Transient Increase Research Articles

The AMPK allosteric activator MK-8722 improves thehistology and spliceopathy in myotonic dystrophy type1(DM1) skeletal muscle.

Multiple signaling pathways have been reported to be altered in Myotonic Dystrophy type 1 (DM1) skeletal muscle, contributing to pathogenicity. In particular, previous work established that AMPK signaling, a key sensor of energy metabolism, is repressed in DM1 mouse muscle and that activating AMPK through exercise and/or with pharmacological activators is beneficial for the DM1 muscle phenotype. Here, we explored the effects of a newer, more specific allosteric AMPK activator acting directly on AMPK. We treated male and female HSALR mice for 1 and 4 weeks with a daily injection of the allosteric activator MK-8722, the AMP mimetic AICAR, or vehicle. Our results show that 1 and 4 weeks of treatment with MK-8722 improves alternative splicing toward wild-type levels in male and female HSALR muscle. However, the effects of MK-8722 were more modest compared to AICAR. In contrast, 4 weeks of treatment with MK-8722 improved muscle histology to a greater extent than AICAR. As expected with AMPK activation, 4 weeks of treatment with MK-8722 and AICAR promoted the expression of slower, more oxidative fibers. Finally, acute injections of MK-8722 and AICAR triggered the rapid and transient increase in phospho-AMPK in muscle. However, the peak of AMPK phosphorylation was lower with MK-8722 compared to AICAR, thereby explaining the more modest effects of AMPK allosteric activation. Altogether, our data demonstrate that chronic activation of AMPK with specific pharmacological activators is beneficial for the DM1 muscle. They further indicate that at least a portion of the beneficial effects seen following the administration of these drugs occurs through AMPK.

Double-blinded, randomized tolerance study of a biologically enhanced Nanogel with endothelin-1 and bradykinin receptor antagonist peptides via intra-articular injection for osteoarthritis treatment in horses

BackgroundOsteoarthritis is a leading cause of pain and retirement in athletic horses. Hydro-expansive functionalized nanogels, acting as Drug Delivery Systems, constitute one of the current therapeutic prospects. These nanogels have the potential to combine mechanical benefits through polymers with the biological effect of prolonged release of bioactive molecules. The purpose of this double-blinded randomized tolerance study versus negative control was to evaluate the response of healthy joints to a single injection of the expected efficient dose (further referred to as the trial dose) and overdose of nanogels composed of chitosan and hyaluronic acid and featuring a type A endothelin receptor antagonist and a type B1 bradykinin receptor antagonist. The metacarpophalangeal joints of 8 healthy horses were randomly injected with 2.4 mL of functionalized nanogels and 2.4 mL of saline as control on the contralateral limb. Injections were repeated twice at one-week intervals, followed by injection of a triple dose of nanogel on week four. Clinical, ultrasonographic and synovial fluid cellular and biochemical follow-ups were performed up to three months following the first injection.ResultsNo change in general clinical parameters, lameness or sensitivity to passive flexion of the fetlocks was noted. Mild to moderate synovitis was noted on the day following injection in the treated group, with a significant difference (p < 0.05) compared to the control group. It spontaneously resolved on day 3 following the injections and did not increase with repeated injections. Similar effects were noted after injection of the triple dose but lasted for a week. Synovial fluid markers of inflammation also showed a transient significant increase in the treated group one week after each injection, but no differences were detected at the end of the study.ConclusionsInjections of the expected therapeutic dose of functionalized nanogel in healthy joints induced a mild transient inflammatory response in the joint. Three injections of the trial dose at one-week intervals and injection of thrice the trial dose induce a mildly greater inflammation without harmful effects on joints. Functionalized nanogels are well tolerated prospects for the treatment of osteoarthritis in horses. Their beneficial effects on arthritic joints have yet to be evaluated to determine their therapeutic potential.

Effects of 3,4-methylenedioxymethamphetamine on neural activity in the nucleus accumbens of male mice engaged in social behavior.

3,4-methylenedioxymethamphetamine (MDMA), a commonly abused recreational drug, induces prosocial effects such as increased sociability and empathy. The nucleus accumbens (NAc) has been suggested to play a crucial role in these MDMA-mediated prosocial effects. However, the relationship between social behavior and NAc neural activity, and the effects of MDMA on this relationship, remain unknown. In this study, we measured NAc neural activity using fiber photometry and classified the behaviors of mice at times of transient increases in NAc neural activity during the social approach test (SAT). We found that NAc neural activity transiently increased at the onset of turning toward and sniffing novel mice during the SAT, although the frequency of turning was relatively low. We then examined the effects of MDMA on behavior and NAc neural activity and found that MDMA decreased the duration of sniffing per bout but did not alter NAc neural activity at the onset of turning toward or sniffing novel mice. These results suggest that MDMA does not affect the transient increase in NAc neural activity at the onset of social behaviors.

COVID-19 Vaccination and Transient Increase in CD4/CD8 Cell Counts in People with HIV: Evidence from China

Objectives: Accumulating evidence has confirmed the efficacy and safety of COVID-19 vaccines against SARS-CoV-2 infection. However, the effect of COVID-19 vaccination on immuno-virological parameters in people with HIV (PWH) is uncertain. Methods: A total of 372 PWH treated at Beijing Ditan Hospital were included. Unvaccinated PWH were matched 1:3 with vaccinated PWH using a propensity score matching algorithm. Differences in immuno-virological markers between the matched groups were analyzed. The Wilcoxon signed rank test was used to test for changes in CD4 and CD8 counts and HIV viral load over two months around vaccination. In addition, we investigated the long-term changes in HIV-related markers in different vaccination dose groups and in the entire vaccinated population. Results: Vaccinated PWH had a higher CD4/CD8 ratio (0.64 (0.49, 0.78) vs. 0.80 (0.56, 1.03), p = 0.037) than unvaccinated PWH within a two-month window after the third dose. There were 337 PWH who received COVID-19 vaccination, and 73.9% (n = 249) received three doses of vaccine. We observed a transient increase in CD4 count and CD4/CD8 ratio within a two-month window after vaccination, especially after the second dose (CD4 count: 583.5 (428.5, 706.8) vs. 618.0 (452.0, 744.0), p = 0.018; CD4/CD8 ratio: 0.70 (0.50, 0.91) vs. 0.71 (0.53, 0.96), p &lt; 0.001)) and the third dose (CD4 count: 575.5 (435.5, 717.0) vs. 577.5 (440.8, 754.8), p = 0.001; CD4/CD8 ratio: 0.70 (0.52, 0.93) vs. 0.79 (0.53, 1.00), p &lt; 0.001)). Recent CD4 counts and CD4/CD8 ratios were lower than after COVID-19 but remained higher than before COVID-19 in vaccinated PWH. In addition, COVID-19 vaccination had no negative effect on HIV viral load. Conclusions: A transient increase in CD4 count and CD4/CD8 ratio was observed after COVID-19 vaccination. However, the enhanced cellular immune response induced by vaccination may diminish over time and return to normal levels. There is no adverse effect of vaccination on HIV viral load.

Real-World Evaluation of Dupilumab in the Long-Term Management of Eosinophilic Chronic Rhinosinusitis with Nasal Polyps: A Focus on IL-4 and IL-13 Receptor Blockade

Background and Objectives: Chronic rhinosinusitis (CRS) is a complex inflammatory condition of the nasal passages that severely impairs quality of life. Type 2 CRS is characterized by eosinophilic inflammation, driven by cytokines like IL-4, IL-5, and IL-13. These cytokines are key to CRS pathogenesis and contribute to a heavy disease burden, especially with comorbidities. This study assessed dupilumab, a monoclonal antibody targeting IL-4 and IL-13 signaling, to evaluate its efficacy in reducing the disease burden in patients with CRS with nasal polyps (CRSwNP). Materials and Methods: The patients received subcutaneous dupilumab for 42 weeks. The outcomes included Nasal Polyp Score (NPS); Sino-Nasal Outcome Test (SNOT-22), Numeric Rating Scale (NRS), and Visual Analog Scale (VAS) scores; total IgE; and olfactory function. Results: Significant improvements were observed across the NPS and SNOT-22, NRS, and VAS scores after 42 weeks. Their total IgE levels were reduced, though a transient increase in peripheral eosinophilia appeared at 16 weeks. The patients also reported substantial improvements in olfactory function and high satisfaction with the treatment, supporting dupilumab’s potential in reducing both symptom severity and inflammation in CRSwNP. Conclusions: These results indicate that dupilumab may be an effective treatment for CRSwNP, offering significant symptom relief, improved olfactory function, and enhanced quality of life. High satisfaction levels suggest that dupilumab may provide therapeutic advantages over the conventional CRS treatments, though further studies are warranted to confirm its long-term benefits.

Real-time Neurochemical Sensing of Hydrogen Peroxide Production in Brain Tissue using Advanced Nanostructured Au Microelectrodes Functionalized with Ruthenium Purple Film

Real-time monitoring of H2O2 is essential for understanding its role in neurological physio(path)ology. In this study, we developed an advanced electrochemical sensor utilizing nanostructured gold wire microelectrodes functionalized with a Ruthenium Purple (RP) film, a polynuclear transition metal hexacyanoferrate analog of the prototypical Prussian blue (PB). The RP film exhibits enhanced stability in neutral buffer solutions and reduced interference from biologically relevant cations such as Na+, Mg2+, and Ca2+. By integrating gold nanoparticles onto a nanoporous gold surface, we significantly increased the electroactive surface area of the microwire (ρ=26.1 ± 10.2). The electrodeposition of a thin RP film (4.23 ± 1.2 nm) resulted in a highly selective H2O2 sensor, operating at an optimal potential of -0.05 V vs. Ag/AgCl, with a linear detection range of 0.5-500 µM, sensitivity of 1.18 ± 0.37 µA µM-1 cm-2, and a low limit of detection (LOD) of 66.6 ± 34.9 nM. Adding a Nafion® layer enhanced the sensor's operational stability, maintaining optimal performance over three hours under physiological conditions of pH and ion concentration. We validated the sensor's capability to monitor transient changes in H2O2 concentration in brain tissue by assessing its response to exogenously applied H2O2. Furthermore, we demonstrated that glutamate receptor activation in hippocampal slices induces a rapid and transient increase in extracellular H2O2 levels, underscoring the sensor's potential for studying oxidative stress in neurobiological contexts.

Polystyrene nanoplastics sequester the toxicity mitigating potential of probiotics by altering gut microbiota in grass carp (Ctenopharyngodon idella)

This study evaluated the role of probiotics in enhancing intestinal immunity and mitigating polystyrene nanoplastics (PS-NPs)-induced toxicity in grass carp (Ctenopharyngodon idella). Grass carp were fed probiotics (Bacillus subtilis, Bacillus velezensis, Lactobacillus reuteri, and Lactococcus lactis) for two weeks before being exposed to PS-NPs for five days. Probiotic pretreatment alleviated PS-NPs-induced intestinal damage, with Bacillus velezensis and Lactococcus lactis groups showing milder vacuolation and villus breakage than other groups. Probiotic-treated fish exhibited transient increases in antioxidant enzyme activities (CAT, SOD, MPO) and immune gene expression (IL-6, IL-8, IL-10, IL-1β, TNF-α, and IFN-γ2) shortly after exposure, followed by significant downregulation over time. Higher abundance of the gut dominant phylum Proteobacteria was observed in four probiotic groups exposed to PS-NPs than that in the blank control group. The Clostridium phylum showed a significant decrease in the abundance both in the LRS-PS100 and LLS-PS100 groups, while the abundance of the Thick-walled phylum increased. The Spearman correlation matrix revealed that specific gut microbiota, such as Serratia, Neisseria, and Lactococcus, were significantly associated with enzymatic activities and immune system related genes’ expressions. Probiotic pretreatment enhanced the intestinal immune response of grass carp. However, this enhanced immune response was insufficient to counteract the toxic effects of PS-NPs exposure, particularly in terms of oxidative stress levels and gut microbial diversity. This study offers new insights into the potential of probiotics to combat NPs pollution in aquaculture. It emphasizes the need for further research to explore various probiotic combinations. Future studies should also investigate optimal dosages and durations to effectively mitigate the biological toxicity of NPs pollution.

A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination which is reproduced in hyperammonemic rats. Hyperammonemia induces peripheral inflammation which triggers neuroinflammation and enhanced GABAergic neurotransmission in cerebellum and motor incoordination. The mechanisms involved remain unknown. The aims were to assess if the early increase of peripheral IL-17 triggers motor incoordination in hyperammonemic rats and to identify some underlying mechanisms. We assessed if blocking peripheral IL-17 with anti-IL-17 at 2–4 days of hyperammonemia prevents motor incoordination and analyzed underlying mechanisms. Hyperammonemia induces a transient blood IL-17 increase at days 3–4. This is associated with increased IL-17 receptor membrane expression and activation in cerebellum, leading to NADPH oxidase activation, increased superoxide production and MLCK that induce blood–brain barrier (BBB) permeabilization by reducing occludin and ZO-1. BBB permeabilization facilitates the entry of IL-17, which increases in cerebellum and activates microglia. This increases TNFα and the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway. This enhances GABAergic neurotransmission which impairs motor coordination. Blocking peripheral IL-17 with anti-IL-17 prevents all the above process and prevents motor incoordination. Early treatment to reduce blood IL-17 may be a useful treatment to reverse motor incoordination in patients with MHE.Graphical abstract

Characterising the anxiogenic network from functional connectivity analysis of the CO2 challenge model

The CO2 challenge model (CCM) is a gas inhalation paradigm that provides precisely controlled anxiety induction in experimental settings. Despite its potential as an experimental model of anxiety, our understanding of the neural effects of the CCM is incomplete. This study employs resting-state functional magnetic resonance imaging (rs-fMRI) to explore functional connectivity (FC) changes underlying the CCM. Following a preliminary CO2 tolerance assessment, participants completed an MRI session that included three rs-fMRI scans: during inhalation of control air (pre and post), and during a 6% CCM exposure. Here, we confirm that 6% CCM is a tolerable anxiogenic model in the MRI setting. We demonstrate that a transient CCM-induced increase in subjective anxiety is associated with an increase in FC within limbic and anxiety-related regions, with the insula emerging as a central node in this altered connectivity pattern. Further analysis revealed a significant correlation between the levels of subjective anxiety and enhanced FC between the brainstem and medial frontal cortex, highlighting the dynamic role of the brainstem in response to CO2-induced anxiety. These findings underscore the value of combining CCM and rs-fMRI to characterise the neural mechanisms of anxiety, with important implications for evaluating potential therapeutic interventions.

Melodic contour supersedes short-term statistical learning in expressive accentuation.

Sensory systems are permanently bombarded with complex stimuli. Cognitive processing of such complex stimuli may be facilitated by accentuation of important elements. In the case of music listening, alteration of some surface features -such as volume and duration- may facilitate the cognitive processing of otherwise high-level information, such as melody and harmony. Hence, musical accents are often aligned with intrinsically salient elements in the stimuli, such as highly unexpected notes. We developed a novel listening paradigm based on an artificial Markov-chain melodic grammar to probe the hypothesis that listeners prefer structurally salient events to be consistent with salient surface properties such as musical accents. We manipulated two types of structural saliency: one driven by Gestalt principles (a note at the peak of a melodic contour) and one driven by statistical learning (a note with high surprisal, or information content [IC], as defined by the artificial melodic grammar). Results suggest that for all listeners, the aesthetic preferences in terms of surface properties are well predicted by Gestalt principles of melodic shape. In contrast, despite demonstrating good knowledge of novel statistical properties of the melodies, participants did not demonstrate a preference for accentuation of high-IC notes. This work is a first step in elucidating the interplay between intrinsic, Gestalt-like and acquired, statistical properties of melodies in the development of expressive musical properties, with a focus on the appreciation of dynamic accents (i.e. a transient increase in volume). Our results shed light on the implementation of domain-general and domain-specific principles of information processing during music listening.

Investigation on thermal response of high temperature heat pipe under thermal mismatch conditions

As an efficient and reliable passive heat transfer equipment, high temperature heat pipes (HTHPs) plays an important role in HTHP solid state reactor system. HTHPs often encounter thermal mismatch in reactor applications, which will lead to capillary action, entrainment, and other characteristics, resulting in HTHP failure due to heat transfer limits. In this paper, the thermal response test of liquid metal HTHP under thermal mismatch conditions is studied, and the simulation test platform of HTHP mismatch is designed and built to measure the important physical parameters. The test results show that the heat transfer performance of the HTHP is the best under the condition of horizontal inclination of 60°, and the condenser power is 5.66 kW. This condition is selected as the reference condition for the transient condition test. When the HTHP experienced a transient power increase, the middle of the evaporator section, as the part with the largest heat flux of heating power, appeared a severe overheating phenomenon. The wall temperature of the evaporator section soared from 750 ℃ to 1050 ℃ in a short time, and the heating rate reached 18.9 ℃/min, which affected the smooth operation of the HTHP. When the HTHP encounters an inclination angle transient increase condition, the entrainment phenomenon is more severe, the temperature fluctuation of the condenser section is intensified, and the heat transfer of the HTHP is in an unstable state. When the HTHP encounters an inclination angle transient decrease condition, the temperature rise of the evaporator section is less than 10 ℃, the temperature at the end of the condenser section is increased, and the start-up performance of the HTHP is improved. In summary, this paper obtains the thermal response rule of HTHPs under thermal mismatch conditions through experimental research, which provides support for the safe application of HTHPs for special equipment.

Induction of Alkaline Bands in Chara by External Electric Current Reveals the Influence of Plasma Membrane H+ Fluxes on Cyclosis-Mediated Signaling

Long-distant communications in plants and giant plant cells are essential for optimal cell functioning under variable environmental conditions. In characean internodal cells exposed to spotted or flickering light, the redox balance in dimly lit chloroplasts is sensitive to the reducing power produced in brightly illuminated chloroplasts of a distal cell region located upstream in the directed cytoplasmic flow. The distant communication is mediated by excessive production in the high-light region of reducing metabolites that are exported into the streaming cytoplasm and delivered by cytoplasmic flow to light-starving chloroplasts. These target chloroplasts perceive the transportable metabolic signal, which is reflected in the transient increase of modulated chlorophyll fluorescence F '. Previous studies of cyclosis-mediated F ' transients revealed that they are sensitive to natural H+ fluxes across the plasma membrane and that the signal transduction is suppressed in cell areas with massive H+ influx. In this study with Chara australis R. Br., we show that the injection of inward electric current is accompanied by proton influx sufficient for the creation of artificial alkaline band. The combined application of PAM chlorophyll microfluorometry, local light stimuli, and measurements of pericellular pH showed that the microfluidic signal transduction is notably suppressed under artificially produced alkaline band where H+ influx acidifies the cytoplasm. It is hypothesized that changes in cytoplasmic pH regulate the rates of electron flows directed to NADP reduction and O2 reduction, which may disturb long-distance redox control system involving production and consumption of reducing equivalents.

PTSD Increases Risk for Hypertension Development Through PVN Activation and Vascular Dysfunction in Sprague Dawley Rats.

This study investigates the impact of single prolonged stress (SPS), a model of post-traumatic stress disorder (PTSD), on cardiovascular responses, hypothalamic paraventricular nucleus (PVN) activity, and vascular function to elucidate the mechanisms linking traumatic stress to hypertension. Although SPS did not directly cause chronic hypertension in male Sprague Dawley (SD) rats, it induced acute but transient increases in blood pressure and heart rate and significantly altered the expression of hypertension-associated genes, such as vasopressin, angiotensin II type 1 receptor (AT1R), and FOSL1 in the PVN. Notably, mitochondrial reactive oxygen species (mtROS) were predominantly elevated in the pre-autonomic regions of the PVN, colocalizing with AT1R- and FOSL1-expressing cells, suggesting that oxidative stress may amplify sympathetic activation and stress responses. SPS also increased mRNA levels of pro-inflammatory cytokines (TNFα and IL1β) and inducible nitric oxide synthase (iNOS) in the aorta, and impaired vascular reactivity to vasoconstrictor and vasodilator stimuli, reflecting compromised vascular function. These findings suggest that SPS-sensitize neuroendocrine, autonomic, and vascular pathways create a state of cardiovascular vulnerability that could predispose individuals to hypertension when exposed to additional stressors. Understanding these mechanisms provides critical insights into the pathophysiology of stress-related cardiovascular disorders and underscores the need for targeted therapeutic interventions that address oxidative stress and modulate altered PVN pathways to mitigate the cardiovascular impact of PTSD and related conditions.

Sex-specific temporal trends in incidence and prevalence of chronic kidney disease: a Danish population-based cohort study

Abstract Background Rates of chronic kidney disease (CKD) may change with ageing populations, rising metabolic and cardiovascular disease prevalence, increasing CKD awareness and new treatments. We examined sex-specific temporal trends in CKD incidence and prevalence from 2011 through 2021. Methods We conducted a population-based cohort study among adults residing in the North and Central Denmark Regions (population ∼1.5 million in 2021), utilising routinely collected individual-level laboratory data. We identified individuals with incident or prevalent CKD, using data on plasma creatinine and urine albumin-creatinine ratios from samples performed in outpatient hospital settings or primary care. We estimated annual sex-specific crude and age-standardised incidence and prevalence and tabulated clinical characteristics. Results Throughout 2011–2021, CKD incidence and prevalence remained higher among females than males. A transient increase in the crude incidence was observed during 2011–2013, followed by a decrease from 11.8 per 1000 person-years in 2013 (95% confidence interval (CI): 11.5–12.1) to 10.7 in 2021 (95% CI: 10.5–11.0) among females and from 10.9 (95% CI: 10.7–11.2) to 10.6 (95% CI: 10.3–10.8) among males. During 2011–2021, the crude prevalence increased among females from 85.1 per 1000 individuals (95% CI: 84.4–85.8) to 99.9 (95% CI: 99.2–100.6) and among males from 55.3 (95% CI: 54.7–55.9) to 82.4 (95% CI: 81.8–83.0). After age-standardisation, declines in incidence persisted, while the prevalence was stable among females, and the increase persisted among males. Conclusions The CKD incidence and prevalence remained higher among females than males during 2011–2021. Despite a notable decline in incidence rates from 2013 onwards, the crude prevalence increased during 2011–2021.

A NOTCH2 pathogenic variant and HES1 regulate osteoclastogenesis in induced pluripotent stem cells

Hajdu Cheney Syndrome (HCS), a monogenic disorder associated with NOTCH2 pathogenic variants, presents with neurological, craniofacial and skeletal abnormalities. Mouse models of the disease exhibit osteopenia. To determine the consequences of a HCS pathogenic variant in human cells, induced pluripotent NCRM1 and NCRM5 stem (iPS) cells harboring a NOTCH26949C>T mutation or null for HES1 alleles were created. Parental iPSCs, NOTCH26949C>T, HES1 null and control cells, free of chromosomal aberrations were cultured under conditions of neural crest, mesenchymal and osteogenic cell differentiation, or of embryoid body, hematopoietic and osteoclast cell differentiation. The expected cell phenotype was confirmed by cell surface markers and gene signature. NOTCH26949C>T cells displayed enhanced expression of Notch target genes demonstrating the presence of a NOTCH2 gain-of-function. There was a modest enhancement of osteogenesis in NOTCH26949C>T cells manifested by increased mineralized nodule formation and SP7, ALPL and BGLAP mRNA expression. There was enhanced osteoclastogenesis in NOTCH26949C>T cells as evidenced by increased number of osteoclasts and a transient increase in ACP5, CALCR and CTSK transcripts. Osteoblastogenesis was minimally affected by the HES1 deletion, but osteoclast differentiation was significantly impaired. In conclusion, a NOTCH2 pathogenic variant causes modest increases in osteoblastogenesis and osteoclastogenesis and HES1 is required for osteoclast differentiation in human iPS cells in vitro.

Efficacy and Safety of Fixed-Dose Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel in Participants with Moderate-to-Severe Acne: The Patient Journey

Introduction: The main goal of acne treatment is to clear lesions quickly to manage and/or mitigate sequelae. Topical clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (CAB) gel is the only fixed-dose, triple-combination approved for acne. In three published clinical studies of participants with moderate to severe acne, CAB gel demonstrated superior efficacy to vehicle and component dyads, with good safety/tolerability. Herein are presented detailed efficacy and safety data from 5 clinical study patients to document their CAB treatment journey. Methods: In two phase 3 (NCT04214652, NCT04214639), double-blind, 12-week studies, participants aged ≥9 years with moderate-to-severe acne were randomized to once-daily CAB or vehicle gel. Endpoints included percentage of participants achieving treatment success (≥2-grade reduction from baseline in Evaluator’s Global Severity Score and clear/almost clear skin) and percent change from baseline in inflammatory/ noninflammatory lesion counts. Dosing compliance, treatment-emergent adverse events (TEAEs) and cutaneous safety/tolerability were also assessed. Descriptive data from 5 selected cases who completed 12 weeks of CAB treatment are summarized. Results: Participants (n=5) ranged from 13-32 years. At week 12, 3 achieved treatment success, 1 achieved a 2-grade reduction from severe to mild, and 1 achieved a 1-grade reduction from moderate to mild. Reductions from baseline to week 12 in inflammatory/ noninflammatory lesion counts ranged from 74.7-100%. No participants reported TEAEs/serious AEs. Some cutaneous safety/tolerability scores increased at weeks 2, 4, or 8, but generally decreased back to/below baselines levels by week 12, similar to the overall study populations. Most scores at week 12 were 0 (none) or 1 (mild), with only one participant reporting scores of 2 (moderate) for itching, burning, and stinging. Conclusions: In the overall phase 3 clinical trials, fixed-dose, triple-combination CAB gel has demonstrated good efficacy, safety, and tolerability. All 5 cases presented here achieved substantial (&gt;70%) acne lesion reductions, with 4/5 cases achieving treatment success or a 2-grade EGSS reduction by week 12. While patterns in cutaneous safety/tolerability were variable across cases, transient increases with CAB generally resolved to baseline values within two months of treatment. These clinical study cases reinforce the importance of patient education regarding efficacy and safety of acne treatment, including the importance of treatment adherence, managing patient expectations, and the potential for cutaneous effects, which are often transient. Support: Ortho Dermatologics

Hippocampal neurogenesis in adult primates: a systematic review.

It had long been considered that no new neurons are generated in the primate brain beyond birth, but recent studies have indicated that neurogenesis persists in various locations throughout the lifespan. The dentate gyrus of the hippocampus is of particular interest due to the postulated role played by neurogenesis in memory. However, studies investigating the presence of adult hippocampal neurogenesis (AHN) have reported contradictory findings, and no systematic review of the evidence has been conducted to date. We searched MEDLINE, Embase and PsycINFO on 27th June 2023 for studies on hippocampal neurogenesis in adult primates, excluding review papers. Screening, quality assessment and data extraction was done by independent co-raters. We synthesised evidence from 112 relevant papers. We found robust evidence, primarily supported by immunohistochemical examination of tissue samples and neuroimaging, for newly generated neurons, first detected in the subgranular zone of the dentate gyrus, that mature over time and migrate to the granule cell layer, where they become functionally integrated with surrounding neuronal networks. AHN has been repeatedly observed in both humans and other primates and gradually diminishes with age. Transient increases in AHN are observed following acute insults such as stroke and epileptic seizures, and following electroconvulsive therapy, and AHN is diminished in neurodegenerative conditions. Markers of AHN correlate positively with measures of learning and short-term memory, but associations with antidepressant use and mood states are weaker. Heterogeneous outcome measures limited quantitative syntheses. Further research should better characterise the neuropsychological function of neurogenesis in healthy subjects.

Transient Elevation of Liver Function Tests and Bilirubin Levels After Laparoscopic Cholecystectomy.

Background and Objectives: Laparoscopic cholecystectomy constitutes the current "gold standard" treatment of symptomatic gallstone disease. In order to avoid intraoperative vasculobiliary injuries, it is mandatory to establish the "critical view of safety". In cases of poor identification of the cystic duct and artery leading to a missed intraoperative injury, patients present with elevated liver function tests (LFTs) or increased bilirubin postoperatively. The aim of this study is to present a series of patients of our institute with elevated liver enzymes and bilirubin after laparoscopic cholecystectomy in the absence of intraoperative injury or any other obvious etiology and to provide a possible explanation of this finding. Materials and Methods: From 2019 to 2023, 200 patients underwent elective laparoscopic cholecystectomy at the Papageorgiou General Hospital and at the European Interbalkan Medical Center of Thessaloniki utilizing the "critical view of safety" method. We retrospectively collected the intraoperative reports, and the pre- and postoperative imaging and laboratory studies of the patients included in this series. Postoperative LFTs and bilirubin levels were extracted and the reason for their transient elevation was examined. Results: From 200 cases of laparoscopic cholecystectomy, elevated LFTs and bilirubin were found in six patients on the first postoperative day, which is suggestive of a missed intraoperative injury. All patients were asymptomatic. During the investigatory workup, a triple-phase CT of the liver and/or an MRCP were ordered, but no pathological findings, such as biliary injury, hepatic artery injury or choledocholithiasis, were found. On postoperative day 3, LFTs and bilirubin levels decreased or normalized without any intervention. No postoperative complications were reported. Conclusions: In select cases, a transient increase in LFTs and/or bilirubin may be observed in the early postoperative period after elective laparoscopic cholecystectomy in the absence of an obvious etiology. A possible interpretation of these findings could involve the pneumoperitoneum or the anesthesia regimens used intra- or perioperatively. The specific cause, however, remains undetermined and yet to be examined by future studies.

An increase of lysosomes through EGF-triggered endocytosis attenuated zinc-mediated lysosomal membrane permeabilization and neuronal cell death

In the context of acute brain injuries, where zinc neurotoxicity and oxidative stress are acknowledged contributors to neuronal damage, we investigated the pivotal role of lysosomes as a potential protective mechanism. Our research commenced with an exploration of epidermal growth factor (EGF) and its impact on lysosomal dynamics, particularly its neuroprotective potential against zinc-induced cytotoxicity. Using primary mouse cerebrocortical cultures, we observed the rapid induction of EGFR endocytosis triggered by EGF, resulting in a transient increase in lysosomal vesicles. Furthermore, EGF stimulated lysosomal biogenesis, evident through elevated expression of lysosomal-associated membrane protein 1 (LAMP-1) and the induction and activation of prominent lysosomal proteases, particularly cathepsin B (CTSB). This process of EGFR endocytosis was found to promote lysosomal augmentation, thus conferring protection against zinc-induced lysosomal membrane permeabilization (LMP) and subsequent neuronal death. Notably, the neuroprotective effects and lysosomal enhancement induced by EGF were almost completely reversed by the inhibition of clathrin-mediated and caveolin-mediated endocytosis pathways, along with the disruption of retrograde trafficking. Furthermore, tyrosine kinase inhibition of EGFR nullified EGFR endocytosis, resulting in the abrogation of EGF-induced lysosomal upregulation and neuroprotection. An intriguing aspect of our study is the successful replication of EGF’s neuroprotective effects through the overexpression of LAMP-1, which significantly reduced zinc-induced LMP and cell death, demonstrated in both primary mouse cerebrocortical neuronal cultures and human embryonic kidney (HEK) cells. Our research extended beyond zinc-induced neurotoxicity, as we observed EGF’s protective effects against other oxidative stressors linked to intracellular zinc release, including hydrogen peroxide (H2O2) and 1-methyl-4-phenylpyridinium ion (MPP+). Collectively, our findings unveil the intricate interplay between EGF-triggered EGFR endocytosis, lysosomal upregulation, an increase in the regulatory capacity for zinc homeostasis, and the subsequent alleviation of zinc-induced neurotoxicity. These results present promising avenues for therapeutic interventions to enhance neuroprotection by targeting lysosomal augmentation.

Dynamic changes in the structure and function of brain mural cells around chronically implanted microelectrodes

Integration of neural interfaces with minimal tissue disruption in the brain is ideal to develop robust tools that can address essential neuroscience questions and combat neurological disorders. However, implantation of intracortical devices provokes severe tissue inflammation within the brain, which requires a high metabolic demand to support a complex series of cellular events mediating tissue degeneration and wound healing. Pericytes, peri-vascular cells involved in blood-brain barrier maintenance, vascular permeability, waste clearance, and angiogenesis, have recently been implicated as potential perpetuators of neurodegeneration in brain injury and disease. While the intimate relationship between pericytes and the cortical microvasculature have been explored in other disease states, their behavior following microelectrode implantation, which is responsible for direct blood vessel disruption and dysfunction, is currently unknown. Using two-photon microscopy we observed dynamic changes in the structure and function of pericytes during implantation of a microelectrode array over a 4-week implantation period. Pericytes respond to electrode insertion through transient increases in intracellular calcium and underlying constriction of capillary vessels. Within days following the initial insertion, we observed an influx of new, proliferating pericytes which contribute to new blood vessel formation. Additionally, we discovered a potentially novel population of reactive immune cells in close proximity to the electrode-tissue interface actively engaging in encapsulation of the microelectrode array. Finally, we determined that intracellular pericyte calcium can be modulated by intracortical microstimulation in an amplitude- and frequency-dependent manner. This study provides a new perspective on the complex biological sequelae occurring at the electrode-tissue interface and will foster new avenues of potential research consideration and lead to development of more advanced therapeutic interventions towards improving the biocompatibility of neural electrode technology.