Pathophysiological Perspective Research Articles

Homeostasis: understanding the effects of impaired mechanisms.

This article focuses on homeostasis and offers a pathophysiological perspective. The dynamic mechanisms responsible for maintaining internal balance and disruptive processes will be analysed through the lens of key systems including the nervous, endocrine and renal systems. The environmental factors and their potential impact on homeostasis have been considered. A clinical case study will contextualise homeostasis in clinical practice.

The relationship between postoperative cognitive dysfunction and cerebral small vessel disease: A comprehensive review.

Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients, and cerebral small vessel disease (CSVD) has been suggested as a potential risk factor. This review examines the relationship between POCD and CSVD from epidemiological, pathophysiological, and clinical perspectives, while also considering the role of Alzheimer's disease (AD) pathology. We conducted a comprehensive literature search of major databases, supplemented by reference list checking, to ensure a thorough review of studies published between 2000 and 2023 on the relationship between POCD and CSVD. Epidemiological studies have shown that POCD and CSVD are associated in terms of common risk factors, including advanced age, vascular comorbidities, impaired baseline cognitive function, and certain population characteristics. Animal studies have revealed that CSVD and POCD share similar neuropathological changes, including abnormal cerebral hypoperfusion, inflammatory responses, and blood-brain barrier disruption. Furthermore, recent research suggests a complex interplay between CSVD, AD pathology, and POCD, with potential synergistic effects on cognitive decline. Neuroimaging studies have further demonstrated that preoperative CSVD burden and postoperative CSVD progression are associated with the development of POCD, and the presence of both CSVD and AD markers may increase the risk of cognitive decline. The association between CSVD and POCD has important implications for the perioperative management of elderly patients, including preoperative assessment, choice of anesthesia and surgical methods, intraoperative management, postoperative care, and long-term follow-up. A better understanding of the relationship between CSVD and POCD will guide evidence-based strategies to prevent and manage this debilitating complication in the aging population.

An Integrated Pathophysiological and Clinical Perspective of the Synergistic Effects of Obesity, Hypertension, and Hyperlipidemia on Cardiovascular Health: A Systematic Review.

This review paper explores the synergistic effects of obesity, hypertension (HTN), and hyperlipidemia on cardiovascular health by integrating pathophysiological and clinical perspectives. Obesity, characterized by excessive body fat, HTN, defined by elevated blood pressure, and hyperlipidemia, indicated by high blood lipid levels, are globally prevalent conditions that significantly increase the risk of cardiovascular diseases (CVDs). The interplay between these conditions exacerbates cardiovascular risk through mechanisms such as chronic inflammation, insulin resistance, endothelial dysfunction, arterial stiffness, and atherogenesis. This review synthesizes epidemiological evidence and highlights the prevalence and co-occurrence of these conditions, with an emphasis on their combined impact on cardiovascular health. The literature search encompassed various databases, and data extraction included key study characteristics and outcomes. The findings underscore the importance of integrated management strategies, involving lifestyle interventions, pharmacological treatments, and regular monitoring, to mitigate the heightened cardiovascular risk posed by these conditions. In addition, the various public health implications are addressed, advocating for community-based interventions and policy changes. Future research directions may include exploring novel therapeutic approaches, personalized medicine strategies, and longitudinal studies to enhance the understanding and management of the synergistic effects of obesity, HTN, and hyperlipidemia on cardiovascular health.

MINOCA: A Pathophysiological Approach of Diagnosis and Treatment-A Narrative Review.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a clinical entity characterized by the absence of significant coronary artery obstruction in epicardial arteries (<50%) on coronary angiography in the setting of acute myocardial infarction (AMI). This article aims to provide a narrative review of the pathophysiological mechanisms, diagnostic challenges, and prognosis associated with MINOCA based on pathophysiology regarding the atherosclerotic and non-atherosclerotic causes. Etiological factors, including thromboembolism, coronary artery spasm, spontaneous coronary artery dissection, coronary microvascular disease, and supply-demand mismatch, are addressed. Imaging modalities such as echocardiography, advances in coronary angiography like intravascular ultrasound (IVUS) and optical coherence tomography (OCT), cardiac magnetic resonance (CMR), and coronary computed tomography angiography (CCTA) are also analyzed. MINOCA patients have a better short-term prognosis compared to those with obstructive coronary artery disease but face significant long-term risks, underscoring the need for precise diagnosis and management strategies. Elevated inflammatory markers and specific genetic predispositions are also associated with adverse outcomes in MINOCA. This review focused on MINOCA from a pathophysiological perspective on the diverse underlying mechanisms, the challenges in achieving accurate diagnosis, the importance of a tailored therapeutic approach and the necessity for further investigation of clinical outcomes.

Obesity Nephropathy: A Current Overview

The obesity pandemic is a public health problem that is evolving at high speed with both functional and vital outcomes. Recently, many studies have shown that obesity is a driver of chronic kidney disease onset and progression. The mechanisms underlying this fact are multiple including inflammation, oxidative stress, insuline resistance and hemodynamic change with inappropriate RAAS and SNS activation; occuring on a particularly genetic basis of individual predisposition. In this field, Obesity-related glomerulopathy is characterized by glomerulomegaly with localized and segmental glomerulosclerosis lesions. Main symptoms are non specific, dominated by microproteinuria, rarely nephrotic syndrome and a slowed decline in glomerular filtration rate. As for treatment, it starts essentially with lifestyle interventions targeting a meaningful and sustainable weight loss, accompanied by antiobesity medications (AOMS) including RAAS blockers, SGLT2inhibitors and since very recently, long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RA) which were shown to be effective in managing weight loss in non-chronic kidney disease (CKD) patients. Preliminary results of more definitive studies in CKD patients are currently being finalized. Bariatric surgery could reduce the risk of mortality in obese CKD patients; it is recommended for patients with severe morbid obesity, poor tolerance to AOMS, particularly GLP RA, or those whose long-term medication costs represent a barrier to sustainable results. In this review, we summarize epidemiological data on obesity nephropathy, its pathophysiological mechanisms, clinical features and perspectives on its treatment.

Internal Supravesical Hernia Revealed by Small Bowel Obstruction

The supravesical hernia is a rare cause of internal hernia, characterized by the protrusion of the intestine through an abnormal intra-abdominal opening located in the supravesical compartment. This anomaly is infrequently reported in the literature, and its incidence remains uncertain [1]. Supravesical hernias predominantly affect men over the age of 50 [2]. From a pathophysiological perspective, supravesical hernias develop from the supravesical fossae. They form medial to the umbilical arteries and often expand into the Retzius space, though they can also engage laterally, resulting in laterovesical hernias. These hernias are almost always acquired and can sometimes be associated with inguinal hernias. Clinically, they present as acute bowel obstruction. An abdominal CT scan can confirm the diagnosis of obstruction but rarely provides an etiological diagnosis [3]. In such cases, a median laparotomy is necessary, and intraoperative diagnosis is typically straightforward. Treatment involves sectioning the hernial neck and reducing the hernia, followed by simple closure of the opening using separate sutures with absorbable thread [4]. We report a case of a 56-year-old patient with no notable medical history was admitted to the emergency department with an internal supravesical hernia revealed by obstructive syndrome.

Neutrophil dynamics in pulmonary fibrosis: pathophysiological and therapeutic perspectives.

The shared pathobiological mechanisms driving progressive fibrosis in interstitial lung diseases (ILDs) remain unclear. Neutrophils, the most common immune cells in the human body, contain an extensive array of proteinases that are important for cell function, including tissue repair and remodelling. Increasing observational studies have reported elevated neutrophil counts in the respiratory tract and circulation of patients with ILD and suggest a role as a biomarker of disease severity. Neutrophils and their contents (including the formation of neutrophil extracellular traps (NETs)) are present in fibrotic lung tissue. Proteinases and NETs may drive fibrogenesis in animal and in vitro models and may impact transforming growth factor-β1 activation. However, the effect of neutrophil action, whether reparative or pathologically destructive to the delicate lung architecture, has yet to be determined. This review aims to summarise the current literature surrounding the potential role of the neutrophil as a biomarker and contributor to the pathogenesis of ILD. There is currently a paucity of treatment options in ILD driven by the knowledge gap underlying the overall disease mechanisms. This review concludes that neutrophils warrant further evaluation as manipulation of recruitment and function could provide a novel and much needed therapeutic strategy.

A pathophysiological perspective on wine induced headaches

Abstract Headaches are one of the most common reasons why patients seek help in the emergency department, and alcohol consumption is a well-known cause. Wine, in particular, is associated with headaches not only due to its alcohol content but also due to the presence of polyphenols and biogenic amines such as tyramine, putrescine, and, notably, histamine. Wine consumption is on the rise around the world and is likely to be reflected in headache prevalence. Understanding the mechanisms underlying wine-induced headaches can help in their management and prevention Therefore, we provide a comprehensive review of the pathophysiology of wine induced headaches.

Understanding the Complex Dynamics of Immunosenescence in Multiple Sclerosis: From Pathogenesis to Treatment.

Immunosenescence, the gradual deterioration of immune function with age, holds profound implications for our understanding and management of multiple sclerosis (MS), a chronic autoimmune disease affecting the central nervous system. Traditionally diagnosed in young adults, advancements in disease-modifying therapies and increased life expectancy have led to a growing number of older individuals with MS. This demographic shift underscores the need for a deeper investigation into how age-related alterations in immune function shape the course of MS, influencing disease progression, treatment effectiveness, and overall patient outcomes. Age-related immunosenescence involves changes such as shifts in cytokine profiles, the accumulation of senescent immune cells, and compromised immune surveillance, collectively contributing to a state known as "inflammaging". In the context of MS, these immunological changes disturb the intricate balance between inflammatory and regulatory responses, thereby impacting mechanisms of central immune tolerance and peripheral regulation. This paper stands out by combining the most recent advancements in immunosenescence with both pathophysiological and treatment perspectives on multiple sclerosis, offering a cohesive and accessible discussion that bridges theory and practice, while also introducing novel insights into underexplored concepts such as therapy discontinuation and the latest senolytic, neuroprotective, and remyelination therapies. Enhancing our understanding of these complexities will guide tailored approaches to MS management, ultimately improving clinical outcomes for affected individuals.

Rosacea in East Asian populations: Clinical manifestations and pathophysiological perspectives for accurate diagnosis.

Rosacea is a chronic inflammatory disorder primarily affecting the facial skin, prominently involving the cheeks, nose, chin, forehead, and periorbital area. Cutaneous manifestations encompass persistent facial erythema, phymas, papules, pustules, telangiectasia, and flushing. The pathogenesis of rosacea is associated with various exacerbating or triggering factors, including microbial infestation, temperature fluctuations, sunlight exposure, physical exertion, emotional stress, consumption of hot beverages and spicy foods, and exposure to airborne pollen. These environmental factors interact with genetic predispositions in the development of rosacea. The roles of the lipophilic microbiome, ultraviolet radiation, nociceptive responses, and vascular alterations have been proposed as significant factors in the pathogenesis. These insights contribute to understanding the anatomical specificity of facial involvement and the progressive nature of rosacea. East Asian skin, predominantly classified as Fitzpatrick skin phototypes III to IV, is characterized by relatively diminished skin barrier function and increased sensitivity to irritants. Airborne pollen exposure may particularly act as a trigger in East Asian individuals, possibly mediated through toll-like receptors. The lack of specificity in objective clinical and histopathological findings leads to diagnostic challenges for individuals with colored skin, including East Asians, particularly when erythema is the sole objective manifestation. An alternative diagnostic scheme may thus be necessary. A diagnostic approach emphasizing vascular manifestations and nociceptive symptoms potentially holds promise for individuals with darker skin tones. More research focusing on potential variations in skin physiology across different racial groups is essential to establish more effective diagnostic schemes applicable to both dark and light skin colors.

Uveal Melanoma: Comprehensive Review of Its Pathophysiology, Diagnosis, Treatment, and Future Perspectives.

Uveal melanoma (UM) is the most common intraocular malignancy in adults. Recent advances highlight the role of tumor-derived extracellular vesicles (TEV) and circulating hybrid cells (CHC) in UM tumorigenesis. Bridged with liquid biopsies, a novel technology that has shown incredible performance in detecting cancer cells or products derived from tumors in bodily fluids, it can significantly impact disease management and outcome. The aim of this comprehensive literature review is to provide a summary of current knowledge and ongoing advances in posterior UM pathophysiology, diagnosis, and treatment. The first section of the manuscript discusses the complex and intricate role of TEVs and CHCs. The second part of this review delves into the epidemiology, etiology and risk factors, clinical presentation, and prognosis of UM. Third, current diagnostic methods, ensued by novel diagnostic tools for the early detection of UM, such as liquid biopsies and artificial intelligence-based technologies, are of paramount importance in this review. The fundamental principles, limits, and challenges associated with these diagnostic tools, as well as their potential as a tracker for disease progression, are discussed. Finally, a summary of current treatment modalities is provided, followed by an overview of ongoing preclinical and clinical research studies to provide further insights on potential biomolecular pathway alterations and therapeutic targets for the management of UM. This review is thus an important resource for all healthcare professionals, clinicians, and researchers working in the field of ocular oncology.

Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.

Atrial fibrillation and heart failure

Atrial fibrillation and heart failure are among the most common cardiovascular diseases and have a significant impact on the mortality and morbidity of affected patients. From a pathophysiological perspective, the two diseases are closely related and often perpetuate each other. Therefore, effective management of atrial fibrillation is now a central component of modern heart failure treatment. Based on current data, sinus rhythm should primarily be permanently maintained in patients with systolic heart failure. Catheter ablation has recently proven to be advantageous over purely pharmacological therapy and is therefore the treatment of choice for many patients with heart failure and atrial fibrillation. In patients with diastolic heart failure (heart failure with preserved ejection fraction [HFpEF]), the effect of catheter ablation is less clear. Data from randomized studies are urgently needed in order to further assess efficacy in this population.

Recent insights in striated muscle laminopathies.

To highlight recent insights in different aspects of striated muscle laminopathies (SMLs) related to LMNA mutations. Clinical and genetic studies allow better patient management and diagnosis, with confirmation of ventricular tachyarrhythmias (VTA) risk prediction score to help with ICD implantation and development of models to help with classification of LMNA variants of uncertain significance. From a pathophysiology perspective, characterization of lamin interactomes in different contexts revealed new lamin A/C partners. Expression or function modulation of these partners evidenced them as potential therapeutic targets. After a positive phase 2, the first phase 3 clinical trial, testing a p38 inhibitor targeting the life-threatening cardiac disease of SML, has been recently stopped, thus highlighting the need for new therapeutic approaches together with new animal and cell models. Since the first LMNA mutation report in 1999, lamin A/C structure and functions have been actively explored to understand the SML pathophysiology. The latest discoveries of partners and altered pathways, highlight the importance of lamin A/C at the nuclear periphery and in the nucleoplasm. Modulation of altered pathways allowed some benefits, especially for cardiac involvement. However, additional studies are still needed to fully assess treatment efficacy and safety.

Fertility Preservation and Ovarian Hyperstimulation Syndrome Management in Cancer Care: A Pathophysiological Perspective on Gonadotropin-Releasing Hormone Agonists and Antagonists.

This narrative review delves into the evolving landscape of fertility preservation techniques, with a particular focus on their use in patients undergoing oncology treatment that carries a risk of ovarian insufficiency. Advances in established methods such as cryopreservation of oocytes and embryos are highlighted, and the increasing use of gonadotropin-releasing hormone (GnRH) agonists is discussed. The review also addresses the complexities and controversies associated with these approaches, such as the 'flare-up' effect associated with GnRH agonists and the potential of GnRH antagonists to reduce the risk of ovarian hyperstimulation syndrome. Despite advances in fertility preservation, the report highlights the challenges we face, including the need for personalized treatment protocols and the management of associated risks. It calls for continued research and collaboration between healthcare professionals to refine these techniques and ultimately improve reproductive outcomes for patients facing the prospect of fertility-impairing treatment.

P-glycoprotein activity in vivo in older adults: physiological, pathophysiological and pharmacokinetic interplay at the blood-brain barrier

p-glycoprotein (P-gp) is an efflux transporter of xenobiotic and endogenous compounds across the blood-brain barrier (BBB). P-gp plays an essential role by limiting passage of these compounds into the brain tissue. It is susceptible to drug-drug interactions when interactors drugs are co-administrated. The efficiency of P-gp may be affected by the aging process and the development of neurodegenerative diseases. Studying this protein in older adults is therefore highly relevant for all these reasons. Understanding P-gp activity in vivo is essential when considering the physiological, pathophysiological, and pharmacokinetic perspectives, as these aspects seem to be interconnected to some extent. In vivo exploration in humans is based on neuroimaging techniques, which have been improving over the last years. The advancement of exploration and diagnostic tools is opening up new prospects for understanding P-gp activity at the BBB.

P-glycoprotein activity in vivo in older adults: physiological, -pathophysiological and pharmacokinetic interplay at the blood-brain barrier

p-glycoprotein (P-gp) is an efflux transporter of xenobiotic and endogenous compounds across the blood-brain barrier (BBB). P-gp plays an essential role by limiting passage of these compounds into the brain tissue. It is susceptible to drug-drug interactions when interactors drugs are co-administrated. The efficiency of P-gp may be affected by the aging process and the development of neurodegenerative diseases. Studying this protein in older adults is therefore highly relevant for all these reasons. Understanding P-gp activity in vivo is essential when considering the physiological, pathophysiological, and pharmacokinetic perspectives, as these aspects seem to be interconnected to some extent. In vivo exploration in humans is based on neuroimaging techniques, which have been improving over the last years. The advancement of exploration and diagnostic tools is opening up new prospects for understanding P-gp activity at the BBB.

Unraveling TAFRO Syndrome: An In-Depth Look at the Pathophysiology, Management, and Future Perspectives.

TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman's disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman's disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives.

White spot lesions in fixed orthodontic treatment: Etiology, pathophysiology, diagnosis, treatment, and future research perspectives.

White spot lesions (WSLs) refer to localized areas of hypo-mineralization limited to the enamel of the teeth surface, which is noticeable clinically to the naked eye on drying of the teeth. During fixed orthodontic treatment, it is very hard for the patient to maintain excellent oral hygiene as the brackets, bands, wires, elastics, and other appliances and attachments worn intra-orally provide a platform for food retention, plaque formation, and then colonization by acidogenic bacteria like Streptococcus mutans and Lactobacillus. This review aims to elaborate and focus on etiology, pathophysiology, diagnosis, treatment aspect, and future scope for research about the WSLs occurring due to fixed orthodontic treatment.

Pathophysiological Link and Treatment Implication of Heart Failure and Preserved Ejection Fraction in Patients with Chronic Kidney Disease.

Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological mechanism for those patients at risk of developing HFpEF. Heart failure (HF) and CKD are intertwined conditions sharing common disease pathways; the so-called "kidney tamponade", explained by an increase in intracapsular pressure caused by fluid retention, is only the latest model to explain renal injury in HF. Recognizing the different phenotypes of HFpEF remains a real challenge; the pathophysiological mechanisms of renal dysfunction may differ across the HF spectrum, as well as the prognostic role. A better understanding of the role of cardiorenal interactions in patients with HF in terms of symptom status, disease progression, and prognosis remains essential in HF management. Historically, patients with HF and CKD have been scarcely represented in clinical trial populations. Current concerns affect the practical approach to HF treatment, and, in this context, physicians are frequently hesitant to prescribe and titrate both new and old treatments. Therefore, the extensive application of HF drugs in diverse HF subtypes with numerous comorbidities and different renal dysfunction etiologies remains a controversial matter of discussion. Numerous recently introduced drugs, such as sodium-glucose-linked transporter 2 inhibitors (SGLT2i), constitute a new therapeutic option for patients with HF and CKD. Because of their protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. The present review delves into the phenotype of patients with HFpEF and CKD from a pathophysiological perspective, proposing a treatment approach that suggests a practical stepwise algorithm for the proper application of life-saving therapies in clinical practice.