B cells are essential components of the adaptive immune system and have important roles in the pathogenesis of several central nervous system (CNS) diseases. Besides producing antibodies, B cells ...perform other functions, including antigen presentation to T cells, production of proinflammatory cytokines and secretion of anti-inflammatory cytokines that limit immune responses. B cells can contribute to CNS disease either through their actions in the periphery (meaning that they have an 'outside-in' effect on CNS immunopathology) or following their compartmentalization within the CNS. The success of B cell-depleting therapy in patients with multiple sclerosis and CNS diseases with an autoantibody component, such as neuromyelitis optica spectrum disorder and autoimmune encephalitides, has underscored the role of B cells in both cellular and humoral-mediated CNS conditions. Emerging evidence suggests B cells also contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer disease and Parkinson disease. Advancing our understanding of the role of B cells in neuroinflammatory and neurodegenerative diseases could lead to novel therapeutic approaches.
Estimates of disease burden can inform national health priorities for research, clinical care, and policy. We aimed to estimate health care use and spending among gastrointestinal (GI) (including ...luminal, liver, and pancreatic) diseases in the United States.
We estimated health care use and spending based on the most currently available administrative claims from commercial and Medicare Supplemental plans, data from the GI Quality Improvement Consortium Registry, and national databases.
In 2015, annual health care expenditures for gastrointestinal diseases totaled $135.9 billion. Hepatitis ($23.3 billion), esophageal disorders ($18.1 billion), biliary tract disease ($10.3 billion), abdominal pain ($10.2 billion), and inflammatory bowel disease ($7.2 billion) were the most expensive. Yearly, there were more than 54.4 million ambulatory visits with a primary diagnosis for a GI disease, 3.0 million hospital admissions, and 540,500 all-cause 30-day readmissions. There were 266,600 new cases of GI cancers diagnosed and 144,300 cancer deaths. Each year, there were 97,700 deaths from non-malignant GI diseases. An estimated 11.0 million colonoscopies, 6.1 million upper endoscopies, 313,000 flexible sigmoidoscopies, 178,400 upper endoscopic ultrasound examinations, and 169,500 endoscopic retrograde cholangiopancreatography procedures were performed annually. Among average-risk persons aged 50–75 years who underwent colonoscopy, 34.6% had 1 or more adenomatous polyps, 4.7% had 1 or more advanced adenomatous polyps, and 5.7% had 1 or more serrated polyps removed.
GI diseases contribute substantially to health care use in the United States. Total expenditures for GI diseases are $135.9 billion annually—greater than for other common diseases. Expenditures are likely to continue increasing.
Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal ...molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank.
Extra-intestinal manifestations (EIMs) are reported frequently in patients with inflammatory bowel disease (IBD) and may be diagnosed before, concurrently or after the diagnosis of IBD. EIMs in IBD ...may be classified based on their association with IBD disease activity. The first group has a direct relationship with the activity of the bowel disease and includes pauciarticular arthritis, oral aphthous ulcers, erythema nodosum and episcleritis. The second group of EIMs appears to follow an independent course from the underlying bowel disease activity and include ankylosing spondylitis and uveitis. The third group includes EIMs that may or may not be related to intestinal inflammation, such as pyoderma gangrenosum and probably primary sclerosing cholangitis (PSC). Genetic susceptibility, aberrant self-recognition and immunopathogenic autoantibodies against organ-specific cellular antigens shared by the colon and extra-colonic organs may contribute to the pathogenesis and development of these EIMs. The use of biological agents in the IBD armamentarium has expanded the treatment options for some of the disabling EIMs and these agents form the cornerstone in managing most of the disabling EIMs. PSC is one of the most common hepatobiliary manifestations associated with IBD in which no clear treatment options exist other than endoscopic therapy and liver transplantation. Future research targeting the pathogenesis, early diagnosis and treatment of these EIMs is required.
Involvement of the gastrointestinal (GI) tract is an infrequent extrathoracic presentation of sarcoidosis. We reviewed 305 cases of GI involvement reported in 238 patients, in whom GI sarcoidosis was ...the first sign of the disease in half the cases. The disease does not affect the GI tract uniformly, with a clear oral-anal gradient (80% of reported cases involved the esophagus, stomach, and duodenum). Clinicopathological mechanisms of damage may include diffuse mucosal infiltration, endoluminal exophytic lesions, involvement of the myenteric plexus, and extrinsic compressions. Ten percent of patients presented with asymptomatic or subclinical disease found on endoscopy. The diagnosis is relevant clinically because 22% of cases reviewed presented as life threatening. In addition, initial clinical/endoscopic findings may be highly suggestive of GI cancer. The therapeutic approach is heterogeneous and included wait-and-see or symptomatic approaches, glucocorticoid/immunosuppressive therapy, and surgery. Sarcoidosis of the gut is a heterogeneous, potentially life-threatening condition that requires a multidisciplinary approach and early clinical suspicion to institute personalized therapeutic management and follow-up.
Autophagy, a lysosome-dependent homeostatic process inherent to cells and tissues, has emerging significance in the pathogenesis of human disease. This process enables the degradation and turnover of ...cytoplasmic substrates via membrane-dependent sequestration in autophagic vesicles (autophagosomes) and subsequent lysosomal delivery of cargo. Recent Advances: Selective forms of autophagy can target specific substrates (e.g., organelles, protein aggregates, and lipids) for processing. Autophagy is highly regulated by oxidative stress, including exposure to altered oxygen tension, by direct and indirect mechanisms, and contributes to inducible defenses against oxidative stress. Mitochondrial autophagy (mitophagy) plays a critical role in the oxidative stress response, through maintenance of mitochondrial integrity.
Autophagy can impact a number of vital cellular processes including inflammation and adaptive immunity, host defense, lipid metabolism and storage, mitochondrial homeostasis, and clearance of aggregated proteins, all which may be of significance in human disease. Autophagy can exert both maladaptive and adaptive roles in disease pathogenesis, which may also be influenced by autophagy impairment. This review highlights the essential roles of autophagy in human diseases, with a focus on diseases in which oxidative stress or inflammation play key roles, including human lung, liver, kidney and heart diseases, metabolic diseases, and diseases of the cardiovascular and neural systems.
Investigations that further elucidate the complex role of autophagy in the pathogenesis of disease will facilitate targeting this pathway for therapies in specific diseases.
Calcium (Ca
) signaling is critical for cell function and cell survival. Mitochondria play a major role in regulating the intracellular Ca
concentration (Ca
). Mitochondrial Ca
uptake is an ...important determinant of cell fate and governs respiration, mitophagy/autophagy, and the mitochondrial pathway of apoptosis. Mitochondrial Ca
uptake occurs via the mitochondrial Ca
uniporter (MCU) complex. This review summarizes the present knowledge on the function of MCU complex, regulation of MCU channel, and the role of MCU in Ca
homeostasis and human disease pathogenesis. The channel core consists of four MCU subunits and essential MCU regulators (EMRE). Regulatory proteins that interact with them include mitochondrial Ca
uptake 1/2 (MICU1/2), MCU dominant-negative β-subunit (MCUb), MCU regulator 1 (MCUR1), and solute carrier 25A23 (SLC25A23). In addition to these proteins, cardiolipin, a mitochondrial membrane-specific phospholipid, has been shown to interact with the channel core. The dynamic interplay between the core and regulatory proteins modulates MCU channel activity after sensing local changes in Ca
, reactive oxygen species, and other environmental factors. Here, we highlight the structural details of the human MCU heteromeric assemblies and their known roles in regulating mitochondrial Ca
homeostasis. MCU dysfunction has been shown to alter mitochondrial Ca
dynamics, in turn eliciting cell apoptosis. Changes in mitochondrial Ca
uptake have been implicated in pathological conditions affecting multiple organs, including the heart, skeletal muscle, and brain. However, our structural and functional knowledge of this vital protein complex remains incomplete, and understanding the precise role for MCU-mediated mitochondrial Ca
signaling in disease requires further research efforts.
Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to ...life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients.
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•Respiratory system is the main target of SARS-CoV-2.•SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions.•SARS-CoV-2 can cause central and peripheral neurological manifestations.•SARS-CoV-2 can affect the cardiovascular system and promote renal dysfunction.•Cancer patients are at a higher risk of contracting the SARS-CoV-2 virus.
Despite the availability of renal replacement therapy, acute kidney injury (AKI) is associated with high mortality and morbidity. In humans, it is difficult to determine whether AKI is a cause or ...consequence of excess morbidity. In animal models, however, it is increasingly clear that AKI induces distant organ dysfunction. Identified pathways include inflammatory cascades, apoptosis, the induction of remote oxidative stress, and differential molecular expression. Specifically, growing evidence implicates renal injury as an instigator and multiplier of pulmonary, cardiac, hepatic, and neurologic dysfunction. Accurate identification of these pathways will be critical in developing targeted therapies to improve outcomes in AKI. The purpose of this review is to summarize both clinical and preclinical studies of AKI and its role in distant organ injury.
The Sustainable Development Goal (SDG) target 3.4 is to reduce premature mortality from non-communicable diseases (NCDs) by a third by 2030 relative to 2015 levels, and to promote mental health and ...wellbeing. We used data on cause-specific mortality to characterise the risk and trends in NCD mortality in each country and evaluate combinations of reductions in NCD causes of death that can achieve SDG target 3.4. Among NCDs, ischaemic heart disease is responsible for the highest risk of premature death in more than half of all countries for women, and more than three-quarters for men. However, stroke, other cardiovascular diseases, and some cancers are associated with a similar risk, and in many countries, a higher risk of premature death than ischaemic heart disease. Although premature mortality from NCDs is declining in most countries, for most the pace of change is too slow to achieve SDG target 3.4. To investigate the options available to each country for achieving SDG target 3.4, we considered different scenarios, each representing a combination of fast (annual rate achieved by the tenth best performing percentile of all countries) and average (median of all countries) declines in risk of premature death from NCDs. Pathways analysis shows that every country has options for achieving SDG target 3.4. No country could achieve the target by addressing a single disease. In at least half the countries, achieving the target requires improvements in the rate of decline in at least five causes for women and in at least seven causes for men to the same rate achieved by the tenth best performing percentile of all countries. Tobacco and alcohol control and effective health-system interventions—including hypertension and diabetes treatment; primary and secondary cardiovascular disease prevention in high-risk individuals; low-dose inhaled corticosteroids and bronchodilators for asthma and chronic obstructive pulmonary disease; treatment of acute cardiovascular diseases, diabetes complications, and exacerbations of asthma and chronic obstructive pulmonary disease; and effective cancer screening and treatment—will reduce NCD causes of death necessary to achieve SDG target 3.4 in most countries.
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