Recent Advances for Global Perspectives on Etiology, Pathophysiology, Clinical Presentations, and Management of Moyamoya Disease

Moyamoya disease (MMD) is a condition characterized by the gradual narrowing and blockage of blood vessels in the brain, specifically those in the circle of Willis and the arteries that supply it. This results in reduced blood flow and oxygen to the brain, leading to progressive symptoms and potential complications. The underlying pathophysiological mechanism remains elucidated. However, recent studies have highlighted numerous etiologic factors: abnormal immune complex responses, susceptibility genes, branched-chain amino acids, antibodies, heritable diseases, and acquired diseases, which may be the great potential triggers for the development of moyamoya disease. Its clinical presentation has varying degrees from transient asymptomatic events to significant neurological deficits. Moyamoya disease (MMD) shows different patterns in children and adults. Children with MMD are more susceptible to ischemic events due to decreased blood flow to the brain. Conversely, adults with MMD are more prone to hemorrhagic events involving brain bleeding. Children with MMD may experience a range of symptoms including motor impairments, sensory issues, seizures, headaches, dizziness, cognitive delays, or ongoing neurological problems. Although adults may present with similar clinical symptoms as children, they are more prone to experiencing sudden onset intraventricular, subarachnoid, or intracerebral hemorrhages. One of the challenges in moyamoya disease is the potential for misdiagnosis or delayed diagnosis, particularly when physicians fail to consider MMD as a possible cause in stroke patients. This review aims to provide a comprehensive overview of recent global studies on the pathophysiology of MMD, along with advancements in its management. Additionally, the review will delve into various surgical treatment options for MMD, as well as its rare occurrence alongside atrioventricular malformations. Exciting prospects include the use of autologous bone marrow transplant and the potential role of Connexin 43 protein treatment in the development of moyamoya disease.

Complications of Ziv-Aflibercept in Choroidal and Retinal Vascular Diseases

Introduction: The modern ophthalmology trends are changing rapidly every day with the introduction of much newer studies and research. Numerous anti-vascular endothelial growth factors (VEGF) are utilized as the mainstay in the treatment of intraocular vascular pathologies. The rationale of this study is to add to the literature regarding the safety and efficacy profile of the ziv-aflibercept as there is insubstantial data in patients with intraocular vascular pathologies being treated with this injection with prime focus on the complications of the injection. Materials and Methods: A prospective observational study was conducted at Opthalmology Department, Lahore General Hospital, Lahore between 14 August 2018 and 23 December 2019. Patients with choroidal and retinal vascular diseases like diabetic macular edema (DME), age-related macular degeneration (AMD) and retinal vein occlusion (RVO) who had no active infection of eye and had no history of myocardial infarction or cerebrovascular accident were added in this study. Results: Best-corrected visual acuity was significantly improved at 4, 8, and 12 weeks as compared to the baseline (p Conclusion: The use of ziv-aflibercept injection via intravitreal route under aseptic conditions for choroidal and retinal vascular diseases is effective as well as safe with mild and treatable ocular side effects.

Toll-like receptors in pathophysiology of liver diseases

Toll-like receptors(TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte(i.e., hepatocellular injury and regeneration) or hepatic stellate cell(i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases.

Gastroesophageal reflux disease:From pathophysiology to treatment

This review focuses on the pathophysiology of gastroesophageal reflux disease (GERD) and its implications for treatment. The role of the natural anti-reflux mechanism (lower esophageal sphincter, esophageal peristalsis, diaphragm, and trans-diaphragmatic pressure gradient), mucosal damage, type of refluxate, presence and size of hiatal hernia, Helicobacter pylori infection, and Barrett’s esophagus are reviewed. The conclusions drawn from this review are: (1) the pathophysiology of GERD is multifactorial; (2) because of the pathophysiology of the disease, surgical therapy for GERD is the most appropriate treatment; and (3) the genesis of esophageal adenocarcinoma is associated with GERD.

Metabolic dysfunction-associated steatotic liver disease:Navigating terminological evolution,diagnostic frontiers and therapeutic horizon-an editorial exploration

Metabolic dysfunction-associated steatotic liver disease(MASLD),once known as non-alcoholic fatty liver disease(NAFLD),represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes.The redefinition of NAFLD in 2023 marked a significant reposition in terminology,emphasizing a broader understanding of liver steatosis and its associated risks.MASLD is now recognized as a major risk factor for liver cirrhosis,hepatocellular carcinoma,and systemic complications such as cardiovascular diseases or systemic inflammation.Diagnostic challenges arise,particularly in identifying MASLD in lean individuals,necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools.Therapeutically,there is an urgent need for effective treatments targeting MASLD,with emerging pharmacological options focusing on,among others,carbohydrate and lipid metabolism.Additionally,understanding the roles of bile acid metabolism,the microbiome,and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches.There is a strong need to emphasize the importance of collaborative efforts in understanding,diagnosing,and managing MASLD to improve physicians’approaches and patient outcomes.

Metabolic dysfunction-associated steatotic liver disease:The question of long-term high-normal alanine aminotransferase as a screening test

The growing prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)is being driven by the obesity epidemic.The quest for solutions continues particularly with regard to early detection.This editorial comments on the utility of long-term high-normal alanine aminotransferase(ALT)in screening for MASLD.Chen et al found that new onset MASLD can be detected by repetitively high normal ALT.Implicit in this concept is the question of what should be the accepted upper limit of normal(ULN)for ALT.It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females.Thus,when Chen et al defines the ULN as 40 U/L,others may view it as excessively high.It is important to recognize the variables affecting ULN e.g.instrumentation,diurnal variations,exercise and ageing.These variables matter when the distinctions are subtle e.g.normal vs high-normal.In this regard,the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers,imaging and MASLD genetics to create machine learning classifiers.All in all,Chen et al’s work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.

Systemic treatment of hepatocellular carcinoma secondary to nonalcoholic fatty liver disease

Hepatocellular carcinoma(HCC)is the third leading cause of cancer death globally,with 15%of cases arising on a background of non-alcoholic fatty liver disease(NAFLD).NAFLD is a heterogenous condition ranging from fatty liver to cirrhosis and is itself a growing global problem,with estimated worldwide prevalence of 50%in 2040.Pathophysiology of NAFLD-HCC is not well understood,there are no dedicated screening programs,and there have been no clinical studies of anticancer treatments in this population specifically.However,the NAFLD-HCC population appears different than other aetiologies-patients tend to be older,diagnosed at more advanced stages,have more comorbidities,and overall worse prognosis.Understanding of best treatment options for this group of patients is an urgent unmet clinical need.This narrative review discusses NAFLD-HCC pathophysiology and systemic treatment,and offers suggestions for future directions in this therapy area.

Recent advances in cytokines:Therapeutic implications for inflammatory bowel diseases

Inflammatory bowel diseases （IBDs） are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems. Cytokines are essential mediators between activated immune and non-immune cells, including epithelial and mes- enchymal cells. They are immunomodulatory peptides released by numerous cells and these have significant effects on immune function leading to the differentiation and survival of T cells. The physiology of IBD is becom- ing a very attractive field of research for development of new therapeutic agents. These include cytokines involved in intestinal immune inflammation. This review will focus on mechanisms of action of oytokines involved in IBD and new therapeutic opportunities for these diseases.

Neurodegenerative diseases as proteinopathies-driven immune disorders

In the pathophysiology of neurodegenerative disorders,the role of misfolded protein deposition leading to neurodegeneration has been primarily discussed.In the last decade,however,it has been proposed a parallel involvement of innate immune activation,chronic inflammation and adaptive immunity in the neurodegeneration mechanisms triggered by proteinopathies.New insights in the neurodegenerative field strongly suggest a role for the immune system in the pathophysiology of neurodegenerative disorders.Therefore,the hypothesis underlining the modulation of the innate and the adaptive immune system in the events linked to brain deposition of misfolded proteins could open new perspectives in the setting of specific immunotherapeutic strategies for the treatment of neurodegenerative diseases.Therefore,we have reviewed the pathogenic hypothesis in neurodegenerative pathologies,underling the links between the deposition of misfolded protein mechanisms and the immune activation.

Non-pulmonary allergic diseases and inflammatory bowel disease: A qualitative review

While the etiological underpinnings of inflammatory bowel disease(IBD) are highly complex, it has been not-ed that both clinical and pathophysiological similarities exist between IBD and both asthma and non-pulmonary allergic phenomena. In this review, several key points on common biomarkers, pathophysiology, clinical manifesta-tions and nutritional and probiotic interventions for both IBD and non-pulmonary allergic diseases are discussed.Histamine and mast cell activity show common behav-iors in both IBD and in certain allergic disorders. IgE also represents a key immunoglobulin involved in both IBD and in certain allergic pathologies, though these links require further study. Probiotics remain a critically important intervention for both IBD subtypes as well as multiple allergic phenomena. Linked clinical phenomena, especially sinonasal disease and IBD, are discussed. In addition, nutritional interventions remain an underuti-lized and promising therapy for modification of both al-lergic disorders and IBD. Recommending new mothers breastfeed their infants, and increasing the duration of breastfeeding may also help prevent both IBD and al-lergic diseases, but requires more investigation. While much remains to be discovered, it is clear that non-pulmonary allergic phenomena are connected to IBD in a myriad number of ways and that the discovery of com-mon immunological pathways may usher in an era of vastly improved treatments for patients.

New insights into the pathophysiology of achalasia and implications for future treatment

Idiopathic achalasia is an archetype esophageal motor disorder, causing significant impairment of eating ability and reducing quality of life. The pathophysiological underpinnings of this condition are loss of esophageal peristalsis and insufficient relaxation of the lower esophageal sphincter(LES). The clinical manifestations include dysphagia for both solids and liquids, regurgitation of esophageal contents, retrosternal chest pain, cough, aspiration, weight loss and heartburn. Even though idiopathic achalasia was first described more than 300 years ago, researchers are only now beginning to unravel its complex etiology and molecular pathology. The most recent findings indicate an autoimmune component, as suggested by the presence of circulating anti-myenteric plexus autoantibodies, and a genetic predisposition, as suggested by observed correlations with other well-defined genetic syndromes such as Allgrove syndrome and multiple endocrine neoplasia type 2 B syndrome. Viral agents(herpes, varicella zoster) have also been proposed as causative and promoting factors. Unfortunately, the therapeutic approaches available today do not resolve the causes of the disease, and only target the consequential changes to the involved tissues, such as destruction of the LES, rather than restoring or modifying the underlying pathology. New therapies should aim to stop the disease at early stages, thereby preventing the consequential changes from developing and inhibiting permanent damage. This review focuses on the known characteristics of idiopathic achalasia that will help promote understanding its pathogenesis and improve therapeutic management to positively impact the patient's quality of life.

Updates in the pathophysiological mechanisms of Parkinson's disease: Emerging role of bone marrow mesenchymal stem cells

AIM: To explore the approaches exerted by mesenchymal stem cells (MSCs) to improve Parkinson’s disease (PD) pathophysiology.METHODS: MSCs were harvested from bone marrow of femoral bones of male rats, grown and propagated in culture. Twenty four ovariectomized animals were classified into 3 groups: Group (1) was control, Groups (2) and (3) were subcutaneously administered with rotenone for 14 d after one month of ovariectomy for induction of PD. Then, Group (2) was left untreated, while Group (3) was treated with single intravenous dose of bone marrow derived MSCs (BM-MSCs). SRY gene was assessed by PCR in brain tissue of the female rats. Serum transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1) and brain derived neurotrophic factor (BDNF) levels were assayed by ELISA. Brain dopamine DA level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) and nestin gene expression were detected by semi-quantitative real time PCR. Brain survivin expression was determined by immunohistochemical procedure. Histopathological investigation of brain tissues was also done.RESULTS: BM-MSCs were able to home at the injured brains and elicited significant decrease in serum TGF-β1 (489.7 ± 13.0 vs 691.2 ± 8.0, P < 0.05) and MCP-1 (89.6 ± 2.0 vs 112.1 ± 1.9, P < 0.05) levels associated with significant increase in serum BDNF (3663 ± 17.8 vs 2905 ± 72.9, P < 0.05) and brain DA (874 ± 15.0 vs 599 ± 9.8, P < 0.05) levels as well as brain TH (1.18 ± 0.004 vs 0.54 ± 0.009, P < 0.05) and nestin (1.29 ± 0.005 vs 0.67 ± 0.006, P < 0.05) genes expression levels. In addition to, producing insignificant increase in the number of positive cells for survivin (293.2 ± 15.9 vs 271.5 ± 15.9, P > 0.05) expression. Finally, the brain sections showed intact histological structure of the striatum as a result of treatment with BM-MSCs.CONCLUSION: The current study sheds light on the therapeutic potential of BM-MSCs against PD pathophysiology via multi-mechanistic actions.

COVID-19 pandemic:Pathophysiology and manifestations from the gastrointestinal tract

The pandemic of coronavirus disease 2019(COVID-19),caused by a newly identifiedβ-coronavirus(SARS-CoV-2)has emerged as a dire health problem,causing a massive crisis for global health.Primary method of transmission was firstly thought to be animal to human transmission.However,it has been observed that the virus is transmitted from human to human via respiratory droplets.Interestingly,SARS-CoV-2 ribonucleic acid(RNA)has been isolated from patient stools,suggesting a possible gastrointestinal(GI)involvement.Most commonly reported clinical manifestations are fever,fatigue and dry cough.Interestingly,a small percentage of patients experience GI symptoms with the most common being anorexia,diarrhea,nausea and vomiting.The presence of viral RNA in stools is also common and fecal tests can be positive even after negative respiratory samples.The exact incidence of digestive symptoms is a matter of debate.The distribution of Angiotensin converting enzyme type 2 receptors in multiple organs in the body provides a possible explanation for the digestive symptoms’mechanism.Cases with solely GI symptoms have been reported in both adults and children.Viral RNA has also been detected in stool and blood samples,indicating the possibility of liver damage,which has been reported in COVID-19 patients.The presence of chronic liver disease appears to be a risk factor for severe complications and a poorer prognosis,however data from these cases is lacking.The aim of this review is firstly,to briefly update what is known about the origin and the transmission of SARS-CoV-2,but mainly to focus on the manifestations of the GI tract and their pathophysiological background,so that physicians on the one hand,not to underestimate or disregard digestive symptoms due to the small number of patients exhibiting exclusively this symptomatology and on the other,to have SARS-CoV-2 on their mind when the“gastroenteritis”type symptoms predominate.

Mechanopathology of red blood cell diseases—Why mechanics matters

During the onset of a disease a cell may experience alterations in both the composition and organization of its cellular and molecular structures.These alterations may eventually lead to changes in its geometrical and mechanical properties such as cell size and shape,deformability and adhesion.As such,knowing how diseased cells respond to mechanical forces can reveal ways by which they differ from healthy ones.Here,we will present biomechanistic insights into red blood cell related diseases that manifest mechanical property changes and how they directly contribute to the pathophysiology of diseases.By conducting cell and molecular mechanics studies,not only can we elucidate changes in the structure-property-function relationship of diseased cells,we can also exploit the new knowledge gained to develop biomechanics based devices that may better detect and diagnose these diseases as well as help identify important biomechanical targets for possible therapeutic interventions.

COVID-19 and comorbidities of hepatic diseases in a global perspective

The worldwide outbreak of coronavirus disease 2019(COVID-19) has challenged the priorities of healthcare system in terms of different clinical management and infection transmission, particularly those related to hepatic-disease comorbidities. Epidemiological data evidenced that COVID-19 patients with altered liver function because of hepatitis infection and cholestasis have an adverse prognosis and experience worse health outcomes. COVID-19-associated liver injury is correlated with various liver diseases following a severe acute respiratory syndrome-coronavirus type 2(SARS-CoV-2) infection that can progress during the treatment of COVID-19 patients with or without pre-existing liver disease. SARS-CoV-2 can induce liver injury in a number of ways including direct cytopathic effect of the virus on cholangiocytes/hepatocytes, immune-mediated damage, hypoxia, and sepsis. Indeed, immediate cytopathogenic effects of SARSCoV-2 via its potential target, the angiotensin-converting enzyme-2 receptor, which is highly expressed in hepatocytes and cholangiocytes, renders the liver as an extra-respiratory organ with increased susceptibility to pathological outcomes. But, underlying COVID-19-linked liver disease pathogenesis with abnormal liver function tests(LFTs) is incompletely understood. Hence, we collated COVID-19-associated liver injuries with increased LFTs at the nexus of pre-existing liver diseases and COVID-19, and defining a plausible pathophysiological triad of COVID-19, hepatocellular damage, and liver disease. This review summarizes recent findings of the exacerbating role of COVID-19 in pre-existing liver disease and vice versa as well as international guidelines of clinical care, management, and treatment recommendations for COVID-19 patients with liver disease.

The choroid plexus-cerebrospinal fluid interface in Alzheimer's disease:more than just a barrier

The choroid plexus is a complex structure which hangs inside the ventricles of the brain and consists mainly of choroid plexus epithelial（CPE） cells surrounding fenestrated capillaries.These CPE cells not only form an anatomical barrier,called the blood-cerebrospinal fluid barrier（BCSFB）,but also present an active interface between blood and cerebrospinal fluid（CSF）.CPE cells perform indispensable functions for the development,maintenance and functioning of the brain.Indeed,the primary role of the choroid plexus in the brain is to maintain homeostasis by secreting CSF which contains different molecules,such as nutrients,neurotrophins,and growth factors,as well as by clearing toxic and undesirable molecules from CSF.The choroid plexus also acts as a selective entry gate for leukocytes into the brain.Recent findings have revealed distinct changes in CPE cells that are associated with aging and Alzheimer＇s disease.In this review,we review some recent findings that highlight the importance of the CPE-CSF system in Alzheimer＇s disease and we summarize the recent advances in the regeneration of brain tissue through use of CPE cells as a new therapeutic strategy.

Pathophysiology of Graves’ Ophthalmopathy: A Literature Review

Graves’ ophthalmopathy (GO), an autoimmune condition associated with Graves’ disease (GD), occurs at a prevalence of nearly 40% in patients diagnosed with GD. Ocular involvement is probably due to the presence of autoantibodies in the orbital tissues, regardless of the control state of thyroid hormones in individuals with GD, even during euthyroid or hypothyroid states, which are associated with thyroid hormone treatment. In addition to the immunological role present in the pathophysiology of GO, the genetic component, proteins and cytokines, minerals (e.g., selenium), and environmental factors (e.g., smoking) also contribute to its development and occurrence of clinical manifestations in varying degrees. Until now, the interaction of causal, intermediary, and triggering factors of GO is still unclear, so the purpose of this article is to review literature on the theme.

COVID-19 and Chronic Viral Liver Diseases

Coronavirus causes an outbreak of viral pneumonia that spread throughout the world. Liver injury is becoming more widely recognized as a component of the clinical picture of COVID-19 infection. We aimed to review this relation in a concise way. This review article includes a large number of patients from both western and eastern countries with no clear difference of liver affection. The more severe and frequent liver injury, the more severe COVID-19 infection. Up to half of patients developed hepatitis with serum ALT elevation. Both hepatocellular and/or ductular injury were observed as evidenced by alkaline phosphatase elevation. Increase incidence of morbidity and mortality had been recorded in patients with CLD. Cirrhosis mortality extended in line with the Child-Turcotte-Pugh class. The incidence of ACLF in CLD patients with COVID 19 is not clear. There are no significant associations with the etiology of liver disease and death in cirrhosis. COVID-19 hinders HCV elimination by 2030. Patients should continue their medications if already receiving treatment. Patients with occult or resolved HBV and COVID-19 who are receiving immunosuppressive agents should use antiviral therapy to prevent viral flare-ups.

Recent advances in lung-on-a-chip technology for modeling respiratory disease

Tissue engineering approaches,including those to functional lung tissues,are finely honed by the inclusion of upgraded devices that mimic biophysical and biochemical features in vivo.Perfusion culture is one of these essential biophysical characteristics enabled by the introduction of microfluidic devices in recent years.This review links the importance of dynamic culture for in vitro maintenance of functional lung cells to the modeling of respiratory disease.We identify and discuss different parameters for fabricating the requisite microfluidic models for lung cells,as well as their application in modeling lung diseases caused by external factors such as smoking and pollution.The possibility of creating a multi-organ-on-a-chip to establish a more physiologically relevant model is highlighted.Overall,the focus is on different prospects for the in vitro modeling approach and for lungs-on-a-chip for developing advanced,reliable technology to analyze the pathophysiology of respiratory diseases and screen potential treatments.

Evaluation of macular choroidal and microvascular network changes by activity scores and serum antibodies in thyroid eye patients and healthy subjects

AIM:To investigate the choroidal thickness and the microvascular network changes around the macula in thyroid eye disease(TED)patients at different stages and the relationship of those changes with risk factors,serum antibodies and the severity of TED.METHODS:A total of 85 participants were enrolled.All participants underwent ophthalmology and endocrinology examinations.Subfoveal choroidal thickness(SFCT),superficial(s)and deep(d)foveal avascular zone(FAZ)area,mean(m)and central(c)superficial vascular density(SVD),deep vascular density(DVD)measurements of the enrolled cases were performed with Topcon swept source optical coherence tomography(OCT)/OCT angiography(OCTA)DRI OCT Triton.Multiple linear regression analysis was used to explore the associations between SFCT,FAZ area,SVD,DVD and the relevant factors of TED.RESULTS:Those with active TED patients had higher c-DVD and m-DVD levels(P<0.05),however there is no statistically significant difference in SFCT between active and stable TED patients.Among the serum antibodies,it was observed that s-FAZ and d-FAZ increased,c-SVD and m-SVD decreased in patients with high thyroid stimulating hormone-receptor autoantibodies(TRAB)level,whereas SFCT thickened in patients with high levels of both TRAB and human thyroglobulin(hTG).There was no significant difference in SFCT,FAZ,SVD and DVD measurement at gender,between hyperthyroid and euthyroid patients and among those with or without thyroid papillary carcinoma.CONCLUSION:The results show that both disease activation and serum antibodies differentially affect both superficial and deep retinal vascular density.It has also been shown that high serum antibody levels affect choroidal thickness independent of clinical activity.