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The Lancet. Neurology Mar 2021Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrP). Effective therapeutics are currently not available and... (Review)
Review
Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrP). Effective therapeutics are currently not available and accurate diagnosis can be challenging. Clinical diagnostic criteria use a combination of characteristic neuropsychiatric symptoms, CSF proteins 14-3-3, MRI, and EEG. Supportive biomarkers, such as high CSF total tau, could aid the diagnostic process. However, discordant studies have led to controversies about the clinical value of some established surrogate biomarkers. Development and clinical application of disease-specific protein aggregation and amplification assays, such as real-time quaking induced conversion (RT-QuIC), have constituted major breakthroughs for the confident pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Updated criteria for the diagnosis of sporadic Creutzfeldt-Jakob disease, including application of RT-QuIC, should improve early clinical confirmation, surveillance, assessment of PrP seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under investigation.
Topics: Biomarkers; Creutzfeldt-Jakob Syndrome; Genetic Markers; Guidelines as Topic; Humans; Neuroimaging; Sensitivity and Specificity
PubMed: 33609480
DOI: 10.1016/S1474-4422(20)30477-4 -
Intensive Care Medicine Oct 2022Multiple organ failure following a septic event derives from immune dysregulation. Many of the mediators of this process are humoral factors (cytokines), which could... (Review)
Review
Multiple organ failure following a septic event derives from immune dysregulation. Many of the mediators of this process are humoral factors (cytokines), which could theoretically be cleared by direct adsorption through a process called hemoperfusion. Hemoperfusion through devices, which bind specific molecules like endotoxin or theoretically provide non-specific adsorption of pro-inflammatory mediators has been attempted and studied for several decades with variable results. More recently, technological evolution has led to the increasing application of adsorption due to more biocompatible and possibly more efficient biomaterials. As a result, new indications are developing in this field, and novel tools are available for clinical use. This narrative review will describe current knowledge regarding technical concepts, safety, and clinical results of hemoperfusion. Finally, it will focus on the most recent literature regarding adsorption applied in critically ill patients and their indications, including recent randomized controlled trials and future areas of investigation. Clinical trials for the assessment of efficacy of hemoperfusion in septic patients should apply the explanatory approach. This includes a highly selected homogenous patient population. Enrichment criteria such as applying genetic signature and molecular biomarkers allows the identification of subphenotypes of patients. The intervention must be delivered by a multidisciplinary team of trained personnel. The aim is to maximize the signals for efficacy and safety. In a homogenous cohort, confounding uncontrolled variables are less likely to exist. Trials with highly selected populations have a high internal validity but poor generalizability. The parallel design described in the figure is robust and usually is required by regulatory agencies for the approval of a new treatment. Allocation concealment and randomization are key to minimize bias such as confirmation bias, observer bias. The intervention should be delivered following a strict protocol. Deviations from the protocol might negatively influence the potential effects of the therapies. Surrogates such as cytokine measurement are adequate primary outcomes in phase 3 trials with small sample size because there is a higher likelihood of finding positive results concerning surrogate markers than in respect with clinical outcomes. Once a trial shows positive results concerning surrogate markers, a rationale for another phase 3 trial exploring clinical outcomes is built, justifying the allocation of financial sources to the intended trial.
Topics: Biomarkers; Critical Illness; Endotoxins; Hemoperfusion; Humans; Intensive Care Units
PubMed: 35984473
DOI: 10.1007/s00134-022-06810-1 -
JAMA Network Open Sep 2023Body mass index (BMI) is an easily obtained adiposity surrogate. However, there is variability in body composition and adipose tissue distribution between individuals...
IMPORTANCE
Body mass index (BMI) is an easily obtained adiposity surrogate. However, there is variability in body composition and adipose tissue distribution between individuals with the same BMI, and there is controversy regarding the BMI associated with the lowest mortality risk.
OBJECTIVE
To evaluate which of BMI, fat mass index (FMI), and waist-to-hip (WHR) has the strongest and most consistent association with mortality.
DESIGN, SETTING, AND PARTICIPANT
This cohort study used incident deaths from the UK Biobank (UKB; 2006-2022), which includes data from 22 clinical assessment centers across the United Kingdom. UKB British participants of British White ancestry (N = 387 672) were partitioned into a discovery cohort (n = 337 078) and validation cohort (n = 50 594), with the latter consisting of 25 297 deaths and 25 297 controls. The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses. Exposure-outcome associations were analyzed through observational and mendelian randomization (MR) analyses.
EXPOSURES
BMI, FMI, and WHR.
MAIN OUTCOMES AND MEASURES
All-cause and cause-specific (cancer, cardiovascular disease [CVD], respiratory disease, or other causes) mortality.
RESULTS
There were 387 672 and 50 594 participants in our observational (mean [SD] age, 56.9 [8.0] years; 177 340 [45.9%] male, 210 332 [54.2%], female), and MR (mean [SD] age, 61.6 [6.2] years; 30 031 [59.3%] male, 20 563 [40.6%], female) analyses, respectively. Associations between measured BMI and FMI with all-cause mortality were J-shaped, whereas the association of WHR with all-cause mortality was linear using the hazard ratio (HR) scale (HR per SD increase of WHR, 1.41 [95% CI, 1.38-1.43]). Genetically determined WHR had a stronger association with all-cause mortality than BMI (odds ratio [OR] per SD increase of WHR, 1.51 [95% CI, 1.32-1.72]; OR per SD increase of BMI, 1.29 [95% CI, 1.20-1.38]; P for heterogeneity = .02). This association was stronger in male than female participants (OR, 1.89 [95% CI, 1.54-2.32]; P for heterogeneity = .01). Unlike BMI or FMI, the genetically determined WHR-all-cause mortality association was consistent irrespective of observed BMI.
CONCLUSIONS AND RELEVANCE
In this cohort study, WHR had the strongest and most consistent association with mortality irrespective of BMI. Clinical recommendations should consider focusing on adiposity distribution compared with mass.
Topics: Humans; Female; Male; Middle Aged; Adiposity; Cohort Studies; Obesity; Body Fat Distribution; Biomarkers
PubMed: 37728925
DOI: 10.1001/jamanetworkopen.2023.34836 -
Physiological Research Mar 2020Asthma is a complex disease with a variable course. Efforts to identify biomarkers to predict asthma severity, the course of disease and response to treatment have not... (Review)
Review
Asthma is a complex disease with a variable course. Efforts to identify biomarkers to predict asthma severity, the course of disease and response to treatment have not been very successful so far. Biomarker research has expanded greatly with the advancement of molecular research techniques. An ideal biomarker should be suitable to identify the disease as well the specific endotype/phenotype, useful in the monitoring of the disease and to determine the prognosis, easily to obtain with minimum discomfort or risk to the patient. An ideal biomarker should be suitable to identify the disease as well the specific endotype/phenotype, useful in the monitoring of the disease and to determine the prognosis, easily to obtain with minimum discomfort or risk to the patient - exhaled breath analysis, blood cells and serum biomarkers, sputum cells and mediators and urine metabolites could be potential biomarkers of asthma bronchiale. Unfortunately, at the moment, an ideal biomarker doesn't exist and the overlap between the biomarkers is a reality. Using panels of biomarkers could improve probably the identification of asthma endotypes in the era of precision medicine.
Topics: Animals; Asthma; Biomarkers; Humans; Precision Medicine; Predictive Value of Tests; Sputum
PubMed: 32228009
DOI: 10.33549/physiolres.934398 -
Gastroenterology Jul 2021Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are chronic, progressive, immune-mediated diseases of adults and children that have... (Review)
Review
Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are chronic, progressive, immune-mediated diseases of adults and children that have no cure. IBD can cause significant morbidity and lead to complications such as strictures, fistulas, infections, and cancer. In children, IBD can also result in growth impairment and pubertal delays. IBD is highly heterogenous, with severity ranging from mild to severe and symptoms ranging from mild to debilitating. Delay in IBD diagnosis, especially in Crohn's disease, is common and associated with adverse outcomes. Early diagnosis and prompt institution of treatment are the cornerstones for improving outcomes and maximizing health. Early diagnosis requires a low threshold of suspicion and red flags to guide early specialist referral at the primary provider level. Although the armamentarium of IBD medications is growing, many patients will not respond to treatment, and the selection of first-line therapy is critical. Risk stratification of disease severity, based on clinical, demographic, and serologic markers, can help guide selection of first-line therapy. Clinical decision support tools, genomics, and other biomarkers of response to therapy and risk of adverse events are the future of personalized medicine. After starting appropriate therapy, it is important to confirm remission using objective end points (treat to target) with continued control of inflammation with adjustment of therapy using surrogate biomarkers (tight control). Lastly, IBD therapy extends far beyond medications, and other aspects of the overall health and wellbeing of the patient are critical. These include preventive health, nutrition, and psychobehavioral support addressing patients' concerns around complementary therapy and medication adherence, prevention of disability, and ensuring open communication.
Topics: Adult; Age Factors; Biomarkers; Child; Disease Progression; Gastroenterology; Humans; Inflammatory Bowel Diseases; Prognosis; Risk Assessment
PubMed: 33940007
DOI: 10.1053/j.gastro.2021.04.063 -
Critical Care (London, England) Aug 2021Sepsis is a common consequence of infection, associated with a mortality rate > 25%. Although community-acquired sepsis is more common, hospital-acquired infection... (Review)
Review
Sepsis is a common consequence of infection, associated with a mortality rate > 25%. Although community-acquired sepsis is more common, hospital-acquired infection is more lethal. The most common site of infection is the lung, followed by abdominal infection, catheter-associated blood steam infection and urinary tract infection. Gram-negative sepsis is more common than gram-positive infection, but sepsis can also be due to fungal and viral pathogens. To reduce mortality, it is necessary to give immediate, empiric, broad-spectrum therapy to those with severe sepsis and/or shock, but this approach can drive antimicrobial overuse and resistance and should be accompanied by a commitment to de-escalation and antimicrobial stewardship. Biomarkers such a procalcitonin can provide decision support for antibiotic use, and may identify patients with a low likelihood of infection, and in some settings, can guide duration of antibiotic therapy. Sepsis can involve drug-resistant pathogens, and this often necessitates consideration of newer antimicrobial agents.
Topics: Anti-Infective Agents; Biomarkers; Humans; Sepsis; Time Factors; Time-to-Treatment
PubMed: 34446092
DOI: 10.1186/s13054-021-03736-w -
Molecular Therapy : the Journal of the... Jan 2021Ferroptosis is primarily caused by intracellular iron catalytic activity and lipid peroxidation. The potential interplay between ferroptosis and apoptosis remains poorly...
Ferroptosis is primarily caused by intracellular iron catalytic activity and lipid peroxidation. The potential interplay between ferroptosis and apoptosis remains poorly understood. Here, we show that the expression of a nuclear long non-coding RNA (lncRNA), LINC00618, is reduced in human leukemia and strongly increased by vincristine (VCR) treatment. Furthermore, LINC00618 promotes apoptosis by increasing the levels of BCL2-Associated X (BAX) and cleavage of caspase-3. LINC00618 also accelerates ferroptosis by increasing the levels of lipid reactive oxygen species (ROS) and iron, two surrogate markers of ferroptosis, and decreasing the expression of solute carrier family 7 member 11 (SLC7A11). Interestingly, VCR-induced ferroptosis and apoptosis are promoted by LINC00618, and LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis. LINC00618 attenuates the expression of lymphoid-specific helicase (LSH), and LSH enhances the transcription of SLC7A11 after the recruitment to the promoter regions of SLC7A11, further inhibiting ferroptosis. Knowledge of these mechanisms demonstrates that lncRNAs related to ferroptosis and apoptosis are critical to leukemogenesis and chemotherapy.
Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Nucleus; Ferroptosis; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Protein Binding; RNA, Long Noncoding; Reactive Oxygen Species
PubMed: 33002417
DOI: 10.1016/j.ymthe.2020.09.024 -
Current Neuropharmacology 2021Neurological disorders (ND) are the central nervous system (CNS) related complications originated by enhanced oxidative stress, mitochondrial failure and overexpression... (Review)
Review
Neurological disorders (ND) are the central nervous system (CNS) related complications originated by enhanced oxidative stress, mitochondrial failure and overexpression of proteins like S100B. S100B is a helix-loop-helix protein with the calcium-binding domain associated with various neurological disorders through activation of the MAPK pathway, increased NF-kB expression resulting in cell survival, proliferation and gene up-regulation. S100B protein plays a crucial role in Alzheimer's disease, Parkinson's disease, multiple sclerosis, Schizophrenia and epilepsy because the high expression of this protein directly targets astrocytes and promotes neuroinflammation. Under stressful conditions, S100B produces toxic effects mediated through receptor for advanced glycation end products (AGE) binding. S100B also mediates neuroprotection, minimizes microgliosis and reduces the expression of tumor necrosis factor (TNF-alpha) but that are concentration- dependent mechanisms. Increased level of S100B is useful for assessing the release of inflammatory markers, nitric oxide and excitotoxicity dependent neuronal loss. The present review summarizes the role of S100B in various neurological disorders and potential therapeutic measures to reduce the prevalence of neurological disorders.
Topics: Astrocytes; Biomarkers; Humans; Nervous System Diseases; Parkinson Disease; S100 Calcium Binding Protein beta Subunit
PubMed: 32727332
DOI: 10.2174/1570159X18666200729100427 -
Molecular and Cellular Biochemistry Mar 2021The assessment and monitoring of the tissue perfusion is extremely important in critical conditions involving circulatory shock. There is a wide range of established... (Review)
Review
The assessment and monitoring of the tissue perfusion is extremely important in critical conditions involving circulatory shock. There is a wide range of established methods for the assessment of cardiac output as a surrogate of oxygen delivery to the peripheral tissues. However, the evaluation of whether particular oxygen delivery is sufficient to ensure cellular metabolic demands is more challenging. In recent years, specific biochemical parameters have been described to indicate the status between tissue oxygen demands and supply. In this review, the authors summarize the application of some of these biochemical markers, including mixed venous oxygen saturation (SO), lactate, central venous-arterial carbon dioxide difference (PCO gap), and PCO gap/central arterial-to-venous oxygen difference (CO) for hemodynamic assessment of tissue perfusion. The thorough monitoring of the adequacy of tissue perfusion and oxygen supply in critical conditions is essential for the selection of the most appropriate therapeutic strategy and it is associated with improved clinical outcomes.
Topics: Arteries; Biomarkers; Carbon Dioxide; Glucose; Hemodynamics; Humans; Hypoxia; Lactic Acid; Microcirculation; Monitoring, Physiologic; Oxygen; Oxygen Consumption; Perfusion; Prognosis; Spectroscopy, Near-Infrared
PubMed: 33387216
DOI: 10.1007/s11010-020-04019-8 -
International Journal of Molecular... Mar 2023Soft tissue tumors are rare mesenchymal tumors with divergent differentiation. The diagnosis of soft tissue tumors is challenging for pathologists owing to the diversity... (Review)
Review
Soft tissue tumors are rare mesenchymal tumors with divergent differentiation. The diagnosis of soft tissue tumors is challenging for pathologists owing to the diversity of tumor types and histological overlap among the tumor entities. Present-day understanding of the molecular pathogenesis of soft tissue tumors has rapidly increased with the development of molecular genetic techniques (e.g., next-generation sequencing). Additionally, immunohistochemical markers that serve as surrogate markers for recurrent translocations in soft tissue tumors have been developed. This review aims to provide an update on recently described molecular findings and relevant novel immunohistochemical markers in selected soft tissue tumors.
Topics: Humans; Sarcoma; Translocation, Genetic; In Situ Hybridization, Fluorescence; Diagnosis, Differential; Soft Tissue Neoplasms; Biomarkers, Tumor
PubMed: 36983010
DOI: 10.3390/ijms24065934