Nonischemic dilated cardiomyopathy (DCM) is a complex cardiovascular condition often characterized by genetic pathogenesis. Comprehensive genetic testing has become a crucial aspect of DCM diagnosis and management, offering insights into prognosis and the identification of at-risk individuals. This case series and mini literature review examines the diagnostic and therapeutic dimensions of DCM, emphasizing the role of genetic evaluation. We delve into distinct genetic pathways associated with DCM and their pathogenetic mechanisms, emphasizing the evolving significance of genetic markers, particularly in cases where arrhythmia risk is heightened. The historical reliance on cardiac morphology to subtype cardiomyopathies is being complemented by the identification of genetic variants, further refining DCM subtypes, and aiding in clinical management.The giant sarcomere protein, titin, is a pivotal determinant of cardiomyocyte stiffness and plays a crucial role in cardiac strain sensing. Titin's extensive size and complexity make it susceptible to dysregulation, which has far-reaching consequences in cardiac disorders. This case series with a literature review explores the molecular mechanisms governing titin-based forces in both health and disease. It highlights the influence of isoform diversity and post-translational modifications on myocardial stiffness and contractility. In the context of cardiac diseases, we discuss how titin properties are altered, focusing on changes in titin stiffness and protein quality control. Notably, we address the pathomechanisms associated with truncation in the titin gene (TTN) in human cardiomyopathy, shedding light on potential therapeutic approaches for conditions such as HFpEF and TTN-truncation cardiomyopathy.This comprehensive understanding of DCM and Titin’s role in cardiac physiology and pathology provides a solid foundation for addressing cases like that of our patients, who were presented with features of heart failure and arrhythmias. Despite immediate and extensive resuscitative measures, the patient's protracted response to the treatment raised questions about the potential underlying genetic factors contributing to their clinical presentation. These cases underscore the importance of genetic evaluation in unraveling the complexity of cardiomyopathies, ultimately enhancing our ability to manage and treat such challenging cases.

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.

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.

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.

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.

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.

: 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.

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.

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.

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.

Stainless steel 316L (SS316L) and titanium-alloy Ti6AL4V exhibit properties for bio-medical applications; however their tribocorrosion associated with metallosis is still a major concern. Therefore smoothing DLC coatings aiming for the improvement of tri-bocorrosion and cell viability of stainless steel 316L (SS316L) and titanium-alloy Ti6AL4V with and without DLC coatings were compared. The motivation was due to many papers detailing metallosis caused by metal debris in the body's soft tissues. Nowadays, metallosis is responsible for almost of prosthesis replacement surgeries. DLC coatings were produced using the Plasma Enhanced Chemical Vapor Deposition (PECVD) technique; acetylene gas was used as a carbon precursor, and silane gas produced an amorphous silicon interface between the DLC coating and metal substrate. A combined setup of techniques thoroughly evaluated the coatings considering chemical composition, coatings adhesion at a metallic substrate, scratch resistance, and tribocorrosion susceptibility. The cytotoxicity and genotoxicity of metallic samples with and without DLC coatings were analyzed, considering cell viability and its correlation with coatings’ chemical composition

Long non-coding RNA (lncRNA) aberrant expression have been found in several types of cancer, including acute lymphoblastic leukemia (ALL), but lncRNA mapped in transcribed ultraconserved regions (T-UCRs) are little explored. The T-UCRs uc.112, uc.122, uc.160 and uc.262 were evaluated in pediatric ALL and uc.112 expression was higher in T-ALL compared to patients with B-ALL and in patients with hyperdiploid karyotype. These findings suggest a potential role of this uc.112 in pediatric ALL and emphasize the need for further investigation of T-UCR in pediatric ALL.

This study focuses on mimicking constitutive phosphorylation in the N-terminus of the myosin regulatory light chain (S15D-RLC) as a rescue strategy for the mutation-induced cardiac dysfunction in transgenic (Tg) models of restrictive (RCM) and dilated (DCM) cardiomyopathy caused by mutations in myosin essential (ELC) or regulatory (RLC) light chains. S15D-RLC phosphomimetic was reconstituted in left ventricular papillary muscle (LVPM) fibers from two mouse models of cardiomyopathy, RCM-E143K ELC and DCM-D94A RLC, along with their corresponding Tg-ELC and Tg-RLC wild type (WT) mice. The beneficial effects of S15D-RLC in rescuing cardiac function were manifested by S15D-RLC-induced destabilization of the super-relaxed (SRX) state that was observed in both models of cardiomyopathy. S15D-RLC promoted a shift from the SRX state to the disordered relaxed (DRX) state, increasing the number of heads readily available to interact with actin and produce force. Additionally, S15D-RLC reconstituted fibers demonstrated significantly higher maximal isometric force per cross-section of muscle compared with reconstitution with WT-RLC protein. The effects of the phosphomimetic S15D-RLC were compared to those observed for Omecamtiv Mecarbil (OM), a myosin activator shown to bind to the catalytic site of cardiac myosin and increase myocardial contractility. A similar SRX↔DRX equilibrium shift was observed in OM=treated fibers as in S15D-RLC-reconstituted preparations. Additionally, treatment with OM resulted in significantly higher maximal pCa 4 force per cross-section of muscle fibers in both cardiomyopathy models. Our results suggest that both treatments with S15D-RLC and OM may improve the function of myosin motors and cardiac muscle contraction in RCM-ELC and DCM-RLC mice.

Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics profiling of 1305 plasma proteins in 12 HCM patients with documented LVOT obstruction referred for surgical myectomy. Plasma was collected at the surgical preoperative visit approximately one month prior to surgery and then at the post surgical visit approximately 3 months later. Proteomic profiles were generated using the aptamer-based SOMAscan assay. Principal Component Analysis using the highest statistically significant proteins separated all preoperative samples from all postoperative samples. Further analysis revealed a set of 25 proteins that distinguished the preoperative and postoperative states with a paired t-test p value of <0.01. Ingenuity Pathway analysis facilitated the generation of protein interaction networks and the elucidation of key upstream regulators of the differentially expressed proteins such as interferon-, TGF-1 and TNF. Biological pathways affected by the surgery included organ inflammation, migration and motility of leukocytes, fibrosis, vasculogenesis, angiogenesis, acute coronary events, endothelial proliferation, eicosanoid metabolism, calcium flux, apoptosis and morphology of the cardiovascular system. Our results indicate that surgical relief of dynamic outflow tract obstruction in HCM patients is associated with unique alterations in plasma proteomic profiles that likely reflect improvement in organ inflammation and physiological function.

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.

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.

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.

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.

The impact of systemic vascular resistance (SVR) in hypertrophic (HCM) and amyloid cardio-myopathies has been seldom investigated. We studied pressure-strain loop derived myocardial work (MW) indices and SVR in patients with either sarcomere HCM or wild type transthyretin cardiac amyloidosis (ATTR), presented with heart failure and preserved left ventricular ejection fraction (HFpEF) at the outpatient cardiology units at Messina and Catania University Hospitals (Italy). Patients were in sinus rhythm and needed to have good transthoracic ultrasound imaging quality to undergo transthoracic strain-echocardiography. Other than conventional parameters, SVR and GWI (global work index) were measured. Based on cross-tabulation (a way to assess the ventricular-arterial coupling), the patients were then classified in 4 classes according to the cut-off values suggested by previous studies of 1,440 dyne/s/cm-5 for SVR (Stefadouros et al., 1973) and 1576 mm Hg% for GWI (Olsen et al., 2022). Sixty patients, 30 in each group, aged 61±16 years, 78% males, were studied. HCM were younger than ATTR patients and in a better clinical status (23% HCM vs 77% ATTR were NYHA class 3, p<0.001). Overall, 51 patients (85%) showed high SVR, of whom 21 were HCM (70%) and 30 ATTR (100%) (p<0.005). Both, SVR and GWI were impaired (the poorest class C) in 43% HCM patients (with greater left ventricular concentric hypertrophy) vs 93% of ATTR patients (in advanced NYHA class) (p<0.001). In conclusion, assessing SVR and GWI in HFpEF patients with HCM or ATTR can help clinicians to interpret the pathophysiological and clinical features of such complex diseases.

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disorder complicated by left ventricle outflow tract (LVOT) obstruction, which can be treated with surgical myectomy. To date, no reliable biomarkers for LVOT obstruction exist. To determine whether metabolomic biomarkers for obstruction can be identified, we conducted metabolomic profiling on plasma samples of 18 HCM patients before and after undergoing surgical myectomy to measure changes in the plasma metabolome in the postoperative state. Plasma was collected approximately 4 weeks before surgery at the preoperative visit and approximately 3 months after the surgery at the postoperative visit. We found that 215 metabolites were altered in the postoperative state (p-value &lt; 0.05). Identified metabolites that were significantly reduced post-myectomy included metabolites of heme, such as bilirubin, and phenylacetylglutamine, a biomarker of urea cycle disorders, which suggests that liver and kidney function are improved in the postoperative state. Markers of arginine metabolism such as homoarginine and dimethylarginine are also decreased in the postoperative state, suggestive of reduction in nitric oxide production, inflammation and heart failure after surgery. 3-hydroxybutyrate (BHBA) was also decreased, suggesting possible increased fatty acid utilization and a return to normal heart function. 12 of these metabolites were notably significant after adjusting for multiple comparisons (q-value &lt; 0.05), including bilirubin, PFOS, PFOA, 3,5-dichloro-2,6-dihydroxybenzoic acid, 2-hydroxylaurate, trigonelline and 6 unidentified compounds, which support improved kidney and liver function and increased lean soft tissue mass. These findings suggest improved organ metabolic function after surgical relief of LVOT obstruction in HCM and further underscore the beneficial systemic effects of surgical myectomy.

Selecting drought-tolerant and more water-efficient wheat genotypes is a research priority, spe-cifically in regions with irregular rainfall or areas where climate change is expected to result in reduced water availability. The objective of this work was to use high-throughput measurements with morphophysiological traits to characterize wheat genotypes in relation to water stress. Field experiments were conducted from May to September 2018 and 2019, using a sprinkler bar irriga-tion system to control water availability to eighteen wheat genotypes: BRS 254; BRS 264; CPAC 01019; CPAC 01047; CPAC 07258; CPAC 08318; CPAC 9110; BRS 394 (irrigated biotypes) and Aliança; BR 18_Terena; BRS 404; MGS Brilhante; PF 020037; PF 020062; PF 120337; PF 100368; PF 080492; TBIO Sintonia (rainfed biotypes). The water regimes varied from 22 to 100% of the crop evapotranspiration replacement. Water stress negatively affected gas exchange, vegetation indices and grain yield. High throughput variables TCARI, NDVI, OSAVI, SAVI, PRI, NDRE and GNDVI had higher correlation with yield and morphophysiological measurements. The drought re-sistance index indicated that genotypes Aliança BRS 254, BRS 404, CPAC 01019, PF 020062, and PF 080492 were more drought tolerant.

Background: Pharmacists need up-to-date knowledge and decision-making support in HIV care. We aim to develop MARVIN-Pharma, an adapted artificial intelligence-based chatbot initially for people with HIV, to assist pharmacists, considering evidence-based needs. Methods: From Dec 2022 to Dec 2023, an online needs-assessment survey evaluated Québec pharmacists' knowledge, attitudes, involvement, and barriers relative to HIV care, alongside perceptions relevant to the usability of MARVIN-Pharma. Recruitment involved convenience and snowball sampling, targeting National HIV and Hepatitis Mentoring Program affiliates. Results: Forty-one pharmacists (28 community, 13 hospital-based) across 15 Québec municipalities participated. Participants perceived their HIV knowledge as moderate (M=3.74/6). They held largely favorable attitudes towards providing HIV care (M=4.02/6). They reported a “little” involvement in the delivery of HIV care services (M=2.08/5), most often ART adherence counseling, refilling, and monitoring. The most common barriers reported to HIV care delivery were a lack of time, staff resources, clinical tools, and HIV information/training, with pharmacists at least somewhat agreeing that they experienced each (M≥4.00/6). On average, MARVIN-Pharma's acceptability and compatibility were in the ‘undecided’ range (M=4.34, M=4.13/7, respectively), while pharmacists agreed to their self-efficacy to use online health services (M=5.6/7). Conclusion: MARVIN-Pharma might help address pharmacists' knowledge gaps and barriers to HIV treatment and care, but pharmacist engagement in the chatbot’s development seems vital for its future uptake and usability.

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.

Introduction and objectives: arrhythmogenic cardiomyopathy (ACM) is a hereditary heart disease defined by the progressive replacement of the ventricular myocardium with fibroadipose tissue, which can act as a substrate for arrhythmias, sudden death, or even give rise to heart failure (HF). Sudden death is frequently the first manifestation of the disease, particularly among young patients. The aim of this study is to describe a new pathogenic variant in the PKP2 gene. Methods: A descriptive observational study that included 8 initially non-interrelated families with a diagnosis of ACM undergoing follow-up at our HF and Familial Cardiomyopathies Unit, who were carriers of the NM_004572.3:c.775_776insG; p. (Glu259Glyfs*77) variant in PKP2 gene. The genetic testing employed next-generation sequencing for the index cases, and the Sanger method for the targeted study with family members. We compiled personal and family histories, demographic and clinical characteristics, data from the additional tests at the time of diagnosis, and arrhythmic events at diagnosis and during follow-up. Results: We included 47 subjects, of whom 8 were index cases (17%). Among the evaluated family members, 16 (34%) were carriers of the genetic variant, 3 of whom also had a diagnosis of ACM. The majority were women (26 patients; 55.3%), with a mean age on diagnosis of 48.9 ± 18.6 years, and a median follow-up of 39 [24-59] months. Worthy of note are the high incidence of arrhythmic events as the form of presentation and in follow-up (21.5% and 20.9% respectively), and the onset of HF in 25% of the sample. The most frequent ventricular involvements were right (4 patients 16.7%) and biventricular (4 patients 16.7%); we found no statistical differences in any of the variables analysed. Conclusions: This variant is a pathogenic variant of gene PKP2 that has not previously been described and is not present in the control groups associated with ACM. It has incomplete penetrance, a highly variable phenotypic expressivity, and was identified in 8 families of our geographical area in Malaga (Andalusia, Spain), where we can establish a founder effect and describe the clinical and risk characteristics.

The description of the genus Leishmania as causative agents of leishmaniasis occurred during this modern age. But evolutionary studies suggest that the origin of Leishmania can be traced back to the Mesozoic era. Subsequently, during its evolutionary process, it sustained a worldwide dispersion predating the breakup of the Gondwana supercontinent. It is assumed that this parasite evolved from monoxenic Trypanosomatidae. Phylogenetic studies locate the dixenous Leishmania in a well-supported clade, recently named subfamily Leishmaniinae, which includes also monoxenous trypanosomatids. Virus-Like Particles were reported in many species of this family. So far, several Leishmania species have been reported as infected by Leishmania RNA Virus (LRV) and Leishbunyavirus (LBV). Since the first descriptions of LRV decades ago, differences in its genomic structure have been highlighted, leading to the designation of a LRV1 in L. (Viannia) species and a LRV2 in other L. (Leishmania) species. There are strong indications of virus infecting Leishmania spp. ability to enhance parasitic survival both in human and experimental infections, through highly complex and specialized mechanisms. Phylogenetic analyzes of these viruses have shown that their genomic differences correlate with the infected parasite species, suggesting a coevolutionary process. Herein, we will present unpublished results regarding the relationship Leishmania – endosymbiotic Leishmania viruses and will explore what has been described in the literature, and what is known about this association that could contribute to discussions about the worldwide dispersion of Leishmania.

Native plants from the Brazilian Amazon Biome are rich in nutrientes, oils and fats and, therefore, represent a very important regional food resource. Althoung there is a global interest in the nutritional potential of tropical fruits, the potential of Amazonian fruits as source of essential fatty acids is still under exploited, since their composition is still understudied. ¹H Magnetic Resonance Nuclear (¹H NMR) is a robust spectroscopic tool to profile fatty acids components in oils. The objectives of this work were to use ¹H NMR to determine the fatty acids profile and the physicochemical properties of crude oils and fats obtained from fruits of Brazilian Amazon: açaí, ata-brava, bacaba, buriti, buritirana, murici amarelo, murici vermelho, piaçaba braba, tucumanzinho, pupunha red and yellow varieties. Oils were obtained by Soxhlet extraction using hexane as a solvent. After solvent removal by rotoevaporation, the resulting oils and fats were analyzed by ¹H NMR spectroscopy. Unsaturated fatty acids oleic (ω9), linoleic (ω6) and linolenic (ω3) acids were quantified in the oils and their physicochemical properties were determined. It was observed that the oils have predominately ω9 fatty acids, followed by ω6 and ω3 representatives. The physicochemical properties confirmed edibility and good quality of oils and fats present in the aforementioned Amazonian fruits.

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).

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.

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.

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.

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.

Background: Left ventricular noncompaction (LVNC) is a distinct cardiomyopathy characterized by the presence of a two-layer myocardium with prominent trabeculation and deep intertrabecular recesses. The diagnosis of LVNC can be challenging because the diagnostic criteria are not uniform. The aim of our study was to evaluate echocardiographic and CMR findings in a group of children with isolated LVNC. Methods: From February 2008 to July 2021, pediatric patients under 18 years of age at the time of diagnosis with echocardiographic evidence of isolated LVNC were prospectively enrolled. The patients underwent echocardiography and contrast-enhanced cardiovascular magnetic resonance (CMR) with late gadolinium enhancement to assess myocardial noncompaction, ventricular size, and function. Results: A total of 34 patients with a median age of 11.9 years were recruited. Patients were followed prospectively for a median of 5.1 years. Of the 31 patients who met Jenni’s criteria in echocardiography, CMR was performed in 27 (79%). Further comprehensive analysis was performed in the group of 25 patients who met the echocardiographic and CMR criteria for LVNC. In echocardiography, the median NC/C ratio in systole was 2.60 and in diastole 3.40. In 25 out of 27 children (93%), LVNC was confirmed by CMR according to Petersen’s criteria, with a median NC/C ratio of 3.27. Conclusions: 1) Echocardiography precisely identifies patients with LVNC. 2) Echocardiography is a good method for monitoring LV systolic function, but CMR is indicated for the precise assessment of LV remodeling and RV size and function as well as for the detection of myocardial fibrosis.

Mimosa acutistipula is endemic to Brazil and grows in ferruginous outcrops (canga) in Serra dos Carajás, eastern Amazon, where one of the largest iron ore deposits in the world is located. Plants that develop in these ecosystems are subject to severe environmental conditions and must have adaptive mechanisms to grow and thrive in cangas. Mimosa acutistipula is a native species used to restore biodiversity in post-mining areas in canga. Understanding the molecular mechanisms involved in the adaptation of M. acutistipula in canga is essential to deduce the ability of native species to adapt to possible stressors in rehabilitating minelands over time. In this study, the root proteomic profiles of M. acutistipula grown in a native canga ecosystem and rehabilitating minelands were compared to identify essential proteins involved in the adaptation of this species in its native environment and that should enable its establishment in rehabilitating minelands. The results showed differentially abundant proteins, where 436 proteins with significant values (p < 0.05) and fold change ≥ 2 were more abundant in canga and 145 in roots from the rehabilitating minelands. Among them, a representative amount and diversity of proteins were related to responses to water deficit, heat, and responses to metal ions. Other identified proteins are involved in biocontrol activity against phytopathogens and symbiosis. This research provides insights into proteins involved in M. acutistipula responses to environmental stimuli, suggesting critical mechanisms to support the establishment of native canga plants in rehabilitating minelands over time.

Sleep disturbances and chronic pain are prevalent and interrelated conditions that significantly impact individuals' quality of life. Understanding the intricate dynamics between sleep and pain is crucial for developing effective treatments that enhance the well-being of affected individuals and reduce the economic burden of these debilitating conditions. This narrative review examines the complex relationship between sleep disturbances and chronic pain. We describe the prevalence and types of sleep disturbances and sleep disorders in chronic pain patients. Posteriorly we critically review the clinical and experimental evidence investigating the relationship between sleep disturbances and chronic pain aiming to clarify the impact of chronic pain on sleep and, conversely, the impact of sleep disturbances on pain perception. We conclude that a bidirectional relationship between chronic pain and sleep disturbances is almost a consensus in the literature, however, the strength of each direction of the association is less clear. As of now, the literature suggests that sleep impairment is a stronger predictor of pain than pain is a predictor of sleep impairment. Additionally, addressing sleep disturbances in chronic pain patients is crucial, as poor sleep has been linked to higher levels of disability, depression, and pain-related catastrophizing.

Indigenous Peoples in Canada are disproportionately affected by chronic hepatitis C virus (HCV) infection. HCV prevalence in Indigenous Peoples is estimated at approximately five to 10-fold higher than it is in non-Indigenous persons, while the reported rate of newly diagnosed HCV cases in First Nations communities was six times the respective rate in the general Canadian population in 2022. This review explores the reasons underlying the disproportionate burden of hepatitis C virus (HCV) infection in Indigenous Peoples, including significant over-representation of Indigenous Peoples in the major risk categories for HCV acquisition, such as substance abuse, incarceration, homelessness or inadequate shelter, and disruption of family/social supports. The impact of these risk factors is aggravated by many access barriers to healthcare services despite the availability of universal healthcare system and free curative antiviral therapies. These stem from the legacy of colonialism, discrimination and disenfranchisement, and are exacerbated by racism in the justice and healthcare systems, stigmatization and victimization. Recent recognition of historical harms and early steps towards nation-to-nation reconciliation along with support for culturally safe, wholistic and Indigenous People-led wellness programs instill hope that elimination strategies to eradicate HCV infection in Indigenous populations will be successful in Canada.

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.

Chronic Kidney Disease is a medical condition that causes the decrease in the kidney function and can eventually derive in a total cessation of the work of the organ. It currently affects >10% of the global population, and the number is expected to grow within the next few years, since the correlated diabetes condition is escalating too. Diagnosing the disease on its early stages is crucial to improve life quality, and to increase the chances of survival. The traditional diagnostic methods, which include a biopsy, are invasive, expensive and dangerous. With the use of machine learning algorithms like neural networks, random forest and genetic algorithms, this paper seeks to discover an algorithm with high accuracy, whose selected attributes will be the most optimal combination aiming to reduce the cost, level of invasiveness, and easiness to obtain.

Intense alterations of mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and represent an important cause of morbidity and decreased quality of life. These disor-ders have traditionally been defined as renal osteodystrophy and classified based on bone biop-sy, but due to a lack of bone biopsy data and validated radiological methods to evaluate bone morphology in children, it has been difficult to adequately evaluate renal osteodystrophy in pe-diatric CKD. This has led to suboptimal management of bone disorders in children. CKD-mineral and bone disorder (CKD-MBD) is a new term used to describe a systemic disorder of mineral and bone metabolism as a result of CKD. CKD-MBD is a triad of biochemical imbalances of cal-cium, phosphate, parathyroid hormone and vitamin D, bone abnormalities and soft tissue calci-fication. This literature review aims to explore the pathogenesis, diagnostic approach, and treat-ment of CKD-MBD in children and the specific consequences of renal osteodystrophy on growing skeleton, with a specific focus on the biological basis of this peculiar condition.

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.

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

Patients with bilateral vestibulopathy (BVP) suffer from postural imbalance during daily life conditions which in turn leads to a high frequency of falls. Unfortunately, vestibular rehabilitation has only modest and somewhat inconsistent effects in this patient group. Approximately fifty percent of BVP-patients show an improved postural control after conventional vestibular rehabilitation training. New and more promising approaches are required. The individualized vibrotactile neurofeedback training (IVNT) in stance and gait conditions has already been described as highly effective in patients with various vestibular disorders. The purpose of the present multicenter study was to determine the efficacy of the IVNT in improving balance, reducing self-perceived disability, and improving gait in patients with confirmed BVP. In total, 22 patients performed the IVNT with the Vertiguard^®-system for 10 daily sessions. The dizziness handicap inventory (DHI), the stance stability score of the sensory organization test (SOT) and the score for everyday life mobility in stance and gait tasks (SBDT) were obtained immediately before and after the rehabilitation training period as well as 3 and 12 months later. All measures improved significantly after the IVNT. Between 77.3 % and 94.4 % of patients showed an individual benefit (depending on outcome measure). The effect was not significantly reduced within the follow-up period of 12 months. The results demonstrate a high efficacy of the IVNT for vestibular rehabilitation in BVP patients.

Background: Sulforaphane (SFN) is an isothiocyanate of vegetables origin with potent antioxidant and immunomodulatory properties. The pleiotropic activities characterization in human dendritic cells (DCs) is poorly summarized. The aim of this work was the study of the immunomodulatory power of SFN in response to an inflammatory microenvironment on human monocyte derived DCs (moDCs). Methods: The immunological response induced by SFN was studied, evaluating apoptosis and autophagy assays by flow cytometry in moDCs and cancer cell line (THP-1), including moDCs maturation, lymphocyte proliferation and cytokines production under different experimental conditions associated or not with an inflammatory microenvironment, which was induced by lipopolysaccharide (LPS). Results: Our results demonstrated that SFN can interact with moDCs, significantly reducing autophagy process and enhancing apoptosis, such as THP-1 cells, in chronic inflammatory microenvironment. Under this chronic inflammation, SFN modulated the phenotypical characteristics of moDCs, which reduction the expression of all markers (CD80, CD83, CD86, HLA-DR and PD-L1), and significantly reduced the Th2 proliferative response together with the reduction of the IL-9 and IL-13 levels. Although we did not find changes in the regulatory proliferative response, we observed an increase in IL-10 levels. Conclusion: These findings demonstrate that SFN exerts protective effects against LPS-induced inflammation through moDCs/T-cells modulation towards a regulatory profile. Therefore, SFN may be a potential candidate for use in the treatment of pathologies with an inflammatory profile.

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen and is the leading cause of infection in patients with cystic fibrosis (CF). The ability of P. aeruginosa to evade host responses and develop into chronic infection causes significant morbidity and mortality. Several mouse models have been developed to study chronic respiratory infections induced by P. aeruginosa, with the bead agar model being the most widely used. However, this model has several limitations, including the requirement for surgical procedures and high mortality rates. Herein, we describe novel and adapted biologically relevant models of chronic lung infection caused by P. aeruginosa. Three methods are described, a clinical isolate infection model, utilizing isolates obtained from patients with CF, an incomplete antibiotic clearance model, leading to bacterial bounce-back and the establishment of chronic infection, and an adapted water bottle chronic infection model. These models circumvent the requirement for surgical procedure and importantly, can be induced with clinical isolates of P. aeruginosa and in wild-type mice. We also demonstrate successful induction of chronic infection in the transgenic βENaC murine model of CF. We envisage that the models described will facilitate the investigations of host and microbial factors, and the efficacy of novel antimicrobials, during chronic P. aeruginosa respiratory infections.

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.

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.

In the present research, chronic viral hepatitis in children is approached from a multidisciplinary point of view, considering social status, economic and medical aspects. We conducted a 4-year observational prospective study. A questionnaire regarding the socio-economic status of pediatric patients diagnosed with chronic viral hepatitis B or C was applied. In total, 159 patients were included, 52 % from urban areas, 2.5 % coming from centres for abandoned children. Among 119 school-aged children, 66% were attending classes. All patients are registered with a general practitioner. Regarding the monthly income per family, 49% had less than 1000 RON (5 RON = 1$), of which 17% had no income, 28% had an income ranging between 1000 and 2000 RON and in only 23% of cases the income exceeded 2000 RON (5% had more than 4000 RON). There were between 3 and 12 members per family. Concerning parents` educational level, the average years of study for mothers was 7.8, while for fathers, it was 8.2. For 17 % of children, at least one of the parents was illiterate, and for 5.6 %, both parents were illiterate. For a third of patients, both parents were unemployed. Regarding social living conditions, 38.4% did not have water facilities or sewerage, and 32 % used personal objects (scissors, nail clippers) in common. The socio-economic level can have a significant impact on disease epidemiology (infectiousness) and access to treatment, and it is tightly related to educational level and access to information, which are critical factors in disease prevention through general and specific measures and in disease management (treating infected patients and limiting the transmission).

A two-year-old male Pomeranian dog visited the hospital due to side effects of surgical correction for patellar luxation. Stifle joint arthrodesis (SJA) was performed on the patient’s right leg using autologous bone grafting techniques. The right leg’s femur and tibial joint were angled 120-130◦ and the SJA plate was fixed on the front of the two bones. After performing joint fusion of the right limb, medial patellar luxation (MPL)-corrective surgery was performed to cut the tibial tuberosity on the left leg and the fixing force was increased using the figure-of-eight tension band wiring technique. The results were observed for walking and trotting of the right hind limb, evaluated for 27 days after surgery. It was difficult for the patient to walk because weight loading was not performed for 3 days after surgery; short strides and partial weight bearing were possible 5 to 7 days after surgery. After 10 days, the patient was able to move while bearing weight with a slight disruption. For trotting, the patient showed intermittent normal steps 5 to 7 days after surgery, but the disruption continued. After 14 days, trotting was possible and movements were shown to be maintained during everyday activities.

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.

Numerous genes expression lead to inflammation in the individuals’ lungs that have chronic obstructive pulmonary disease (COPD) may be affected by epigenetic alteration. Important epigenetic processes include methylation of DNA and different histones post-translational changes, including ubiquitination, phosphorylation, methylation, SUMOylation and acetylation. Smoking can trigger the enzymes that control these epigenetic changes. According to the majority of publications, both environmental and genetic variables have a substantial role in the development of COPD. Although, the information about COPD epigenetic is not much but, a better perception of the disease pathophysiology and identifying new markers to create novel therapeutics for patients can be achieved via a better understanding of the epigenetic processes involved.

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 diseases are characterised by cell’s autophagy and proteins disarrangement resulting in sarcopenia, hypoalbuminemia and hypo-haemoglobinaemia. Hypo-haemoglobinaemia couses worse prognosis independentely of the principal disease. Currently, the cornerstone of therapy of anaemia is iron supplementation, with or without erythropoietin for the stimulation of hematopoiesis. However, treatment strategies should incorporate the addition of heme, the principal biochemical constituent of haemoglobin. Heme synthesis follows a complex biochemical pathway. The limiting step of heme synthesis is D-ALA availability which, for its synthesis, requires Glycine and Succinil-CoA. Consequently, treatment of anaemia should not be based only on iron availability, but also on the availability of the molecules fundamental for heme synthesis. Therefore, an adequate clinical therapeutic strategy should integrate the standard iron infusion and the supply of essential amino acids and vitamins involved in the heme synthesis. We report preliminary data in selected elderly anaemic patients with congestive heart failure (CHF) and catabolic disarrangement, who, in addition to standard iron therapy, received personalized therapy with essential-AAs and vitamins involved in the maintenance of heme. Notably, such individualized therapy resulted in a significant increase in the serum concentration of haemoglobin after 30 days of treatment compared to standard iron therapy.

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

We examined special roles of the Central Nervous System (CNS) in an attempt to resolve the puzzle that chronic diseases cannot be cured by medicine. By exploring a skill-learning model, we found that the CNS is able to remember certain information reflecting biochemical and cellular (B&C) processes in the body. From the skill using ability, we found that the CNS is able to control basic B&C processes that drive and power the skill. From the ability to adjust forces and force direction of a physical act, we found that the CNS is able to adjust B&C processes that drive the physical act. From this adjustment capability, we further inferred that the CNS must also store information on the baseline B&C processes. As a whole, we found that the CNS can maintain information on baseline B&C processes, up-regulate or down-regulate the processes, and make comparisons in performing its regulatory functions. We found that chronic diseases are the results of deviated baseline B&C processes. Per the proved hypothesis, the CNS maintains deviated baseline B&C processes, and thus protects the body states of fully developed diseases. We then used the three CNS roles to explain that cancer progresses with increasing malignancy, cancer quickly returns after a surgery, cancer cells repopulate after chemotherapy and radiotherapy, cancer develops drug resistance inevitably, immune cells rebound after suppression, generally poor benefits of cancer drugs such as beta-blockers, etc. We further showed that long-term exercises generally push most, if not all, baseline B&C processes in diametrical opposing directions against the diseased B&C processes, implying that exercises play unique roles in reversing chronic diseases. Finally, we proposed several strategical approaches to resetting the CNS’ state memory as the essential condition for curing chronic diseases.

Pediatric rhinosinusitis are common encountered disorders caused by different pathogenic factors or predisposing conditions with a proportion of them progressing to chronicity with a meaningful impact on quality of life and related adverse effects. A deep understanding of pathophysiology, disease course and prognosis are the fundamental building block to an appropriate management of rhinosinusitis in order to avoid risks related to complications. This review gives concise answers to clinicians who want to know "when do we need imaging?" "what do we aspect from imaging?" and "what are the appropriate imaging modalities in different settings?” in pediatric patients in order to increase the appropriateness of imaging examinations.

Blood and/or urine levels of 27 heavy metals were determined by ICPMS in 41 patients with dilated cardiomyopathy (DCM) and 29 presumably healthy subjects from the Katanga Copperbelt (KC), in the Democratic Republic of Congo (DRC). After adjusting for age, gender, education level, and renal function, DCM probability was almost maximal for blood concentrations above 0.75 and 150 µg/dl for arsenic and copper, respectively. Urinary concentrations above 1 for chromium, 20 for copper, 600 for zinc, 30 for selenium, 2 for cadmium, 0.2 for antimony, 0.5 for thallium and 0.05 for uranium, all in μg/g of creatinine, were also associated with increased DCM probability. Concurrent and multiple exposures to heavy metals, well beyond permissible levels, are associated with increased probability for DCM. Study findings warrant screening for metal toxicity in case of DCM and prompt public health measures to reduce exposures in the KC, DRC.

Myocardial deformation imaging (strain imaging) is a technique to directly quantify the extent of myocardial contractility and overcomes several of the limitations of ejection fraction. The application of the most commonly used strain imaging method; speckle-tracking echocardiography to patients with sepsis cardiomyopathy heralds an exciting development to the field. However; the body of evidence and knowledge on the utility, feasibility and prognostic value of left ventricular global longitudinal strain in sepsis cardiomyopathy is still evolving. We conducted a review of literature on utility of left ventricular global longitudinal strain in sepsis cardiomyopathy. We discuss the role of left ventricular global longitudinal strain in mortality prediction, utility and limitations of the technique in the context of sepsis cardiomyopathy.

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

Adult human thymus degenerates into adipose tissue (TAT). In contrast to subcutaneous adipose tissue (SAT), TAT has been reported to exhibit enhanced angiogenic properties in elderly people. We have previously shown that vascular endothelial growth factor A (VEGFA) is the most abundant angiogenic growth factor in TAT of patients with ischemic cardiomyopathy (IC), and that VEGFA levels are increased in elderly (&gt;70 years) compared with middle-aged patients. This makes TAT a promising candidate for angiogenic therapies and the regeneration of ischemic tissues following coronary surgery. MicroRNAs (miRNAs) have emerged as attractive therapeutic targets, especially those that regulate angiogenic processes. The study's purpose is to determine the miRNA network associated with both VEGFA pathway regulation and enrichment of age-linked angiogenesis in the TAT.

Both aging and chronic obstructive pulmonary disease (COPD) are strongly associated with changes in the metabolome; however, it is unknown whether there are common aging/COPD metabolomic signatures and if accelerated aging is associated with COPD. Plasma from 5,704 subjects from COPDGene and 2,449 subjects from SPIROMICS were profiled using the Metabolon global metabolomics platform (1,013 annotated metabolites). Post-bronchodilator spirometry measures of airflow obstruction (forced expiratory volume at one second (FEV₁)/forced vital capacity (FVC) < 0.7) were used to define COPD. Elastic net regression was trained on never and former smokers with normal spirometry and no emphysema to create a metabolomic age score which was validated in SPIROMICS subjects. Our metabolic age score was strongly associated with chronic age in the validation cohort (correlation coefficient 0.8). COPD subjects with accelerated aging (> 7 years difference between metabolic and actual age) had more severe disease compared with those who had decelerated aging (< -7 years difference between metabolic and actual age). COPD and aging metabolites were shared more than expected (P < 0.001) with overrepresented included amino acid and glutathione metabolism pathways. These findings suggesting a common mechanism between aging and COPD and that COPD is associated with accelerated metabolic aging.

Abstract: Chronic Obstructive Pulmonary Disease (COPD) is a continually advancing respiratory disorder, characterized by enduring airflow limitation along with long-lasting inflammation in the airways. An expanding pool of evidence is emphasizing how mitochondrial dysfunction directly impacts the development and progression of COPD. This comprehensive review delves deeper into the intricate cellular and molecular biology of mitochondria within the framework of COPD, spotlighting significant alterations in structure and function that accompany mitochondrial dysfunction. In this narrative, we delve into the observed changes in mitochondrial shape, behavior, and respiratory chain complex alterations seen in individuals afflicted with COPD. The discussion includes implications on cellular signaling pathways and how this affects the natural process of programmed cellular death (apoptosis) and cellular aging, particularly in reference to COPD. Additionally, we consolidate ongoing therapeutic strategies, honing in on the management of COPD through a focus on mitochondrial dysfunction. Prominent among these strategies is the potential role of antioxidants and mitochondrial biogenesis inducers, which are emerging as promising fields of intervention. Furthermore, we embark on an overview of the possible use of mitochondrial biomarkers as innovative tools in diagnosing COPD, evaluating disease progression, and monitoring the efficacy of COPD treatments. As we unravel the rather complex interplay between mitochondrial biology and COPD, this review highlights the critical importance of formulating treatments that target mitochondrial dysfunction. The ultimate goal of these strategic interventions is to slow down the rate of COPD progression and significantly improve patient outcomes. Lastly, though our understanding of the nexus between COPD and mitochondrial dysfunction has significantly enhanced, ample scope remains for further investigation. Improved insights into the mechanisms of mitochondrial dysfunction, discovered biomarkers, and targeted therapies could encompass a revolutionary step towards comprehensive disease management. The future of COPD treatment seems to lean towards a combination of strategies, prioritizing not only the management of symptoms but also focused on preserving and restoring lung function, improving physical capacity, and enhancing quality of life for COPD patients.

Chronic rhinosinusitis (CRS) is a complex inflammatory condition affecting the nasal and paranasal sinus mucosa. Gastroesophageal reflux disease (GERD) has been implicated as a potential exacerbating factor in CRS, but the specific endoscopic features of nasopharyngeal pathology in this context remain poorly understood. Background and Objectives: CRS is a multifactorial disease with various underlying etiologies, including inflammation, anatomical factors, and environmental triggers. While GERD has been suggested as a potential contributor to CRS, the specific endoscopic features indicative of nasopharyngeal pathology in CRS patients with GERD symptoms have not been clearly elucidated. Our aim is to identify specific endoscopic features of nasopharyngeal pathology in patients with CRS associated with GERD symptoms, and to propose a method for assessing the influence of GERD on the mucosal layer of the nose and nasopharynx. Materials and Methods: We conducted a cross-sectional observational study involving 521 adult patients presenting with symptoms suggestive of CRS. From this cohort, 95 patients with the highest scores on the Reflux Symptom Index (RSI) and Reflux Symptom Score-12 (RSS-12) questionnaires were selected as the main group. Endoscopic examinations were performed to assess the nasal and nasopharyngeal mucosa. Results: Our study revealed significant alterations in the nasopharyngeal mucosa of patients with CRS associated with GERD symptoms. Increased vascularity of the nasopharyngeal mucosa was observed in 91 patients (95.7%), while hypertrophy was noted in 83 patients (87.4%). Mucus was present in the nasopharynx of 77 patients (81.1%), exhibiting varying characteristics of color and consistency. Asymmetric hypertrophy of the oropharyngeal mucosa was noted in 62 patients (65.3%). Conclusions: We propose a method for assessing the influence of GERD on the mucosal layer of the nose and nasopharynx, which may aid in diagnostic and management decisions. Further research is warranted to explore the potential impact of GERD symptoms on the course and severity of CRS exacerbations.

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.

Cardiovascular diseases (CVDs) and chronic kidney disease (CKD) are frequently interconnected and their association leads to an exponential increase in the risk of both fatal and non-fatal events. In addition, the burden of arrhythmias in CKD patients is increased. On the other hand, the presence of CKD is an important factor that influences the decision to pursue cardiac device therapy. Data on CKD patients with device therapy is scarce and mostly derives from observational studies and case reports. Cardiac resynchronization therapy (CRT) is associated with decreased mortality, reduced heart failure symptoms and improved renal function in early stages of CKD. Implantable cardioverter defibrillators (ICDs) are associated with a significant reduction in the mortality of CKD patients only for the secondary prevention of sudden cardiac death. Cardiac resynchronization therapy defibrillator (CRT-D) is preferred in patients that meet the established criteria. The need for cardiac pacing is 3-fold higher in dialysis patients. CKD is an independent risk factor for infections associated with cardiac devices.

Fungal-bacterial co-colonization and co-infections are emerging among TB-suspected patients, yet the underlying mechanisms that enable and arise from their interactions are poorly understood. Understanding how environmental microbes such as fungi and bacteria co-evolve and develop traits to evade host immune responses and resist treatment is critical to controlling opportunistic co-infections. Our previous work has demonstrated that fungal-bacterial interactions can have dramatic impacts on fungal pathogenesis and drug resistance. Here, we, therefore, hypothesize that cross-kingdom synergistic interactions between environmental fungi and bacteria may influence both fungal and bacterial virulence, antimicrobial resistance patterns and aetiology. Through this, we aimed to establish the prevalence of fungal–bacterial microbial communities associated with chronic primary or opportunistic pulmonary infections. Concordantly, through surveilling 302 clinical samples from 151 patients, we established the prevalence of TB (0.7%) to be lower than that of fungi (1.3%) and non-TB bacterial (4.6%) mono-aetiologies Figure 2. However, our main observation was the unexpected taxonomic diversity with a striking twist of fungal-bacterial di-kingdom aetiological conformities. Interestingly, the majority of the patients presented with at least a di or mono-kingdom aetiological pairings. Importantly, fungi and non-TB bacteria formerly regarded as atypical opportunists are now frequently isolated as possible aetiology for chronic pulmonary infection. Hence, we revealed many di-kingdom aetiological pairings here but their significance remains a question of further examination. Among which Acremonium spp + K. pneumoniae (n=5), Acremonium spp +Streptococcus pneumoniae (n=4), Acremonium spp + C. albicans + K. pneumoniae (n=3) were among the most dominant aetiological pairings observed. Interestingly, Acremonium spp + K. pneumoniae pairings were also seen to be the most commonly associated with pulmonary TB both during and after treatment. Isolation from the same infection niche as seen here calls for further investigations into any interaction signatures that may exist between these organisms. Taken together, our data suggest that fungal-bacterial co-existence may influence their virulence attributes and antimicrobial resistance patterns, with relevance to patient outcomes. Therefore, our data reveals an array of fungal-bacterial pairings that may influence the prognosis of chronic pulmonary disease. Importantly, suggesting that the diversity of pulmonary infective fungi and bacteria, and their complex population structures may pose challenges to the analysis and interpretation of conventional data. Thus, there is a need to redirect our diagnostic approaches to encompass polymicrobial aetiology in order to enhance our suspicion index for better management of opportunistic fungal-bacterial co-infections.

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 plasma, 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 we will find a haematocrit value at the high extreme of the reference range, and an albumin value at the low extreme of the reference range in most Long COVID patients before the start of the treatment, because the liver can not keep up with the recovery of the red bone marrow.

Chronic Mesenteric Ischemia (CMI) arises from the inability to achieve adequate intestinal blood flow after meals, leading to an imbalance between oxygen and metabolite supply and demand. The true incidence of CMI remains uncertain. However, the occurrence of mesenteric artery occlusive disease (MAOD) is relatively common among the elderly population. Delays in diagnosing CMI can often be attributed to several factors, including the variability of patient symptoms, the range of potential causes for chronic abdominal pain with weight loss. Mikkelson pioneered the introduc-tion of a surgical treatment for occlusive lesions of the superior mesenteric artery (SMA) in 1957. The inaugural performance of endovascular revascularization (ER) for visceral vessels took place in 1980. The literature has documented two types of endovascular revascularization (ER) methods: percutaneous transluminal angioplasty (PTA) and primary stenting (PMAS). Despite the limited quality of available evidence, the consensus among experts is strongly in favor of PMAS over PTA alone for the treatment of atherosclerotic mesenteric artery stenosis. There are several key areas of focus for chronic mesenteric ischemia (CMI) treatment. Randomized controlled trials comparing different stent types, such as covered stents versus bare metal stents, are needed to evaluate effi-cacy, patency rates, and long-term outcomes in CMI patients.

Atherogenic lipoproteins may impair vascular reactivity, leading to tissue damage in various organs, including the eye. This study aimed to investigate whether ophthalmic artery reactivity is affected in mice lacking the apolipoprotein E gene (ApoE-/-), a model for hypercholesterolemia and atherosclerosis. Twelve-month-old male ApoE-/- mice and age-matched wild-type controls were used to assess vascular reactivity using videomicroscopy. Moreover, vascular mechanics, lipid content, levels of reactive oxygen species (ROS), expression of pro-oxidant redox enzymes and of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were determined in vascular tissue. Unlike the aorta, the ophthalmic artery of ApoE-/- mice developed no signs of endothelial dysfunction and no signs of excessive lipid deposition. Remarkably, levels of ROS, nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), NOX2, NOX4, and of LOX-1 were increased in the aorta but not in the ophthalmic artery of ApoE-/- mice. Our findings suggest that ApoE-/- mice develop endothelial dysfunction in the aorta by increased oxidative stress via involvement of LOX-1, NOX1 and NOX2, whereas NOX4 may participate in media remodeling. In contrast, the ophthalmic artery appears to be resistant to chronic apolipoprotein E deficiency. Lack of LOX-1 expression/overexpression in response to increased ox-LDL levels may be a possible mechanism of action.

(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.

Background: The burden of resistant fungal infection is rising in patients with pulmonary disease. Options for antifungal therapy are limited, and the only orally-available antifungals, the triazoles, demonstrate inter and intra-patient variability, non-linear kinetics, toxicity, drug interactions and increasing antifungal resistance. Therapeutic drug monitoring (TDM) of itraconazole, voriconazole and posaconazole has been necessary to ensure their safety and efficacy, but is considered unnecessary for the newest triazole isavuconazole, use of which is increasing. Aims: To characterise isavuconazole susceptibility of Aspergillus fumigatus isolates in a tertiary respiratory referral centre to understand prevalence of isavuconazole antimicrobial resistance. To retrospectively review experience of isavuconazole use in this setting, assessing tolerability and therapeutic drug monitoring. Methods: A retrospective observational analysis of adult patients with respiratory disease in a tertiary hospital setting between Sept 2016 and Aug 2021. Clinical cultures were collected and triazole Minimum inhibitory concentration (MIC) were recorded (based on Clinical &amp; Laboratory Standards Institute (CLSI method)). Isavuconazole trough drug levels were carried out as part of the standard of care. Clinical outcomes of treatment were evaluated, along with drug tolerance and TDM. Results: During the study period, isavuconazole susceptibility testing was performed on 26 Aspergillus spp isolates. 80.8% of Aspergillus fumigatus isolates were non-wild type and had isavuconazole MIC &gt; 1mg/L, and 73.0% had MIC above the EUCAST (European Committee on Antimicrobial Susceptibility Testing) epidemiological cut-off (ECOFF) of 2mg/L. There was good correlation between isavuconazole MIC and voriconazole MIC (r =0.7, p=0.0002). 54 patients had isavuconazole therapy over the study period with a median duration of 7.7 months (IQR 0.79 - 16.42). 67% of patients were able to tolerate isavuconazole, despite toxicity with prior azole treatment being the primary indication for use (in 61.8%). Increased age (r=0.29; p=0.03 (95%CI 0.02,0.52)) and gender (r for female sex=-0.31; p=0.027 (95%CI -0.52,0.036) were associated risk factors for development of adverse events (AEs). 127 Isavuconazole TDM levels were performed over the study period with 90% &gt;1mg/L and 72% &gt;2mg/L. Dose change from manufacturer’s dose recommendation, however, was required in 15% of patients to achieve a serum drug concentration above the EUCAST ECOFF or Area of technical uncertainty (ATU) value of 2mg/L. Conclusion: In our study, we show use of Isavuconazole as salvage therapy in chronic pulmonary fungal disease setting with high prevalence of azole resistance. Isavuconazole MICs demonstrated good correlation with voriconazole MICs suggesting the latter could be a useful surrogate marker for isavuconazole susceptibility. Although Isavuconazole achieved excellent serum drug concentrations at standard dose compared to other azole drugs, we highlight the importance of antifungal stewardship and TDM monitoring to optimise therapy in this setting.

Statistical data extracted from national databases demonstrate a continuous growth in the incidence and prevalence of chronic kidney disease (CKD) and the ineffectiveness of current policies and strategies based on individual risk factors to reduce them, as well as their mortality and costs. Some innovative programs, telemedicine and government interest in the prevention of CKD, did not facilitate timely access to care, continuing the increased demand for dialysis and transplants, high morbidity and long-term disability. In contrast, new forms of kidney disease of unknown etiology affected populations in developing countries and underrepresented minorities, who face socioeconomic and cultural disadvantages. With this background, we analyze in the existing literature the effects of social determinants in CKD, concluding that it is necessary to strengthen current kidney health strategies, designing in a transdisciplinary way, a model that considers demographic characteristics integrated into individual risk factors and risk factors population, incorporating the population health perspective in public health policies to improve results in kidney health care, since CKD continues to be an important and growing contributor to chronic diseases.

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.

This review provides a snapshot of chronic bacterial infections through the lens of Burkholderia pseudomallei; detailing its ability to establish multi-nucleated giant cells (MNGC) within the host, leading to the formation of pyogranulomatous lesions. We explore the role of MNGC in melioidosis disease progression and pathology by comparing the similarities and differences of melioidosis to tuberculosis, outlining the concerted events in pathogenesis that lead to MNGC formation, discussing the factors that influence MNGC formation and how they fit into clinical findings reported in chronic cases. Finally, we speculate about future models and techniques that can be used to delineate the mechanisms of MNGC formation and function.

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.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of cardiotoxicity post-chemotherapeutic exposure, assess how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-β) pathway and discuss its role as a mediator of cardiomyopathy. We highlight recent findings demonstrating TGF-β inhibition as a potent method to prevent cardiac re-modeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-β pathway is associated with negative patient outcomes across 32 types of cancer including TNBC. We then highlight how TGF-β modulation may be a potent method to target mesenchymal (CD44+/CD24-) and epithelial (ALDHhigh) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to plasticity and differential regulation these populations remain difficult to target and persist as a major barrier barring successful therapy. TGF-β inhibition represents an intersection of two fields: cardiology and oncology. Through inhibiting cardiomyopathy, cardiac damage and heart failure may be prevented and through CSC targeting, patient prognosis may be improved. Together, both approaches, if successfully implemented would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy.

Chronic stress is a pervasive issue that significantly impacts both physical and mental health. Unlike acute stress, which is short-lived and can be beneficial, chronic stress persists over extended periods, leading to a range of adverse health outcomes. This paper explores the myriad physical, mental, and behavioral consequences of chronic stress, emphasizing the underlying physiological mechanisms and potential long-term health implications. Through a comprehensive literature review and data analysis utilizing Python, we aim to provide an in-depth understanding of chronic stress and its effects. Key findings include the critical roles of cortisol and other stress-related chemicals in exacerbating health issues, and the potential for the normalization of high stress levels as an adaptive yet harmful response.

Chronic granulomatous disease (CGD) is a group of rare primary inborn errors of immunity characterised by a defect in the phagocyte respiratory burst, which leads to severe and life-threatening infective and inflammatory complications. Despite recent advances in our understanding of the genetic and molecular pathophysiology of X-linked and autosomal recessive CGD, and growth in the availability of functional and genetic testing, there remain significant barriers to early and accurate diagnosis. In the current review, we provide an up-to-date summary of CGD pathophysiology, which underpins methods of diagnostic testing for CGD and closely related disorders. We present an overview of the benefits of early diagnosis and when to suspect and test for CGD. We discuss current and historical methods for functional testing of NADPH oxidase activity, as well as assays for measuring protein expression of NADPH oxidase subunits. Lastly, we focus on genetic and genomic methods employed to diagnose CGD, including gene-targeted panels, comprehensive genomic testing and ancillary methods. Throughout, we highlight general limitations of testing, and caveats specific to interpretation of results in the context of CGD and related disorders, and provide an outlook for newborn screening and the future.

Osteoarthritis and chronic pancreatitis comorbidity are insufficiently studied, and the reciprocal impact of these conditions remains poorly understood. This study aimed to investigate potential predictors for the development of osteoarthritis and chronic pancreatitis comorbidity, as well as complications associated with this comorbidity. A cohort of 150 patients was categorized into three groups: a control group (n=30), patients with osteoarthritis (n=68), and patients with comorbid osteoarthritis and chronic pancreatitis (n=52). Potential predictors for comorbidity development and associated complications were explored. The study revealed that concurrent osteoarthritis and chronic pancreatitis exacerbate each other's progression and contribute to malnutrition. Body Mass Index (BMI) emerged as a potential predictor for chronic pancreatitis development in osteoarthritis patients. In osteoarthritis patients, fecal elastase-1 levels were identified as potential predictors for exocrine pancreatic insufficiency. Factors such as WOMAC total score, fecal elastase-1, C-reactive protein (CRP), ferritin, retinol, tocopherol, 25-hydroxy vitamin D3, and BMI were found to influence comorbidity development between osteoarthritis and chronic pancreatitis. Additionally, Gastrointestinal Symptom Rating Scale-Diarrhea Syndrome (GSRS-DS), Gastrointestinal Symptom Rating Scale-Constipation syndrome (GSRS-CS), Qualitative Assessment of the Symptoms and Impact of Pancreatic Exocrine Insufficiency domain A (PEI-Q-A), retinol, tocopherol, and iron were identified as potential predictors for exocrine pancreatic insufficiency in osteoarthritis patients. In conclusion, the comorbidity of osteoarthritis and chronic pancreatitis exacerbates disease progression and complications, necessitating further investigation.

In Southeast Asia, the incidence of Leukemia, a malignant blood cancer originating from hema-topoietic progenitor cells, is on the rise, marked by a concerning 54% mortality rate. This study focuses on enhancing early-stage prediction to improve patient recovery prospects significantly. Leveraging Machine Learning and Data Science, we employ protein sequential data from frequently mutated genes such as BCL2, HSP90, PARP, and RB to predict Chronic Myeloid Leukemia (CML). Our approach relies on robust feature extraction techniques, namely Di-peptide Composition (DPC), Amino Acid Composition (AAC), and Pseudo amino acid composition (Pse-AAC), with prior attention to addressing outliers and validating feature selection through the Pearson Corre-lation Coefficient. Data augmentation ensures a well-rounded dataset for analysis. Employing a range of Machine Learning models, including Support Vector Machine (SVM), XGBoost, Random Forest (RF), K Nearest Neighbor (KNN), Decision Tree (DT), and Logistic Regression (LR), we achieve accuracy rates spanning from 66% to 94%. These classifiers undergo comprehensive as-sessment using performance metrics such as accuracy, sensitivity, specificity, F1-score, and the confusion matrix. Our proposed solution, encompassing a user-friendly web application dashboard, presents an invaluable tool for early CML diagnosis with profound implications for practitioners, offering a deploy-able asset within healthcare institutions and hospitals.

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

Background and objective: Chronic subdural hematoma (cSDH) is one of the most common neurosurgical entities affecting mostly elderly patients. In this study, we aimed to provide detailed characteristics of surgically treated patients with cSDH and evaluate outcomes between the two conventional treatment methods. Materials and methods: Patients with cSDH surgically treated with burr hole craniostomy (BHC) and craniotomy (CO) in tertiary centers in Croatia and Serbia during 2017-2019 were included in the study. Characteristics and outcomes of these patients were prospectively collected. Results: In total, 155 patients (mean age 72.3±13.4) were included in the study. BHC group consisted of 124 (80 %) and CO group of 31 (20 %) patients. 32 (20.6 %) patients presented with bilateral cSDH, head trauma was documented in 92 (59.4 %), and anticoagulant therapy in 37 (23.9 %) individuals. The most common symptom was hemiparesis (n=85, 54.8 %). The two groups did not differ by age. CO group had higher Glasgow Coma Scale (GCS) score at the admission, with a significant decrease at discharge compared to admission (12.6±4.8 vs 14.4±1.7, p

Objective Rhinosinusitis is a chronic condition characterized by frequent episodes of recurrence; its main treatment is pharmacological and this therapy should be continued for a long time until stabilization of the problem. Some patients, however, often must resort to targeted therapies for disease recurrences, which is why targeted preventive treatments are sought. Methods In the study performed, Pistacia lentiscus oil was used. Two groups of patients were studied with endoscopy, SNOT 22 and Nasal Cytology to evaluate nasal cellularity and ciliar motility. Results Pistacia lentiscus oil has the ability to reduce mucosal inflammation, by destroying and preventing the formation of biofilm. Conclusion The study showed that daily administration of Pistacia lentiscus oil significantly reduced the presence of biofilm. Moreover, continuous use of a lentiscus oil wash significantly reduced patients’ symptoms and improved their quality of life according to the Snot 22 questionnaire.

Novel drugs profoundly changed the outcomes in CLL patients and traditional prognostic/predictive factors that were delineated in the era of chemo-immunotherapy need to be validated in the contest of these new targeted therapies. Currently, the most important prognostic genetic biomarkers are immunoglobulin heavy chain variable (IGHV) mutational status, genetic aberrations including del(17p)/TP53 abnormalities and the complex karyotype. In this review we discuss the prognostic/predictive role of these genetic markers in relation to novel treatments. Moreover, we present and discuss the new score systems that were elaborated and validated in the era of new drugs. Given the deeper responses obtained with small molecules, new prognostic/predictive markers, including measurable residual disease, and validated prognostic scores could possibly be incorporated into routine prognostic scores, to better identify “very-high” CLL patients, who will need more effective treatments.

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.