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Ugeskrift For Laeger Jan 2024This is a case report of two men aged 39 and 43 years with dissection of the coeliac trunk involving the splenic arteries causing splenic infarction. One case was...
This is a case report of two men aged 39 and 43 years with dissection of the coeliac trunk involving the splenic arteries causing splenic infarction. One case was associated with an increase in abdominal pressure during defaecation and the other occurred during treatment with methylphenidate. Based on the published 43 cases, risk factors include male sex, increased intraabdominal pressure or increased vascular pressure. Methylphenidate most likely increased the blood pressure, and dissections of other arteries have been described during treatment with this and the similar drug amphetamine.
Topics: Humans; Male; Amphetamine; Blood Pressure; Celiac Artery; Methylphenidate; Splenic Artery; Adult
PubMed: 38235724
DOI: 10.61409/V07230468 -
Molecular Medicine (Cambridge, Mass.) May 2023Renal interstitial fibrosis (RIF) is a common pathway to end-stage renal disease regardless of the initial etiology. Currently, the molecular mechanisms for RIF remains...
BACKGROUND
Renal interstitial fibrosis (RIF) is a common pathway to end-stage renal disease regardless of the initial etiology. Currently, the molecular mechanisms for RIF remains not fully elucidated. Nuclear receptor subfamily 4 group A member 1(Nr4a1), a member of the NR4A subfamily of nuclear receptors, is a ligand-activated transcription factor. The role of Nr4a1 in RIF remains largely unknown.
METHODS
In this study, we determined the role and action mechanism of Nr4a1 in RIF. We used unilateral ureteral obstruction (UUO) mice and transforming growth factor (TGF)-β1-treated human renal proximal tubular epithelial cells (HK-2 cells) as in vivo and in vitro models of RIF. A specific Nr4a1 agonist Cytosporone B (Csn-B) was applied to activate Nr4a1 both in vivo and in vitro, and Nr4a1 small interfering RNA was applied in vitro. Renal pathological changes were evaluated by hematoxylin and eosin and Masson staining, and the expression of fibrotic proteins including fibronectin (Fn) and collagen-I (Col-I), and phosphorylated p38 MAPK was measure by immunohistochemical staining and western blot analysis.
RESULTS
The results showed that Nr4a1 was upregulated in UUO mouse kidneys, and was positively correlated with the degree of interstitial kidney injury and the levels of fibrotic proteins. Csn-B treatment aggravated UUO-induced renal interstitial fibrosis, and induced p38 MAPK phosphorylation. In vitro, TGF-β induced Nr4a1 expression, and Nr4a1 downregulation prevented TGF-β1-induced expression of Fn and Col-I and the activation of p38 MAPK. Csn-B induced fibrotic proteins expression and p38 MAPK phosphorylation, and moreover Csn-B induced fibrotic proteins expression was abrogated by treatment with p38 MAPK inhibitor SB203580. We provided further evidence that Csn-B treatment promoted cytoplasmic accumulation of Nr4a1.
CONCLUSION
The findings in the present study indicate that Nr4a1 promotes renal fibrosis potentially through activating p38 MAPK kinase.
Topics: Humans; Animals; Mice; Phosphorylation; Kidney Diseases; Phenylacetates; Kidney; Collagen Type I; Nuclear Receptor Subfamily 4, Group A, Member 1
PubMed: 37161357
DOI: 10.1186/s10020-023-00657-y -
Clinical & Experimental Optometry Apr 2022The role of topical non-steroidal anti-inflammatory drugs (NSAIDs) in routine cataract surgery has been established since decades. Topical NSAIDs have been shown to... (Review)
Review
The role of topical non-steroidal anti-inflammatory drugs (NSAIDs) in routine cataract surgery has been established since decades. Topical NSAIDs have been shown to reduce postoperative ocular inflammation and pain, preserve intraoperative mydriasis, and reduce the risk of postoperative cystoid macular oedema, whilst carrying a very low side-effect profile. Nepafenac is one of the currently available topical NSAIDs. The studies have shown that is has a high ocular penetration, allowing for potentially better results than other NSAIDs. This review gathers the current literature on the role of nepafenac in cataract surgery aiming to help surgeons maximise the benefits of its use to achieve improved surgical outcomes.
Topics: Benzeneacetamides; Cataract; Cataract Extraction; Humans; Phenylacetates; Postoperative Complications
PubMed: 34210237
DOI: 10.1080/08164622.2021.1945412 -
Molecular Metabolism Sep 2023Our goal is to investigate if microbiota composition modulates reward signaling and assess the role of the vagus in mediating microbiota to brain communication.
OBJECTIVE
Our goal is to investigate if microbiota composition modulates reward signaling and assess the role of the vagus in mediating microbiota to brain communication.
METHODS
Male germ-free Fisher rats were colonized with gastrointestinal contents from chow (low fat (LF) ConvLF) or HF (ConvHF) fed rats.
RESULTS
Following colonization, ConvHF rats consumed significantly more food than ConvLF animals. ConvHF rats displayed lower feeding-induced extracellular DOPAC levels (a metabolite of dopamine) in the Nucleus Accumbens (NAc) as well as reduced motivation for HF foods compared to ConvLF rats. Dopamine receptor 2 (DDR2) expression levels in the NAc were also significantly lower in ConvHF animals. Similar deficits were observed in conventionally raised HF fed rats, showing that diet-driven alteration in reward can be initiated via microbiota. Selective gut to brain deafferentation restored DOPAC levels, DRD2 expression, and motivational drive in ConvHF rats.
CONCLUSIONS
We concluded from these data that a HF-type microbiota is sufficient to alter appetitive feeding behavior and that bacteria to reward communication is mediated by the vagus nerve.
Topics: Rats; Male; Animals; Brain-Gut Axis; 3,4-Dihydroxyphenylacetic Acid; Feeding Behavior; Reward; Bacteria
PubMed: 37380023
DOI: 10.1016/j.molmet.2023.101764 -
Science Advances Jun 2023To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain's rich...
To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain's rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically induced macroscale functional reorganization, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from positron emission tomography, and the regional changes in functional magnetic resonance imaging connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, lysergic acid diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), ayahuasca, 3,4-methylenedioxymethamphetamine (MDMA), modafinil, and methylphenidate. Our results reveal a many-to-many mapping between psychoactive drugs' effects on brain function and multiple neurotransmitter systems. The effects of both anesthetics and psychedelics on brain function are organized along hierarchical gradients of brain structure and function. Last, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganization of the brain's functional architecture.
Topics: Humans; Brain; Ketamine; Membrane Transport Proteins; Methylphenidate; Modafinil
PubMed: 37315149
DOI: 10.1126/sciadv.adf8332 -
Rheumatic Diseases Clinics of North... Feb 2019Despite many effective treatments for gout, its management remains a challenge internationally. Options for optimizing gout management may differ in different practice... (Review)
Review
Despite many effective treatments for gout, its management remains a challenge internationally. Options for optimizing gout management may differ in different practice sizes and settings. Gout incidence is rising and it continues to be associated with increased mortality. Education of patients and medical providers is essential, and newer gout medications need to be used in the most appropriate ways for cost-effective therapy. Special consideration needs to be given to such populations as the elderly and those with renal and cardiovascular disease in gout management. New agents are in development, which may add to the armamentarium for gout management.
Topics: Acetamides; Allopurinol; Antibodies, Monoclonal, Humanized; Colchicine; Diet Therapy; Febuxostat; Gout; Gout Suppressants; Humans; Medication Adherence; Patient Education as Topic; Phenylacetates; Polyethylene Glycols; Quality of Health Care; Rheumatology; Thioglycolates; Triazoles; Urate Oxidase; Uric Acid
PubMed: 30447743
DOI: 10.1016/j.rdc.2018.09.009 -
Molecular Psychiatry Nov 2023Neuroinflammatory disorders preferentially impair the higher cognitive and executive functions of the prefrontal cortex (PFC). This includes such challenging disorders... (Review)
Review
Neuroinflammatory disorders preferentially impair the higher cognitive and executive functions of the prefrontal cortex (PFC). This includes such challenging disorders as delirium, perioperative neurocognitive disorder, and the sustained cognitive deficits from "long-COVID" or traumatic brain injury. There are no FDA-approved treatments for these symptoms; thus, understanding their etiology is important for generating therapeutic strategies. The current review describes the molecular rationale for why PFC circuits are especially vulnerable to inflammation, and how α2A-adrenoceptor (α2A-AR) actions throughout the nervous and immune systems can benefit the circuits in PFC needed for higher cognition. The layer III circuits in the dorsolateral PFC (dlPFC) that generate and sustain the mental representations needed for higher cognition have unusual neurotransmission and neuromodulation. They are wholly dependent on NMDAR neurotransmission, with little AMPAR contribution, and thus are especially vulnerable to kynurenic acid inflammatory signaling which blocks NMDAR. Layer III dlPFC spines also have unusual neuromodulation, with cAMP magnification of calcium signaling in spines, which opens nearby potassium channels to rapidly weaken connectivity and reduce neuronal firing. This process must be tightly regulated, e.g. by mGluR3 or α2A-AR on spines, to prevent loss of firing. However, the production of GCPII inflammatory signaling reduces mGluR3 actions and markedly diminishes dlPFC network firing. Both basic and clinical studies show that α2A-AR agonists such as guanfacine can restore dlPFC network firing and cognitive function, through direct actions in the dlPFC, but also by reducing the activity of stress-related circuits, e.g. in the locus coeruleus and amygdala, and by having anti-inflammatory actions in the immune system. This information is particularly timely, as guanfacine is currently the focus of large clinical trials for the treatment of delirium, and in open label studies for the treatment of cognitive deficits from long-COVID.
Topics: Humans; Calcium Signaling; Cognitive Dysfunction; Delirium; Guanfacine; Neuroinflammatory Diseases; Post-Acute COVID-19 Syndrome; Prefrontal Cortex
PubMed: 37029295
DOI: 10.1038/s41380-023-02057-4 -
Journal of Neural Transmission (Vienna,... Feb 2020Monoamine oxidase (MAO) plays a central role in the metabolism of the neurotransmitters dopamine, norepinephrine, and serotonin. This brief review focuses on... (Review)
Review
Monoamine oxidase (MAO) plays a central role in the metabolism of the neurotransmitters dopamine, norepinephrine, and serotonin. This brief review focuses on 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is the immediate product of MAO acting on cytoplasmic dopamine. DOPAL is toxic; however, normally DOPAL is converted via aldehyde dehydrogenase (ALDH) to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. In addition to vesicular uptake of dopamine via the vesicular monoamine transporter (VMAT), the two-enzyme sequence of MAO and ALDH keeps cytoplasmic dopamine levels low. Dopamine oxidizes readily to form toxic products that could threaten neuronal homeostasis. The catecholaldehyde hypothesis posits that diseases featuring catecholaminergic neurodegeneration result from harmful interactions between DOPAL and the protein alpha-synuclein, a major component of Lewy bodies in diseases such as Parkinson disease, dementia with Lewy bodies, and pure autonomic failure. DOPAL potently oligomerizes alpha-synuclein, and alpha-synuclein oligomers impede vesicular functions, shifting the fate of cytoplasmic dopamine toward MAO-catalyzed formation of DOPAL-a vicious cycle. When MAO deaminates dopamine to form DOPAL, hydrogen peroxide is generated; and DOPAL, hydrogen peroxide, and divalent metal cations react to form hydroxyl radicals, which peroxidate lipid membranes. Lipid peroxidation products in turn inhibit ALDH, causing DOPAL to accumulate-another vicious cycle. MAO inhibition decreases DOPAL formation but concurrently increases the spontaneous oxidation of dopamine, potentially trading off one form of toxicity for another. These considerations rationalize a neuroprotection strategy based on concurrent treatment with an MAO inhibitor and an anti-oxidant.
Topics: 3,4-Dihydroxyphenylacetic Acid; Aldehyde Dehydrogenase; Animals; Dopamine; Humans; Monoamine Oxidase; Neurodegenerative Diseases; Neurons
PubMed: 31807952
DOI: 10.1007/s00702-019-02106-9 -
International Journal of Molecular... Aug 2023Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, although the aetiology of ADHD is not yet understood. One... (Review)
Review
Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, although the aetiology of ADHD is not yet understood. One proposed theory for developing ADHD is N-methyl-D-aspartate receptors (NMDARs) dysfunction. NMDARs are involved in regulating synaptic plasticity and memory function in the brain. Abnormal expression or polymorphism of some genes associated with ADHD results in NMDAR dysfunction. Correspondingly, NMDAR malfunction in animal models results in ADHD-like symptoms, such as impulsivity and hyperactivity. Currently, there are no drugs for ADHD that specifically target NMDARs. However, NMDAR-stabilizing drugs have shown promise in improving ADHD symptoms with fewer side effects than the currently most widely used psychostimulant in ADHD treatment, methylphenidate. In this review, we outline the molecular and genetic basis of NMDAR malfunction and how it affects the course of ADHD. We also present new therapeutic options related to treating ADHD by targeting NMDAR.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Receptors, N-Methyl-D-Aspartate; Methylphenidate; Brain; Central Nervous System Stimulants
PubMed: 37629164
DOI: 10.3390/ijms241612983 -
Research on Child and Adolescent... Sep 2022The conceptual overlap between mind-wandering and attention-deficit/hyperactivity disorder (ADHD)-related impairments is considerable, yet little experimental research...
The conceptual overlap between mind-wandering and attention-deficit/hyperactivity disorder (ADHD)-related impairments is considerable, yet little experimental research examining this overlap among children is available. The current study aims to experimentally manipulate mind-wandering among children with and without ADHD and examine effects on task performance. Participants were 59 children with ADHD and 55 age-matched controls. Participants completed a novel mind-wandering sustained attention to response task (SART) that included non-self-referential and self-referential stimuli to experimentally increase self-referential mind-wandering, reflected by increases in reaction time variability (RTV) following self-referential stimuli. The ADHD group participated in a classroom study with analogue conditions aimed at encouraging self-referential future-oriented thinking (free play/movie before and after class work) compared to a control condition (newscast) and a cross-over methylphenidate trial. The significant interaction between ADHD status and self-referential stimuli on SART performance indicated that self-referential stimuli led to greater RTV among children with ADHD (within-subject d = 1.29) but not among controls. Methylphenidate significantly reduced RTV among youth with ADHD across self-referential (d = 1.07) and non-self-referential conditions (d = 0.72). In the ADHD classroom study, the significant interaction between mind-wandering condition and methylphenidate indicated that methylphenidate led to higher work completion (ds > 5.00), and the free-play mind-wandering condition had more consistent detrimental effects on productivity (ds ≥ 1.25) than the movie mind-wandering condition. This study is the first to manipulate mind-wandering and assess effects among children with ADHD using a behavioral task. Results provide evidence that children with ADHD are uniquely susceptible to mind-wandering interference.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Child; Humans; Methylphenidate; Task Performance and Analysis
PubMed: 35247108
DOI: 10.1007/s10802-022-00912-6