAR-T cells with approval by different regulatory agencies around the globe. In the USA the Food and Drug Administration (FDA) has approved 6 commercial CAR-T cells that are widely distributed worldwide. At the time of this writing, several clinical trials have been performed in patients with solid tumours such as glioblastoma, renal and pancreatic cancer, as well as in patients with autoimmune conditions such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SS). There are also several studies showing the potential benefit of CAR-T cells for other non-malignant diseases such as asthma and even fungal infections. In this review, without pretending to cover all the current areas of treatments with CAR-T cells, we offer a brief summary of some of the most relevant aspects of the use of CAR-T cells for some of these conditions.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder. Diagnosis can take a long time, especially in the presence of confounding factors, and it is, at least in part, of exclusion. AOSD is generally mild, however a small percentage of patients can develop a fearsome as well potentially fatal complication, the macrophage activation syndrome (MAS), which is also referred to as hemophagocytic lymphohistocytosis (HLH). This condition is correlated with a cytokine storm production and monocyte/macrophage overactivation, and typically occurs with rash, pyrexia, pancytopenia, hepatosplenomegaly and systemic involvement. Exitus occurs in approximately 10% of cases. The Histiocyte Society, which is a nonprofit organization committed to improving the lives of patients with histiocytic disorders, currently suggests etoposide in combination with dexamethasone for the treatment of HLH/MAS, although a multidisciplinary collaboration using the resources and expertise of several specialists (e.g. rheumatologist, infectiologist, critical care medicine specialist) is always recommended. Hereby we propose the detailed description of the clinical case of a previously healthy young woman in which MAS was the dramatic onset manifestation of AOSD and whose diagnosis posed a real clinical challenge.

The article describes the rational for inhibition of the angiotensin-converting enzyme 2 (ACE2) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent the establishment of positive feedback loops triggered by COVID-19 in some predisposed subjects. Making use of a large quantity of published reports in which human/rodent ACE2 pathway inhibitors were administered in vivo, it is hypothesized a possible therapeutic pharmacological intervention through an inhibition strategy of the zinc metalloprotease ACE2 and its downstream pathway for SARS-CoV-2 patients. Of even more interest, metal (zinc) chelators and renin inhibitors (both FDA approved drugs) may also work alone or in combination in inhibiting the positive feedback loops, initially triggered by COVID-19 and subsequently sustained by hypoxia independently on viral trigger, when both arms of renin-angiotensin system (ACE2 and ACE) are upregulated, leading to critical, advanced and untreatable stages of the disease.

The multidimensionality of chronic pain forces us to look beyond isolated pain assessment such as pain intensity, which does not consider multiple key parameters, particularly in patients suffering from post-operative Persistent Spinal Pain Syndrome (PSPS-T2). Our ambition was to provide a novel Multi-dimensional Clinical Response Index (MCRI), including not only pain intensity but also functional capacity, anxiety-depression, quality of life and objective quantitative pain mapping assessments, the objective being to capture patient condition instantaneously, using machine learning techniques. Two hundred PSPS-T2 patients were enrolled in a real-life observational prospective PREDIBACK study with 12-month follow-up and received various treatments. From a multitude of questionnaires/scores, specific items were combined using exploratory factor analyses to create an optimally accurate MCRI; as a single composite index, using pairwise correlations between measurements, it appeared to better represent all pain dimensions than any other classical score. It appeared to be the best compromise among all existing indexes, showing the highest sensitivity/specificity related to Patient Global Impression of Change (PGIC). Novel composite indexes could help to refine pain assessment by changing the physician’s perception of patient condition on the basis of objective and holistic metrics, and by providing new insights to therapy efficacy/patient outcome assessments, before ultimately being adapted to other pathologies.

CAR-T cell therapy has emerged as a groundbreaking approach in cancer treatment, leveraging the immune system to target and eliminate cancer cells. While currently focused on hematologic malignancies, the future holds promise for expanding CAR-T cell therapy to diverse cancers, enhancing its efficacy, and improving safety profiles. Recent advances in tumor immunology have propelled CAR-T cell therapy as a game-changer in treating diseases such as relapsed/refractory B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Six CAR-T cell products have received FDA approval for treating R/R B cell malignancies. However, challenges persist, including complications like cytokine release syndrome (CRS), coagulopathy, and cytopenias. Strategies to mitigate these complications involve targeting distinct antigens with dual- or multi-targeted CAR-T cells and enhancing immunogenicity. Additionally, γδ CAR-T cells show promise in recognizing antigen- negative leukemia cells in an MHC-independent manner while reducing the risk of inducing graft-versus-host disease (GVHD). As CAR-T cell therapy continues to evolve through innovation and discovery, it holds the potential to revolutionize cancer treatment, offering new hope to patients and reshaping the landscape of oncology with its precision and efficacy.

Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phos-phorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank-Ter Haar syndrome (FTHS). Based on our earlier investigation, the absence of TKS4 triggers migration, invasion, and epithelial-mesenchymal transition (EMT)-like phenomena while concurrently suppressing cell proliferation in HCT116 colorectal carcinoma cells. This indicates that TKS4 may play a unique role in the progression of cancer. In this study, we demonstrated that the enhancer of zeste homolog 2 (EZH2) and the histone methyltransferase of polycomb repressive complex 2 (PRC2) are involved in the migration, invasion, and EMT-like changes in TKS4-deficient cells (KO). EZH2 is responsible for the maintenance of the trimethylated lysine 27 on histone H3 (H3K27me3). Methods: We performed the transcriptome sequencing, chromatin immunoprecipitation, protein and RNA quantitative studies, cell mobility, invasion, and proliferation studies combined with/without EZH2 activity inhibitor 3-deazanoplanocine (DZNep) Results: We detected an elevation of global H3K27me3 levels in the TKS4 KO cells, which could be reduced with treatment with DZNep, an EZH2 inhibitor. Inhibition of EZH2 activity reversed the phenotypic effects of the knockout of TKS4, reducing the migration speed and wound healing capacity of the cells as well as decreasing the invasion capacity, while the decrease in cell prolif-eration became stronger. In addition, inhibition of EZH2 activity also reversed most epithelial and mesenchymal markers. We investigated the wider impact of TKS4 deletion on the gene expression profile of colorectal cancer cells using transcriptome sequencing of wild-type and TKS4 knockout cells, particularly before and after treatment with DZNep. Additionally, we observed changes in the expression of several protein-coding genes and long non-coding RNAs that showed a recovery in expression levels following EZH2 inhibition. Conclusions: Our results indicate that the removal of TKS4 causes a notable disruption in the gene expression pattern, leading to the disruption of several signal transduction pathways. Inhibiting the activity of EZH2 can restore most of these transcriptomics and phenotypic effects.

Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function – and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. Recent discoveries of FEVR-linked variants in two other Catenin genes (CTNND1, CTNNA1) and the Endoplasmic Reticulum Membrane Complex Subunit-1 gene (EMC1) suggest that we will continue to find additional genes that impact the neural retinal vasculature, especially in multi-syndromic conditions. The goals of this review are to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases.

KLEPTOSE® CRYSMEB is a methylated cyclodextrin derivative displaying less methylated group substitution than randomly methylated cyclodextrin. It has demonstrated an impact on atherosclerosis and neurological diseases. linked in part to cholesterol complexation and immune response, but the impact on inflammatory cascade pathways was not clear. Thus, the impact of KLEPTOSE® CRYSMEB on various pharmacological targets was assessed using human umbilical vein endothelial cells in physiological and inflammatory conditions, followed by screening against twelve human primary cell-based systems designed to model complex human tissue and disease biology of the vasculature, skin, lung, and inflammatory tissues using the BioMAP® Diversity PLUS® Panel. Finally, the anti-inflammatory mechanism was investigated on peripheral blood mononuclear cells to evaluate anti-inflammatory or pro-resolving properties. The results showed that KLEPTOSE® CRYSMEB can modulate the immune system in vitro and potentially manage vascular issues by stimulating the expression of molecules involved in the crosstalk between immune cells and other cell types. It showed anti-inflammatory effects driven by pro-inflammatory cytokine secretion inhibition and could have different impacts on different tissue types. Moreover, this cyclodextrin showed no clear impact on pro-resolving lipid mediators. Finally, it appeared that the mechanism of action of KLEPTOSE® CRYSMEB seems to not be shared by well-known anti-inflammatory molecules.

Ground-based high-power lasers enable to, in principle, deorbit any kind of space debris object from the low Earth orbit (LEO) by remotely inducing laser-ablative momentum. However, the assessment of efficiency and operational safety depends on many factors like atmospheric constraints or the risk of debris disintegration during irradiation. We analyze laser momentum for a great variety of target geometries and sizes, and – for the first time in a large-scale simulation – include thermal constraints for laser irradiation configuration. Using a coherently coupled 100 kJ laser system at 1030 nm wavelength, 5 ns pulse duration in an optimized pointing elevation angle range, the pulse frequency should amount to less than 10 Hz to prevent fragment meltdown. For mechanically intact payloads or rocket bodies, repetition rates should be even lower. Small debris fragments sized between 10 and 40 cm can be de-orbited by around 100 to 400 station passes with head-on irradiation while objects exceeding 2 m typically require far more than 1000 irradiations for deorbit. Hence, laser-based debris removal cannot be considered a prime space sustainability measure tackling the top-risk large debris, yet it can provide for remediation of a multitude of small-sized debris using small networks of globally distributed laser sites.