Features Of Disease Research Articles

Role of STIM1 in Stretch-induced Signaling in Human Airway Smooth Muscle.

Alteration in the normal mechanical forces of breathing can contribute to changes in contractility and remodeling characteristic of airway diseases, but the mechanisms that mediate these effects in airway cells are still under investigation. Airway smooth muscle (ASM) cells contribute to both contractility and extracellular matrix (ECM) remodeling. In this study, we explored ASM mechanisms activated by mechanical stretch, focusing on mechanosensitive piezo channels and the key Ca2+ regulatory protein stromal interaction molecule 1 (STIM1). Expression of Ca2+ regulatory proteins, including STIM1, Orai1 and caveolin-1, mechanosensitive ion channels Piezo-1 and Piezo-2, and NLRP3 inflammasomes were upregulated by 10% static stretch superimposed on 5% cyclic stretch. These effects were blunted by STIM1 siRNA. Histamine-induced [Ca2+]i responses and inflammasome activation were similarly blunted by STIM1 knockdown. These data show that the effects of mechanical stretch in human ASM cells are mediated through STIM1, which activates multiple pathways including Piezo channels and the inflammasome, leading to potential downstream changes in contractility and ECM remodeling.

Preclinical models of bladder cancer: BBN and beyond.

Preclinical modelling is a crucial component of advancing the understanding of cancer biology and therapeutic development. Several models exist for understanding the pathobiology of bladder cancer and evaluating therapeutics. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced bladder cancer is a commonly used model that recapitulates many of the features of human disease. Particularly in mice, BBN is a preferred laboratory model owing to a high level of reproducibility, high genetic fidelity to the human condition, and its relative ease of use. However, important aspects of the model are often overlooked in laboratory studies. Moreover, the advent of new models has yielded a variety of methodologies that complement the use of BBN. Toxicokinetics, histopathology, molecular genetics and sex can differ between available models and are important factors to consider in bladder cancer modelling.

Prevalence and risk factors of depression among patients with perianal fistulizing Crohn’s disease

BACKGROUND Psychological distress, especially depression, associated with perianal fistulizing Crohn’s disease (PFCD) is widespread and refractory. However, there is a surprising paucity of studies to date that have sought to identify the prevalence and risk factors of depression associated with PFCD. AIM To estimate the prevalence of depressive symptoms and investigate the depression-related risk factors in patients with PFCD. METHODS The study was conducted in the form of survey and clinical data collection via questionnaire and specialized medical staff. Depressive symptoms, life quality, and fatigue severity of patients with PFCD were assessed by Patient Health Questionnaire-9, Inflammatory Bowel Disease Patient Quality of Life Questionnaire (IBDQ), and Inflammatory Bowel Disease (IBD) Fatigue Patient Self-assessment Scale. The basic demographic information, overall disease features, perianal clinical information, and laboratory inflammation indicators were also gathered. Multivariate regression analysis was ultimately used to ascertain the risk factors of depression associated with PFCD. RESULTS A total of 123 patients with PFCD were involved, and 56.91% were suffering from depression. According to multivariate logistic regression analysis, Perianal Disease Activity Index (PDAI) score [odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.50 to 0.95], IBDQ score (OR = 0.93, 95%CI: 0.88 to 0.97), modified Van Assche index (OR = 1.24, 95%CI: 1.01 to 1.53), and IBD Fatigue score (OR = 1.72, 95%CI: 1.23 to 2.42) were independent risk factors of depression-related prevalence among patients with PFCD (P < 0.05). Multiple linear regression analysis revealed that the increasing perianal modified Van Assche index (β value = 0.166, 95%CI: 0.02 to 0.31) and decreasing IBDQ score (β value = -0.116, 95%CI: -0.14 to -0.09) were independently associated with the severity of depression (P < 0.05). CONCLUSION Depressive symptoms in PFCD patients have significantly high prevalence. PDAI score, modified Van Assche index, quality of life, and fatigue severity were the main independent risk factors.

Tear film hTERT and corneal nerve characteristics in dry eye disease

ABSTRACT Clinical relevance The behaviour of human telomerase reverse transcriptase (hTERT) in tears reflects its role in maintaining the ocular surface homoeostasis, as it is increased after the initial fitting of contact lenses and post-overnight lid closure. Background hTERT has been shown to respond to cellular stress in neurodegenerative diseases and to enhance axonal regeneration after peripheral axotomy in an animal model. This work investigated whether the behaviour of hTERT in the tear film reflects ocular surface inflammation and neuronal changes in the presence of dry eye disease. Methods Flush tears were collected from 18 participants with dry eye disease (14 females, 4 males, mean age 34.7 ± 5.2 years) and from 18 healthy participants without dry eye disease (8 females, 10 males, mean age 31.9 ± 5.8 years). Dry eye disease status was defined using the TFOS DEWS II diagnostic criteria. hTERT levels in tears were measured using enzyme-linked immunosorbent assays. Confocal images were taken at the level of the subbasal nerve plexus at the central cornea and at the inferior whorl, and the densities of corneal immune cells were evaluated as well as corneal nerve morphology metrics using a fully automated technique (University of Manchester, United Kingdom). Results In participants with dry eye disease, hTERT levels were significantly higher compared to controls (median [interquartile range]: 434 [320–600] ng/ml, and 184 [42–390] ng/ml, respectively, p = 0.01). Increased nerve fibre width at the inferior whorl, was seen in those with dry eyes (0.0219 [0.0214–0.0236] mm/mm compared to controls 0.0217 [0.0207 0.0222] p < 0.001), but no significant differences were found in the density of corneal immune cells. Conclusions hTERT levels were elevated in participants with dry eye disease, and this was accompanied by increased nerve thickness in the inferior cornea. The hTERT response may reflect the stress induced to the ocular surface and corneal nerves due to having dry eye disease.

Proteomic Blood Profiles Obtained by Totally Blind Biological Clustering in Stable and Exacerbated COPD Patients

Although Chronic Obstructive Pulmonary Disease (COPD) is highly prevalent, it is often underdiagnosed. One of the main characteristics of this heterogeneous disease is the presence of periods of acute clinical impairment (exacerbations). Obtaining blood biomarkers for either COPD as a chronic entity or its exacerbations (AECOPD) will be particularly useful for the clinical management of patients. However, most of the earlier studies have been characterized by potential biases derived from pre-existing hypotheses in one or more of their analysis steps: some studies have only targeted molecules already suggested by pre-existing knowledge, and others had initially carried out a blind search but later compared the detected biomarkers among well-predefined clinical groups. We hypothesized that a clinically blind cluster analysis on the results of a non-hypothesis-driven wide proteomic search would determine an unbiased grouping of patients, potentially reflecting their endotypes and/or clinical characteristics. To check this hypothesis, we included the plasma samples from 24 clinically stable COPD patients, 10 additional patients with AECOPD, and 10 healthy controls. The samples were analyzed through label-free liquid chromatography/tandem mass spectrometry. Subsequently, the Scikit-learn machine learning module and K-means were used for clustering the individuals based solely on their proteomic profiles. The obtained clusters were confronted with clinical groups only at the end of the entire procedure. Although our clusters were unable to differentiate stable COPD patients from healthy individuals, they segregated those patients with AECOPD from the patients in stable conditions (sensitivity 80%, specificity 79%, and global accuracy, 79.4%). Moreover, the proteins involved in the blind grouping process to identify AECOPD were associated with five biological processes: inflammation, humoral immune response, blood coagulation, modulation of lipid metabolism, and complement system pathways. Even though the present results merit an external validation, our results suggest that the present blinded approach may be useful to segregate AECOPD from stability in both the clinical setting and trials, favoring more personalized medicine and clinical research.

The E592K variant of SF3B1 creates unique RNA missplicing and associates with high-risk MDS without ring sideroblasts.

Among the most common genetic alterations in the myelodysplastic syndromes (MDS) are mutations in the spliceosome gene SF3B1. Such mutations induce specific RNA missplicing events, directly promote ring sideroblast (RS) formation, and generally associate with more favorable prognosis. However, not all SF3B1 mutations are the same, and little is known about how distinct hotspots influence disease. Here we report that the E592K variant of SF3B1 associates with high-risk disease features in MDS, including a lack of RS, increased myeloblasts, a distinct co-mutation pattern, and a lack of the favorable survival seen with other SF3B1 mutations. Moreover, compared to other hotspot SF3B1 mutations, E592K induces a unique RNA missplicing pattern, retains an interaction with the splicing factor SUGP1, and preserves normal RNA splicing of the sideroblastic anemia genes TMEM14C and ABCB7. These data have implications for our understanding of the functional diversity of spliceosome mutations, as well as the pathobiology, classification, prognosis, and management of SF3B1-mutant MDS.

Assessment of smell disturbances 6months after COVID-19 in Polish population.

Considering the frequency and severity of olfactory disorders associated with SARS-CoV-2 infection, attention to the olfactory loss has expanded. The aim of our study was to assess of smell disturbances 6months after COVID-19. The study population consisted of 2 groups: 196 Post-COVID-19 patients who were hospitalized because of COVID-19, control sample-130 patients without reported smell disorders from general population-Bialystok PLUS study. People from both groups were asked to participate in the Sniffin Sticks Test (half year after the disease). Sniffin Sticks Test consisted of 12 standardized smell samples. The participant's test score was counted based on correct scent recognition. Middle/older age was related with lower likelihood of olfaction recovery. The biggest differences in recognition of particular fragrances were observed for: orange and lemon, lemon and coffee (p.adj < 0.001). Patients had the greatest problem in assessing smell of lemon. The comparison of scores between Delta, Omicron, Wild Type, Wild Type Alpha waves showed statistically significant difference between Delta and Wild Type waves (p = 0.006). Duration of the disease (r = 0.218), age (r = -0.253), IL-6 (r = -0.281) showed significant negative correlations with the score. Statistically significant variables in the case of smell disorders were Omicron wave (CI = 0.045-0.902; P = 0.046) and Wild Type wave (CI = 0.135-0.716; P = 0.007) compared to Delta wave reference. Moreover, patients with PLT count below 150 000/μl had greater olfactory disorders than those with PLT count over 150 000/μl. There are: smell differences between post-COVID-19 patients and healthy population; statistically significant difference between Delta and Wild Type waves in Post-COVID-19 group in score of the Sniffin Sticks Test. Smell disturbances depend on the age, cognitive impairments, clinical characteristics of the COVID-19 disease and sex of the patient.

Amyloid β accelerates age-related proteome-wide protein insolubility.

Loss of proteostasis is a highly conserved feature of aging across model organisms and results in the accumulation of insoluble protein aggregates. Protein insolubility is also a unifying feature of major age-related neurodegenerative diseases, including Alzheimer's Disease (AD), in which hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven generalized protein insolubility as a contributing factor. However, proteins that become insoluble during aging in model organisms are capable of accelerating Aβ aggregation in vitro and lifespan in vivo. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. Specifically, we uncovered that Aβ expression drives proteome-wide protein insolubility in C. elegans, even in young animals, and this insoluble proteome is highly similar to the insoluble proteome driven by normal aging, this vulnerable sub-proteome we term the core insoluble proteome (CIP). We show that the CIP is enriched with proteins that modify Aβ toxicity in vivo, suggesting the possibility of a vicious feedforward cycle in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the geroprotective, gut-derived metabolite, Urolithin A, relieves Aβ toxicity, supporting its use in clinical trials for dementia and age-related diseases.

Efficient IoT-based heart disease prediction framework with Weight Updated Trans-Bidirectional Long Short Term Memory-Gated Recurrent Unit

The integrated system has generated numerous features for the users, like as identifying heart disease by its symptoms, forwarding the information to the doctors regarding the phase of the probability of disease as well as aiding to fix it. When an emergency situation exists, the system forwards the emergency alert to the respective doctor. Moreover, the automatic system is needed to diagnose heart disease but, the larger data is not sufficient to train the model. Thus, the Internet of Things (IoT) is employed to manage the huge amount of data. Therefore, a novel prediction of heart diseases is implemented with the aid of IoT-based deep learning approaches. Here, the collected data is collected from the three standard databases and then perform preprocessed over the gathered data. Here, the IoT assisted deep learning model is performed to predict heart related diseases accurately. Further, the acquired features of heart diseases are selected using the developed Hybrid Chameleon Electric Fish Swarm Optimization (HCEFSO) via Chameleon Swarm Algorithm (CSA) and Electric Fish Optimization (EFO). Then, the optimally selected features are fed to the training process, where the Trans-Bi-directional Long Short-Term Memory with Gated Recurrent Unit (Trans-Bi-LSTM-GRU) is adopted for predicting heart diseases. Here, the weights are updated with the developed HCEFSO while validating the training phase. The trained Trans-Bi-LSTM-GRU network is used in the testing phase for predicting heart diseases.

Impact of distinct cognitive domains on gait variability in individuals with mild cognitive impairment and dementia.

Gait variability is a common feature in neurodegenerative diseases and has been linked to cognitive impairment. Despite this link, the influence of specific cognitive domains, such as memory, visual spatial skills, executive function, and verbal function on gait variability is not well-understood. To investigate the predictive value of these specific cognitive domains on gait variability in people with mild cognitive impairment (MCI) and dementia during preferred and dual task walking. One hundred and two participants with either MCI or dementia underwent a comprehensive cognitive assessment and completed preferred and dual-task walking trials on a pressure-sensing walkway. Gait variability was assessed using the PKMAS software. Lower extremity function was evaluated with a self-reported validated scale. Our findings indicate that only visual spatial abilities had a moderate predictive value on gait variability [F (1, 78) = 17.30, p < 0.01, r = 0.43], both in preferred pace walking (70% direct effect) and dual-task walking (90% direct effect) (p's < 0.05). Additionally, lower extremity functional skills had a significant indirect effect (30%) on gait variability in preferred walking contexts. For individuals diagnosed with MCI or dementia, increased gait variability may be driven by deficits in visual spatial processing. An increased understanding of the role of visual spatial processing in gait variability can aid in the assessment and management of individuals with MCI or dementia, potentially leading to targeted interventions to improve mobility and safety.

IMPROVING THE KNOWLEDGE, RISK STRATIFICATION AND OUTCOMES IN ADVANCED HEART FAILURE. THE ISMETT HEART FAILURE REGISTRY

Abstract Background Advanced heart failure (AdHF) accounts for approximately 10% of patients in HF clinics worldwide. Clinical management of patients with AdHF remains challenging and most of the available studies focus on chronic but not advanced HF. Registry studies may provide important insights into this specific population. Methods All consecutive patients referred to our centre for AdHF therapies candidacy (left ventricular assist device (LVAD), heart transplant (HTx)) are prospectively studied and enrolled in the registry. On the same day, all patients undergo a comprehensive clinical and instrumental examination, including electrocardiogram, echocardiography, extended laboratory tests and right heart catheterisation. Most patients also undergo a cardiopulmonary exercise test and, in the case of a non–ischaemic aetiology, cardiac magnetic resonance imaging and genetic testing, if not already performed. Echocardiography is also performed to assess advanced echocardiographic measures (biventricular and atrial strain, myocardial work, 3–D chambers assessment). Results Forty–five patients were enrolled from March 1, 2023 to December 22, 2023 (enrolment rate 4.5 patients/month). Mean age was 54 years and 2/3 were male. Median disease duration was 69 (28–165) months. Non–ischemic HF was the most common aetiology with a NYHA IV prevalence of 4% (all others were in NYHA III). 31% of patients had chronic kidney disease and overall liver function was preserved. 67% of patients were treated with sacubitril/valsartan, &amp;gt; 90% were taking beta–blockers (median dose 4.8 mg bisoprolol–equivalent dose) and 84% SGLT2 inhibitors. Both standard and advanced echocardiography showed features of advanced disease. Over a median follow–up of 4 (2 – 6) months 2 (4%) patients died, 5 (11%) underwent urgent HTx and 8 (18%) underwent LVAD implantation. For most variables, there was a trend showing that patients with events were sicker but, currently, the sample size limited the statistical power. Conclusions A systematic comprehensive evaluation of patients with AdHF evaluated for advanced HF therapies could help to reduce the knowledge gap for this high–risk HF population.

Chylomicron retention disease caused by SAR1B gene variations in 2 cases and literatures review

Objective: To summarize the genotype and clinical characteristics of chylomicron retention disease (CMRD) caused by secretion associated Ras related GTPase 1B (SAR1B) gene variations. Methods: Clinical data and genetic testing results of 2 children with CMRD treated at Children's Hospital of Fudan University and Jiangxi Provincial Children's Hospital from May 2022 to July 2023 were summarized. To provide an overview of the clinical and genetic characteristics of CMRD caused by SAR1B gene variations, all of the literature was searched and reviewed from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China VIP database, China Biology Medicine disc and PubMed database (up to January 2024) with "chylomicron retention disease" "Anderson disease" or "Anderson syndrome" as the search terms. All relevant literatures were reviewed to summarize the clinical and genetic features of CMRD caused by SAR1B gene variations. Results: One 11-year-old boy and one 4-month-old girl with CMRD. Both patients had lipid malabsorption, failure to thrive, decreased cholesterol, elevated transaminase and creatine kinase, and vitamin E deficiency, with homozygous variations (c.224A>G) and compound heterozygous variations (c.224A>G and c.554G>T) in SAR1B gene, respectively. Case 1 was followed up for over a month, and he still occasionally experienced lower limb muscle pain. Case 2 was followed up for more than a year, and her had caught up to normal levels. Both patients had no other significant discomfort. Literature search retrieved 0 Chinese literature and 22 English literatures. In addition to the 2 cases reported in this study, a total of 51 patients were identified as CMRD caused by SAR1B gene variations. Twenty-one types of SAR1B variants 10 missense, 4 nonsense, 3 frameshift, 1 in-frame deletion, 1 splice, 1 gross deletion, and 1 gross insertion-deletion were found among the 51 CMRD cases. Among all the patients, 49 cases had lipid malabsorption (43 cases had diarrhea or fatty diarrhea, 17 cases had vomiting, and 12 cases had abdominal distension), 45 cases had lipid soluble Vitamin deficiency (43 cases had Vitamin E deficiency, 10 cases had Vitamin A deficiency, 9 case had Vitamin D deficiency, and 5 cases had Vitamin K deficiency), 35 cases had failure to thrive, 32 cases had liver involvement (32 cases had elevated transaminases, 5 cases had fatty liver, and 3 cases had hepatomegaly), 29 cases had white small intestinal mucosa under endoscopy, and 17 cases had elevated creatine kinase, 14 cases had neuropathy, 5 cases had ocular lesions, 2 cases had acanthocytosis, 1 case had decreased cardiac ejection fraction, and 1 case was symptom-free. Conclusions: Early infancy failure to thrive and lipid malabsorption are common issues for CMRD patients. The Laboratory tests are characterized by hypocholesterolemia with or without fat-soluble vitamin deficiency, elevated liver enzymes and (or) creatine kinase. Currently, missense variations are frequent among the primarily homozygous SAR1B genotypes that have been described.

Understanding Role of Pesticides in Development of Parkinson's Disease: Insights from Drosophila and Rodent Models.

Parkinson's disease is a neurodegenerative illness linked to ageing, marked by the gradual decline of dopaminergic neurons in the midbrain. The exact aetiology of Parkinson's disease (PD) remains uncertain, with genetic predisposition and environmental variables playing significant roles in the disease's frequency. Epidemiological data indicates a possible connection between pesticide exposure and brain degeneration. Specific pesticides have been associated with important characteristics of Parkinson's disease, such as mitochondrial dysfunction, oxidative stress, and α-synuclein aggregation, which are crucial for the advancement of the disease. Recently, many animal models have been developed for Parkinson's disease study. Although these models do not perfectly replicate the disease's pathology, they provide valuable insights that improve our understanding of the condition and the limitations of current treatment methods. Drosophila, in particular, has been useful in studying Parkinson's disease induced by toxins or genetic factors. The review thoroughly analyses many animal models utilised in Parkinson's research, with an emphasis on issues including pesticides, genetic and epigenetic changes, proteasome failure, oxidative damage, α-synuclein inoculation, and mitochondrial dysfunction. The text highlights the important impact of pesticides on the onset of Parkinson's disease (PD) and stresses the need for more research on genetic and mechanistic alterations linked to the condition.

Graphene Oxide, a Prominent Nanocarrier to Reduce the Toxicity of Alzheimer's Proteins: A Revolution in Treatment.

Graphene oxide, a derivative of graphene, has recently emerged as a promising nanomaterial in the biomedical field due to its unique properties. Its potential as a nanocarrier in the treatment of Alzheimer's disease represents a significant advancement. This abstract outlines a study focused on utilizing graphene oxide to reduce the toxicity of Alzheimer's proteins, marking a revolutionary approach in treatment strategies. The pathological features of Alzheimer's disease, primarily focusing on the accumulation and toxicity of amyloid-beta proteins, have been described in this review. These proteins are known to form plaques in the brain, leading to neuronal damage and the progression of Alzheimer's disease. The current therapeutic strategies and their limitations are briefly reviewed, highlighting the need for innovative approaches. Graphene oxide, with its high surface area, biocompatibility, and ability to cross the blood-brain barrier, is introduced as a novel nanocarrier. The methodology involves functionalizing graphene oxide sheets with specific ligands that target amyloid-beta proteins. This functionalization facilitates the binding and removal of these toxic proteins from the brain, potentially alleviating the symptoms of Alzheimer's disease. Preliminary findings indicate a significant reduction in amyloid-beta toxicity in neuronal cell cultures treated with graphene oxide nanocarriers. The study also explores the biocompatibility and safety profile of graphene oxide in biological systems, ensuring its suitability for clinical applications. It calls for further research and clinical trials to fully understand and harness the benefits of this nanotechnology, paving the way for a new era in neurodegenerative disease therapy.

Altered skeletal muscle function and beneficial effects of exercise training in a rat model of induced pulmonary emphysema.

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction and development of emphysema. Among the comorbidities associated with COPD, skeletal muscle dysfunction is known to affect exercise capacity and the survival rate of patients. Pulmonary rehabilitation (PR), via exercise training, is essential for COPD patients. However, the response to PR is most often moderate. An animal model that recapitulates critical features of chronic human disease and provides access to muscle function should therefore be useful to improve PR benefits. We used a rat model of induced emphysema based on pulmonary instillations of elastase (ELA) and lipopolysaccharides (LPS). We assessed the long-term effects of ELA/LPS and the potential effectiveness of endurance training on the skeletal muscle function. Invivo strength of the animals, and exvivo contractility, endurance, type 1 fiber proportion, fiber cross-sectional area, and capillarization of both soleus and extensor digitorum longus (EDL) were assessed. An impaired overall muscle strength with decreased force, reduced capillarization, and atrophy of type 1 fiber of EDL was observed in ELA/LPS rats. Soleus was not affected. Endurance training was able to reduce fatigability, and increase type 1 fiber proportion and capillarization of soleus, and improve force, endurance, and capillarization of EDL in control and ELA/LPS rats. Our rat model of induced emphysema, which shares some features with the phenotype present in patients with COPD, could represent a suitable model to study skeletal muscle dysfunction and the effects of exercise training on muscle function in patients.

ROF-2 as an Aggregation-Induced Emission (AIE) Probe for Multi-Target Amyloid Detection and Screening of Amyloid Inhibitors.

Misfolding and aggregation of amyloid peptides into β-structure-rich fibrils represent pivotal pathological features in various neurodegenerative diseases, including Alzheimer's disease (AD), type II diabetes (T2D), and medullary thyroid carcinoma (MTC). The development of effective amyloid detectors and inhibitors for probing and preventing amyloid aggregation is crucial for diagnosing and treating debilitating diseases, yet it poses significant challenges. Here, an aggregation-induced emission (AIE) molecule of ROF2 with multifaceted functionalities as an amyloid probe and a screening tool for amyloid inhibitors using different biophysical, cellular, and worm assays, are reported. As an amyloid probe, ROF2 outperformed ThT, demonstrating its superior sensing capability in monitoring, detecting, and distinguishing amyloid aggregates of different sequences (Amyloid-β, human islet amyloid polypeptide, or human calcitonin) and sizes (monomers, oligomers, or fibrils). More importantly, the utilization of ROF2 as a screening molecule to identify and repurpose cardiovascular drugs as amyloid inhibitors is introduced. These drugs exhibit potent amyloid inhibition properties, effectively preventing amyloid aggregation and reducing amyloid-induced cytotoxicity both in cells and nematode. The findings present a novel strategy to discovery AIE-based amyloid probes and to be used to repurpose amyloid inhibitors, expanding diagnostic and therapeutic options for neurodegenerative diseases while addressing vascular congestion and amyloid aggregation risks.

Expert assessment of ChatGPT’s ability to generate illness scripts: an evaluative study

BackgroundAn illness script is a specific script format geared to represent patient-oriented clinical knowledge organized around enabling conditions, faults (i.e., pathophysiological process), and consequences. Generative artificial intelligence (AI) stands out as an educational aid in continuing medical education. The effortless creation of a typical illness script by generative AI could help the comprehension of key features of diseases and increase diagnostic accuracy. No systematic summary of specific examples of illness scripts has been reported since illness scripts are unique to each physician.ObjectiveThis study investigated whether generative AI can generate illness scripts.MethodsWe utilized ChatGPT-4, a generative AI, to create illness scripts for 184 diseases based on the diseases and conditions integral to the National Model Core Curriculum in Japan for undergraduate medical education (2022 revised edition) and primary care specialist training in Japan. Three physicians applied a three-tier grading scale: “A” denotes that the content of each disease’s illness script proves sufficient for training medical students, “B” denotes that it is partially lacking but acceptable, and “C” denotes that it is deficient in multiple respects.ResultsBy leveraging ChatGPT-4, we successfully generated each component of the illness script for 184 diseases without any omission. The illness scripts received “A,” “B,” and “C” ratings of 56.0% (103/184), 28.3% (52/184), and 15.8% (29/184), respectively.ConclusionUseful illness scripts were seamlessly and instantaneously created using ChatGPT-4 by employing prompts appropriate for medical students. The technology-driven illness script is a valuable tool for introducing medical students to key features of diseases.

Rituximab retention rate in systemic sclerosis: a long term real-life multicenter study.

to report real-life data on rituximab retention-rate as indicator of safety and efficacy in a multicentric national cohort of systemic sclerosis patients. SSc patients treated with rituximab and followed for at least 36 months were included, clinically characterized, and longitudinally monitored. A competing risk analysis with sub-Hazard Ratio(sHR) definition was performed to explore the clinical variables linked to specific cause of rituximab discontinuation. One-hundred-fifty-two SSc-patients (mean age 47.3 ± 12.3 years; females 79.6%; diffuse disease 77.6%; anti-topoisomerase-I positivity 63.2%) were evaluated over a median(IQR) time of 3.3(1.7-5.0) years. The primary indication for rituximab were interstitial lung disease (ILD)(38.8%), worsening skin fibrosis(36.8%), and arthritis(13.8%); 138 patients(90.8%) received more than one rituximab course. The 5-years rituximab retention rate was 59.9%(44.6-64.7%). Clinical response was the most common reason for rituximab discontinuation[5.7(3.7-8.4) per 100 patient-year] and was associated with a shorter disease duration[sHR 0.8(0.7-0.9)], anti-topoisomerase-I negativity[sHR 0.4(0.2-0.9)], previous digital ulcers[sHR 2.6(1.1-6.2] and no history of arthritis[sHR 0.3 (0.1-0.8)]. Treatment failure was the second cause of rituximab discontinuation[3.7(2.2-6.0) per 100 patient-year] and was associated with anti-centromere antibody positivity[sHR 2.8(1.1-7.4)] and anti-topoisomerase-I negativity[sHR 0.2(0.1-0.6)]. Adverse events(AEs) were the less common cause of discontinuation[3.1(1.7-5.2) per 100 patient-year], associated with limited cutaneous subset[sHR 3.4(1.2-9.7)] and previous mycophenolate mofetil treatment[sHR 4.5(1.2-16.3)]. rituximab is a safe and effective treatment in SSc: clinical response emerged as the primary reason for rituximab discontinuation, and AEs had a limited impact on treatment persistence. The identification of specific disease features associated with a response to rituximab will be useful in the management of SSc-patients.

Nursing care for patients with Alzheimer in Primary Care

Introduction: Alzheimer's is a significant challenge for healthcare systems, due to the increasing global aging population, which requires a comprehensive and patient-centered approach. Objective: The research has the general objective of analyzing nursing care for patients with Alzheimer's in primary care, and the specific objectives of contextualizing Alzheimer's disease and its characteristics; describe the pathophysiology, diagnosis and treatment of Alzheimer's Disease; present the importance of the role of nursing professionals and what interventions are carried out. Methodology: This study is a systematic and integrative literature review, the search was carried out virtually from September 2023 to April 2014, in the databases: Scientific Electronic Library Online (Scielo), PUBMED (National Library of Medicine), Latin American and Caribbean Literature in Health Sciences (LILACS) and BDENF. Results: The 15 articles selected for results and discussion addressed the contextualization and characteristics of Alzheimer's disease, described the pathophysiology, diagnosis and treatment and concluded by integrating nursing into primary care, in addition to realizing the importance of patient-family monitoring. nursing. Conclusion: During primary care, nursing collaboration is crucial to providing holistic, personalized care to individuals and families affected by this debilitating condition. Recognizing the importance of early diagnosis, education and continuous monitoring, it is clear that nurses play a central role in the comprehensive approach to Alzheimer's, standing out as agents of change and support amidst the growing challenges faced by this increasingly growing population. vulnerable.

Disease-Associated Q159X Mutant Prion Protein Is Sufficient to Cause Fatal Degenerative Disease in Mice.

PRNP Q160X is one of the five dominantly inheritable nonsense mutations causing familial prion diseases. Till now, it remains unclear how this type of nonsense mutations causes familial prion diseases with unique clinical and pathological characteristics. Human prion protein (PrP) Q160X mutation is equivalent to Q159X in mouse PrP, which produces the mutant fragment PrP1-158. Through intracerebroventricular injection of recombinant adeno-associated virus in newborn mice, we successfully overexpressed mouse PrP1-158-FLAG in the central nervous system. Interestingly, high level PrP1-158-FLAG expression in the brain caused death in these mice with an average survival time of 60 ± 9.1 days. Toxicity correlated with levels of PrP1-158-FLAG but was independent of endogenous PrP. Histopathological analyses showed microgliosis and astrogliosis in mouse brains expressing PrP1-158-FLAG and most of PrP1-158-FLAG staining appeared intracellular. Biochemical characterization revealed that the majority of PrP1-158-FLAG were insoluble and a significant part of PrP1-158-FLAG appeared to contain an un-cleaved signal peptide that may contribute to its cytoplasmic localization. Importantly, an ~10-kDa proteinase K-resistant PrP fragment was detected, which was the same as those observed in patients suffering from this type of prion diseases. To our knowledge, this is the first animal study of familial prion disease caused by Q159X that recapitulates key features of human disease. It will be a valuable tool for investigating the pathogenic mechanisms underlying familial prion diseases caused by nonsense mutations.