Pathophysiological Mechanisms Research Articles

Intestinal Dialysis Research Progress and the Early Treatment of a NonDiabetic Patient with Symptomatic Uremia and Fatty Liver with Intestinal Dialysis: The Practice of Evidence-Based Medicine

Background: Chronic renal failure results from a variety of pathophysiological mechanisms and etiologies, and is associated with progressive and irreversible damage and loss of the kidneys’ tissue leading to failure of the kidneys to excrete waste products, and also failure to perform some other functions. Many patients with chronic renal failure in a country like Iraq has been reported to be reluctant to accept dialysis therapies because of the wide spread notion of its association with high mortality. The lack of effective, convenient, and affordable therapy for chronic renal failure in many regions of the world should not mean should that the patients with advanced chronic renal failure are left without other suitable, convenient and acceptable care. The aim of this paper is to describe the early treatment of a patient with symptomatic uremia with intestinal dialysis. Patients and Methods: A 60-year non-diabetic male patient was experiencing progressive symptomatic uremia. On the 18th of November, 2023, blood urea was elevated at 217 mg/dL, serum creatine was 5.2 mg/dL, and he had symptomatic uremia with nausea, vomiting, fatigue, pruritus and anemia. The patient was treated with intestinal dialysis (Acacia gum supplementation plus conservative dietary and pharmacological management of chronic renal failure) which was prescribed according to the latest published guidelines. It was necessary during the first week of treatment to eliminate almost all dietary protein, and his diet was consisting mainly of high calorie juices, grapes, and water melon. Results: When the patient was seen on the 2nd of December, 2023, treatment was associated with marked symptomatic and laboratory improvements. Blood urea was 115 mg /dL, serum creatine was 3.6 mg /dL However, and serum calcium was 5.3 mg/dL (Normal ranges: 8-10.5 mg/dL). Therefore, oral alphacalcidol was added in a dose of 1 microgram daily. Conclusion: Intestinal dialysis will continue to be used to improve the management of chronic renal failure and symptomatic uremia as long as there is no convenient and affordable therapy for chronic renal failure in many regions of the world.

Distinctive Pattern of Metal Deposition in Neurologic Wilson Disease: Insights From 7T Susceptibility-Weighted Imaging.

Noninvasive and accurate biomarkers of neurologic Wilson disease (NWD), a rare inherited disorder, could reduce diagnostic error or delay. Excessive subcortical metal deposition seen on susceptibility imaging has suggested a characteristic pattern in NWD. With submillimeter spatial resolution and increased contrast, 7T susceptibility-weighted imaging (SWI) may enable better visualization of metal deposition in NWD. In this study, we sought to identify a distinctive metal deposition pattern in NWD using 7T SWI and investigate its diagnostic value and underlying pathophysiologic mechanism. Patients with WD, healthy participants with monoallelic ATP7B variant(s) on a single chromosome, and health controls (HCs) were recruited. NWD and non-NWD (nNWD) were defined according to the presence or absence of neurologic symptoms during investigation. Patients with other diseases with comparable clinical or imaging manifestations, including early-onset Parkinson disease (EOPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and neurodegeneration with brain iron accumulation (NBIA), were additionally recruited and assessed for exploratory comparative analysis. All participants underwent 7T T1, T2, and high-resolution SWI scanning. Quantitative susceptibility mapping and principal component analysis were performed to illustrate metal distribution. We identified a linear signal intensity change consisting of a hyperintense strip at the lateral border of the globus pallidus in patients with NWD. We termed this feature "hyperintense globus pallidus rim sign." This feature was detected in 38 of 41 patients with NWD and was negative in all 31 nNWD patients, 15 patients with EOPD, 30 patients with MSA, 15 patients with PSP, and 12 patients with NBIA; 22 monoallelic ATP7B variant carriers; and 41 HC. Its sensitivity to differentiate between NWD and HC was 92.7%, and specificity was 100%. Severity of the hyperintense globus pallidus rim sign measured by a semiquantitative scale was positively correlated with neurologic severity (ρ = 0.682, 95% CI 0.467-0.821, p < 0.001). Patients with NWD showed increased susceptibility in the lenticular nucleus with high regional weights in the lateral globus pallidus and medial putamen. The hyperintense globus pallidus rim sign showed high sensitivity and excellent specificity for diagnosis and differential diagnosis of NWD. It is related to a special metal deposition pattern in the lenticular nucleus in NWD and can be considered as a novel neuroimaging biomarker of NWD. The study provides Class II evidence that the hyperintense globus pallidus rim sign on 7T SWI MRI can accurately diagnose neurologic WD.

The Dual Roles of S-Nitrosylation of Proteins in Cancer: Molecular Mechanisms and Recent Advancements

&lt;p class="MsoNormal" style="text-align: justify;"&gt;&lt;span lang="EN-US" style="font-family: Nunito; color: #212529; background: white;"&gt;Protein S-nitrosylation (SNO), emerging as an important posttranslational modification, involves covalent addition of nitric oxide (NO) to the sulfur atom of cysteine in proteins. Accumulated evidence suggests that protein SNO plays crucial roles in pathophysiological mechanisms in cancer, which is attracting great attention. However, there are still controversies about whether S-nitrosylated proteins act as oncogenic proteins or tumor suppressors in cancer. In this review, we provide an overview of the early and latest evidence regarding the underlying mechanism and dual roles of SNO in cancer, in an effort to clarify its contribution in tumor progression. It has been well established that S-nitrosylated proteins restrain tumor progression in several types of cancer, while they have exhibited activities in promoting cell proliferation and inhibiting apoptosis in some other kinds of cancer. Interestingly, emerging evidence also has highlighted both its anti-cancer and pro-tumorigenic roles in several other cancer diseases. Finally, current limitations and future research prospects are presented. The overview of targeting SNO in cancer will provide new opportunities for drug development through in-depth exploration of SNO-mediated signaling pathways.&lt;/span&gt;&lt;/p&gt;

Novel and Emerging Treatments to Target Pathophysiological Mechanisms in Various Phenotypes of Multiple Sclerosis.

The objective is to comprehensively review novel pharmacotherapies used in multiple sclerosis (MS) and the possibilities they may carry for therapeutic improvement. Specifically, we discuss pathophysiological mechanisms worth targeting in MS, ranging from well known targets, such as autoinflammation and demyelination, to more novel and advanced targets, such as neuroaxonal damage and repair. To set the stage, a brief overview of clinical MS phenotypes is provided, followed by a comprehensive recapitulation of both clinical and paraclinical outcomes available to assess the effectiveness of treatments in achieving these targets. Finally, we discuss various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials. SIGNIFICANCE STATEMENT: This comprehensive review discusses pathophysiological mechanisms worth targeting in multiple sclerosis. Various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials, are reviewed.

Cervicovaginal metabolome and tumor characteristics for endometrial cancer detection and risk stratification.

Endometrial cancer is highly prevalent and lacking non-invasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The objective of this study was to investigate the cervicovaginal environment to improve understanding of metabolic reprogramming related to endometrial cancer and identify potential biomarker candidates for non-invasive diagnostic and prognostic tests. Cervicovaginal lavages were collected from 192 participants with endometrial cancer (n=66) and non-malignant conditions (n=108), and global untargeted metabolomics was performed. Using the metabolite data (n=920), we completed a multivariate biomarker discovery analysis. We analyzed grade 1/2 endometrioid carcinoma (n=53) and other endometrial cancer subtypes (n=13) to identify shared and unique metabolic signatures between the subtypes. When compared to non-malignant conditions, downregulation of proline (p<0.0001), tryptophan (p<0.0001), and glutamate (p<0.0001) was found among both endometrial cancer groups, relating to key hallmarks of cancer including immune suppression and redox balance. Upregulation (q<0.05) of sphingolipids, fatty acids, and glycerophospholipids was observed in endometrial cancer in a type-specific manner. Furthermore, cervicovaginal metabolites related to tumor characteristics, including tumor size and myometrial invasion. Our findings provide insights into understanding the endometrial cancer metabolic landscape and improvement into diagnosis. The metabolic dysregulation described in this paper linked specific metabolites and pathophysiological mechanisms including cellular proliferation, energy supply, and invasion of neighbouring tissues. Furthermore, cervicovaginal metabolite levels related to tumor characteristics, which are used for risk stratification. Overall, development of non-invasive diagnostic can improve both the acceptability and accessibility of diagnosis.

Advanced glycation end product-modified low-density lipoprotein promotes pro-osteogenic reprogramming via RAGE/NF-κB pathway and exaggerates aortic valve calcification in hamsters

BackgroundAdvanced glycation end product-modified low-density lipoprotein (AGE-LDL) is related to inflammation and the development of atherosclerosis. Additionally, it has been demonstrated that receptor for advanced glycation end products (RAGE) has a role in the condition known as calcific aortic valve disease (CAVD). Here, we hypothesized that the AGE-LDL/RAGE axis could also be involved in the pathophysiological mechanism of CAVD.MethodsHuman aortic valve interstitial cells (HAVICs) were stimulated with AGE-LDL following pre-treatment with or without interleukin 37 (IL-37). Low-density lipoprotein receptor deletion (Ldlr−/−) hamsters were randomly allocated to chow diet (CD) group and high carbohydrate and high fat diet (HCHFD) group.ResultsAGE-LDL levels were significantly elevated in patients with CAVD and in a hamster model of aortic valve calcification. Our in vitro data further demonstrated that AGE-LDL augmented the expression of intercellular cell adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and alkaline phosphatase (ALP) in a dose-dependent manner through NF-κB activation, which was attenuated by nuclear factor kappa-B (NF-κB) inhibitor Bay11-7082. The expression of RAGE was augmented in calcified aortic valves, and knockdown of RAGE in HAVICs attenuated the AGE-LDL-induced inflammatory and osteogenic responses as well as NF-κB activation. IL-37 suppressed inflammatory and osteogenic responses and NF-κB activation in HAVICs. The vivo experiment also demonstrate that supplementation with IL-37 inhibited valvular inflammatory response and thereby suppressed valvular osteogenic activities.ConclusionsAGE-LDL promoted inflammatory responses and osteogenic differentiation through RAGE/NF-κB pathway in vitro and aortic valve lesions in vivo. IL-37 suppressed the AGE-LDL-induced inflammatory and osteogenic responses in vitro and attenuated aortic valve lesions in a hamster model of CAVD.Graphic

Pulmonary inflammation and viral replication define distinct clinical outcomes in fatal cases of COVID-19.

COVID-19 has affected more than half a billion people worldwide, with more than 6.3 million deaths, but the pathophysiological mechanisms involved in lethal cases and the host determinants that determine the different clinical outcomes are still unclear. In this study, we assessed lung autopsies of 47 COVID-19 patients and examined the inflammatory profiles, viral loads, and inflammasome activation. Additionally, we correlated these factors with the patient's clinical and histopathological conditions. Robust inflammasome activation was detected in the lungs of lethal cases of SARS-CoV-2. Experiments conducted on transgenic mice expressing hACE2 and infected with SARS-CoV-2 showed that Nlrp3-/- mice were protected from disease development and lethality compared to Nlrp3+/+ littermate mice, supporting the involvement of this inflammasome in disease exacerbation. An analysis of gene expression allowed for the classification of COVID-19 patients into two different clusters. Cluster 1 died with higher viral loads and exhibited a reduced inflammatory profile than Cluster 2. Illness time, mechanical ventilation time, pulmonary fibrosis, respiratory functions, histopathological status, thrombosis, viral loads, and inflammasome activation significantly differed between the two clusters. Our data demonstrated two distinct profiles in lethal cases of COVID-19, thus indicating that the balance of viral replication and inflammasome-mediated pulmonary inflammation led to different clinical outcomes. We provide important information to understand clinical variations in severe COVID-19, a process that is critical for decisions between immune-mediated or antiviral-mediated therapies for the treatment of critical cases of COVID-19.

Diabetes-Related Macrovascular Complications Are Associated With an Increased Risk of Diabetic Microvascular Complications: A Prospective Study of 1518 Patients With Type 1 Diabetes and 20 802 Patients With Type 2 Diabetes in the UK Biobank.

Diabetic vascular complications share common pathophysiological mechanisms, but the relationship between diabetes-related macrovascular complications (MacroVCs) and incident diabetic microvascular complications remains unclear. We aimed to investigate the impact of MacroVCs on the risk of microvascular complications. There were 1518 participants with type 1 diabetes (T1D) and 20 802 participants with type 2 diabetes from the UK Biobank included in this longitudinal cohort study. MacroVCs were defined by the presence of macrovascular diseases diagnosed after diabetes at recruitment, including coronary heart disease, peripheral artery disease, stroke, and ≥2 MacroVCs. The primary outcome was incident microvascular complications, a composite of diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy. During a median (interquartile range) follow-up of 11.61 (5.84-13.12) years and 12.2 (9.50-13.18) years, 596 (39.3%) and 4113 (19.8%) participants developed a primary outcome in T1D and type 2 diabetes, respectively. After full adjustment for conventional risk factors, Cox regression models showed significant associations between individual as well as cumulative MacroVCs and the primary outcome, except for coronary heart disease in T1D (T1D: diabetes coronary heart disease: 1.25 [0.98-1.60]; diabetes peripheral artery disease: 3.00 [1.86-4.84]; diabetes stroke: 1.71 [1.08-2.72]; ≥2: 2.57 [1.66-3.99]; type 2 diabetes: diabetes coronary heart disease: 1.59 [1.38-1.82]; diabetes peripheral artery disease: 1.60 [1.01-2.54]; diabetes stroke: 1.50 [1.13-1.99]; ≥2: 2.66 [1.92-3.68]). Subgroup analysis showed that strict glycemic (glycated hemoglobin <6.5%) and blood pressure (<140/90 mm Hg) control attenuated the association. Individual and cumulative MacroVCs confer significant risk of incident microvascular complications in patients with T1D and type 2 diabetes. Our results may facilitate cost-effective high-risk population identification and development of precise prevention strategies.

Symmetric and Profound Monoaminergic Degeneration in Parkinson's Disease with Premotor REM Sleep Behavior Disorder.

Rapid eye movement sleep behavior disorder (RBD) may precede or follow motor symptoms in Parkinson's disease (PD). While over 70% of idiopathic RBD cases phenoconvert within a decade, a small subset develops PD after a more extended period or remains nonconverted. These heterogeneous manifestations of RBD in PD prompt subtype investigations. Premotor RBD may signify "body-first" PD with bottom-up, symmetric synucleinopathy propagation. Explore brainstem and nigrostriatal monoaminergic degeneration pattern differences based on premotor RBD presence and duration in de novo PD patients. In a cross-sectional analysis of de novo PD patients (n = 150) undergoing FP-CIT PET and RBD Single-Question Screen, the cohort was categorized into groups with and without premotor RBD (PDRBD+/-), with further classification of PDRBD+ based on a 10-year duration of premotor RBD. Analysis of FP-CIT binding in the striatum and pons, striatal asymmetry, and striatum-to-pons ratios compared patterns of nigrostriatal and brainstem monoaminergic degeneration. PDRBD+ exhibited more severe and symmetrical striatal dopaminergic denervation compared to PDRBD-, with the difference in severity accentuated in the least-affected hemisphere. The PDRBD+<10Y subgroup displayed the most prominent striatal symmetry, supporting a more homogeneous "body-first" subtype. Pontine uptakes remained lower in PDRBD+ even after adjusting for striatal uptake, suggesting early degeneration of pontine monoaminergic nuclei. Premotor RBD in PD is associated with severe, symmetrical nigrostriatal and brainstem monoaminergic degeneration, especially in cases with PD onset within 10 years of RBD. This supports the concept of a "widespread, bottom-up" pathophysiological mechanism associated with premotor RBD in PD.

When the diagnosis is in the patient's hand and in the neurologist's eye.

The objective of this study was to encompass current knowledge about pathophysiological mechanisms of those specific hand postures or deformities caused by central nervous system disorders. In the era of high-resolution neuroimaging and molecular biology, clinicians are progressively losing confidence with neurological examination. Careful hand observation is of key importance in order to differentiate neurological from non-neurological conditions, central from peripheral aetiologies, and organic from functional disorders. Localizing the potential anatomical site is essential to properly conduct subsequent exams. We provided a practical guide for clinicians to recognize hand patterns caused by central nervous system disorders, avoiding mimicking conditions, thus optimizing and prompting the diagnostic pathway.

Deciphering pathophysiological mechanisms underlying cystathionine beta-synthase-deficient homocystinuria using targeted metabolomics, liver proteomics, sphingolipidomics and analysis of mitochondrial function

BackgroundCystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, and a limited knowledge about underlying pathophysiological processes. Here we aimed at getting an in-depth insight into disease mechanisms using a transgenic mouse model of HCU (I278T). MethodsWe assessed metabolic, proteomic and sphingolipidomic changes, and mitochondrial function in tissues and body fluids of I278T mice and WT controls. Furthermore, we evaluated the efficacy of methionine-restricted diet (MRD) in I278T mice. ResultsIn WT mice, we observed a distinct tissue/body fluid compartmentalization of metabolites with up to six-orders of magnitude differences in concentrations among various organs. The I278T mice exhibited the anticipated metabolic imbalance with signs of an increased production of hydrogen sulfide and disturbed persulfidation of free aminothiols. HCU resulted in a significant dysregulation of liver proteome affecting biological oxidations, conjugation of compounds, and metabolism of amino acids, vitamins, cofactors and lipids. Liver sphingolipidomics indicated upregulation of the pro-proliferative sphingosine-1-phosphate signaling pathway. Liver mitochondrial function of HCU mice did not seem to be impaired compared to controls. MRD in I278T mice improved metabolic balance in all tissues and substantially reduced dysregulation of liver proteome. ConclusionThe study highlights distinct tissue compartmentalization of sulfur-related metabolites in normal mice, extensive metabolome, proteome and sphingolipidome disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.

Uric acid in atherosclerosis and cardiovascular diseases: innocent bystander or ruthless killer?

Medical attention to uric acid (UA) has been increasing in recent years, mainly because this molecule has been shown to be associated with increased cardiovascular risk, both in the general population and in the hypertensive patients. A growing body of clinical and experimental data supports this view and prompts reconsideration of the role of UA in the development of atherosclerosis and the genesis of cardiovascular disease. It is known that this substance, in certain plasma concentrations, induces increased oxidative stress, a chronic inflammatory state, and a whole series of other modifications that are potentially deleterious at the cardiovascular level leading to hypertension, atherosclerosis, atrial fibrillation (AF), and other metabolic changes such as diabetes, metabolic syndrome, non-alcoholic fatty liver disease and kidney failure. Despite this epidemiologic and mechanistic evidence, the current guidelines from international cardiology scientific societies do not give precise indications in this regard, and some of them only suggest UA evaluation as part of an initial screening of the hypertensive patient. The purpose of this review is to briefly describe the main clinical and epidemiological evidence supporting the role of hyperuricemia as a possible emerging cardiovascular risk factor and to analyze the potential pathophysiological mechanisms through which elevated UA levels may exert a detrimental effect on the cardiovascular system.

Basic host response parameters to classify mortality risk in COVID-19 and community-acquired pneumonia

Improved phenotyping in pneumonia is necessary to strengthen risk assessment. Via a feasible and multidimensional approach with basic parameters, we aimed to evaluate the effect of host response at admission on severity stratification in COVID-19 and community-acquired pneumonia (CAP). Three COVID-19 and one CAP multicenter cohorts including hospitalized patients were recruited. Three easily available variables reflecting different pathophysiologic mechanisms—immune, inflammation, and respiratory—were selected (absolute lymphocyte count [ALC], C-reactive protein [CRP] and, SpO2/FiO2). In-hospital mortality and intensive care unit (ICU) admission were analyzed as outcomes. A multivariable, penalized maximum likelihood logistic regression was performed with ALC (< 724 lymphocytes/mm3), CRP (> 60 mg/L), and, SpO2/FiO2 (< 450). A total of 1452, 1222 and 462 patients were included in the three COVID-19 and 1292 in the CAP cohort for the analysis. Mortality ranged between 4 and 32% (0 to 3 abnormal biomarkers) and 0–9% in SARS-CoV-2 pneumonia and CAP, respectively. In the first COVID-19 cohort, adjusted for age and sex, we observed an increased odds ratio for in-hospital mortality in COVID-19 with elevated biomarkers altered (OR 1.8, 3, and 6.3 with 1, 2, and 3 abnormal biomarkers, respectively). The model had an AUROC of 0.83. Comparable findings were found for ICU admission, with an AUROC of 0.76. These results were confirmed in the other COVID-19 cohorts Similar OR trends were reported in the CAP cohort; however, results were not statistically significant. Assessing the host response via accessible biomarkers is a simple and rapidly applicable approach for pneumonia.

Gut-directed hypnosis and hypnotherapy for irritable bowel syndrome: a mini-review.

Irritable bowel syndrome (IBS) is a frequent health condition which can be associated with functional disability and reduced health-related quality of life. IBS is classified as a disorder of the brain-gut axis. IBS is a very heterogenous condition with regards to the underlying pathophysiological mechanisms, the clinical picture and the amount of functional impairment. Within a biopsychosocial model of IBS psychosocial factors can play a role in the in the predisposition, triggering and development of chronicity. Somatic or psychosocial or a mixture of both factors might predominate in an individual patient. Gut-directed hypnosis is a special type of medical hypnosis combining standardised gut-directed suggestions (hypnosis) with suggestions tailored to the psychological characteristics of the patient (hypnotherapy). Of brain-gut behavioral therapies, cognitive bahvioral-based interventions and gut-directed hypnosis have the largest evidence for both short-term and long-term efficacy in controlled trials for IBS and are recommended by current European and North American gastroenterology guidelines as second line treatment options. Standardised gut-directed hypnosis is available by audiotapes and can be part of a multicomponent self-management approach by digital health applications. It can be used - based on the patient's preferences-as first line therapy for mild forms of IBS. Severe forms of IBS require face-to-face interdisciplinary management. Standardised gut-directed hypnosis and hypnotherapy tailored to the individual patient can be part of this approach.

Revolutionizing Stroke Care: Nanotechnology-Based Brain Delivery as a Novel Paradigm for Treatment and Diagnosis.

Stroke, a severe medical condition arising from abnormalities in the coagulation-fibrinolysis cycle and metabolic processes, results in brain cell impairment and injury due to blood flow obstruction within the brain. Prompt and efficient therapeutic approaches are imperative to control and preserve brain functions. Conventional stroke medications, including fibrinolytic agents, play a crucial role in facilitating reperfusion to the ischemic brain. However, their clinical efficacy is hampered by short plasma half-lives, limited brain tissue distribution attributed to the blood-brain barrier (BBB), and lack of targeted drug delivery to the ischemic region. To address these challenges, diverse nanomedicine strategies, such as vesicular systems, polymeric nanoparticles, dendrimers, exosomes, inorganic nanoparticles, and biomimetic nanoparticles, have emerged. These platforms enhance drug pharmacokinetics by facilitating targeted drug accumulation at the ischemic site. By leveraging nanocarriers, engineered drug delivery systems hold the potential to overcome challenges associated with conventional stroke medications. This comprehensive review explores the pathophysiological mechanism underlying stroke and BBB disruption in stroke. Additionally, this review investigates the utilization of nanocarriers for current therapeutic and diagnostic interventions in stroke management. By addressing these aspects, the review aims to provide insight into potential strategies for improving stroke treatment and diagnosis through a nanomedicine approach.

Type 1 Myocardial Infarction in Patients With Acute Ischemic Stroke

Elevated values of high-sensitivity cardiac troponin (hs-cTn) are common in patients with acute ischemic stroke and are associated with poor prognosis. However, diagnostic and therapeutic implications in patients with ischemic stroke remain unclear. To identify factors indicative of myocardial infarction (MI) in patients with acute ischemic stroke and hs-cTn elevation. The primary hypothesis was that a dynamic change of hs-cTn values (>50% change) in patients with acute ischemic stroke indicates MI. This cross-sectional study was a prospective, observational study with blinded end-point assessment conducted across 26 sites in Germany. Patients were included if they had acute ischemic stroke within 72 hours and either (1) highly elevated hs-cTn values on admission (>52 ng/L) or (2) hs-cTn levels above the upper limit of normal and a greater than 20% change at repeated measurements. Patients were enrolled between August 2018 and October 2020 and had 1 year of follow-up. Statistical analysis was performed between April 2022 and August 2023. Standardized electrocardiography, echocardiography, and coronary angiography. Diagnosis of MI as adjudicated by an independent end-point committee based on the findings of electrocardiography, echocardiography, and coronary angiography. In total, 254 patients were included. End points were adjudicated in 247 patients (median [IQR] age, 75 [66-82] years; 117 were female [47%] and 130 male [53%]). MI was present in 126 of 247 patients (51%) and classified as type 1 MI in 50 patients (20%). Dynamic change in hs-cTn value was not associated with MI in univariable (32% vs 38%; χ2 P = .30) or adjusted comparison (odds ratio, 1.05; 95% CI, 0.31-3.33). The baseline absolute hs-cTn value was independently associated with type 1 MI. The best cutoffs for predicting type 1 MI were at hs-cTn values 5 to 10 times the upper limit normal. This study found that in patients with acute ischemic stroke, a dynamic change in hs-cTn values did not identify MI, underscoring that dynamic changes do not identify the underlying pathophysiological mechanism. In exploratory analyses, very high absolute hs-cTn values were associated with a diagnosis of type 1 MI. Further studies are needed how to best identify patients with stroke who should undergo coronary angiography.

Paroxysmal Kinesigenic Dyskinesia Secondary to Novel Variant in PRRT2: A Case Report

AbstractParoxysmal kinesigenic dyskinesia (PKD) is a movement disorder characterized by frequent, brief episodes of choreiform or dystonic movements, often triggered by voluntary movement or a startle sensation. Here, we report a case of PKD associated with a novel variant in PRRT2 gene. A 19-year-old male with no medical history presented with hyperkinetic movement disorder symptoms consistent with PKD. Clinical evaluation, laboratory studies, and genetic testing were performed to confirm the diagnosis. Treatment with carbamazepine was initiated, and the patient's response was monitored over a 9-month period. The patient exhibited classic clinical criteria for PKD, including brief episode duration, an identified kinesigenic trigger, and responsiveness to pharmacological treatment. Genetic testing revealed a pathogenic variant in PRRT2 gene not previously reported in association with PKD. Treatment with carbamazepine led to complete resolution of symptoms, with sustained improvement observed during follow-up. This case highlights the importance of considering PKD in the differential diagnosis of hyperkinetic movement disorders and emphasizes the role of genetic testing in confirming the diagnosis. Furthermore, it underscores the efficacy of carbamazepine in managing PKD symptoms associated with PRRT2 gene. Further research is warranted to elucidate the underlying pathophysiological mechanisms and optimize treatment strategies for PKD.

Hexamerization: explaining the original sin of IgG-mediated complement activation in acute lung injury.

Although antibody-mediated lung damage is a major factor in transfusion-related acute lung injury (ALI), autoimmune lung disease (for example, coatomer subunit α [COPA] syndrome), and primary graft dysfunction following lung transplantation, the mechanism by which antigen-antibody complexes activate complement to induce lung damage remains unclear. In this issue of the JCI, Cleary and colleagues utilized several approaches to demonstrate that IgG forms hexamers with MHC class I alloantibodies. This hexamerization served as a key pathophysiological mechanism in alloimmune lung injury models and was mediated through the classical pathway of complement activation. Additionally, the authors provided avenues for exploring therapeutics for this currently hard-to-treat clinical entity that has several etiologies but a potentially focused mechanism.

New Molecules of Importance in the Prevention and Treatment of Acne: A Systematic Patent Review (2016-2020).

Acne is a highly prevalent disease that mainly affects the pilosebaceous units associated with sebaceous glands, causing inflammatory skin lesions and affecting the self-esteem, mental health, and quality of life of those who suffer from this disease. Different treatments exist today to prevent, reduce, and improve symptoms; however, over the years, there have been problems with bacterial resistance and slight effectiveness with prolonged use. The purpose of this article is based on the review of patents of new products of principal topical administration for the treatment of acne in recent years 2016-2020, to evaluate and analyze novel synthetic molecules and semi-synthetics with potential therapeutic and preventive in the acne treatment. A systematic review of patents was conducted through the official database of the European Patent Office - Espacenet, where the search focused on the keywords: "acne and bacteria" in the title or abstract. Only patents granted between the years 2016-2020 were included, with products having molecules with a synthetic and semi-synthetic origin, without considering natural, biological products or those used as diagnostic means. A total of 19 patents were selected, most with principally antimicrobial and antiinflammatory action, where the reduction in the appearance of resistance by C. acnes is verified, and its action is complemented by inhibiting the different pathophysiological mechanisms that lead to the worsening of the disease. Novel approaches in the treatment and prevention of acne, mainly topically, are focused on the reduction of bacterial resistance and irritation compared to current treatments. The use of combined formulations provides better results with additional benefits, improving treatment times and patient adherence.

A Narrative Review on the Clinical Relevance of Imaging the Circumventricular Brain Organs and Performing Their Anatomical and Histopathological Examination in Acute and Postacute COVID-19.

Autopsy followed by histopathological examination is foundational in clinical and forensic medicine for discovering and understanding pathological changes in disease, their underlying processes, and cause of death. Imaging technology has become increasingly important for advancing clinical research and practice, given its noninvasive, in vivo and ex vivo applicability. Medical and forensic autopsy can benefit greatly from advances in imaging technology that lead toward minimally invasive, whole-brain virtual autopsy. Brain autopsy followed by histopathological examination is still the hallmark for understanding disease and a fundamental modus operandi in forensic pathology and forensic medicine, despite the fact that its practice has become progressively less frequent in medical settings. This situation is especially relevant with respect to new diseases such as COVID-19 caused by the SARS-CoV-2 virus, for which our neuroanatomical knowledge is sparse. In this narrative review, we show that ad hoc clinical autopsies and histopathological analyses combined with neuroimaging of the principal circumventricular organs are critical to gaining insight into the reconstruction of the pathophysiological mechanisms and the explanation of cause of death (ie, atrium mortis) related to the cardiovascular effects of SARS-CoV-2 infection in forensic and clinical medicine.