Early Stages Of Disease Research Articles

Diagnosis and management of a more advanced stage of preclinical myxomatous mitral valve disease in dogs without echocardiography.

Myxomatous mitral valve disease (MMVD) is the most common cardiac disease in dogs. Appropriate diagnosis and staging can be performed by means of an echocardiographic examination. Early disease stages might be accompanied by valvular insufficiency and, in more advanced phases, by cardiac dilatation. A correct diagnosis of this preclinical phase and identification of cardiac enlargement should be carried out in order to advise appropriate medical treatment. When echocardiography is not available or declined by the dog's owners, alternative methods to identify the disease and predict clinically relevant cardiomegaly, can be performed. Among these, cardiac auscultation and assessment of heart murmur intensity, cardiac dimensions obtained by thoracic radiography, by means of vertebral heart size, and cardiac biomarkers, in particular N-terminal pro-B-type natriuretic peptide (NT-proBNP), can be carried out as single tests or in combination, in order to identify dogs with increased risk of congestive heart failure, and needing an early treatment with pimobendan. In particular, a heart murmur intensity ≥3/6 (moderate or louder), a vertebral heart size ≥11,5 units obtained from a latero-lateral thoracic radiographic view, and plasma concentrations of N-terminal pro-B-type natriuretic peptide value > 1100 pmol/l, are findings that might suggest presence of clinically relevant cardiomegaly with a good specificity. A practical algorithm to guide clinicians in managing dogs with suspicion of valvular disease has been created, starting from clinical examination, and using the aforementioned additional tests in order to advise the appropriate controls and therapy.

TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV.

Loss of function mutations in the lysosomal channel TRPML-1 cause mucolipidosis type IV (MLIV), a rare lysosomal storage disease characterized by neurological defects, progressive vision loss, and achlorhydria. Recent reports have highlighted kidney disease and kidney failure in patients with MLIV during the second to third decade of life; however, the molecular mechanisms driving kidney dysfunction remain poorly understood. A cross-sectional review of medical records from 21 MLIV patients (ages 3-43 years) was conducted to assess kidney function impairment. Additionally, we examined the kidney phenotype of MLIV mice at various ages, along with human kidney cells silenced for TRPML-1 and primary tubular cells from wild-type and MLIV mice. Immunohistology and cell biology approaches were used to phenotype nephron structure, the endolysosomal compartment, and inflammation. Kidney function was assessed through proteomic analysis of mouse urine and in vivo renal filtration measurements. Of the 21 MLIV patients only adults were diagnosed with stage 2-3 chronic kidney disease. Laboratory abnormalities included decreased eGFR, higher levels BUN/Creatine in bloodand proteinuria. In MLIV mice, we observed significant alterations in endolysosomal morphology, function, and impaired autophagy in proximal and distal tubules. This led to the accumulation of megalin (LRP2) in the subapical region of proximal tubular cells, indicating a block in apical receptor-mediated endocytosis. In vivo and in vitro experiments confirmed reduced fluid-phase endocytosis and impaired uptake of ligands, including β-lactoglobulin, transferrin, and albumin in MLIV proximal tubular cells. Urine analysis revealed tubular proteinuria and enzymuria in mice with MLIV. Additionally, early-stage disease was marked by increased inflammatory markers, fibrosis, and activation of the pro-inflammatory transcription factor NF-κB, coinciding with endolysosomal defects. Importantly, AAV-mediated TRPML-1 gene delivery reversed key pathological phenotypes in Mucolipidosis type IV mice, underscoring TRPML-1's critical role in kidney function. Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV, providing new insights into its pathogenesis and potential therapeutic targets.

TTF-1 negativity in synchronous M1b/M1c wildtype lung adenocarcinoma brain metastases predicts worse survival with increased risk of intracranial progression.

Thyroid Transcription Factor-1 (TTF-1) expression in lung adenocarcinoma (LUAD) has been studied for its prognostic value in early-stage and metastatic disease. Its role in brain metastasis remains unexplored. This study investigates the predictive value and association of TTF-1 status with clinicopathological variables in patients with synchronous LUAD brain metastases. In this bicentric retrospective study, 245 patients with newly diagnosed, treatment-naïve brain metastasis undergoing resection were included. Patient data were retrieved from electronic records. Outcomes included overall and progression-free survival. Statistical analysis included Kaplan-Meier estimates and Cox proportional hazards regression. Mean Ki67 index in TTF-1 negative patients was 43% [95% CI 38-48%] compared to 32% [95% CI 29-35%] in TTF-1 positive (TTF-1 +) patients (p < 0.001). Tumor volume was significantly larger in TTF-1 negative (TTF-1-) patients (mean volume 24mL [95% CI 18-31mL]) vs. 15mL [95% CI 12-17mL] in TTF-1 + patients (padjust = 0.003). Perifocal edema was smaller in TTF-1- patients (mean volume: 58mL [95% CI 45-70mL]) vs. 84mL [95% CI 73-94mL] in TTF-1 + patients (padjust = 0.077). Tumor and edema volume did not correlate. TTF-1- patients showed worse overall, intracranial, and extracranial progression-free survival. In a multivariable Cox model, positive TTF-1 status was independently associated with improved outcomes. Negative TTF-1 status was associated with increased hazard for intracranial disease progression compared to extracranial progression. In synchronous LUAD brain metastases, TTF-1 negativity reflects an aggressive phenotype with larger proliferation capacity and tumor volume. Future research should explore the underlying cellular and molecular alterations of this phenotype.

Patient-Centric Mobile Medical Services Accessed Through Smartphones in the Top 100 Chinese Public Hospitals: Cross-Sectional Survey Study.

Smartphone-based technology has been used to enhance the delivery of health care services to the public in numerous countries. This study aims to investigate the application of patient-centric mobile medical services accessed through smartphones in the top 100 Chinese public hospitals. Data on 124 tertiary public hospitals, ranked among the top 100 by the China Hospital Science and Technology Evaluation Metrics of the Chinese Academy of Medical Sciences (2019) and China's Hospital Rankings of the Hospital Management Institute of Fudan University (2019), were collected from the WeChat platform (Tencent Inc), mobile phone apps, and official websites until February 10, 2021. A total of 124 tertiary public hospitals, all of which were among the top 100 hospitals according to the 2 ranking lists, were selected for this study. Almost all (122/124, 98.39%) of the hospitals offered basic services such as appointment scheduling, registration, and health education. The majority also provided online access to test reports (95/124, 76.61%), consultations (72/124, 58.06%), and prescriptions (61/124, 49.19%). Among the hospitals offering online prescriptions, the majority (54/61, 88.52%) supported home delivery through third-party carriers. Slightly less than half (57/124, 45.97%) used artificial intelligence for medical guidance. Only a small fraction (8/124, 6.45%) managed chronic diseases through online monitoring and supervision by experienced doctors. Approximately half (60/124, 48.39%) of the included hospitals were officially licensed as internet hospitals approved to provide full online services. Hospitals with official internet hospital licenses provided more extensive digital health offerings. A significantly higher proportion of approved hospitals offered online consultations (29.69% vs 88.33%, r=43.741; P<.001), test reports (62.5% vs 91.67%, r=14.703; P<.001), and chronic disease management (1.56% vs 11.67%, r=5.238; P<.05). These officially approved hospitals tended to provide over 6 mobile medical services, mainly in the regions of Shanghai and Guangdong. This geographic distribution aligned with the overall layout of hospitals included in the study. Patient-centric mobile medical services offered by the top 100 Chinese public hospitals accessed through smartphones primarily focus on online appointment scheduling, registration, health education, and accessing test reports. The most popular features include online consultations, prescriptions, medication delivery, medical guidance, and early-stage chronic disease management. Approved internet hospitals offer a significantly greater variety of patient-centric mobile medical services compared with unapproved ones.

The role of the glucagon-FGF21 axis in improving beta cell function during glucose intolerance and SGLT2 inhibition.

Although primarily secreted by the liver, Fibroblast Growth Factor 21 (FGF21) is also expressed in the pancreas, where its function remains unclear. This study aims to elucidate the role of the glucagon-FGF21 interaction in the metabolic benefits of SGLT2 inhibition (SGLT2i) and hypothesizes it is key to enhancing glucose and lipid metabolism in individuals with glucose intolerance or type 2 diabetes (T2D). FGF21, FGF1R, and β-klotho expression in human pancreas was analysed by RNAscope, qPCR and immunofluorescent techniques. Glucose-stimulated insulin secretion (GSIS) assay was used to investigate the effects of recombinant FGF21 (rFGF21) on islets from donors with glucose intolerance or T2D. To explore the role of the glucagon-FGF21 axis in the benefits of SGLT2i, we used WT and Sglt2 knockout (KO) mice fed a chow diet (CD) or a high-fat diet (HFD) and chronically treated with vehicle or dapagliflozin. Chronic rFGF21 treatment enhanced GSIS in islets from donors with glucose intolerance, with increased FGFR1 expression, suggesting FGF21's greater efficacy in the early stages of disease. In diet-induced insulin-resistant mice, dapagliflozin reduced postprandial glycaemia and elevated plasma glucagon and FGF21 levels. Sglt2 KO mice on a CD showed increased fasting plasma glucagon without changes in FGF21. In diet-induced insulin-resistant Sglt2 KO mice, elevated glucagon and FGF21 levels paralleled chronic dapagliflozin treatment, indicating similar metabolic adaptations in both models. Our findings indicate FGF21 as a crucial mediator in liver-pancreas crosstalk, improving lipid and glucose metabolism, enhancing pancreatic function, and potentiating the therapeutic efficacy of SGLT2i, thereby representing a target for prediabetes treatment.

Andrographolide prevents renal fibrosis via decelerating lipotoxicity-mediated premature senescence of tubular epithelial cells

Excessive lipid accumulation often occurs in the early stage of chronic kidney disease (CKD) which is prone to induce oxidative stress and mitochondrial damage, promoting the progression of kidney fibrosis. Andrographolide (AP), a multifunctional natural terpenoids derived from Andrographis paniculate, has been suggested to play beneficial roles in metabolic disorders-associated disease. Here, we reported that AP effectively counteracts tubule injury and interstitial fibrosis in mice fed with a long-term high-fat diet (HFD). AP treatment decreased HFD-induced lipid accumulation in kidney parenchyma and attenuated lipotoxicity-mediated oxidative stress and mitochondrial dysfunction, resulting in a marked decrease in of tubular cell senescence. Importantly, AP inhibited senescence-associated secretory phenotype (SASP) secretion by senescent tubular cells, and in turn suppressed proliferation and activation of fibroblasts in a paracrine effect. Furthermore, we revealed that AP functions as an AMP-activated protein kinase (AMPK) activator to ameliorate renal lipid accumulation through coordinately modulating AMP-activated protein kinase AMPK target genes. By stimulation of AMPK activity, AP protects injured kidney against tubular cell senescence and fibroblast activation. These results suggest the potential therapeutic application of AP in the prevention and treatment of CKD, highlighting the promising drug strategy of targeting the lipotoxicity-mediated premature senescence in tubular cells.

Genetics and Neuropathology of Neurodegenerative Dementias.

This article provides an overview of the current understanding of the genetic and pathologic features of neurodegenerative dementias, with an emphasis on Alzheimer disease and related dementias. In recent years, there has been substantial progress in genetic research, contributing significant knowledge to our understanding of the molecular risk factors involved in neurodegenerative dementia syndromes. Several genes have been linked to monogenic forms of dementia (eg, APP, PSEN1, PSEN2, SNCA, GRN, C9orf72, MAPT) and an even larger number of genetic variants are known to influence susceptibility for developing dementia. As anti-amyloid therapies for patients with early-stage Alzheimer disease have entered the clinical arena, screening for the apolipoprotein E ε4 high-risk allele has come into focus, emphasizing the importance of genetic counseling. Similarly, advances in the pathologic classifications of neurodegenerative dementia syndromes and molecular pathology highlight their heterogeneity and overlapping features and provide insights into the pathogenesis of these conditions. Recent progress in neurogenetics and molecular pathology has improved our understanding of the complex pathogenetic changes associated with neurodegenerative dementias, facilitating improved disease modeling, enhanced diagnostics, and individualized counseling. The hope is that this knowledge will ultimately pave the way for the development of novel therapeutics.

Minimally Invasive Surgery for the Management of Ovarian Cancer

OBJECTIVE: To examine perioperative and survival outcomes of patients with ovarian cancer managed by minimally invasive surgery compared with laparotomy in the context of 1) early-stage epithelial ovarian cancer, 2) primary cytoreduction for advanced disease, and 3) interval debulking after neoadjuvant chemotherapy. DATA SOURCES: A literature search was conducted PubMed, MEDLINE and ClinicalTrials.gov, Web of Science, Cochrane Library, and meeting abstract libraries (International Gynecological Cancer Society, Society of Gynecologic Oncology, American Society of Clinical Oncology) from 1994, the year of the first published laparoscopic clinical study in ovarian cancer, to May 2024. Studies that compared minimally invasive surgery with laparotomy for staging of ovarian cancer and reported perioperative or survival outcomes data were included. Single-arm studies, case studies, meeting abstracts, and studies involving borderline tumors, fertility-sparing surgery, or management of recurrent disease were excluded. METHODS OF STUDY SELECTION: Three authors independently screened citations for relevance and inclusion and exclusion criteria and assessed the risk of bias of individual studies using the methodologic index for nonrandomized studies criteria for nonrandomized studies. TABULTATION, INTEGRATION, AND RESULTS: From a total of 2,777 identified citations, 36 nonrandomized studies were included: 21 early-stage, five primary debulking for advanced stages, seven interval debulking after neoadjuvant chemotherapy, and three with heterogeneous populations. No randomized studies were identified. For early-stage cancer, nine studies found no difference in progression-free survival (risk ratio [RR] 1.05, 95% CI, 1.00–1.10, I 2=34.7%, P=.151), and 12 studies found no difference in overall survival (RR 1.00, 95% CI, 0.98–1.03, I 2=49.7%, P=.025). For primary debulking of advanced disease, rate of optimal debulking (five studies) (RR 1.11, 95% CI, 1.00–1.25, I 2=41.5%, P=.144) slightly favored minimally invasive techniques. For interval debulking, there was no difference in rates of optimal debulking (five studies) (RR 1.03, 95% CI, 0.96–1.11, I 2=54.6%, P&lt;.051) between the two surgical modalities. CONCLUSION: The inclusion of observational studies in this analysis with a fair amount of bias warrants caution in the interpretation of the findings. However, minimally invasive surgery may offer some perioperative advantages over laparotomy and may be an acceptable alternative for selected patients. For early-stage disease, there was no difference in survival outcomes between minimally invasive surgery and laparotomy. For those with advanced disease, rates of optimal debulking were similar. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022359051.

Mind's eye in the Alzheimer's disease spectrum continuum.

Visual mental imagery (VMI) is the ability to represent stimuli in the mind without sensory visual input. Previous studies have shown alterations in VMI in Alzheimer's disease (AD). However, VMI has not been investigated in the AD prodromal stage, mild cognitive impairment (MCI). We investigated VMI ability in mild AD and MCI patients, hypothesizing that VMI ability could be compromised since early disease stage. We enrolled 14 patients with mild AD, 19 amnestic MCI (aMCI), and 23 healthy control subjects (HC), matched for sex, age, and education. VMI assessment included: 1) the O'clock test that allows disentangling the possible role of visuo-perceptual difficulties in the VMI task's performance; 2) a modified version of The Complete Visual Mental Imagery Battery (CVMIB), including tasks evaluating the different VMI processes (generation, maintenance, inspection and transformation). Results indicated that AD patients performed worse than HC in both perceptual and imaginal tasks of the O'clock test and in all CVMIB's tasks but maintenance. On the contrary, aMCI patients showed difficulties in the generation process and in the imaginal task of the O'clock test. Visual images generation, inspection and transformation processes are impaired in mild AD. Moreover, the generation process is selectively impaired in aMCI patients, suggesting that VMI deficits are already present in the prodromal stage of AD.

A Review of Current and Future Antibody Drug Conjugates in Breast Cancer.

Antibody-drug conjugates (ADCs) are a novel class of anti-cancer agents that have changed the standard of care for patients with breast cancer. Their targeted approach delivers potent anti-cancer drugs to cancer cells bearing specific surface antigens, thereby maximizing anti-cancer effects and minimizing systemic toxicity. Currently, there are three ADCs available for use in breast cancer: trastuzumab emtansine for HER2 positive breast cancer (early stage and metastatic), trastuzumab deruxtecan for HER2 positive and HER2 low breast cancer (metastatic) and sacituzumab govitecan for triple negative and hormone receptor positive (HR +), HER2 negative breast cancer(metastatic). Trials have shown that these drugs have improved both progression free survival and overall survival in the metastatic setting, and trastuzumab emtansine has improved overall survival in early-stage breast cancer as well. The future of this class of compounds is very exciting. This field is rapidly evolving with new ADCs being investigated and clinical trials looking at the use of known ADCs in earlier stage disease.

Lincomycin as a growth-promoting antibiotic induces metabolic and immune dysregulation in animals

Since animal growth promoters (AGPs) are used in large quantities and commonly released to the environment from animal farms, it is necessary to determine whether such agents should be regarded as an environmental toxin that poses a threat to the ecosystem and health risk to wildlife. In this study, a multi-omics approach was employed to explore the effects of a representative AGP, lincomycin, on key metabolic and physiological functions of animals, using a mouse model. The results indicated that exposure to lincomycin resulted in a significant increase in growth rate of mice (50.11 %) over an 8 weeks period, during which significant decrease (61.94 %) and increase (68.64 %) in the relative abundance of Firmicutes and Escherichia coli, respectively, was observed in the gut microbiota, indicating that the gut microbiota structure has been altered. Moreover, the mice exhibited altered lipid profiles and liver damage suggestive of early-stage non-alcoholic fatty liver disease (NAFLD). Disruptions in blood glucose and insulin levels associated with type 2 diabetes mellitus (T2DM) were also observed. Furthermore, lincomycin was found to cause suppression in inflammatory responses, as evidenced by the downregulation of related genes and elevated inflammatory mediators, potentially resulting in increased susceptibility to microbial infection. Our findings underscore the detrimental effects of lincomycin on animal health and highlight the necessity for comprehensive toxicological assessments of lincomycin and other AGPs before their environmental release.

Circulating Fetuin-A concentrations in rheumatic diseases: asystematic review and meta-analysis.

Rheumatic diseases (RDs) include a broad group of disabling conditions with different phenotypes, from autoimmune to autoinflammatory, degenerative, metabolic or mixed manifestations. With the continuous efforts to identify therapeutic targets for new biologic drugs to treat overt clinical manifestations, research is also focusing on the discovery of new biomarkers to diagnose and manage early disease stages. In this context, we conducted a systematic review and meta-analysis of Fetuin-A (FtA), a glycoprotein synthesized by the liver that participates in several biological processes and has been proposed as a biomarker for several disorders, including rheumatoid arthritis. A systematic search in PubMed, Scopus and Web of Science, from inception to the 24th of August 2024, led to the identification of 13 manuscripts from 219 records; six additional studies were identified through reference hand-search, for a total of 19 studies. There was a significant decrease in FtA concentrations in RD patients (standardized mean difference, SMD = -.91; 95% CI -1.43 to -.39, p = .001), with no substantial contribution from any individual study nor publication bias. The effect size was significantly associated with erythrocyte sedimentation rate, various lipid fractions, geographical area of study conduction, study design and specific type of RD. In conclusion, our study identified significant reductions in FtA concentrations in RD patients versus healthy controls. These alterations were significantly associated with specific study and patient characteristics. Further research is required to identify the exact pathophysiological mechanisms underlying these alterations and the possible utility of measuring FtA for the diagnosis and management of RDs.

Clinical Characteristics and Treatment Outcomes in Unilateral Coats disease – a Global Collaborative Study

To evaluate the clinical outcomes and prognostic factors in unilateral Coats disease in the era of anti-VEGF therapy. Global, multicenter, retrospective case series. 656 eyes of 656 subjects with Coats disease were included in this study. Exclusion criteria were Coats disease secondary to retinitis pigmentosa as well as bilateral cases. Clinical data from patients with Coats disease were collected from 20 ophthalmic practices around the world. We compared early-stage (stage 1-2) and advanced-stage (stage 3-5) Coats disease in terms of clinical characteristics and treatment modalities. Functional outcomes include achieving visual acuity (VA) of 0.3 logMAR or better and VA improvement or stability. Anatomical failure was defined as the development of phthisis, chronic retinal detachment, massive fibrosis, or the requirement for enucleation. Subjects with early-stage disease were significantly older, with a mean age of 17.4 ± 17.8 years, compared to 7.1 ± 7.1 years in the advanced-stage group (p < 0.001). There was a male predominance in both early and advanced stages (84.7%). Advanced disease was associated with a higher incidence of strabismus (20.2% vs. 6.7%, p < 0.001) and leukocoria (12.3% vs. 3.2%, p < 0.001). More subjects with early-stage disease received laser photocoagulation as monotherapy (44.7% vs. 21.1%, p < 0.001). Additionally, early-stage disease received more sessions of intravitreal anti-VEGF injections as adjunct therapy (4.4 ± 6.2 vs. 2.7 ± 2.1, p = 0.005). Factors associated with poorer functional outcomes included worse presenting visual acuity, advanced disease stage, and the presence of a foveal nodule. Worse presenting visual acuity and advanced disease stage was associated with lower likelihood of anatomical success while combination therapy increased the odds of anatomical success. Unilateral Coats disease predominantly affects males, regardless of disease stage. Identifying a foveal nodule is crucial for visual prognosis. Laser photocoagulation remains the primary treatment. While anti-VEGF may prevent enucleation, its role in early-stage disease requires further clarification.

Exploring neuropsychiatric symptoms in Friedreich ataxia

Neuropsychiatric symptoms (NPS) are common in hereditary ataxias as a part of the cerebellar cognitive affective syndrome. In Friedreich ataxia (FRDA), one of the most common hereditary ataxias, depressive symptoms were previously reported, but little is known about other NPS. We aimed to study the presence and severity of a broad range of NPS in individuals with FRDA and assess the relationship between the NPS and the disease severity, cognition, and quality of life and to examine the concordance between the NPS reported by the patients and by their informants. Mild Behavioral Impairment Checklist (MBI-C), a questionnaire designed for screening NPS in the early stages of neurodegenerative diseases, was administered to informants of individuals with FRDA and healthy controls and to people with FRDA themselves. Compared to healthy controls, patients with FRDA scored significantly higher in the total MBI-C score, emotion dysregulation domain (corresponding to depression and anxiety), and decreased motivation domain. When assessed by caregiver, the total MBI-C score and several NPS domains correlated with activities of daily living. Only psychotic symptoms were related to ataxia severity and general cognition. When endorsed by patients, only the relation between few MBI-C domains and quality of life was observed. We found slight to moderate agreement between informant-rated and patient-rated scores. NPS, particularly emotion dysregulation and decreased motivation, are common and clinically relevant in FRDA and should receive more attention due to their potential impact on quality of life and the possibility of therapeutic intervention.

Quality of life in patients with progressive supranuclear palsy: a review of literature and implications for practice.

Progressive supranuclear palsy (PSP) is an atypical form of parkinsonism characterized by tauopathy, manifesting as oculomotor dysfunction, postural instability, akinesia, and cognitive/language impairments. The diagnosis and examination of PSP can be challenging, primarily due to the unclear and underexplored pathomechanisms involved, alongside absence of effective treatments. Clinical variants of PSP is the second most common form of neurodegenerative parkinsonism after Parkinson's disease (PD). It is defined by a symmetrical akinetic-rigid syndrome (atypical parkinsonism) and vertical supranuclear gaze palsy. In contrast to PD, PSP often presents with gait instability, backward falls, and cognitive and behavioral changes at early disease stages. The classification of PSP has evolved since Richardson, Steele, and Olszewski's initial reporting of the condition in 1963, which included a cohort of nine patients. Over the years, the definition of this disorder has evolved to encapsulate a group of patients with distinct clinical variants, notably the classical Richardson syndrome (RS) and several atypical phenotypes, each with significant implications for disease progression and quality of life (QoL). The 2017 Movement Disorder Society Diagnostic Criteria by Hoglinger et al., improved the sensitivity for detecting early and variant PSP presentations and provided more specific differential diagnoses for conditions such as PD and other forms of atypical parkinsonian syndromes. Owing to the growing interest in the disease's progression, evaluating the QoL for patients with PSP has become crucial. This review emphasizes the significance of QoL evaluation and its feasibility for practical implications, serving as an initial foundation for future research focused on the well-being of individuals affected by PSP. Progressive supranuclear palsy (PSP) is an atypical form of parkinsonism characterized by tauopathy, manifesting as oculomotor dysfunction, postural instability, akinesia, and cognitive/language impairments. Diagnosing PSP is challenging owing to the lack of tools for differential examination. Additionally, the pathomechanism of this disease is not sufficiently understood, and no treatment is currently available. Owing to the growing interest in the disease's progression, evaluating the quality of life (QoL) for patients with PSP has become crucial. This review emphasizes the significance of QoL evaluation and its feasibility for practical implications, serving as an initial foundation for future research focused on the well-being of individuals affected by PSP.

Ultrasensitive Detection of Chemokines in Clinical Samples with Graphene-Based Field-Effect Transistors.

Due to their ultra-high sensitivity, solution-gated graphene-based field-effect transistors (SG-GFET) have been proposed for applications in bio-sensing. However, challenges regarding the functionalization of GFETs have prevented their applications in clinical diagnostics so far. Here GFET sensors based on van der Waals (vdW) heterostructures of single-layer graphene layered with a molecular ≈1nm thick carbon nanomembrane (CNM) are presented. The CNM acts as an ultrathin molecular interposer between the graphene channel and the analyte and allows bio-functionalization without impairing the graphene properties including its charge carrier mobility. To achieve specificity and reliability in the detection of biomarkers in real patient samples, the functionalization incorporates biostable aptamers in the non-natural l-configuration and hydrophilic polyethylene glycol for avoiding non-specific adsorption. A rapid (≈5min) detection of the clinically relevant inflammatory mediator CXCL8/IL-8 within the concentration range of 0.5 - 500 pM (5 - 5000 pgml-1) is demonstrated in nasal swab samples collected from patients with respiratory tract infections. This detection range may aid in diagnostics of early-stage infectious diseases making the reported approach promising for the development of future medical tools.

The nitrone compound OKN-007 delays motor neuron loss and disease progression in the G93A mouse model of amyotrophic lateral sclerosis.

Our study investigated the therapeutic potential of OKN-007 in the SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS). The impact of OKN-007, known for its antioxidant, anti-inflammatory, and neuroprotective properties, was tested at two doses (150 mg/kg and 300 mg/kg) at onset and late-stage disease. Results demonstrated a significant delay in disease progression at both doses, with treated mice showing a slower advance to early disease stages compared to untreated controls. Motor neuron counts in the lumbar spinal cord were notably higher in OKN-007 treated mice at the time of disease onset, suggesting neuroprotection. Additionally, OKN-007 reduced microglial activation and preserved reduced neuromuscular junction fragmentation, although it did not significantly alter the increase in astrocyte number or the decline in hindlimb muscle mass. MR spectroscopy (MRS) revealed improved spinal cord perfusion and normalized myo-inositol levels in treated mice, supporting reduced neuroinflammation. While the expression of several proteins associated with inflammation is increased in spinal cord extracts from G93A mice, OKN-007 dampened the expression of IL-1β, IL-1ra and IL-1α. Despite its promising effects on early-stage disease progression, in general, the beneficial effects of OKN-007 diminished over longer treatment durations. Further, we found no improvement in muscle atrophy or weakness phenotypes in OKN-007 treated G93A mice, and no effect on mitochondrial function or lifespan. Overall, our findings suggest that OKN-007 holds potential as a disease-modifying treatment for ALS, although further research is needed to optimize dosing regimens and understand its long-term effects.

Large-scale proteomic analyses of incident Alzheimer's disease reveal new pathophysiological insights and potential therapeutic targets.

Pathophysiological evolutions in early-stage Alzheimer's disease (AD) are not well understood. We used data of 2923 Olink plasma proteins from 51,296 non-demented middle-aged adults. During a follow-up of 15 years, 689 incident AD cases occurred. Cox-proportional hazard models were applied to identify AD-associated proteins in different time intervals. Through linking to protein categories, changing sequences of protein z-scores can reflect pathophysiological evolutions. Mendelian randomization using blood protein quantitative loci data provided causal evidence for potentially druggable proteins. We identified 48 AD-related proteins, with CEND1, GFAP, NEFL, and SYT1 being top hits in both near-term (HR:1.15-1.77; P:9.11 × 10-65-2.78 × 10-6) and long-term AD risk (HR:1.20-1.54; P:2.43 × 10-21-3.95 × 10-6). These four proteins increased 15 years before AD diagnosis and progressively escalated, indicating early and sustained dysfunction in synapse and neurons. Proteins related to extracellular matrix organization, apoptosis, innate immunity, coagulation, and lipid homeostasis showed early disturbances, followed by malfunctions in metabolism, adaptive immunity, and final synaptic and neuronal loss. Combining CEND1, GFAP, NEFL, and SYT1 with demographics generated desirable predictions for 10-year (AUC = 0.901) and over-10-year AD (AUC = 0.864), comparable to full model. Mendelian randomization supports potential genetic link between CEND1, SYT1, and AD as outcome. Our findings highlight the importance of exploring the pathophysiological evolutions in early stages of AD, which is essential for the development of early biomarkers and precision therapeutics.

Apathy and Functional Status in Early-Stage Huntington's Disease.

Apathy is common in Huntington's disease (HD) and difficult to treat. Multiple recent calls have been made to increase understanding of apathy across the spectrum of HD severity. Functional status is an important outcome in HD trials; however, no consensus currently exists regarding the impact of apathy on functional status in HD. The authors aimed to identify correlates of apathy and effects on functional status in a primarily early-stage HD sample. This study included secondary analyses of data from a study of neuropsychiatric symptoms in a clinical HD sample. Spearman correlation analyses were used to assess the relationships between apathy (with the Frontal Systems Behavior Scale-Apathy [FrSBe-Apathy] subscore), clinical variables, and patient-reported outcomes. To assess the association of apathy with functional status, two multiple regression analyses were performed, with a different functional status measure (Adult Functional Adaptive Behavior [AFAB] scale or Total Functional Capacity [TFC] scale) as the dependent variable in each analysis. Statistically significant correlates of apathy included the Quality of Life in Neurological Disorders (Neuro-QoL) Satisfaction With Social Roles and Activities and Neuro-QoL Positive Affect and Well-Being scores (N=70 patients). Univariate correlation analyses also revealed statistically significant associations of FrSBe-Apathy scores with both functional status measures. In the multiple regression analyses, apathy significantly contributed to variability in functional status as measured by both the AFAB (N=49 patients) and TFC (N=56 patients) scales. These results underscore the need to address apathy as a target for improving functional status, social satisfaction, and well-being in HD, even for individuals with early-stage HD.

Early detection of verticillium wilt in eggplant leaves by fusing five image channels: a deep learning approach

BackgroundAs one of the world’s most important vegetable crops, eggplant production is often severely affected by verticillium wilt, leading to significant declines in yield and quality. Traditional multispectral disease-imaging equipment is expensive and complicated to operate. Low-cost multispectral devices cannot capture images and cover less information. The traditional approach to early disease diagnosis involves using multispectral disease-imaging equipment in conjunction with machine learning technology. However, this approach has significant limitations in early disease diagnosis, including challenges such as high costs, complex operation, and low model performance.ResultsThe aim of this study was to combine low-cost multispectral cameras with deep learning technology to detect early stage Verticillium wilt in eggplant effectively. Using the Manual FS-3200T-10GE-NNC multispectral camera to perform multispectral imaging of the leaves of eggplant seedlings at the early infection stage, information fusion was performed on the collected multispectral images, and a five-channel image information fusion model was established. Image information fusion technology was combined with deep learning technology, among which the VGG16-triplet attention model performed the best, achieving a precision of 86.73% on the test set. Model validation on 48- and 72-hour data reached a precision of 75% and 82%, respectively, achieving an early diagnosis of Verticillium wilt. This highlighted the potential of multispectral cameras for early disease detection.ConclusionsIn this study, we successfully developed a method for the non-destructive detection of the early stages of eggplant wilt disease by combining multispectral imaging technology with deep learning algorithms. While ensuring high accuracy, this method significantly reduces the cost of experimental equipment. The application of this method can reduce the cost of agricultural equipment and provide a scientific basis for agricultural production practices, helping to reduce losses caused by diseases.