-
Biomedicines Nov 2023Mild autonomous cortisol secretion (MACS) is associated with a higher cardiometabolic risk than that observed in patients with nonfunctioning adrenal adenomas and in the... (Review)
Review
Mild autonomous cortisol secretion (MACS) is associated with a higher cardiometabolic risk than that observed in patients with nonfunctioning adrenal adenomas and in the general population. In patients with MACS, the excess of glucocorticoids affects various metabolic pathways, leading to different manifestations of metabolic syndrome and other comorbidities. Hypertension and diabetes mellitus are two of the most common cardiometabolic comorbidities associated with MACS, reaching a prevalence of up to 80% and up to 40%, respectively. In addition, they are the comorbidities that experienced a greater improvement after adrenalectomy in patients with MACS. Hypertension pathogenesis is multifactorial, including the coexistence of comorbidities such as obesity or diabetes and the role of the different polymorphisms of the glucocorticoid receptor gene, among others. Glucocorticoid-induced diabetes mellitus is mainly related to the detrimental effects of glucocorticoids on insulin-dependent glucose uptake in peripheral tissues, gluconeogenesis and insulin secretion. There are no specific recommendations for hypertension and diabetes treatment in patients with MACS. Thus, considering the similar underlying pathogenesis of hypertension and diabetes mellitus in overt and mild hypercortisolism, our recommendation is to follow this general stepwise approach: surgically remove the adrenal culprit lesion to induce remission from hypercortisolism; control hypercortisolism with steroidogenesis inhibitors; and treat elevated blood pressure or high glucose levels using carefully selected anti-hypertensives and glucose-lowering medications if blood pressure and glucose levels remain uncontrolled, respectively. In this review, we summarize the epidemiology, physiopathology and management of diabetes mellitus and hypertension in patients with MACS.
PubMed: 38137336
DOI: 10.3390/biomedicines11123115 -
Nature Communications Sep 2023A tight synchrony between the DNA and centrosome cycle is essential for genomic integrity. Centriole disengagement, which licenses centrosomes for duplication, occurs...
A tight synchrony between the DNA and centrosome cycle is essential for genomic integrity. Centriole disengagement, which licenses centrosomes for duplication, occurs normally during mitotic exit. We recently demonstrated that mild DNA replication stress typically seen in cancer cells causes premature centriole disengagement in untransformed mitotic human cells, leading to transient multipolar spindles that favour chromosome missegregation. How mild replication stress accelerates the centrosome cycle at the molecular level remained, however, unclear. Using ultrastructure expansion microscopy, we show that mild replication stress induces premature centriole disengagement already in G2 via the ATR-Chk1 axis of the DNA damage repair pathway. This results in a sub-critical Plk1 kinase activity that primes the pericentriolar matrix for Separase-dependent disassembly but is insufficient for rapid mitotic entry, causing premature centriole disengagement in G2. We postulate that the differential requirement of Plk1 activity for the DNA and centrosome cycles explains how mild replication stress disrupts the synchrony between both processes and contributes to genomic instability.
Topics: Humans; Centrioles; Cell Cycle Proteins; Centrosome; Cell Cycle; Separase; Genomic Instability; Mitosis; Ataxia Telangiectasia Mutated Proteins
PubMed: 37773176
DOI: 10.1038/s41467-023-41753-1 -
Frontiers in Neurology 2023Transcranial magnetic stimulation (TMS) is a non-invasive intervention that holds promise for improving cognitive function in individuals with Alzheimer's disease (AD)....
INTRODUCTION
Transcranial magnetic stimulation (TMS) is a non-invasive intervention that holds promise for improving cognitive function in individuals with Alzheimer's disease (AD). However, the effectiveness of this therapy and the optimal TMS parameters has not reached a consensus. The purpose of the meta-analysis was to systematically discern the effectiveness of different components of TMS protocols on cognitive improvement in patients with mild cognitive impairment (MCI) and AD.
METHODS
The meta-analysis was preregistered on Prospero (registration number: CRD42022345482). PubMed, Web of Science, Science Direct, and Cochrane Library databases were used to search, screen and identify eligible studies with the following keywords: Transcranial Magnetic Stimulation OR TMS OR theta burst stimulation AND Alzheimer OR Alzheimers OR Alzheimer's OR mild cognitive impairment OR MCI. Randomized controlled trials (RCTs) of participants with accepted standardized diagnostic criteria were searched by two authors independently. The risk of bias was assessed using an adapted Cochrane Risk of Bias tool. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated using the random-effects models. Subgroup analyses were performed to investigate the influential factors.
RESULTS
A total of 21 studies and 25 trials were included in this meta-analysis. The findings revealed a significant overall cognition improvement of real stimulation compared with sham stimulation (short-term effects: SMD, 0.91; 95% CI 0.44-1.38; < 0.01; long-lasting effects: SMD, 0.91; 95% CI 0.27-1.55; < 0.01). Subgroup analysis demonstrated that stimulation of the left dorsolateral prefrontal cortex and bilateral cerebellums, as well as moderate frequency stimulation (5 Hz and 10 Hz) on mild and moderate cognitive impairment patients, were more effective than other TMS protocols. However, the additional application of cognitive training showed no significant improvement.
CONCLUSION
Cognitive improvement effect of TMS was demonstrated in MCI and AD patients in both short-term assessment and long-lasting outcomes, and the efficiency of TMS is affected by the stimulation frequency, stimulation site, and participant characteristics. Further RCTs are needed to validate the findings of our subgroup analysis.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022345482, identifier: CRD42022345482.
PubMed: 37528850
DOI: 10.3389/fneur.2023.1209205 -
International Journal of Molecular... Sep 2023Cognitive impairment is a serious condition that begins with amnesia and progresses to cognitive decline, behavioral dysfunction, and neuropsychiatric impairment. In the... (Review)
Review
Cognitive impairment is a serious condition that begins with amnesia and progresses to cognitive decline, behavioral dysfunction, and neuropsychiatric impairment. In the final stage, dysphagia and incontinence occur. There are numerous studies and developed drugs for cognitive dysfunction in neurodegenerative diseases, such as Alzheimer's disease (AD); however, their clinical effectiveness remains equivocal. To date, attempts have been made to overcome cognitive dysfunction and understand and delay the aging processes that lead to degenerative and chronic diseases. Cognitive dysfunction is involved in aging and the disruption of inflammation and innate immunity. Recent reports have indicated that the innate immune system is prevalent in patients with AD, and that peripheral neutrophil markers can predict a decline in executive function in patients with mild cognitive impairment (MCI). Furthermore, altered levels of pro-inflammatory interleukins have been reported in MCI, which have been suggested to play a role in the peripheral immune system during the process from early MCI to dementia. Neutrophils are the first responders of the innate immune system. Neutrophils eliminate harmful cellular debris via phagocytosis, secrete inflammatory factors to activate host defense systems, stimulate cytokine production, kill pathogens, and regulate extracellular proteases and inhibitors. This review investigated and summarized the regulation of neutrophil function during cognitive impairment caused by various degenerative diseases. In addition, this work elucidates the cellular mechanism of neutrophils in cognitive impairment and what is currently known about the effects of activated neutrophils on cognitive decline.
Topics: Humans; Neutrophils; Cognitive Dysfunction; Alzheimer Disease; Aging; Disease Progression
PubMed: 37834242
DOI: 10.3390/ijms241914795 -
Alzheimer's Research & Therapy Nov 2023Participant retention is a key factor that affects clinical trial integrity. Trial protocols estimate attrition as a function of sample size calculations. Alzheimer's...
BACKGROUND
Participant retention is a key factor that affects clinical trial integrity. Trial protocols estimate attrition as a function of sample size calculations. Alzheimer's disease (AD) is an area of active treatment development. We aimed to quantify the association between trial duration and completion rates and provide guidance for estimating attrition in AD trial protocols.
METHODS
Using the Alzforum and ClinicalTrials.gov databases, we analyzed retention data from 125 mild-to-moderate AD and 12 mild cognitive impairment (MCI) clinical trials. We compared the rates of completion between trial arms (active vs. control) and ran regression models to test the hypothesis that trials with longer study duration have lower trial completion using all available data and restricting to placebo data. Our primary outcome was the odds of trial completion for a 6-month increase in trial duration. From the regression model, we estimated the proportion of participants completing 6-, 12-, and 18-month trials.
RESULTS
We found that 21 (17%) mild-to-moderate AD trials and 1 (8%) MCI trial demonstrated greater dropout in treatment compared to placebo arms. For every 6-month increase in trial duration, there was a 27% decrease in the odds of trial completion (OR = 0.73; 95% CI 0.66, 0.81; p < 0.001) among participants in mild-to-moderate AD trials and a 55% decrease (OR = 0.45; 95% CI 0.36, 0.57; p < 0.001) among participants in MCI trials. The proportion of participants in the placebo group completing 6-, 12-, and 18-month trials were estimated to be 85.2%, 80.0%, and 73.3% for mild-to-moderate AD trials and 91.9%, 84.2%, and 71.3% for MCI trials, respectively.
CONCLUSIONS
Longer duration trials may be underpowered to demonstrate estimated treatment effects and may suffer from a greater risk of bias than do shorter trials.
Topics: Humans; Alzheimer Disease; Cognitive Dysfunction; Clinical Trials as Topic
PubMed: 37990339
DOI: 10.1186/s13195-023-01352-0 -
Journal of Nanobiotechnology Sep 2023Cancer therapeutic vaccine can induce antigen-specific immune response, which has shown great potential in cancer immunotherapy. As the key factor of vaccine, antigen...
Cancer therapeutic vaccine can induce antigen-specific immune response, which has shown great potential in cancer immunotherapy. As the key factor of vaccine, antigen plays a central role in eliciting antitumor immunity. However, the insufficient antigen delivery and low efficiency of antigen presentation by dendritic cells (DCs) have greatly restricted the therapeutic efficiency of vaccine. Here we developed a kind of DC hybrid zinc phosphate nanoparticles to co-deliver antigenic peptide and photosensitive melanin. Owing to the chelating ability of Zn, the nanoparticles can co-encapsulate antigenic peptide and melanin with high efficiency. The nanovaccine showed good physiological stability with the hydration particle size was approximately 30 nm, and zeta potential was around - 10 mV. The nanovaccine showed homologous targeting effect to DCs in vivo and in vitro, efficiently delivering antigen to DCs. Meanwhile, the nanovaccine could effectively reflux to the tumor-draining lymph nodes. When combined with near-infrared irradiation, the nanovaccine induced effective mild heat in vitro and in vivo to promote antigen presentation. After administrating to MC38 tumor-bearing mice, the hybrid nanovaccine effectively promoted the maturation of DCs, the expansion of cytotoxic T lymphocytes and helper T cells, and the secretion of immunostimulatory cytokines, thereby significantly inhibiting tumor growth.
Topics: Animals; Mice; Hot Temperature; Melanins; Immunotherapy; Immunization; Cancer Vaccines; Dendritic Cells; Neoplasms
PubMed: 37752555
DOI: 10.1186/s12951-023-02106-8 -
Chronic Diseases and Translational... Dec 2023(A) Immunofluorescence staining showed moderate immunoglobulin A depositions in the mesangial areas (++) of glomeruli (Bars = 100 μm). (B) Segmentally mild...
(A) Immunofluorescence staining showed moderate immunoglobulin A depositions in the mesangial areas (++) of glomeruli (Bars = 100 μm). (B) Segmentally mild mesangial proliferation and mesangial matrix expansion (arrowhead) with mild thickening of glomerular capillary walls (PAS, ×400).
PubMed: 37915389
DOI: 10.1002/cdt3.86 -
Heliyon Jul 2023Traumatic brain injury (TBI) is defined as dysfunction or other evidence of brain pathology caused by external physical force. More than 69 million new cases of TBI are... (Review)
Review
Traumatic brain injury (TBI) is defined as dysfunction or other evidence of brain pathology caused by external physical force. More than 69 million new cases of TBI are registered worldwide each year, 80% of them - mild TBI. Based on the physical mechanism of induced trauma, we can separate its pathophysiology into primary and secondary injuries. Many literature sources have confirmed that mechanically induced brain injury initiates ionic, metabolic, inflammatory, and neurovascular changes in the CNS, which can lead to acute, subacute, and chronic neurological consequences. Despite the global nature of the disease, its high heterogeneity, lack of a unified classification system, rapid fluctuation of epidemiological trends, and variability of long-term consequences significantly complicate research and the development of new therapeutic strategies. In this review paper, we systematize current knowledge of biomechanical and molecular mechanisms of mild TBI and provide general information on the classification and epidemiology of this complex disorder.
PubMed: 37519712
DOI: 10.1016/j.heliyon.2023.e18342 -
Neurorehabilitation and Neural Repair Dec 2023After mild stroke persistent balance limitations may occur, creating a risk factor for fear of falling, falls, and reduced activity levels. To investigate whether... (Observational Study)
Observational Study
BACKGROUND
After mild stroke persistent balance limitations may occur, creating a risk factor for fear of falling, falls, and reduced activity levels. To investigate whether individuals in the chronic phase after mild stroke show balance and gait limitations, elevated fall risk, reduced balance confidence, and physical activity levels compared to healthy controls.
METHODS
An observational case-control study was performed. Main outcomes included the Mini-Balance Evaluation Systems Test (mini-BEST), Timed Up and Go (TUG), 10-m Walking Test (10-MWT), and 6-item version Activity-specific Balance Confidence (6-ABC) scale which were measured in 1 session. Objectively measured daily physical activity was measured for 7 consecutive days. Fall rate in daily life was recorded for 12 months. Individuals after a mild stroke were considered eligible when they: (1) sustained a transient ischemic attack or stroke longer than 6 months ago, resulting in motor and/or sensory loss in the contralesional leg at the time of stroke, (2) showed (near-) complete motor function, that is, ≥24 points on the Fugl-Meyer Assessment-Lower Extremity (range: 0-28).
RESULTS
Forty-seven healthy controls and 70 participants after mild stroke were included. Participants with stroke fell more than twice as often as healthy controls, had a 2 point lower median score on the mini-BEST, were 1.7 second slower on TUG, 0.6 km/h slower on the 10-MWT, and had a 12% lower 6-ABC score. Intensity for both total activity (8%) as well as walking activity (6%) was lower in the participants with stroke, while no differences were found in terms of duration.
CONCLUSIONS
Individuals in the chronic phase after a mild stroke demonstrate persistent balance limitations and have an increased fall risk. Our results point at an unmet clinical need in this population.
Topics: Humans; Case-Control Studies; Stroke Rehabilitation; Fear; Stroke; Gait; Walking; Postural Balance
PubMed: 37877724
DOI: 10.1177/15459683231207360