Expression of miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA. In addition, expression of tumor suppressor gene RECK is associated with miR-21 overexpression in high-grade cervical lesions. In the present study we analyze the role of miR-21 in RECK gene regulation in cervical cancer cells. To identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression using siRNAs. We analyzed the expression of miR-21 and RECK, as well as functional effects on cell proliferation and migration. We found that in cervical cancer cells there was an inverse correlation between miR-21 expression and RECK mRNA and protein expression. SiRNAs to miR-21 increased luciferase reporter activity in construct plasmids containing the RECK-3′-UTR microRNA response elements MRE21-1, MRE21-2, and MRE21-3. The role of miR-21 in cell proliferation was also analyzed and cancer cells transfected with siRNAs exhibited a markedly reduced cell proliferation and migration. Our findings indicate that miR-21 post-transcriptionally down-regulates the expression of RECK to promote cell proliferation and cell migration inhibition in cervical cancer cell survival. Therefore, miR-21 and RECK may be potential therapeutic targets in gene therapy for cervical cancer.

Hepatitis C virus (HCV) is a major public health threat associated with serious clinical consequences worldwide. The WHO reports an estimated 58 million people globally living with chronic hepatitis C virus (HCV) infection, with 1.5 million new cases and over 350,000 deaths annually due to HCV-related diseases. Despite the existence of multiple diagnostic methods, the accessibility of diagnosis and treatment is often hindered across the continent by limited resources, insufficient healthcare infrastructure, and low public awareness of Hepatitis C virus Hepatitis C virus infection is a major public health concern in African countries, which have the highest prevalence rates of HCV in the world (1–26%). Egypt, African country which had the highest prevalence of Hepatitis C virus infection in the world. Its national hepatitis C elimination initiative emerges as an exemplary case of success an having screened over 60 million individuals, and treated more than 4 million, thereby markedly diminishing both the prevalence and incidence of the disease. The strategies employed by Egypt offer critical insights and adaptable frameworks for other African Countries facing analogous challenges. The Aim of this Review is to highlight the triumphs and hurdles of Egypt's approach, while also providing strategic guidance for African Countries to accelerate the journey towards the eradication of hepatitis C.

Keywords: olfactory rehabilitation; chronic pain; fMRI;

Background: Chronic lateral epicondylitis challenges the therapeutical approach; underlying mechanisms are incompletely understood; neuropathic pain and central and peripheral sensitization may explain the fact that botulinum toxin was found to play a role in pain and function management. Methods: We searched the literature for MeSH terms: lateral epicondylitis or synonyms and botulinum toxin. Results: We found 14 papers containing trials on botulinum toxin injection into the tendon or into the extensor muscles (particularly extensor carpi radialis brevis and extensor communis digitorum). We followed the administration pathways, doses, timing and side effects. Conclusion: With chronic course, the focus of the therapy shifts from the afflicted tendon to the inserting muscles, as muscle contracture may create a vicious loop to perpetuate and aggravate the disease. Doses, timing and side effects are discussed.

Tumid Lupus Erythematosus has been the subject of heated debate as to its correct nosographic classification. In particular, its definition has changed over time, depending on the different studies performed. In this review we address the initial definition of TLE, the changes that have taken place in the understanding and placement within the classification of Lupus Erythematosus (LE), and focus on clinical, histopathological, immunophenotypical and differential diagnosis aspects.

The blood count is crucial for assessing bone marrow's cell production and differentiation during infections, gauging disease severity, and monitoring therapeutic responses. The profile of blood count in chronic form of paracoccidioidomycosis (PCM) has been insufficiently explored. To better understand the changes in hematological cells in different stages of the PCM chronic form, we evaluated the blood count, including immature blood cells in automated equipment, before and during the treatment follow-up of 62 chronic PCM patients. Predominantly male (96.8%) with an average age of 54.3 (SD 6.9) years, participants exhibited pre-treatment conditions such as anemia (45.2%), monocytosis (38.7%), and leukocytosis (17.7%) which became less frequent after clinical cure. Anemia was more prevalent in severe cases. Notably, hemoglobin and reticulocyte hemoglobin content increased, while leukocytes, monocytes, neutrophils, immature granulocytes, and platelets decreased. Chronic PCM induced manageable hematological abnormalities, mainly in the red blood series. Monocytosis, indicating monocytes' role in PCM's immune response, was frequent. Post-treatment, especially after achieving clinical cure, significant improvements were observed in various hematological indices, including immature granulocytes and reticulocyte hemoglobin content, underscoring the impact of infection on these parameters.

Palmitoylethanolamide (PEA) has been prescribed for neuropathic pain for several years. This study is mainly addressed to summarize what has been published on the topic in the last decades, and how appropriate the numerous prescriptions are. Among others, it examines the innovative EquiPEA^® patent, which aims to address obstacles encountered with conventional PEA formulations. EquiPEA^® seems to partially ameliorate the bioavailability and the targeted distribution. It seems to introduce novel advancements that have the potential to enhance the therapeutic effectiveness of PEA in terms of its anti-inflammatory, antioxidant, and analgesic properties. The deep literature analysis aims to examine the potential advantages of this innovative formulation, in the context of several pathological conditions that may benefit from this molecule. In particular, it investigates the potential enhanced bioavailability and targeted delivery system of EquiPEA^®. Also, it tries to understand if it can modernize the field of therapy based on PEA, thus offering a better treatment option for individuals with long-term inflammation, oxidative stress, and neuropathic or mixed pain with a neuropathic component. The study examines the possible impact of EquiPEA^® on personalized medicine strategies and its potential for translation into clinical practice. It analyses the possibilities that EquiPEA^® has in enhancing patient outcomes in a range of central nervous system and inflammatory conditions. This narrative review makes a valuable contribution to the ongoing comprehension of PEA therapy. It establishes a foundation for further exploration in research and potential uses in clinical settings.

Chronic inflammation may have a detrimental impact on human health as it tends to result in cancer. In addition, it is often linked to different steps that participate in tumorigenesis, including cellular transformation, survival, promotion, invasion, proliferation, angiogenesis, and metastasis. Hence, inflammation predisposes cancer development and plays a vital role in promoting all tumorigenesis stages. Inflammation is caused by many factors, such as bacterial and viral infections, tobacco smoking, autoimmune diseases, obesity, asbestos exposure, and many others, increasing cancer risk. Moreover, cancer can be enhanced by mutations that proceed to cancer progression. Consequently, it leads to immunosuppression and provides a favorable background for tumor development. Although many studies address the question of relationships between inflammation and cancer development, little attention is paid to the link between inflammation and blood cancer. Therefore, the current study reviews the role of inflammation in cancer development, particularly in blood cancer. A meta-analysis research approach meets the research objective and answers the research question. The review results indicate that chronic inflammation directly relates to the development of many cancer types, blood cancer in particular.

Background: Aging is commonly accepted as a time period of declining heath. Aims: This review aimed to examine the research base concerning the use of term ‘successful aging’, a process and outcome deemed desirable, but challenging to attain. A second was to provide related information to demonstrate how health professionals as well as individuals can aim for a ‘successful aging’ process and outcome, despite the presence of disabling osteoarthritis. Methods: Information specifically focusing on ‘successful aging’ and the concept of improving opportunities for advancing ‘successful aging’ despite osteoarthritis was sought. Results: Among the many articles on ‘successful aging’, several authors highlight the need to include, a broader array of older adults into the conceptual framework. Moreover, conditions such as osteoarthritis should not necessarily preclude the individual from attaining a personally valued successful aging outcome. Conclusion: Pursuing more inclusive research and research designs, and not neglecting to include people with chronic osteoarthritis can potentially heighten the life quality of all aging individuals, while reducing pain and depression, among other adverse aging and disability correlates among those with osteoarthritis

Abstract Background: Periodontitis is associated with systemic chronic inflammatory diseases. There is limited evidence on the influence of anti-cytokine therapies on the periodontal condition and microbiome in the tooth pocket of such patients, so the aim of this study was to elucidate this issue. Methods: In this observational trial, the periodontal status and the gingival crevicular fluid of 13 patients with different chronic inflammatory diseases were obtained before initiation of anti-cytokine treatment and 14 weeks after. Gingival crevicular fluid was collected for 16S rRNA gene sequencing from a clinically healthy tooth and the deepest measured pocket. Results: In participants with advanced attachment loss at baseline, the clinical attachment level significantly decreased from 2.9 (2.3-3.4) to 2.4 (1.3-3.0) mm (p = 0.04), and the bleeding- on-probing index dropped from 19.4 (10.0-21.0) to 7.3 (6.9-9.9) mm (p = 0.02) without any further periodontal treatment. Shannon’s diversity index significantly increased in the deepest pockets of patients (p = 0.039). Conclusion: The data showed alterations in diversity of the subgingival microbiome and improvement of periodontal parameters over the course of the study, implying a shift towards a healthier condition after starting anti-cytokine therapy. Additional investigations are needed to analyze whether the administration of selective biologicals can improve periodontal conditions in patients with or without chronic inflammatory diseases.

Background: Clinical trails have revealed that patients with depression generally accompanied with learning and memory impairment, which critically impact on individual’s health and development. Danggui-Shaoyao-San (DSS), a famous Chinese complex prescription, significantly overcame depression and relieved cognitive disorder based on previous research and publication. However, its effectsand potential mechanism against chronic restraint stress (CRS) remained unknown. Methods: CRS animal model was established and mice were divided to six groups while they were oral administrated with Danggui-Shaoyao-San at doses of 1.25, 2.5 and 5 g/kg for 14 days. Emotional and cognitive performances were detected by behavior tests, meanwhile neural plasticity and its molecular mechanism were examined by Dil staining, western blot and immunofluorescence. Results: DSS treatment dose-dependently improved locomotion ability in open filed test, overcame depression behavior in forced swimming test and elevated plus maze test, enhanced learning and memory ability in Morris water maze test. CRS decreased number of total spines and mushroom spines, while DSS treatment dose-dependently restored these by Dil staining. Expression of BDNF and GluR1 were significantly down-regulated in CRS group, which were significantly normalized by DSS. Conclusions: DSS treatment dose-dependently reversed CRS-induced cognitive impairments by inducing structural remodeling of neurons.

As of now, anthropogenic habitat injury via dissemination of manufactured chemicals is injuring the world’s ecosystems, but doctors have yet to recognize its consequences to humans. Recognition of overt toxicity due to chronic low-dose exposure will open the door to diagnosis, sequential elimination studies, and prescriptions for preventive cure that represent a first step in preventing escalating chronic diseases. This paper offers a diagnostic construct for such use: chronic ambient poisoning. Incorporating it into clinical practice can reduce misdiagnosis of gastro- and near-toxicity that doctors and patients presently suppress rather than remove, and reduce patient co-dependence with proton-pump inhibitors, anxiolytics, and antidepressants—and the thriving “alternative” health industry. This diagnostic elephant-in-the-room is presently missed for reasons of habit (when an ailment is not recognized, it cannot be included in the differential diagnosis) and of poor conduct and interpretation of non-clinical research studies that are taken to mean an absence of evidence is evidence of absence. Moreover, modern methods fail when: the exposure comprises a “daily cocktail” of poisons acting additively, interactively, and cumulatively over a lifetime; when there is no normal, unexposed comparison group; and when absence of a robust etiopathogenetic model disallows inapt statistics. Only patient-led, consultant-informed sequential elimination studies can “peel the onion” of toxicity and its recognition and “preventive cure”. Clinical use of the chronic ambient poisoning diagnosis can thus open the door to stemming and reversing anthropogenic epidemics.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by a defect in the phagocytic function of the innate immune system owing to mutations in genes encoding the five subunits of the nicotinamide adenine dinucleotide (NADPH) oxidase enzyme complex. This review aimed to provide a comprehensive approach to the pathogens associated with chronic granulomatous disease (CGD) and its management. The topics covered included common pathogens infecting CGD patients, granulomas, and CGD-related infectious diseases, including invasive aspergillosis, Mulch pneumonitis, and liver abscesses. In addition, we also covered the differential diagnosis of CGD and its management. Patients with CGD, often children, have recurrent life-threatening infections and may develop infectious or inflammatory complications. The most common microorganisms observed in the patients with CGD are Staphylococcus aureus, Aspergillus spp, Candida spp, Nocardia spp, Burkholderia spp, Serratia spp, and Salmonella spp. Triple-dose antimicrobial prophylaxis with empiric regimens is recommended. Therefore, therapeutics against this disease must be optimised, considering the lack of curative therapies and the long-term side effects of prophylactic regimens. Consequently, allogeneic haematopoietic stem cell transplantation from a human leukocyte antigen-identical donor has been proven to cure CGD.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by a defect in the phagocytic function of the innate immune system owing to mutations in genes encoding the five subunits of the nicotinamide adenine dinucleotide (NADPH) oxidase enzyme complex. This review aimed to provide a comprehensive approach to the pathogens associated with chronic granulomatous disease (CGD) and its management. The topics covered included common pathogens infecting CGD patients, granulomas, and CGD-related infectious diseases, including invasive aspergillosis, Mulch pneumonitis, and liver abscesses. In addition, we also covered the differential diagnosis of CGD and its management. Patients with CGD, often children, have recurrent life-threatening infections and may develop infectious or inflammatory complications. The most common microorganisms observed in the patients with CGD are Staphylococcus aureus, Aspergillus spp, Candida spp, Nocardia spp, Burkholderia spp, Serratia spp, and Salmonella spp. Triple-dose antimicrobial prophylaxis with empiric regimens is recommended. Therefore, therapeutics against this disease must be optimised, considering the lack of curative therapies and the long-term side effects of prophylactic regimens. Consequently, allogeneic haematopoietic stem cell transplantation from a human leukocyte antigen-identical donor has been proven to cure CGD.

Background: It has been reported that general adiposity in adulthood and early adulthood, and greater height may increase the risk of almost all types of lympho-haematopoietic cancers while a study done in MD Anderson found that obesity and adult weight gain are independent risk factors for CML however no study evaluated the role of obesity in the disease progression while more studies investigate the impact of translocation types. Method: We conducted a retrospective analysis of the files of 37 patients being treated in our center for CML in chronic phase (CMP-CP) with known BCR-ABL1 breakpoints, Results: patients’ management and response assessment was done based on ELN 2013 guidelines. Analysis is done based on two main groups, obese vs normal BMI, and then based on BCR-ABL1 transcripts: e13a2 vs e14a2. Although the number of cases is limited, in the patient-cohort studied an e14a2 BCR-ABL1 transcript type / normal body weight was associated with an inferior outcome when compared to e13a2 transcript / obesity groups Conclusion: our finding suggest the need to enlarge the series to better evaluate a potential role of altered metabolism and/or specific transcripts in the response to TKI in CML.

In chronic myeloid leukemia (CML), a clonal proliferative disorder of granulocytic lineage, the 90%‐95% of cases are characterized by t(9;22) (q34.1;q11.2) translocation, leading to the Philadelphia chromosome (1). Rarely, CML patients directly present a blast crisis, mostly of myeloid origin (2, 3). Herein, we describe one rare CML case, showing an unusual early T lymphoid blastic crisis.

Background: Obesity among pregnant women is common, and their offspring are predisposed to obesity, insulin resistance, and diabetes. Circulating metabolites that are related to insulin resistance and are associated with this decreased tissue-specific uptake are unknown. Here, we assessed metabolite profiles in elderly women and who were either female offspring from obese mothers (OOM) or offspring of lean mothers (OLM). Metabolic changes were tested for associations with metrics for insulin resistance. Methods: 37 elderly women were separated into an elderly offspring from obese mothers (OOM; n = 17) and elderly offspring from lean/normal weight mothers (OLM; n = 20) groups. We measured plasma metabolites using 1H-NMR and also insulin-dependent tissue specific glucose uptake in skeletal muscle were assessed. Associations were made between metabolites and glucose uptake. Results: Compared to the OLM group, we found that the 22:6 docosahexaenoic acid percentage of the total long chain n-3 fatty acids (DHA/FA) was significantly lower in OOM (P = 0.015). DHA/FA associated significantly to skeletal muscle GU (P = 0.031) and M-value in the OLM group only (P = 0.050). Conclusions: DHA/FA is associated with insulin-dependent skeletal muscle glucose uptake and that this association is significantly weakened in the offspring of obese mothers.

Vitamin D has important anti-inflammatory, anti-microbial properties and plays a central role in host immune response. Due to the crucial role of the kidneys in the metabolism of vitamin D, patients with chronic kidney disease (CKD), are prone to vitamin D deficiency. The resultant reduction in the production of calcitriol, the activated form of vitamin D in patients with CKD is responsible for exacerbating the existing renal impairment and periodontal inflammation. Recent evidence suggests a bidirectional, causal relationship between periodontitis and renal functional status. Both conditions have shared pathophysiologic mechanisms including oxidative stress, increases in the systemic inflammatory burden and impaired host response. This review explores the association between vitamin D, CKD and periodontitis. The review summarises the current evidence base for the classical and non-classical vitamin D metabolic pathways, the biological mechanisms linking vitamin D deficiency, CKD and periodontitis, as well as the bidirectional relationship between the two chronic inflammatory conditions. Finally, the paper explores the impact of vitamin D deficiency on CKD, periodontitis, and related co-morbidities.

In Chronic Myeloid Leukemia (CML) patients, CD34+/CD38-/CD26+ cell population represents a “CML specific” Leukemia Stem Cell (LSC) compartment. Indeed, preliminary studies showed that the expression of CD26 discriminates bone marrow CML Leukemic Stem Cells (LSCs) from nor-mal Hematopoietic Stem Cells (HSCs) or from LSCs of other myeloid neoplasms. We were first to demonstrate that at diagnosis CD34+/CD38-/CD26+ cells are easily measurable also in Peripheral Blood (PB) and that residual circulating CD26+LSCs persist, with a fluctuating trend, in most pa-tients in optimal response during treatment with Tyrosine Kinase Inhibitors (TKIs) and even after successful TKI discontinuation. These data corroborate and confirm the possibility of using flow-cytometry CD26+ evaluation as an important diagnostic tool that, combined with molecular biology and cytogenetic, could provide a rapid diagnosis of Chronic Phase (CP) CML starting from a simple PB sample. Yet, few data are available regarding the behavior of CD26+LSCs during Accelerated Phase (AP) or Blast Phase (BP) CML and the role, if any, this peculiar staminal cell compartment may play in disease progression. In the present study we compared the presence and phenotypic characteristics of circulating CD26+LSCs in CP CML patients at diagnosis, during AP and in cases of progression to lymphoid BP, inquiring a possible role of these cells during dis-ease evolution.

: This article was not intended to be a complete report of a standard clinical trial. It is a report of the outcomes of preliminary data for validation of the CMECD procedure (Coletti Method of EMG ChemoDenervation) protocol for the treatment of chronic pain resulting from chronic muscle spasm. Methods are here detailed on how to approach the patient with chronic pain, identify the presence of chronic muscle spasm, undertake the treatment protocol and how to perform the follow up process to confirm that chronic pain secondary to chronic muscle spasm was the accurate diagnosis. Furthermore, this article presents the results of a cohort of more than 90 patients treated by the CMECD procedure regarding location and duration of prior pain, prior treatment strategies, degree of success in resolving pain and duration of relief. Outcome data consisting of patient and staff reporting of specific situations in which the chronic pain treatment was successful has been included to help establish the “believability” of outcome successes and to elucidate the potential life altering effects of successful treatment of chronic pain secondary to chronic muscle spasm. This article will hopefully increase the interest in this treatment protocol and increase the chance that a classical international clinical trial will be undertaken.

Vascular calcification (VC), is a common complication in patients with chronic kidney disease and increases mortality. Although oxidative stress is involved in the onset and progression of this disorder, the specific role of some main redox regulators such as catalase, the main scavenger of H2O2, remains unclear. In the present study, epigastric arteries of kidney transplant recipients, an in vivo model of VC and an in vitro model of VC exhibiting catalase overexpression (Cts) were analyzed. Peri-calcification areas of human epigastric arteries have increased levels of catalase and cytoplasmic rather than nuclear RUNX2. In the in vivo model, advanced aortic VC concurs with lower levels of the H2O2 scavenger, glutathione peroxidase 3 compared to controls. In an early model of calcification using vascular smooth muscle cells (VSMCs), Cts VSMCs showed the expected increase in RUNX2 total levels. However, Cts VMSC also exhibited lower percentage of the nucleus stained for RUNX2 in response to calcifying media. At this early model of VC we did not observe dysregulation of mitochondrial redox state, an increase in general redox state was observed in the cytoplasm. These in vivo and in vitro results highlight the complex role of antioxidant enzymes as catalase in the process of VC by regulation of RUNX2 location.

There are presently more than 18 known aflatoxins (>18) most of which have been insufficiently studied for their incidence, health-risk, and mechanisms of toxicity to allow effective intervention and control means that would significantly and sustainably reduce their incidence and adverse effects on health and economy. Among these, aflatoxin B1 (AFB1) has by far been the most studied; and yet, many aspects of the range and mechanisms of the diseases it causes remain to be elucidated. Its mutagenicity, tumorigenicity, and carcinogenicity, which are the best known still suffer from many limitations regarding the relative contribution of the oxidative stress and the reactive epoxide derivative (Aflatoxin-exo 8,9-epoxide) in the induction of the diseases, as well as its metabolic and synthesis pathways. Additionally, despite the well-established additive effects for carcinogenicity between AFB1 and other risk factors, e.g., hepatitis viruses B and C, and the algal hepatotoxic microcystins, the mechanisms of this synergy remain unclear. This study reviews the most recent advances in the mechanisms of toxicity of aflatoxins and the adverse health effects that they cause in humans and animals.

Chronic pain is a serious health concern and potentially debilitating condition, leading to anxiety, depression, reduced productivity and functionality, and poor quality of life. This condition can be even more detrimental and incapacitating in the pediatric patient population. In low and middle income countries (LMICs), pain services are inadequate or unavailable, leaving most of the world's pediatric population with chronic pain untreated. Many of these children in LMICs are suffering without treatment, and often die in pain. Awareness and advocacy for this population must be prioritized. We reviewed the available literature on the chronic pediatric pain burden in LMICs, barriers to treatments, and current efforts to treat these patients.

Aim: To analyze a single center's experience with Short Bowel Syndrome/ Chronic Intestinal Failure (SBS/CIF) in adult patients treated with Home Parenteral Nutrition (HPN). Materials and methods: In the last thirty years, 13 patients with SBS/CIF were included in an HPN program. Results: Between 1992 and 2023, 13 patients were included in an HPN program. The primary underlying pathology was acute mesenteric ischemia. The median age of the starting HPN was 44 years old. Most are submitted to several surgeries of extensive intestinal resection with posterior intestinal reconstruction. Five of the 13 patients have died while on HPN for a median of 42 months. The causes of death HPN-related were catheter sepsis, endocarditis with cardiac failure, or hepatic failure. One patient died due to underlying pathology: pelvic abscesses and bleeding related to radiotherapy. Eight patients remain alive with a median time of HPN of 173 months. During the HPN support, the most frequent complications were venous catheter infection and venous territory thrombosis. None of the eight patients alive have hepatic failure. Two patients recently started teduglutide, with good tolerance, and need reduction of HPN support. All these eight patients have a satisfactory quality of life (parenteral support needs range between five to two nutrition bags per week). Conclusion: HPN remains the gold standard of SBS/CIF treatment, although Teduglutide may reduce HPN needs and HPN complications and provide a better quality of life. An HPN multidisciplinary healthcare group support is essential to ensure these patients' survival and quality of life. Keywords Short bowel Syndrome, Chronic Intestinal failure, Home Parenteral Nutrition, Teduglutide, Complications of Parenteral Support.

Considering the relevance of the pathogenesis research of different liver diseases, in our study we investigated the possible activity of IL-23/IL-17 axis on the im-munohepatotoxicity of two etiologically different CLD. A total of patients with CHC infection, 19 with NASH and 20 healthy controls (CG) were recruited. After histological verification from liver tissue obtain by liver biopsy, patients with CHC were divided into two groups: CHC-NSF (F0/F1/F2)-non-significant fibrosis, 20 patients, and CHC-SF (F3/F4)-significant fibrosis/cirrhosis, 16 patients. All anthropometric, biochemical, immunological cytokines (IL-6, IL-10, IL-17 and IL-23) tests were performed accordance to standard procedure. The plasma levels of IL-6, Il-17A and IL-23 were significantly higher in CHC-SF and NASH in compared with CG. Also, plasma levels of IL-23/IL-17A were significantly higher in NASH in compared to CHC-SF. In CHC-SF we had significantly lowest IL-10 level in compared with all three groups. Liver tissue levels of IL-17A and IL-23 in CHC-NSF were significantly lower in compared with NASH. IN CHC-SF and NASH, IL17-A and IL-23 in liver tissue were significantly higher in compare to plasma levels. In conclusan, proinflammatory response of IL-23/17A axis is dominant in plasma and liver tissue in CHC with higher levels of liver fibrosis and in NASH patients.

Chitinase 3-like 1 （also known as CHI3L1 or YKL-40）is a mammalian chitinase that has no enzymatic activity, but has the ability to bind to chitin, the polymer of N-acetylglucosamine (GlcNAc). Chitin is a component of fungi, crustaceans, arthropods including insects and mites, and parasites, but is completely absent from mammals, including humans and mice. In general, chitin-containing organisms produce CHI3L1 to protect the body from exogenous pathogen as well as hostile environments, and it was thought that it has a similar effect in mammals. However, recent studies have revealed that CHI3L1 plays a pro-inflammatory role by inducing anti-apoptotic activity in epithelial cells and macrophages. Under chronic inflammatory conditions such as inflammatory bowel disease and chronic obstructive pulmonary disease, many groups already confirmed that the expression of CHI3L1 is significantly induced on the apical side of epithelial cells, and activates many downstream pathways involved in inflammation and carcinogenesis. In this review article, we will summarize the expression of CHI3L1 under the chronic inflammatory conditions in various disorders and would like to discuss the potential roles of CHI3L1 in those disorders on various cell types.

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.

The ingestion of ethanol presents a significant global public health challenge. Chronic alcohol consumption is associated with the development of conditions such as cancer, cirrhosis, hepatic diseases, cardiovascular diseases, and diabetes, as well as neurological impairments that may predispose individuals to dementia, schizophrenia, and behavioral disorders such as violence and suicide. Alcohol-related fatalities constitute 5.3% of worldwide deaths annually, totaling approximately 3 million. Notably, alcohol consumption is implicated in 25% of cirrhosis-related deaths and 4.1% of cancer-related deaths. Taurine (2-aminoethanesulfonic acid) is a non-protein β-amino acid essential for cellular homeostasis, possessing antioxidant, anti-inflammatory, and cytoprotective properties crucial for life maintenance. This study aimed to evaluate the effects of taurine administration on hippocampal neurogenesis, neuronal preservation or reverse damage in rats exposed to forced ethanol consumption. Results demonstrated the neuroprotective effects of taurine on ethanol-treated rats, promoting tissue regeneration and suggesting its pivotal role in this process. However, this aminoacid failed to induce neurogenesis in the tissues of healthy rats, implying that its activity may be contingent upon post-injury stimuli.

In the world, migraine is one of the most common cause of disability in adults. To date, there is no a single cause for this disorder, but rather a set of physio-pathogenic triggers, in combination with a genetic predisposition. Among factors related to the migraine onset, a crucial role seems to be played by gut dysbiosis. In fact, it has been demonstrated how the intestine is able to modulate the central nervous system activities, through the gut-brain axis, and how gut dysbiosis can influence neurological pathologies, including migraine attacks. In this contest, in addition to migraine conventional pharmacological treatments, attention has been paid to an adjuvant therapeutic strategy based on different nutritional approaches and lifestyle changes able to positively modulate the gut microbiota composition. In fact, the restoration of the balance between the different gut bacterial species, the reconstruction of the gut barrier integrity and the control of the release of gut-derived inflammatory neuropeptides, obtained through specific nutritional patterns and lifestyle changes, represent a possible beneficial additive therapy for many migraine subtypes. Herein, this review explores the bi-directional correlation between migraine and the main chronic non-communicable diseases, like diabetes mellitus, arterial hypertension, obesity, cancer and chronic kidney diseases, whose link is represented by gut dysbiosis.

Cardiovascular diseases (CVD) account for about 17.3 million annual deaths worldwide. 85% of these deaths occurred as a result of myocardial infarction (MI) and stroke. Chronic heart diseases, such as arterial hypertension (AH), coronary heart disease, various cerebrovascular diseases, dilated and hypertrophic cardiomyopathies are widespread, with a fairly high incidence of mortality and disability. Most of these diseases are characterized by cardiac arrhythmias, conduction and contractility disorders. Additionally, interruption of the electrical activity of the heart, the appearance of extensive ectopic foci and heart failure are all symptoms of a number of severe hereditary diseases. The molecular mechanisms leading to the development of CVD are associated with impaired permeability and excitability of cell membranes and mainly caused by dysfunction of cardiac Ca2+ channels. Acquired channelopathies are caused by metabolic disorders, increased tone of the sympathetic nervous system, age-related changes that lead to deterioration of coronary blood flow and hemodynamics. Currently known channelopathies, such as the long or short QT syndromes, Brugada and Lenegre syndromes, catecholaminergic polymorphic ventricular tachycardia, etc., are congenital and genetic disorders caused by mutations of genes "responsible" for the conductive properties of certain channel-forming proteins, including pore-forming subunits of Ca2+ channels. Over the past 50 years, more than 100 varieties of ion channels have been found in the cardiovascular system cells. The relationship between the activity of these channels and cardiac pathology, as well as the general cellular biological function, has been intensively studied on several cell types and experimental animal models in vivo и in situ. In this review, we discuss the origin of Ca2+ channelopathies and the role of Ca2+ channels of various types: L- R-, T-types voltage-gated calcium channels, RyR2, non-selective hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, transient receptor potential (TRPC, TRPM7, TRPA1) channels in the development of cardio-vascular pathology.

Background: Overall survival is the most important outcome for treatment response in feline chronic kidney disease (CKD). Beraprost has been shown to reduce the kidney function decline in cats with International Renal Interest Society (IRIS) stage 2 and 3 CKD. However, association with prolonged survival has not yet been examined. Objective: To assess the relationship between beraprost and overall survival in cats with CKD in real clinical practice. Animals: Client-owned cats with IRIS stage 3 CKD (n = 134), evaluated between 2017 and 2020. Methods: Retrospective cohort study based on data from electronic medical records of one hospital. Results: Multivariable Cox regression models on all treatment effects showed that beraprost only was related to better survival (P = 0.028). The cohort was divided into “beraprost therapy” and “no beraprost therapy” groups, and survival analyses revealed that overall survival was significantly longer in the beraprost therapy group, using Kaplan-Meier curves (P = 0.004). However, baseline phosphate is known to be an important prognostic indicator and was not well balanced between the two groups. Therefore, a subcohort of 97 cats was selected (those having baseline phosphate < 6.0 mg/dL) that allowed for this parameter to be balanced between groups. The survival data in this subcohort was consistent with that of the overall study cohort. Conclusions: In feline patients with CKD, beraprost therapy was associated with better overall survival.

Stress plays a central role in functioning for all life forms. As humans, we experience stress in a multitude of ways through various types of stimuli. Due to the constancy of stressors in our lives, the nervous system has learned to allosterically adapt to the stimuli, but when the body cannot adapt, chronic stress can have morphological and degenerative impacts on neuroanatomy and cognitive function that may or may not be reversible. This literature review aimed to identify the specific neuroanatomical structures impacted most by the long-term effects of chronic stress and the subsequent relationship the morphological changes had on cognitive function in rodent models. We examined articles published from PubMed, Google Scholar, and Science Direct, while focusing the search on anatomical and neurodegenerative effects associated with chronic stress stimuli. The degenerative effects of various types simulated physiological chronic stress showed the most impact on neurogenesis and neuronal development, brain plasticity, and spatial learning and memory with association to the hippocampus. The hippocampus, amygdala, prefrontal cortex, and hypothalamic-pituitary-adrenal axis (HPA) all had reversible and non-reversible morphological alterations, which also had a direct impact on the brain’s cognitive abilities. While studies regarding chronic stress are still being conducted, future research may be able to further highlight why stressful stimuli can particularly impact these structures and the tangential impacts that it may have on related or adjacent structures.

Tinnitus is an auditory phantom perception in the ears or head in the absence of a corresponding external stimulus. There is currently no effective treatment available that reliably reduces tinnitus. Educative counseling is a treatment approach that aims to educate patients and inform them about possible coping strategies. For this feasability study, we implemented educational material and self-help advice in a smartphone app. Participants used the educational smartphone unsupervised during their daily routine over a period of 4 months. Comparing the tinnitus outcome measures before and after smartphone-guided treatment, we measured changes in the tinnitus-related distress, but not in tinnitus loudness. Improvements on the Tinnitus Severity numeric rating scale reached an effect size of .408, while the improvements on the THI were much smaller with an effect size of .168. Analysis on the user behavior showed that frequent and intensive use of the app is a crucial factor for treatment success: participants that used the app more often and interacted with the app intensively, reported a stronger improvement of the tinnitus. Between study allocation and final assessment, 26 of 52 participants dropped out of the study. Reasons for the dropouts and lessons for future studies are discussed in this paper.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm constituting approximately 15% of newly diagnosed leukemia in adult patients. Development of tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes in patients with chronic CML in chronic phase. However, adverse drug events (ADEs) associated with TKI therapy have influenced drug adherence, resulting in adverse clinical outcomes and a decline in the quality of life (QoL). In this study, we carried out a unique questionnaire survey to evaluate ADEs, which comprised 14 adverse events. We compared drug adherence rates between patients using imatinib and those who switched from imatinib to nilotinib, a second-generation TKI. Following the switch, the total number of ADEs decreased considerably in most cases. Simultaneously, better QoL was observed in the nilotinib group than in the imatinib group. Drug adherence was measured using Morisky’s 9-item Medication Adherence Scale (MMAS). MMAS increased significantly after switching to nilotinib in all cases. Drug adherence is a critical factor for achieving molecular response in patients with CML. In fact, our results showed a strong inverse correlation between clinical outcome [international scale (IS)] and adherence (MMAS), with a stronger tendency in the nilotinib group than in the imatinib group. In conclusion, low occurrence of ADEs induced a high level of QoL and a good clinical response with second-generation TKI nilotinib treatment.

Cyanobacteria (blue-green algae) may rapidly propagate under favorable conditions, forming dense blooms. As water blooms deteriorate, blue-green algae can generate potent toxins, potentially harmful to companion animals, wildlife, and even humans. One widely recognized cyanobacterial toxin is microcystin. This algal toxin has been implicated in surface waters globally, increasing liver cancer and/or disease risk amongst those who depend on sources prone to microcystin contamination. Interestingly, no study looked at weather conditions when connecting liver health outcomes to freshwater cyanotoxins. The purpose of this study was to determine if climate was an important determinant of liver mortality and total microcystins at the ecological level. Secondary data was used to evaluate the proposed hypothesis. Environmental data (CDC WONDER) and toxin data (USEPA) were used in multivariate regression analysis. Mean daily sunlight and total microcystins were significant predictors of age-adjusted chronic liver disease and cirrhosis death rates. Mean annual precipitation and mean daily max temperature were non-significant predictors. This study demonstrated how microcystins in combination with climate may increase liver mortality. The results can prompt others to study environmental exposures of terminal liver diseases, guiding environmental health and the water industry of human survival needs.

The signs and symptoms of Long COVID can be explained by a shortage of blood in the body and a resulting deficient blood flow through nearly all organs. This shortage arose during the acute phase of COVID19 by an increased breakdown of haematocytes, to which the liver responds by reducing the production of albumin, in order to prevent a too large decrease in haematocrit.In order to ensure the perfusion of organs that are directly necessary for survival, the body takes the emergency measure of diverting blood from other organs and tissues. The perfusion of the blood-producing organs is also affected by this distribution measure, which hinders the smooth recovery of the total blood volume. The body is stuck in this vicious circle: a shortage of circulating blood hinders the recovery of blood production. This explains the long duration of Long COVID. My proposed treatment of Long COVID focuses on the recovery of the correct volume of blood in the body of the right composition by the intravenous administration of donor blood products, starting with albumin concentrate. A trial treatment can be performed in any hospital without much additional preparations, and has a lower associated risk for the patient than analysing the total blood. A diagnosis ex juvantibus, by therapeutic response, is therefore preferable. I suspect that most Long COVID patients will exhibit a high serum ferritin level as a result of internal haemolysis, and haematocrit and albumin values at the high and low extremes of the reference range because the liver can not keep up with the recovery of the red bone marrow.

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which has now become a severe public health problem worldwide. β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous study has demonstrated that Bruton's tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-β related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by β-AR overactivation;(2) Methods: In vivo: Male C57BL/6J mice were treated with or without the β-AR agonist isoproterenol (ISO) to establish cardiac fibrosis animal model. Here, results showed that BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by β-AR. In vitro: Results showed that ZB alleviated β-AR-induced cardiac fibroblast activation and macrophage proinflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited β-AR-induced cardiac fibrosis and inflammation by BTK、STAT3、NF-κB and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates β-AR-induced cardiac fibrosis and inflammation.

Background: Cell-free plasma DNA (cfDNA) is composed of circulating extracellular DNA originating from apoptosis or cell necrosis. It is generally present in healthy individuals, but its levels increase in different clinical conditions, such as kidney disease, sepsis, myocardial infarction, trauma and cancer. Caspase-3 plays a central role in apoptosis, a mechanism of programmed cell death involved in the pathogenesis of chronic kidney disease (CKD). Methods: We compared cfDNA and caspase-3 levels in 25 CKD patients and in 10 healthy subjects, evaluating the modification of their concentrations according to CKD stage. We also analyzed the correlation between cfDNA and caspase-3 levels in CKD patients and the correlation between cfDNA and caspase-3 levels and creatinine and urea. Results: CfDNA and caspase-3 levels were higher in CKD patients compared to healthy subjects, in particular in patients with advanced renal disease. A positive correlation between cfDNA and caspase-3 levels and between cfDNA and caspase-3 and creatinine and urea was also observed. Conclusion: Patients with chronic kidney disease present higher levels of cfDNA and caspase-3 levels compared with healthy subjects. The worsening of renal damage and the increase in uremic toxin concentration are associated to higher levels of cfDNA and caspase-3 levels, thus reflecting a central role of apoptosis in the pathogenesis of CKD.

Increased chronic glucose is associated with pandemic diseases. To date, there is not a practical, as well as accurate sample for reflecting that level. We measured earwax glucose in 37 controls. They provided standard serum samples, Glycated Haemoglobin (HbA1c) and earwax samples on two time-points, one month a part. The specimens measured baseline fasting glucose, a follow-up postprandial glucose level and a between sample chronic glucose, calculated using the average level on the two occasions. The baseline earwax sample was obtained using a clinical method and the follow-up using a novel self-sampling earwax device. The earwax analytic time was significantly faster using the novel device in comparison to the clinical use of the syringe. Earwax accurately reflected glucose at both assessments with stronger correlations than HbA1c. Follow-up postprandial concentrations were more significant than their respective fasting baseline concentrations, reflecting differences in fasting and postprandial glycaemia and more efficient standardisation at follow up. Earwax demonstrated to be more predictable than HbA1c in reflecting systemic fasting, postprandial and long-term glucose levels and immune by confounders. Earwax glucose was approximately 60% more predictable than HbA1c in reflecting glycaemia over a month. The self-sampling device provided a sample that might accurately reflect chronic glycaemia.

Vitamin D (VD) is a pro-hormone essential for life in higher animals. It is present in few types of foods and is produced endogenously in the skin by a photochemical reaction. The final step of VD activation occurs in the kidneys involving a second hydroxylation reaction to generate the biologically active metabolite 1,25(OH)₂-VD. Extrarenal 1α-hydroxylation has also been described to have an important role in autocrine and paracrine signaling. Vitamin D deficiency (VDD) has been in the spotlight as a major public health-care issue with an estimated prevalence of more than a billion people worldwide. Among individuals with chronic kidney disease (CKD), VDD prevalence has been reported to be as high as 80%. Classically VD plays a pivotal role in calcium and phosphorus homeostasis. Nevertheless, there is a growing body of evidence supporting the importance of VD in many vital nonskeletal biological processes such as endothelial function, renin-angiotensin-aldosterone system modulation, redox balance and innate and adaptive immunity. In individuals with CKD, VDD has been associated with albuminuria, faster progression of kidney disease and increased all-cause mortality. Recent guidelines support VD supplementation in CKD based on extrapolation from cohorts conducted in the general population. In this review, we discuss new insights on the multifactorial pathophysiology of VDD in CKD as well as how it may negatively modulate different organs and systems. We also critically review the latest evidence and controversies of VD monitoring and supplementation in CKD patients.

Many people in the USA have lost their lives or become addicted to opioids via prescription opioids given for chronic pain. The chronic pain epidemic has emerged due to a convergence of factors, including the medicalization of pain as well as injuries happening in the workplace, in the home, or during recreation. Opioid prescriptions rose precipitously from the late 1990’s through to approximately 2020, and despite public awareness, still are increasing. This review examines literature on integrative approaches to chronic pain as delineated by pain type. The review is organized by the most common causes of chronic pain, and randomized controlled trials, meta-analyses and systematic reviews are extracted for each cause of chronic pain. Several promising interventions may alleviate chronic pain of some causes, and some interventions may work across pain causes. Lowering inflammation through dietary or lifestyle regimens may be a general way of reducing pain. Pain can be alleviated through several adjunctive and integrative treatment approaches, which may serve to lower the need for opioid medication.

Chronic pancreatitis (CP) is an irreversible and progressive inflammation of the pancreas that can involve both pancreatic parenchyma and pancreatic duct. CP results in morphological change in the gland in the form of fibrosis and calcification along with functional impairment in the form of exocrine and endocrine insufficiency. Studies on the natural history of CP reveal the irreversibility of the condition and the resultant plethora of complications of which pancreatic adenocarcinoma is the most dreaded one. (1,2) In Japanese population-based studies by Otsuki and Fuzino et al, CP was clearly shown to reduce lifespan among males and females by 10.5 years and 16 years, respectively. (3) Most of these patients had occult pancreatic malignancies which were diagnosed late and were detected to be the commonest cause of mortality among these patients with a standardized mortality rate of 7.33. (3) This dismal prognosis is superadded with significant morbidity due to pain and poor quality of life rendering a significant burden on health and health-related infrastructure. These factors have led researchers to conceptualize early CP which theoretically is a reversible stage in the disease spectrum characterized by ongoing pancreatic injury with the presence of clinical symptoms and absence of classical imaging features of CP. Subsequently, the disease is thought to go through a compensated stage, a transitional stage, and culminating into decompensated stage with florid evidence of functional impairment of the gland. (4) In this focused review, we will discuss the definition and concept of early CP, risk factors and natural history of the development of CP, and the role of various modalities of EUS in the timely diagnosis of early CP.

Feeling pain means feeling oneself, as the body feels discomfort as a kind of "disturbance experi-ence". Endometriosis is a disease in which the predominant symptom is pain felt by women pri-marily within the pelvis, but also outside of the body. The clinical biomarker used in the diagnosis of this disease is microRNAs. Treatment of endometriosis is complex and is based mainly on phar-macotherapy. Physiotherapy can complement pharmacological treatment in reducing pain using non-invasive treatments for the body. Therefore, databases have been searched to find the most effective forms of physiotherapy for the treatment of endometriosis. The literature review conducted here suggests that it is necessary to perform multicentre studies in order to establish which forms of physical therapy may be most effective in reducing pain and improving the quality of life of women suffering from endometriosis. Certainly, this type of research in conjunction with the assessment of pain and endometriosis markers would be of great clinical value in order to develop an interdisci-plinary treatment model.

A diagnosis of typical chronic lymphocytic leukemia (CLL) requires the presence of ≥5000 clonal B-lymphocytes/μL with the coexistence of CD19, CD20, CD5, and CD23 and the restriction of light chain immunoglobulin, and the lack of expression of antigens CD22 and CD79b. Atypical CLL (aCLL) can be distinguished from typical CLL morphologically and immunophenotypically. Atypical CLL cells are defined as prolymphocytes; morphologically, these present as deeply-clefted lymphocytes which are larger than those in typical CLL, with condensed chromatin and without prominent nucleoli. However, current aCLL diagnostics rely more on immunophenotypic characteristics rather than atypical morphology. Immunophenotypically, atypical CLL differs from classic CLL in the lack of expression of one or fewer surface antigens, most commonly CD5 and CD23, and the patient does not meet the criteria for a diagnosis of any other B-cell lymphoid malignancy. Morphologically atypical CLL has more aggressive clinical behavior and worse prognosis than classic CLL. Patients with aCLL are more likely to display markers associated with poor prognosis, including trisomy 12, unmutated IGVH, and CD38 expression compared with classic CLL. However, no standard or commonly-accepted criteria exist for differentiating aCLL from classic CLL and the clinical significance of aCLL is still under debate. This review summarizes the current state of knowledge on the morphological, immunophenotypic and genetic abnormalities of aCLL.

Although relatively rare, affecting 8% of the general population, autoimmune disorders are causative linked with chronic diseases and morbidity. Control of the course of the disease is closely dependent on the ability to monitor its onset as well as response to treatment. In the present report, we review the progress in the development of biosensor-based approaches and related tools for the Point-of-Care diagnosis and monitoring of biomarkers related to several autoimmune diseases, such as Myasthenia Gravis, Rheumatoid Arthritis, Multiple Sclerosis, Systemic Erythematosus Lupus, Crohn’s Disease, Diabetes Mellitus, Behcet’s disease, Psoriasis and Celiac Disease. Various biosensing technologies are discussed, including electrochemical, optical and mechanical ones, along with the use of advanced nanomaterials and immobilization techniques for the biorecognition elements. The need for innovative devices with unique features of rapid, low-cost, real-time detection is considered in the context of preventing permanent organ and tissue damage from chronic autoimmune diseases.

Given their severity and non-healing nature, diabetic chronic wounds are a significant concern to the 30.3 million Americans diagnosed with diabetes mellitus (2015). Peripheral arterial diseases, neuropathy, and infection contribute to the development of these wounds, which lead to an increased incidence of lower extremity amputations. Early recognition, debridement, offloading, and controlling infection are imperative for timely treatment. However, wound characterization and treatment are highly subjective and based largely on the experience of the treating clinician. Many wound dressings have been designed to address particular clinical presentations, but a prescriptive method is lacking for identifying the particular state of chronic, non-healing wounds. The authors suggest that recent developments in wound dressings and biosensing may allow for the quantitative, real-time representation of the wound environment, including exudate levels, pathogen concentrations, and tissue regeneration. Development of such sensing capability could enable more strategic, personalized care at the onset of ulceration and limit the infection leading to amputation. This review presents an overview of the pathophysiology of diabetic chronic wounds, a brief summary of biomaterial wound dressing treatment options, and biosensor development for biomarker sensing in the wound environment.

Chronic eosinophilic pneumonia (CEP) is an idiopathic disorder characterized by an abnormal and marked accumulation of eosinophils in the interstitial and alveolar spaces of the lung. Idiopathic chronic eosinophilic pneumonia is reported to comprise anywhere from 0-2.5% of cases within the registries of interstitial lung disease. Diagnosis is based on the clinical constellation of symptoms, characteristic radiographic findings and peripheral blood or BAL eosinophilia, in the absence of infection or drug-induced eosinophilia. There is no consensus on the dose and duration of treatment, but most authors recommend initial doses of prednisone at 0.5–1 mg/kg/day with gradual tapering of the dose for total treatment duration of 6–12 months.

This article provides a thorough overview of biomarkers, pathophysiology, and molecular pathways involved in the transition from acute kidney injury (AKI), acute kidney disease (AKD) to chronic kidney disease (CKD). It categorizes the biomarkers of AKI into stress, damage, and functional markers, highlighting their importance in early detection, prognosis, and clinical application. The pathophysiological mechanisms underlying AKI, AKD, including renal hypoperfusion, sepsis, nephrotoxicity, and immune responses, with the impact on renal injury. In addition, various molecules play pivotal roles in inflammation and hypoxia, triggering maladaptive repair, mitochondrial dysfunction, immune system reactions, and cellular senescence of renal cell. Key signaling pathways, such as Wnt/β-Catenin, TGF-β/SMAD, and Hippo/YAP/TAZ, promote fibrosis and impact renal function. The Renin-Angiotensin-Aldosterone System (RAAS) triggers a cascade leading to renal fibrosis, with aldosterone exacerbating oxidative stress and cellular changes that promote fibrosis. Clinical evidence suggests RAS inhibitors may protect against CKD progression, especially post-AKI, though more extensive trials are needed to confirm their full impact.

We present a case of adult-onset systemic chronic active EBV disease (CAEBV) in a 40-year-old woman with chronic HBV hepatitis. Initial symptoms resembled a viral illness, progressing to recurrent fever, transaminitis, and anasarca. Investigations revealed high-level EBV viremia and an abnormal T-cell population in liver and bone marrow, indicative of CAEBV. Liver biopsy showed CD3+ T-cells lacking TCRbeta and displaying dim/negative CD5, with elevated EBV-infected T-cells. Next-generation sequencing identified rare variants in CREBBP, SPEN, TP73, and PLCG2, suggesting potential contributions to disease pathogenesis. This case underscores diagnostic challenges and management complexities of adult-onset CAEBV, particularly with underlying chronic HBV infection. Genomic profiling offers crucial insights into the molecular landscape of rare lymphoid malignancies, highlighting the importance of personalized treatment strategies. The distinct immunophenotypic features underscore the heterogeneity in EBV-associated T-cell LPDs, urging further research for optimized clinical management

Chronic Fatigue Syndrome (CFS) can be triggered by different factors and create a complex health situation. In the last decades incidence has been increasing. This situation is a clear example of how humans, viruses, and the environment are all connected. In the 90s cases related to CFS, com-plaints about a feeling of chronic fatigue, inability for everyday tasks, dull pain, cephalalgia, de-pression, anxiety, poor concentration. Clinical tests for EBV, HHV, CMV, IgG, IgM, T4 and T8 subsets were tested, along with hormones and hemogram tests. Most of the cases were women. The timeline of the medical history showed also myomas, breast lumps, premenstrual syndrome previously to CFS development. The nature of these conditions promoted the idea of a possible common link among them and CFS. Some cases also suffered from allergies, food intolerances, candidiasis, intestinal impairment, thyroid implications, endometriosis. As an initial working hypothesis, The Liver Link (TLL) was proposed in order to understand those different conditions affecting body, mind and emotional wellbeing. Considering liver implication can make a differ-ence in treatment and recovery. Low grade inflammatory conditions are related to Th2 predom-inance and liver functions. Functional disharmonies are very important because they usually still do not appear in any conventional tests. In 2002, TLL was presented as a framework to explain the concomitance of CFS and other conditions and the relationship with some viruses such as EBV, HHV, CMV, as a lecture in a congress at the University of Westminster (London). When SARS-CoV-2 outbroke, TLL helped to warn about the post-covid syndrome more likely to occur in specific individuals.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one third of global population and became the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) also remain significant challenges to liver health even in the 21st century. The coexistence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. Thorough understanding of the pathobiological interlink and interactions between MAFLD and these two chronic viral hepatitis infections are crucial for appropriate management of patients. We update these interlinks in this comprehensive clinical review.

Gabapentin (GBP), a GABA analogue, is primarily used as an anticonvulsant to treat partial seizures and neuropathic pain. While a majority of the side effects are associated with the nervous system, emerging evidence suggests a high risk for heart diseases in the patients taking GBP. In the present study, we used a preclinical model of rats to investigate (1) the acute cardiovascular responses to GBP (bolus i.v. injection, 50 mg/kg) and (2) the effects of chronic GBP treatment (i.p. 100 mg/kg/day x 7 days) on cardiovascular function and the myocardial proteome. Under isoflurane-anesthesia, rat blood pressure (BP), heart rate (HR), and left ventricular (LV) hemodynamics were measured using Millar pressure transducers. The LV myocardium and brain cortex were analyzed by proteomics, bioinformatics, and western blot to explore the molecular mechanisms underlying GBP-induced cardiac dysfunction. In experiment (1), we found that i.v. GBP significantly decreased BP, HR, maximal LV pressure, and maximal and minimal dP/dt, whereas it increased IRP-AdP/dt, Tau, systolic, diastolic, and cycle durations (*p < 0.05 and **p < 0.01 vs baseline; n = 4/group). In experiment (2), we found that chronic GBP treatment resulted in hypotension, bradycardia, and LV systolic dysfunction, with no change in plasma norepinephrine. In the myocardium, we identified 109 differentially expressed proteins involved in calcium pathways, cholesterol metabolism, and galactose metabolism. Particularly, we found that calmodulin, a key protein of intracellular calcium signaling, was significantly upregulated by GBP in the heart but not in the brain. In summary, we found that acute and chronic GBP treatments suppressed cardiovascular function in rats, which is attributed to abnormal calcium signaling in cardiomyocytes. These data reveal a novel side effect of GBP independent of the nervous system, providing important translational evidence to suggest that GBP can evoke adverse cardiovascular events by depression of myocardial function.

Cardiovascular diseases (CVDs) are the leading cause of death in the globally. Morbidity and disability related to non-fatal events are increasing exponentially. There are several symptoms that may arise after invasive therapeutic approaches such as coronary artery bypass graft (CABG), including chronic pain in anatomical areas connected to the mediastinum; these pains can be found not only initially after surgery, but also years later. We present a case where non-specific neck pain (NNP), in a patient undergoing CABG five years earlier, was approached with an osteopathic technique, working the pericardial area. To the knowledge of the Authors, it is the first case report where osteopathy is associated with a gentle treatment on the pericardial area to resolve a NNP.

Chronic pulmonary diseases such as asthma, COPD, and Idiopathic pulmonary fibrosis are significant causes of mortality and morbidity worldwide. Currently, there is no radical treatment for many chronic pulmonary diseases, and the treatment options focus on relieving the symptoms and improving lung function. Therefore, efficient therapeutic agents are highly needed. Bronchial epithelial cells and airway smooth muscle cells and their crosstalk play a significant role in the pathogenesis of these diseases. Thus, targeting the interactions of these two cell types could open the door to a new generation of effective therapeutic options. However, the studies on how these two cell types interact and how their crosstalk adds up to respiratory diseases are not well established. With the rise of modern research tools and technology, such as lab-on-chip, organoids, co-culture techniques, and advanced immunofluorescence imaging, a substantial degree of evidence about these cell interactions emerged. Hence, this contribution aims to summarize the growing evidence of bronchial epithelial cells and airway smooth muscle cells crosstalk under normal and pathophysiological conditions. The review first deliberates the effects of both healthy and stressed epithelial cells on airway smooth muscle cells, taking into account three themes; contraction, migration, and proliferation. Then, it discusses the impact of airway smooth muscle cells on the epithelium in inflammatory settings. Later, it examines the role of airway smooth muscle cells in the early development of bronchial epithelial cells and their recovery after injury.

CKD in HF patients is very common condition, their dysfunction is closely linked and influence each other, so their management required multidisciplinary and personalized approaches. The diagnosis of HF and CDK relies on signs and symptoms. Several tools, such as blood-based biomarkers and echography help us to clarify and discriminate the main characteristics of these patients. Evidence in improving survival due to new drug-employment in HF, has increasingly challenged physicians to manage patients with multiple diseases, especially in patients with CKD. The difficulty is in the safe administration of these drugs in patients with HF and CKD. Knowing up to which values ​​of creatinine or renal clearance any drug can be administered is fundamental. We wanted to summarize, on this sizable and complex topic, the experiences of various prior study to get clearer ideas and a more precise reference about the assessment and management of HF and CKD.

Chronic heart failure (CHF) results when heart cannot constantly supply the body tissues with oxygen and required nutrients, and it can be categorized as heart failure (HF) with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). There are different causes and mechanisms of the HF pathogenesis; however, the inflammation can be regarded as one of the factors promoting both HFrEF and HFpEF. Monocytes, a subgroup of leucocytes, are known as cellular mediators in response to cardiovascular injury and are closely related to inflammatory reactions. These cells are a vital component of the immune system and are the source of macrophages, which participate in cardiac tissue repair after injury. However, the monocytes are not homogenous as thought, and thus can present different functions under different cardiovascular disease conditions. In addition, there is still an open question whether the functions of monocytes and macrophages should be regarded as a cause or a consequence in CHF development. Therefore, our aim was to summarize the current studies on the function of various monocyte subsets in CHF with a focus on the role of a certain monocyte subset in HFpEF and HFrEF patients, and the relation to inflammatory markers.

Chronic pain is an unpleasant sensory and emotional experience that persists or recurs more than three months and may extend beyond the expected time of healing. Recently nociplastic pain has been introduced as a descriptor of mechanism of pain, which is due to disturbance of neural processing without actual or potential tissue damage, appearing to replace a concept of psychogenic pain. An interdisciplinary task force of the International Association for the Study of Pain (IASP) compiled a systematic classification of clinical conditions associated with chronic pain, which was published in 2018 and will officially come into effect in 2022 in the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization. ICD-11 offers the option for recording the presence of psychological or social factors in chronic pain; however, cognitive, emotional, and social dimensions in the pathogenesis of chronic pain are missing. Earlier pain disorder was defined as a condition with chronic pain associated with psychological factors, but it was replaced with somatic symptom disorder with predominant pain in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) in 2013. Recently clinical nosology is trending toward highlighting neurological pathology of chronic pain, discounting psychological or social factors in the pathogenesis of pain. This review article discusses components of the pain pathway, the component-based mechanisms of pain, central and peripheral sensitization, roles of chronic inflammation, and the involvement of tryptophan-kynurenine pathway metabolites, exploring participations of psychosocial and behavioral factors in central sensitization of diseases progressing into development of chronic pain, comorbid diseases that commonly present a symptom of chronic pain, and psychiatric disorders that manifest chronic pain without obvious actual or potential tissue damage.

Chronic kidney disease (CKD) is a major non-communicable disease associated with high rates of premature morbidity and mortality. The prevalence of hypovitaminosis D (deficiency of 25(OH)D or 25D) is greater in racial/ethnic minorities and in patients with CKD than the general population. Low 25D is associated with bone and mineral disorders as well as immune, cardiometabolic and cardiovascular (CV) diseases. Thus, it has been suggested low 25D contributes to the poor outcomes in patients with CKD. The prevalence of hypovitaminosis D rises progressively with advancing severity of kidney disease with over 30% of patients with CKD stage 3 and 70% patients with CKD stage 5 estimated to have low levels of 25D. This report describes several of the abnormal physiologic and counter-regulatory actions related to low 25D in CKD such as those in oxidative stress and inflammatory systems, and some of the preclinical and clinical evidence or lack of thereof of normalizing serum 25D levels to improve outcomes in patients with CKD, and especially for the high risk subset of racial/ethnic minorities who suffer from higher rates of advanced CKD and hypovitaminosis D.

A large body of evidence reports about the positive effects of physical activity in pathophysiological conditions associated with aging. Physical exercise, alone or in combination with other medical therapies, unquestionably causes reduction of symptoms in chronic non-transmissible diseases often leading to significant amelioration or complete healing. The molecular basis of this exciting outcome, however, remain largely obscure. Epigenetics, exploring at the interface between environmental signals and the remodelling of chromatin structure, promises to shed light on this intriguing matter possibly contributing to the identification of novel therapeutic targets. In this review, we shall focalize on the role of sirtuins (Sirts) a class III histone deacetylases (HDACs) which function has been frequently associated, often with a controversial role, to the pathogenesis of aging-associated pathophysiological conditions including cancer, cardiovascular, muscular, neurodegenerative, bones and respiratory diseases. Numerous studies, in fact, demonstrate that Sirt-dependent pathways are activated upon physical and cognitive exercises linking mitochondrial function, DNA structure remodelling and gene expression regulation to designed medical therapies leading to tangible beneficial outcomes. However, in similar conditions, other studies assign to sirtuins a negative pathophysiological role. In spite of this controversial effect, it is doubtless that studying sirtuins in chronic diseases might lead to an unprecedented improvement of life quality in the elderly.

The main goal of our scientific study is to determine the particular characteristics of the endo-scopic image of the otorhinolaryngologic pathology of nasopharynx, which is called chronic rhinosinusitis in association with gastroesophageal acid reflux disease. Background/Objectives: to identify a specific features in the endoscopic picture of chronic rhinosinusitis associated with acid gastroesophageal reflux disease symptoms. Methods: there were selected 521 adult patients, from this sample as a main group we have selected only 95 patients with the highest scores on the Reflux Symptom Index (RSI) (>20) and Reflux Symptom Score-12 (RSS-12) (>130) questionnaires. As a control group we have selected 41 adult patients only with chronic rhinosinusitis and 10 healthy patients. Results: there were significant changes in the nasopharyngeal mucosa. In-creased vascularity of the nasopharyngeal mucosa was noted in 91 patients (95,7%). Hypertrophy of the nasopharyngeal mucosa was found in 83 patients (87,4%). In 77 (81,1%) patients, mucus was found in the nasopharynx with different characteristics of color and consistency, and no mucus or other secretions were found in the middle nasal passages in these patients. In 62 pa-tients (65,3%) asymmetric hypertrophy of the mucosa of the oropharynx was noted. Conclusions: the presence of specific features of the endoscopic picture of the nose and nasopharynx of pa-tients with chronic rhinosinusitis associated with gastroesophageal disease symptoms and pro-posed a method for assessing the degree of influence of gastroesophageal reflux disease on the mucosal layer of the nose and nasopharynx. The possible influence of symptoms of gas-tro-oesophageal reflux disease on the course and severity of clinical manifestations of exacerba-tions of chronic rhinosinusitis needs further investigation.

Chronic non-bacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), is a rare autoinflammatory bone disease primarily affecting children and adolescents. This review presents a comprehensive analysis of the intricate relationship between CNO and inflammatory bowel disease (IBD), shedding light on shared pathophysiological mechanisms and clinical management. A thorough literature review was conducted, encompassing 24 case reports involving 40 patients. The demographic distribution of patients revealed a near-equal gender ratio, with a median age of diagnosis at 12 years. The diagnosis patterns showed a higher proportion of CNO as the initial diagnosis, while Crohn's disease was more prevalent than ulcerative colitis. The time interval between the clinical presentations varied, ranging from simultaneous detection to a substantial 15-year gap. Treatment modalities included non-steroidal anti-inflammatory drugs (NSAIDs), steroids, aminosalicylates, and biologic agents, such as infliximab, often overlapping in their use, suggesting shared pathophysiological pathways. Both conditions displayed systemic manifestations, and patients often responded well to immunosuppressive medications. The pathophysiology of CNO involves genetic predisposition, cytokine dysregulation, and osteoclast activation. Dysregulated innate immunity results in immune cell infiltration into bones, causing sterile bone lesions. Notably, emerging evidence hints at a potential link between the microbiome and CNO. In contrast, IBD results from imbalanced mucosal immune responses to the intestinal microbiota. Polymorphisms in the promotor region of IL-10, common cytokines, immune cells, and genetic markers indicate shared immunological and genetic factors between CNO and IBD. Both conditions also involve extraintestinal symptoms. This analysis underscores the need for clinical awareness of the co-occurrence of CNO and IBD, especially among pediatric patients. A deepened understanding of the connections between these seemingly distinct diseases could lead to more effective management and improved patient outcomes.

Chronic exposure to the nephrotoxic metal pollutant, cadmium (Cd), has been associated with the pathogenesis of hypertension, but so far, the mechanism has not been well defined. We hypothesize that exposure to Cd causes a decline in the glomerular filtration rate (GFR), which in turn, causes a rise in blood pressure. Data were collected from 447 Thai subjects with a mean age of 51.1 years, of which 48.8% had hypertension, 15.4% had diabetes and 6.9% had an estimated GFR (eGFR) below 60 mL/min/1.73m2 (low eGFR). The mean blood Cd and mean urinary Cd concentrations were 2.75 and 4.23 µg/L, respectively. Prevalence odds ratio (POR) for hypertension rose twofold in those with a medium Cd burden and blood Cd levels of 0.61-1.69 µg/L. In the hypertensive group, the eGFR was inversely associated with age (β =−0.517), the Cd excretion rate (β = −0.177), and diabetes (β = −0.175). Mean eGFR in those with hypertension was 7.5 mL/min/1.73m2 lower than those who were normotensive with the same Cd body burden. In addition, higher systolic blood pressure (SBP) values were associated with older age (β = 0.243), higher BMI (β = 0.113), lower eGFR (β = −0.106) and diabetes (β = 0.216). Mean SBP in those who had low eGFR and medium and heavy Cd body burden was 9.5 mmHg higher than those with the same Cd body burden and a normal eGFR. Thus, chronic environmental exposure to Cd that produces urinary and blood Cd levels of 0.57-0.61 µg/L, increases the risk of hypertension, and this could be mediated by a declining GFR.

Chronic non-communicable diseases (NCDs) are major public health problems and a significant financial burden on public health systems. By 2030, mortality due to NCDs, such as cardiovascular diseases, cancer, respiratory diseases, and diabetes, is predicted to increase in Brazil. A peculiar aspect of NCDs involves their long-term and integrated care management. This paper proposes a chronic disease management platform based on artificial intelligence to deliver digital health services everywhere. The proposed platform is anchored and built with healthcare 4.0 technologies, such as wearable devices, the internet of medical things, and artificial intelligence cloud-based solutions that allow the deployment of a smart healthcare system. In addition, the paper presents the feasibility of the platform in a diabetes prediction study case. For the study case, an initial dataset was established with bio-impedance, oxygen concentration, pulse rate, skin impedance, and skin temperature attributes. A baseline was implemented with ten regression models to assess the prediction performance of the mean squared error, root mean squared error, and r-squared score to compare predictive findings with capillary blood glucose measurements. Results evidence that the decision tree regressor and three ensemble methods (bagging decision tree regressor, random forest regressor, and AdaBoost regressor) yielded improvement over the other models. Moreover, a comparison among those models revealed that the decision tree regressor outperforms them and presents promissory outcomes.

Chronic pain is a source of major alterations in quality of life. It represents significant costs for health systems, and reduces the competitiveness of the working population. Vulnerability can drive the incidence of chronic pain, through its influence on modifiable risk factors, and reduced utilization of health care systems. But vulnerability can also be the consequence of a chronic pain: illness can push people into precariousness. We analysed the factors associated with pain intensity among vulnerable persons with a chronic condition, in five European countries (N=1,364). Pain was, among the whole set of variables, the main predictor of sleep problems, fatigue, depression, self-perceived health, physical and mental quality of life. This is in line with other studies showing the major impact of pain on an individual’s health and life. Multivariable analyses, adjusting for the whole set of variables, showed that women had more intense pain, as well as participants with a lower education level. These results confirm the social component in the complex etiology of pain and clearly plaid in favor of integrated care, taking into account individual characteristics and environment.

The immunomodulatory behaviour of the CCR6/CCL20 axis in multi -system pathophysiology and molecular signalling was investigated at two clinically significant time points, using a Ccr6 - deficient mouse model of spontaneous colitis. Four groups of mice, (C57BL/6J, Ccr6^-/- of C57BL/6J, Winnie x Ccr6 ^-/- and Winnie) were utilized and (I) colonic clinical parameters (2) histology of colon, spleen, kidney and liver (3) T and B lymphocyte distribution in the spleen and MLN by flowcytometry (5) colonic CCL20, phosphorylated PI3K and phosphorylated Akt expression by immunohistochemistry and (6) colonic cytokine expression by RT-PCR were evaluated. CCR6 deficiency was shown to attenuate inflammation in the spleen, liver and gut while renal histology remained unaffected. Marked focal lobular inflammation with reactive nuclear features were observed in hepatocytes and a significant neutrophil infiltration in red pulp with extra medullary hemopoiesis in the spleen existed in Winnie. These changes were considerably reduced in Winnie x Ccr6^-/- with elevated goblet cell numbers and mucus production in the colonic epithelium. Results indicate that Ccr6- deficiency in the colitis model contributes towards resolution of disease. Our findings demonstrate an intricate networking role for CCR6 in immune activation, which is downregulated by Ccr6 deficiency, and could provide newer clinical therapies in colitis.

Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.

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.

Although the parasite Toxoplasma gondii is one of the most pervasive neurotropic pathogens in the world, the host-parasite interactions during CNS infection and consequences of neurological infection are just beginning to be unraveled. The chronic stages of infection have been considered dormant, although several studies have found correlations of infection with an array of host behavioral changes. These may facilitate parasite transmission and impact neurological diseases. During infection, in addition to the presence of the parasites within neurons, host-mediated neuroimmune and hormonal responses to infection are also present. T. gondii induces numerous changes to host neurons during infection and globally alters host neurological signaling pathways, as discussed in this review. Understanding the neurophysiological changes in the host brain is imperative to understanding the parasitic mechanisms and to delineate the effects of this single-celled parasite on health and its contribution to neurological disease.

Chronic lymphocytic leukemia (CLL) is a distinct category of lymphoproliferative disorder characterized by the clonal expansion of mature B cells, followed by their accumulation in primary and secondary lymphoid organs. Cluster of differentiation (CD) markers such as CD20, CD22, CD23, CD5, and CD81 serve as reliable prognostic indicators and disease progression factors in CLL. The human leukocyte antigen (HLA) system is a critical genetic variable in many diseases, with well-documented associations between HLA and various cancers. This study aims to investigate, for the first time, potential connections between HLA typing and CD marker expression in CLL. Despite being one of the most prevalent neoplasms in developed regions, there is a need for biomarkers that can improve survival predictions and identify possible genetic determinants. Methods: This study included 66 CLL patients and 100 controls, with all samples analyzed using biochemical methods, flow cytometry, and cytomorphology. Next-generation sequencing (NGS) was performed for HLA typing. Results: The results indicate that several CD markers are statistically associated with different HLA alleles. Specifically, CD20 was associated with HLA-DRB1*11:04:01; CD45 with HLA-C*07:01:01; CD79b with HLA-DPA1*02:01:02; CD23 with HLA-B*39:01:01; CD43 with HLA-DRB1*15:01:01; CD22 with HLA-B*49:01:01, HLA-C*07:01:01, HLA-DPB1*02:01:02, and HLA-DRB1*07:01:01; and CD81 with HLA-DPB1*04:02:01, HLA-DQA1*01:04:01, and HLA-DQB1*05:03:01.Conclusion: In conclusion, this research demonstrates significant statistical links between HLA genes and immunophenotypic markers in CLL patients, shedding new light on the immunological context of CLL.

Cardiovascular diseases (CVDs) a leading cause of mortality worldwide. Therefore, there is in-creasing interest in dietary interventions to reduce risk factors associated with these conditions. Cherries and berries are rich sources of bioactive compounds and have attracted attention for their potential cardiovascular benefits. This review summarizes the current research on the effects of cherries and berries consumption on cardiovascular health, including in vivo studies and clinical trials. These red fruits are rich in phenolic compounds, such as anthocyanins and flavonoids, which have multiple bioactive properties. These properties include antioxidant, anti-inflammatory, and vasodilatory effects. Studies suggest that regular consumption of these fruits may reducing in-flammation and oxidative stress, leading to lower blood pressure, improved lipid profiles, and enhanced endothelial function. However, interpreting findings and establishing optimal dosages is challenge due to the variability in fruit composition, processing methods, and study design. Despite these limitations, the evidence highlights the potential of cherries and berries as components of preventive strategies against CVD. Further research is needed to maximize their health benefits and improve clinical practice.

Pediatric chronic pain is an important public health issue given its notable impact on numerous domains of living. Pediatric chronic pain is also often comorbid with emotional, developmental, or behavioral conditions which can lead to more severe negative outcomes and an even greater reduction in positive outcomes compared to those without comorbidities. Flourishing is a positive outcome that chronic pain status has been shown to impact. We explored flourishing in children aged 6-17 years living with chronic pain as well as those with chronic pain and comorbidities using data from the 2018/2019 National Survey of Child Health. There were significant associa-tions between chronic pain condition status and all demographic variables (sex, age, race/ethnicity, poverty level, parental education, health insurance status). Results of hierarchical logistic regression found that chronic pain condition status significantly predicted flourishing. Children with chronic pain were 2.33 times less likely to flourish, and children with chronic pain plus an emotional, developmental, or behavioral comorbidity were 13 times less likely to flourish than typical peers. Given their significantly lower likelihood of flourishing, there is an urgent need for interventions targeted at children experiencing chronic pain and mental health comor-bidities.

Despite needs for new therapies and improvements in existing approaches in cardiovascular, pulmonary, endocrine, and renal disease, investment in these areas is lagging relative to other specialties. This article summarizes a meeting of key stakeholders of U.S. Food and Drug Administration (FDA) officials, representatives from academia, national organizations, and patients and caregivers. The purpose was to identify and discuss high-priority issues, establish areas of common interest, and explore opportunities for collaboration. During the meeting (September 2016), the construct of a “multimorbidity continuum” emerged, in which chronic diseases are understood as their effects on the whole rather than individual organ systems. Cross-disciplinary priorities included: 1) the need to generate greater high-quality evidence at lower cost; 2) the imperative to develop and implement patient-centered approaches to clinical investigations; 3) the importance of trial participation in under-represented populations, particularly with comorbid conditions, and 4) the need for progress in tobacco regulation. Representatives from each therapeutic area reported on their consensus priorities, and FDA representatives discussed the agency’s role in facilitating broader approaches to therapeutic development and evaluation of disease as linked across organ systems rather than in isolation, and emphasized the importance of patient engagement, collaboration and communication across stakeholders.

Dyslipidemia presents high levels of serum cholesterol, being characterized as a risk factor for cardiovascular diseases, especially for the development of atherosclerosis. E. oleracea (OFEO), A. esculentus (OFAE), B. orellana (OFBO) and granulated (CHR) oils are rich in bioactive compounds with potential to treat changes in lipid metabolism. This study investigated the effects of treatments with oils from A. esculentus, E. oleracea, B. orellana and granules (Chronic SM®) on saturated fat-induced dyslipidemia Cocos nucifera L. The chromatographic profile showed the majority of unsaturated fatty acids in the tested oils. The quantification of tocotrienols and geranylgeraniol was obtained in OFBO and CHR. Treatments with OFEO, OFAE, OFBO and CHR were able to significantly reduce glycemia with p&gt;0.001, as well as hypertriglyceridemia, total cholesterol and LDL-cholesterol, in addition to increasing HDL-cholesterol. The treatments inhibited the formation of atheromatous plaques in the vascular endothelium of the treated rats. The obtained results suggest that the OFEO, OFAE, OFBO and CHR groups have antidyslipidemic effects and antiatherogenic activity.

Background Sarcopenia is a state with progressive and generalized loss of skeletal muscle mass and strength. It is a serious complication occurring in chronic kidney disease (CKD) patients which increases morbidity and mortality rate. Sarcopenia is diagnosed when loss of both compartments - muscle strength and skeletal muscle quality or quantity are present. However, there are still numerous patients, also with CKD, diagnosed as pre-sarcopenic individuals with low muscle strength and normal skeletal muscle quality or quantity and conversely, with correct muscle strength and decreased skeletal muscle mass, who are prone to develop sarcopenia in future life. It is crucial to examine numerous variables possibly associated with changes of skeletal muscle mass and muscle strength in terms of preventing the development of sarcopenia. The aim of the study was to investigate anthropometric and clinical correlates and sources of variation in both skeletal muscle mass and muscle strength in advanced stages of CKD. Methods The study sample consisted of 84 non-dialysis dependent patients of both sexes (including 45.2% of women) with eGFR < 45 ml/min/1.73m2: 26.2% with eGFR 30-44 mL/min/1.73 m2, 65.5% with eGFR 15-29 mL/min/1.73 m2 and 8.3% with eGFR < 15 mL/min/1.73 m2. Muscle strength was estimated by measuring hand grip strength (HGS) with the use of handheld hydraulic dynamometer. Muscle quantity was measured by bioimpedance spectroscopy using Body Composition Monitor. Appendicular skeletal muscle mass (ASM) was calculated according to Lin’s formula. Serum creatinine, urea, uric acid and albumin were measured. Results In bivariate analysis we found that ASM significantly and positively correlated with anthropometric variables such as body mass (r=0.903, p

Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B-cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flowcytometry. Basal levels of B2M in patients with CLL were measured using an Enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p< 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p< 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. African patients with CLL express elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there is no correlation between these immune checkpoint expressions and B2M levels.

Hydrogen sulfide (H2S) is an environmental toxicant of health concern. The brain is a major target in acute H2S poisoning. This study was to test the hypothesis that acute and subchronic ambient H2S exposures alter the brain metabolome. Male 7-8 week-old C57BL/6J mice were exposed by whole-body inhalation to 1000 ppm H2S for 45 min and euthanized at 5 min or 72 h for acute exposure. For subchronic study, mice were exposed to 5 ppm H2S 2 h/day, 5 days/week for 5 weeks. The brainstem was removed for metabolomic analysis. Enrichment analysis showed the metabolomic profiles in acute and subchronic H2S exposures matched with those of cerebral spinal fluid from patients with seizures or Alzheimer’s disease. Acute H2S exposure decreased excitatory neurotransmitters, aspartate and glutamate, while the inhibitory neurotransmitter, serotonin, was increased, which may explain H2S-induced loss of consciousness. Branched-chain amino acids and glucose were increased by acute H2S exposure. Subchronic H2S exposure within OSHA guideline surprisingly decreased serotonin altering central nervous system. In subchronic H2S exposure, glucose was decreased while polyunsaturated fatty acids, inosine, and hypoxanthine were increased. Collectively, these results provide important mechanistic clues of acute and subchronic ambient H2S poisonings and show that H2S alters brainstem metabolome.

Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Phycocyanin oligopeptide (PC), a phytonutrient found in blue-green algae, has antioxidant and anti-inflammatory properties. This study explored the effects of NR, PC, and their combination on telomere length, inflammatory and antioxidant status in rats under chronic stressed conditions (CS). Forty-nine rats were allocated into seven groups: Control, chronic stress (CS), CS with NR (26.44 mg/kg), a low dose of 2.64 mg/kg of PC (PC-LD), or a high dose of 26.44 mg/kg PC (PC-HD), NR+PC-LD and NR+PC-HF. Rats were given daily corticosterone injections (40 mg/kg) to induce stressed conditions, or NR and PC were orally administered for 21 days. NR and PC supplementation, particularly NR plus PC, increased the serum antioxidant enzyme activities, hepatic nicotinamide adenine (NAD+) content, and telomere length (P&lt;0.001 for all) compared with the CS group. The levels of serum malondialdehyde (MDA), liver interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), IL-1β, and IL-8 were reduced under CS condition (P&lt;0.001). In addition, CS decreased the levels of hepatic telomere-related proteins and sirtuin1 (SIRT1-3), while supplementation of NR and PC alone or in combination increased the levels of telomere-related proteins (e.g., POT1b, TRF1, and TRF2), and SIRT3, NAMPT P&lt;0.05. In conclusion, NR and PC, especially their combination, can alleviate metabolic abnormalities by enhancing hepatic cytokines, SIRT3, NAMPT, and NAD+ levels in CS-exposed rats. More research is needed to elucidate further the potential health effects of the combination of NR and PC in humans.

There is a pressing need for more precise biomarkers of chronic kidney disease (CKD). Plasma samples from 820 subjects [231 with CKD, 325 with end-stage kidney disease (ESKD) and 264 controls] were analyzed by LC-MS/MS to determine a metabolic profile of 28 aminoacids (AA) and biogenic amines to test their value as markers of CKD risk and progression. The Kynurenine/Tryptophan ratio showed the strongest correlation with estimated glomerular filtration rate values (coefficient=-0.731, P&lt;0.0001). Models created with Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) containing the metabolic signature showed high goodness of fit and predictability for controls/CKD (R2X:0.73;R2Y:0.92;Q2:0.92) and lower for CDK/ESKD (R2X:0.56;R2Y:0.59;Q2:0.55). Based on generated VIP scores, the most relevant markers for segregating samples into control/CKD or CKD/ESKD groups were citrulline (1.67) and tryptophan (1.59), respectively. ROC analysis showed that the addition of the metabolic profile to a model including CKD classic risk factors improved AUC from 86.7% (83.6-89.9) to 100% (100-100) for CKD risk (P&lt;0.0001), and from 63.0% (58.2-67.8) to 96.5% (95.3-97.8) for the risk of progression from CKD to ESKD (P&lt;0.0001). Plasma concentrations of AA and related amines may be useful as diagnostic biomarkers of kidney disease, both for CKD risk and for progression of CKD patients to ESKD.

Background: Chronic Back Pain due to Facet Joint Syndrome is a common and debilitating con-dition. Advances in regenerative medicine have shown that Autologous Unmodified Adipose Tissue-Derived Regenerative Cells (ADRC) provide several beneficial effects [1,2]. These regen-erative cells can differentiate into various tissues [3] and exhibit a strong anti-inflammatory po-tential. ADRCs can be obtained from a small amount of fatty tissue derived from the patient´s abdominal fat. Methods: We report long-term results of 37 patients (age 31-78 years, mean 62.5) suffering from “Facet Joint Syndrome” The pathology was confirmed by clinical, radiological examinations and fluoroscopically guided test injections. Then liposuction was performed. 50-100 cc of fat were harvested. To recover stem cells from adipose tissue, we use the CE-certified Transpose RT™ system from InGeneron GmbH. The cells were then injected under fluoroscopic control in the periarticular fat. Follow-up examinations were performed at one week 1 and 5 years. Results: Every patient reported improved VAS pain at any follow-up (1 week, 1, and 5 years) with ADRCs compared to the baseline. Conclusion: Our observational data indicate that facet joint syndrome patients treated with unmodified adipose tissue-derived regenerative cells experience improved quality of life in the long term.

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

The use of recombinant human PTH (1-84) [rhPTH(1-84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy. The objective of this study was to investigate the effects of 12 months of rhPTH (1-84) treatment in a cohort of patients selected according to the indications of recent hypoparathyroidism guidelines. It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers were involved. Fourteen adult subjects with chronic hypoparathyroidism treated with rhPTH (1-84) for 12 months were enrolled. Main outcome measures included serum and urinary parameters of mineral metabolism, renal function, oral calcium and vitamin D doses, and clinical manifestations. At 12 months, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean serum calcium levels quickly normalized after initiation of rhPTH (1-84) treatment compared to baseline (p=0.009). Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p= 0.014). No severe adverse events were described. In conclusion, this study confirm the efficacy and safety of rhPTH (1-84) therapy.

Hepatitis B virus (HBV) infection remains a global public problem despite the availability of effective vaccine. In the past decades, nonalcoholic fatty liver disease (NAFLD) has surpassed HBV as the most common cause of chronic liver disease worldwide. The prevalence of concomitant chronic hepatitis B (CHB) and NAFLD, thus, reaches endemic in geographic regions where both conditions are common. Patients with CHB and NAFLD are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma. Due to complexity of the pathogenesis, accurate diagnosis of NAFLD in CHB patients can be challenging. Liver biopsy is considered the gold standard for diagnosing and determining the disease severity, but it is an invasive procedure with potential complications. There is a growing body of literatures on the application of novel noninvasive serum biomarkers and advanced radiological modalities to diagnose and evaluate NAFLD, but most have not been adequately validated especially for patients with CHB. Currently, there is no approved therapy for NAFLD though many new agents are in different phases of development. This review provides a summary of the epidemiology, clinical features, diagnosis and management of the NAFLD and highlights the unmet needs in the areas of CHB and NAFLD coexistence.

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality globally. Studies show that airway mucus hypersecretion strongly compromises lung function, leading to frequent hospitalization and mortality, highlighting an urgent need for effective COPD treatments. MUC5AC is known to contribute to severe muco-obstructive lung diseases, worsening COPD pathogenesis. Various pathways are implicated in the aberrant MUC5AC production and secretion MUC5AC. These include signaling pathways associated with mucus-secreting cell differentiation [ nuclear factor-κB (NF-кB)and IL-13-STAT6- SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF), as well as epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR)], and signaling pathways related to mucus transport and excretion-ciliary beat frequency (CBF). Various inhibitors of mucus hypersecretion are in clinical use but have had limited benefits against COPD. Thus, novel therapies targeting airway mucus hypersecretion should be developed for effective management of muco-obstructive lung disease. Here, we systematically review the mechanisms and pathogenesis of airway mucus hypersecretion, with emphasis on multi-target and multi-link intervention strategies for the elucidation of novel inhibitors of airway mucus hypersecretion.

Chronic unpredictable environmental stress (CUES) may induce predisposition to diabetes mellitus. This study investigates the role of CUES on impaired homeostasis. Stressed group mice (n = 20) were exposed to CUES for 16 weeks. Weekly body weight, feed consumption, feed efficiency ratio, fasting blood glucose were monitored. Plasma HbA1c, plasma cortisol, plasma epinephrine and plasma insulin, serum lipids, antioxidants and carbohydrate metabolizing enzymes activity were assessed along with DNA damage and histopathological examination of liver, kidney, pancreas, spleen and skeletal muscles. Fasting blood glucose levels & HbA1c in the stressed were significantly higher compared to control (p < 0.001). Serum lipids were found insignificantly higher in stressed mice compared to control. Body weights of the stressed mice and feed efficiency ratio were found significant (p < 0.001). Plasma corticosterone, plasma epinephrine, HOMA-IR was found to be significantly higher in the stressed group (p < 0.001). Plasma insulin level was found to be significantly lower in the stressed group (p < 0.001). Significant changes were observed in antioxidants level, carbohydrate metabolizing enzymes activity, peripheral tissues and DNA integrity. CUES initiates pathogenesis of diabetes.

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.

Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and elderly individuals. DM may accelerate the aging process, and the age-related declines in the estimated Glomerular Filtration Rate (eGFR), can pose a challenge to diagnose diabetic kidney disease (DKD) using standard diagnostic criteria especially with absence of severe albuminuria among the elderly. In the presence of CKD and DM, elderly patients may need multidisciplinary care due to susceptibility to various health issues e.g., cognitive decline, auditory or visual impairment, various comorbidities, complex medical regimens, and increased sensitivity to medication adverse effects. As a result, it can be challenging to apply recent therapeutic advancements for the general population to the elderly. We review the evidence that the benefits from these newer therapies apply equally to elderly and non-elderly patients and propose a framework for the management of DKD by discussing the nonpharmacological measures and pharmacological management with renin angiotensin system inhibitors (RASi), Sodium Glucose Co-Transporter two inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and Glucagon Like Peptide 1 Receptor Agonists (GLP1-RAs).

Chronic venous disease (CVD) occurs in a substantial proportion of the world's population. If the onset of CVD looks like a cosmetic defect, then over time, it can develop into serious problems that require surgical intervention. The aim of the work is to use deep learning (DL) methods for automatic classification of the stage of CVD for self-diagnosis of a patient by using the image of the patient’s legs. The required for DL algorithms images of legs with CVD were obtained by using Internet Data Mining. For images preprocessing, the binary classification problem “legs - no legs” was solved based on Resnet50 with accuracy 0.998. The application of this filter made it possible to collect a data set of 11,118 good quality leg images with various stages of CVD. For classification of various stages of CVD according to CEAP classification, the multi classification problem was set and resolved by using two neural networks with completely different architecture - Resnet50 and DeiT. The model based on DeiT without any tuning shows better results than the model based on Resnet50 (precision = 0.770 (DeiT) and 0.615 (Resnet50)). To demonstrate the results of the work, a telegram bot was developed, in which fully functioning DL algorithms are implemented. This bot allows evaluating the condition of the patient's legs with a fairly good accuracy for the CVD classification.

Although chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) have distinct clinical features, both diseases may coexist in a patient because they share similar risk factors such as smoking, male sex, and old age. Patients with both emphysema in upper lung fields and diffuse ILD are diagnosed with combined pulmonary fibrosis and emphysema (CPFE), which causes substantial clinical deterioration. Patients with CPFE have higher mortality compared with patients who have COPD alone, but results have been inconclusive compared with patients who have idiopathic pulmonary fibrosis (IPF). Poor prognostic factors for CPFE include exacerbation, lung cancer, and pulmonary hypertension. The presence of interstitial lung abnormalities, which may be an early or mild form of ILD, is notable among patients with COPD, and is associated with poor prognosis. Various theories have been proposed regarding the pathophysiology of CPFE. Biomarker analyses have implied that this pathophysiology may be more closely associated with IPF development, rather than COPD or emphysema. Patients with CPFE should be advised to quit smoking and undergo routine lung function tests, and pulmonary rehabilitation may be helpful. Various pharmacologic agents may be beneficial in patients with CPFE, but further studies are needed.

Polyamines are nitrogen-rich polycationic ubiquitous bioactive molecules with diverse evolutionary-conserved functions. Their activity interferes with numerous genes' expression resulting in cell proliferation and signaling modulation. The intracellular levels of polyamines are precisely controlled by evolutionary-conserved machinery. Their transient synthesis is induced by heat stress, radiation, and other traumatic stimuli in a process termed the polyamine stress response (PSR). Notably, polyamine levels decline gradually with age; and external supplementation improves lifespan in model organisms. This corresponds to cytoprotective and reactive oxygen species scavenging properties of polyamines. Paradoxically, age-associated neurodegenerative disorders are characterized by an upsurge in polyamine levels, indicating polyamine pleiotropic, adaptive, and pathogenic roles. Specifically, arginase overactivation and arginine brain deprivation have been shown to play an important role in Alzheimer’s disease (AD) pathogenesis. Here, we assert that a universal short-term PSR associated with acute stimuli is beneficial for survival. However, it becomes detrimental and maladaptive following chronic noxious stimuli, especially in an aging organism. Furthermore, we regard cellular senescence as an adaptive response to stress and suggest that PSR plays a central role in age-related neurodegenerative diseases' pathogenesis. Our perspective on AD proposes an inclusive reassessment of the causal relationships between the classical hallmarks and clinical manifestation. Consequently, we offer a novel treatment strategy predicated upon this view and suggest fine-tuning of arginase activity with natural inhibitors to preclude or halt the development of AD-related dementia.

The constitutively active tyrosine kinase BCR/ABL1 oncogene plays a key role in human chronic myeloid leukemia development and disease maintenance, and determines most of the features of this leukemia. For this reason, tyrosine kinase inhibitors are the first-line treatment, offering most patients a life expectancy like that of an equivalent healthy person. However, since the oncogene is not destroyed, lifelong oral medication is essential, even though this trigger adverse effects in many patients. Furthermore, leukemic stem cells remain quiescent and resistance is observed in approximately 25% of patients. Thus, new therapeutic alternatives are still needed. In this scenario, the emergence of CRISPR technology can offer a definitive treatment based on its capacity to disrupt coding sequences. This review describes CML disease and the main advances in the genome-editing field by which it may be treated in the future.

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.

Depression, anxiety, and pain are part of a common phenomenon that requires to be studied together when evaluating patients with chronic pain. The aim of the study was to examine the correlations between depression, anxiety and pain intensity in patients with chronic pain and how they change when a depressive episode was added. A sample of 120 patients with chronic pain (age: 51.90±11.94; 81.7% female; 18.3% male) was studied in two stages with a three-month period between them. Patients with a depressive episode (n=61) were treated with antidepressants and analgesics, while a patient without depression (n=59) was treated only with analgesics. The scales used to achieve the objectives were: HAM-D-17, Spielberger‘s STAI and VAS. Insignificant correlations were found between depression, state and trait anxiety, and pain intensity (p&lt;0,05) in the group without depression, except for a significant one between depression and state anxiety (p&lt;0,01) in the second stage. Significant correlations were identified between all indicators (p&lt;0,01) in the group with depression at the two stages. Those in the second stage were stronger. The interrelations between sensory and affective aspects of pain were stronger when a depressive episode occurs, the severity of which determines their dynamics.

Cadmium (Cd) is a metal with no nutritional or physiological value, but is found in most people because it is a contaminant in nearly all food types. The intestinal absorption rate determines the body burden of Cd because humans lack a physiologic mechanism for excretion of the metal. Most acquired Cd accumulates in the kidneys, in which the Cd content increases through age 50 but falls thereafter. The decline from maximal kidney content is probably due to release of Cd from injured tubular cells into urine and replacement of destroyed nephrons by scar tissue. Chronic kidney disease is diagnosed when the estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m2, or when albuminuria is present. Albuminuria is defined as an albumin-to-creatinine ratio ≥ 30 mg/g creatinine in women or ≥ 20 mg/g creatinine in men that persists for at least 3 months. Generally, Cd-induced reductions in eGFR are not reversible, and Cd nephropathy may progress to end-stage kidney disease. There is no evidence that elimination of current environmental exposure can reverse Cd nephropathy, and no theoretical reason to believe that such a reversal is possible. This review provides an update of knowledge concerning CKD in population environmentally exposed to Cd. Special attention is devoted to mechanisms of Cd-induced albuminuria concurrently with eGFR reductions, and the difficult challenge of exposure guidelines sufficient to eliminate the risk of Cd-induced CKD is addressed.

Background There is a considerable overlap between clinical presentation of post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) . Many of their common symptoms can be linked to dysregulation of the autonomic nervous system (dysautonomia). This study aimed to objectively assess autonomic function in patients with PCC and in patients with ME/CFS whose disease was not related to COVID-19. Methods Synchronous recordings of an electrocardiogram, continuous dynamics of blood pressure in the digital artery using the Penaz method and ultrasound pneumotachography with the spirography function were obtained with spiroarteriocardiorhythmography method in 34 patients diagnosed with ME/CFS, in whom the onset of the disease was not associated with COVID-19, 29 patients meeting PCC definition and 32 healthy controls. Heart rate variability (HRV), systolic and diastolic blood pressure variability (RV), respiration variability were assessed at rest and in tests with fixed respiratory rates. At rest, indicators of baroreflex regulation were additionally determined (baroreflex effectiveness index and baroreflex sensitivity). Results The total power, power of very low frequency, low-frequency and high-frequency of RR interval variability at rest as well as baroreflex effectiveness index in up-ramps of arterial blood pressure and baroreflex sensitivity were significantly lower both in PCC and ME/CFS patients compared to HC. Several diagnostic prediction models for ME/CFS were developed based on HRV parameters. During slow breathing HRV parameters return to normal in PCC, but not in ME/CFS. Correlation analysis revealed a close relationship of HRV, RV parameters and baroreflex sensitivity with fatigue, but not with HADS depressive/anxiety symptoms in ME/CFS and PCC. Conclusion A similar pattern of HRV and baroreflex failure with signs of a pathological acceleration of age-dependant dysautonomia was identified in ME/CFS and PCC. The clinical, diagnostic and therapeutic implications of these findings are discussed, in light of previously described relationship between inflammation, vascular pathology, atherosclerotic cardiovascular disease and autonomic dysfunction.

Hemoglobin is one of the proteins that are more susceptible to S-glutathionylation and the levels of its modified form, glutathionyl hemoglobin, increase in several human pathological conditions. The scope of the present review is to provide knowledge about how hemoglobin is subjected to be S-glutathionylated and how this modification affects its functionality. The different diseases that showed increased levels of glutathionyl hemoglobin and the methods used for its quantification in clinical investigations will be also outlined. Since there is a growing need for precise and reliable methods of markers of oxidative stress in human blood, this review highlights how glutathionyl hemoglobin is more and more emerging as a good indicator of severe oxidative stress but also as a key pathogenic factor in several diseases.

Tyrosine Kinase Inhibitors work by blocking the tyrosine kinases responsible of the dysregulation of intracellular signalling pathways in tumour cells. This study looked at the impact of age and sex on the levels of imatinib, dasatinib, nilotinib, and ponatinib in plasma and cerebrospinal fluid samples of patients with chronic myeloid leukaemia. Imatinib and dasatinib were used to treat the majority of the enrolled patient and most of them were paediatrics. The 82.4% of patients were men; however, sex-related differences in drugs pharmacokinetics were not found. Age and imatinib plasma concentration were found to be inversely correlated: as patients ages increased, drug levels decreased. The dasatinib concentrations in plasma were found to be substantially lower than those found in cerebrospinal fluid, particularly in paediatrics. Analysing the obtained data, we can state that Therapeutic Drug Monitoring is a useful method for adjusting a patient treatment schedule depending on drug concentrations in biological fluids. The use of Therapeutic Drug Monitoring in conjunction with Tyrosine Kinase Inhibitors for the treatment of chronic myeloid leukaemia is supported by a number of sources of evidence. As a result, as the research develops, Tyrosine Kinase Inhibitors Therapeutic Drug Monitoring classification needs to be refined in terms of factors like sexes and ages.

Chronic hepatitis B (CHB) infection and the Hepatitis B virus X protein (HBx) are major risk factors associated with hepatocellular carcinoma (HCC). In CHB infection, HBx induces mitochondrial dysfunction, exhaustion and impaired function in hepatocytes. Restoring hepatocyte health along with reduction in virus replication could be an ideal treatment for CHB. Thiourea derivatives are well known for their antiviral property though their effect on mitochondrial and/ or hepatocyte health remains obscure. This study focus on the repurposing of thiourea derivatives (DSA-00, DSA-02, and DSA-09) on hepatocyte replenishment. HepG2.2.15 cells were treated with thiourea derivatives, alongside Entecavir (ETV). The proteomics analysis showed both DSA-00 and ETV were enriched with proteins associated with antiviral responses. In addition, DSA-00 additionally showed increase in proteins linked to mitochondrial response. Whereas DSA-02 exhibited association with innate immune system and citric acid cycle and DSA-09 displayed pathways similar to DSA-00 and ETV. Treated groups exhibited enhanced bio-energetic and antiviral response as compared to the untreated group. FACS analysis revealed the restoration of exhausted hepatocytes by thiourea derivatives through targeting mitochondria. Our findings suggest that thiourea derivatives hold potential as a novel therapeutic agent that seems to restore mitochondrial health along with anti-viral response in CHB.

Mesenchymal Stromal Cells (MSCs) are multipotent, non-hematopoietic progenitor cells with a wide range of immune conditioning and regenerative potential which qualify them as potential component of cell based therapy for various autoimmune / chronic inflammatory ailments. Their immunomodulatory properties include the secretion of immunosuppressive cytokines, the ability to suppress T-cell activation and differentiation, and the induction of regulatory T-cells. In view of this and our interest, we here discuss the significance of MSC for the management of Graft-versus-Host Disease (aGVHD), one of the autoimmune manifestation in human.. In pre-clinical models, MSCs have been shown to reduce the severity of aGVHD symptoms, including skin and gut damage, which are the most common and debilitating manifestations of this disease. While initial clinical studies of MSCs in aGVHD cases were promising, the results were variable in randomized studies. So, further studies are warranted to fully understand their potential benefits, safety profile, and optimal dosing regimens. In view of these inevitable issues, here we discuss various mechanisms, how MSCs can be employed in managing aGVHD, as a therapeutic option for this disease.

Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a systemic disease rather than a mere disorder of the lungs. Central (respiratory) and peripheral (limb) muscle weakness are among the main pronounced systemic effects of COPD. While the disease primarily affects the lower limb muscles and contributes to gait impairment, COPD is also associated with an increasing risk of falls in patients (COPDp). Previous studies have reported higher rates of falls among COPDp (1.17 to 1.20 falls/person-year), amounting to four times higher than an age-matched healthy group. Potential fall risk factors include muscle weakness, impaired daily activities, cognitive dysfunction, and gait and balance impairment. Although COPDp often manifest many of these risk factors, there remains a gap in literature regarding falls during walking in this population. This study aimed to 1. analyze the literature to identify the risk factors of falling in COPDp, and 2. investigate the underlying mechanisms by which these risk factors can lead to increased prevalence of falling. The results suggest that in addition to the known risk factors of falling, low back pain and mental fatigue should also be considered as relevant risk factors in the treatment process of these patients. Moreover, respiratory problems, which are common in this population, have demonstrated pronounced effects on energy expenditure, gait, and other types of activities of daily living (ADLs), leading to reduced intensity, disrupted coordination of the trunk-pelvic structure with the lower limbs during gait, and altered motor control performance due to activation of muscles in an inefficient synergic manner. These problems potentially lead to the increased vulnerability of these patients to external disturbances and higher incidence risk of falls and injuries. Cognitive problems, which are typically due to reduced oxygen received by the brain, as well as general inflammation caused by COPD, also play a significant role in gait disruption and balance. Future research is warranted to determine the prevalence of falls in COPDp by examining the response of these patients to Medio-Lateral (ML) and Anterior-Posterior (AP) disturbances during gait in association with traditional and recommended fall risk factors.

Artificial Intelligence (AI) has seen increased application and widespread adoption over the past decade despite, at times, offering a limited understanding of its inner working. AI algorithms are, in large part, built on weights, and these weights are calculated as a result of large matrix multiplications. Computationally intensive processes are typically harder to interpret. Explainable Artificial Intelligence (XAI) aims to solve this black box approach through the use of various techniques and tools. In this study, XAI techniques are applied to chronic wound classification. The proposed model classifies chronic wounds through the use of transfer learning and fully connected layers. Classified chronic wound images serve as input to the XAI model for an explanation. Interpretable results can help shed new perspectives to clinicians during the diagnostic phase. The proposed method successfully provides chronic wound classification and its associated explanation. This hybrid approach is shown to aid with the interpretation and understanding of AI decision-making processes.