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International Journal of Molecular... May 2024Sepsis-associated kidney injury is common in critically ill patients and significantly increases morbidity and mortality rates. Several complex pathophysiological... (Review)
Review
Sepsis-associated kidney injury is common in critically ill patients and significantly increases morbidity and mortality rates. Several complex pathophysiological factors contribute to its presentation and perpetuation, including macrocirculatory and microcirculatory changes, mitochondrial dysfunction, and metabolic reprogramming. Recovery from acute kidney injury (AKI) relies on the evolution towards adaptive mechanisms such as endothelial repair and tubular cell regeneration, while maladaptive repair increases the risk of progression to chronic kidney disease. Fundamental management strategies include early sepsis recognition and prompt treatment, through the administration of adequate antimicrobial agents, fluid resuscitation, and vasoactive agents as needed. In septic patients, organ-specific support is often required, particularly renal replacement therapy (RRT) in the setting of severe AKI, although ongoing debates persist regarding the ideal timing of initiation and dosing of RRT. A comprehensive approach integrating early recognition, targeted interventions, and close monitoring is essential to mitigate the burden of SA-AKI and improve patient outcomes in critical care settings.
Topics: Humans; Acute Kidney Injury; Sepsis; Renal Replacement Therapy; Critical Illness
PubMed: 38892111
DOI: 10.3390/ijms25115924 -
Animals : An Open Access Journal From... May 2024Crotalus snakebites induce various toxicological effects, encompassing neurological, myotoxic, and cytotoxic symptoms, with potentially fatal outcomes. Investigating...
A Comparative Analysis of the Cytotoxic and Vascular Activity Effects of Western Diamondback Rattlesnake () and Eastern Diamondback Rattlesnake () Venoms Using a Chick Embryo Model.
Crotalus snakebites induce various toxicological effects, encompassing neurological, myotoxic, and cytotoxic symptoms, with potentially fatal outcomes. Investigating venom toxicity is essential for public health, and developing new tools allows for these effects to be studied more comprehensively. The research goals include the elucidation of the physiological consequences of venom exposure and the assessment of toxicity using animal models. Chicken embryos serve as valuable models for assessing venom toxicity through the chick embryotoxicity screening test (CHEST) and the chick chorioallantoic membrane (CAM) assay, particularly useful for evaluating vascular impacts. venom application resulted in higher embryotoxicity and morphological abnormalities, such as Siamese twins. The CAM assay demonstrated the hemorrhagic effects of venom, varying with venom type and concentration. The irritant potential of both venom types was classified as slight or moderate depending on their concentration. Additionally, acetylcholinesterase (AChE) activity was performed to receive information about organ toxicity. The results show that both venoms induced changes in the whole embryo, heart, and liver weights, but the venom was identified as more toxic. Specific venom concentrations affected AChE activity in embryonic tissues. These findings underscore the embryotoxic and vasoactive properties of , providing valuable insights into their mechanisms of toxicity and potential applications in biomedicine.
PubMed: 38891681
DOI: 10.3390/ani14111634 -
Annals of Clinical and Translational... Jun 2024Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those... (Review)
Review
OBJECTIVE
Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene-related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years.
METHODS
This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope.
RESULTS
PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results.
INTERPRETATION
Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.
PubMed: 38887982
DOI: 10.1002/acn3.52119 -
Frontiers in Pediatrics 2024The primary aim of this study was to compare non-invasive blood pressure (NIBP) measurement using the automated oscillometric method with invasive blood pressure (IBP)...
Comparison of invasive blood pressure monitoring vs. non-invasive blood pressure monitoring in critically ill children receiving vasoactive agents-a prospective observational study.
OBJECTIVE
The primary aim of this study was to compare non-invasive blood pressure (NIBP) measurement using the automated oscillometric method with invasive blood pressure (IBP) measurement using peripheral arterial line insertion in critically ill children receiving vasoactive agents.
DESIGN
Single-centre, prospective cohort study.
SETTING
Tertiary care 15 bedded Pediatric ICU in Urban Indian city.
SUBJECTS
All critically ill children between the ages of 1 month to 16 years with shock on vasoactive medications and with IBP monitoring.
RESULTS
Forty children with 1,072 paired BP measurements were incorporated in the final analysis. Among all normotensive children (Total number of paired measurements = 623) receiving vasoactive agents, Bland-Altman analysis revealed an acceptable agreement between Invasive mean blood pressure (MBP) and non-invasive MBP with a bias of -2.10 mmHg (SD 11.35). The 95% limits of agreement were from -24.34 to 20.14 mmHg. In children with hypotension (Total number of paired measurements = 449), Bland-Altman analysis showed disagreement between Invasive MBP and non-invasive MBP i.e., a bias of -8.44 mmHg (SD 9.62). The 95% limits of agreement were from -27.29 to 10.41 mmHg.
CONCLUSION
A limited agreement exists between invasive blood pressure (IBP) and non-invasive blood pressure (NIBP) measurements in critically ill children requiring vasoactive agents. This discrepancy can lead to either an underestimation or an overestimation of blood pressure. While NIBP can serve as a screening tool for hemodynamically stable children, those who are hemodynamically unstable and necessitate the initiation of vasoactive agents should undergo IBP monitoring.
PubMed: 38887566
DOI: 10.3389/fped.2024.1376327 -
MedRxiv : the Preprint Server For... Jun 2024Cerebrovascular reactivity (CVR) reflects the ability of blood vessels to dilate or constrict in response to a vasoactive stimulus, and allows researchers to assess the...
Cerebrovascular reactivity (CVR) reflects the ability of blood vessels to dilate or constrict in response to a vasoactive stimulus, and allows researchers to assess the brain's vascular health. Individuals with spinal cord injury (SCI) are at an increased risk for autonomic dysfunction in addition to cognitive impairments, which have been linked to a decline in CVR; however, there is currently a lack of brain-imaging studies that investigate how CVR is altered after SCI. In this study, we used a breath-holding hypercapnic stimulus and functional near-infrared spectroscopy (fNIRS) to investigate CVR alterations in individuals with SCI (n = 20, 14M, 6F, mean age = 46.3 ± 10.2 years) as compared to age- and sex-matched able-bodied (AB) controls (n = 25, 19M, 6F, mean age = 43.2 ± 12.28 years). CVR was evaluated by its amplitude and delay components separately by using principal component analysis and cross-correlation analysis, respectively. We observed significantly delayed CVR in the right inferior parietal lobe in individuals with SCI compared to AB controls (linear mixed-effects model, fixed-effects estimate = 6.565, Satterthwaite's t-test, t = 2.663, p = 0.008), while the amplitude of CVR was not significantly different. The average CVR delay in the SCI group in the right inferior parietal lobe was 14.21 s (sd: 6.60 s), and for the AB group, the average delay in the right inferior parietal lobe was 7.08 s (sd: 7.39 s). CVR delays were also associated with the duration since injury in individuals with SCI, in which a longer duration since injury was associated with a shortened delay in CVR in the right inferior parietal region (Pearson's r-correlation, r = -0.59, p = 0.04). This study shows that fNIRS can be used to quantify changes in CVR in individuals with SCI, and may be further used in rehabilitative settings to monitor the cerebrovascular health of individuals with SCI.
PubMed: 38883754
DOI: 10.1101/2024.06.03.24307819 -
MedComm Jul 2024Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor...
Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs display varying selectivity and exert diverse physiological effects through their interactions with this receptor family. [Pro]-NPY and [Leu, Pro]-NPY, mainly acting on YR, reportedly increases blood pressure and postsynaptically potentiates the effect of other vasoactive substances above all, while N-terminal cleaved NPY variants in human body primary mediates angiogenesis and neurotransmitter release inhibition through YR. However, the recognition mechanisms of YR and YR with specific agonists remain elusive, thereby hindering subtype receptor-selective drug development. In this study, we report three cryo-electron microscopy (cryo-EM) structures of Gi2-coupled YR and YR in complexes with NPY, as well as YR bound to a selective agonist [Leu, Pro]-NPY. Combined with cell-based assays, our study not only reveals the conserved peptide-binding mode of NPY receptors but also identifies an additional sub-pocket that confers ligand selectivity. Moreover, our analysis of YR evolutionary dynamics suggests that this sub-pocket has undergone functional adaptive evolution across different species. Collectively, our findings shed light on the molecular underpinnings of neuropeptide recognition and receptor activation, and they present a promising avenue for the design of selective drugs targeting the NPY receptor family.
PubMed: 38882210
DOI: 10.1002/mco2.565 -
Journal of Nanobiotechnology Jun 2024Oxygen is necessary for life and plays a key pivotal in maintaining normal physiological functions and treat of diseases. Hemoglobin-based oxygen carriers (HBOCs) have... (Review)
Review
Oxygen is necessary for life and plays a key pivotal in maintaining normal physiological functions and treat of diseases. Hemoglobin-based oxygen carriers (HBOCs) have been studied and developed as a replacement for red blood cells (RBCs) in oxygen transport due to their similar oxygen-carrying capacities. However, applications of HBOCs are hindered by vasoactivity, oxidative toxicity, and a relatively short circulatory half-life. With advancements in nanotechnology, Hb encapsulation, absorption, bioconjugation, entrapment, and attachment to nanomaterials have been used to prepare nanomaterial-related HBOCs to address these challenges and pend their application in several biomedical and therapeutic contexts. This review focuses on the progress of this class of nanomaterial-related HBOCs in the fields of hemorrhagic shock, ischemic stroke, cancer, and wound healing, and speculates on future research directions. The advancements in nanomaterial-related HBOCs are expected to lead significant breakthroughs in blood substitutes, enabling their widespread use in the treatment of clinical diseases.
Topics: Humans; Hemoglobins; Blood Substitutes; Oxygen; Animals; Nanostructures; Liposomes; Nanocapsules; Wound Healing; Neoplasms; Shock, Hemorrhagic
PubMed: 38880905
DOI: 10.1186/s12951-024-02606-1 -
Frontiers in Pediatrics 2024To evaluate the incidence, outcome, and prognostic factors of prolonged mechanical ventilation (PMV) in children in Mainland China.
OBJECTIVE
To evaluate the incidence, outcome, and prognostic factors of prolonged mechanical ventilation (PMV) in children in Mainland China.
METHODS
A prospective study was conducted in 11 pediatric intensive care units (PICUs) from May 1, 2021, to April 30, 2022. All pediatric patients on mechanical ventilation meeting the criteria for PMV were included in the study.
RESULTS
Out of 5,292 patients receiving mechanical ventilation, 278 children met the criteria for PMV (5.3%). After excluding case with incomplete data or lost to follow-up, the study included 250 patients. Among them, 115 were successfully weaned from mechanical ventilation, 90 died, and 45 were still on mechanical ventilation. The 6-month survival rate was 64%. The primary associated conditions of PMV were lower airway diseases (36%), central nervous system diseases (32%), and neuromuscular diseases (14%). The stepwise multiple logistic regression analysis indicated that the utilization of vasoactive agents and an elevated pediatric logistic organ dysfunction-2 (PELOD-2) score on the day of PMV diagnosis were significantly associated with an increased of PMV death. Specifically, the odds ratio (OR) for vasoactive agent use was 2.86; (95% CI: 0.15-0.84; = 0.018), and for the PELOD-2 score, it was 1.37; 95% CI: 1.17-1.61; < .001). Conversely, early rehabilitation intervention was negatively associated with the risk of PMV death (OR = 0.45; 95% CI: 0.22-0.93; = .032). Furthermore, the tracheotomy timing emerged as an independent predictor of failure to wean from PMV, with an OR of 1.08, (95% CI: 1.01-1.16; .030).
CONCLUSIONS
The study revealed a 5.3% incidence of PMV in children requiring mechanical ventilation in China. The use of vasoactive agents and a higher PELOD-2 score at PMV diagnosis were significantly associated with an increased risk of PMV death, whereas early rehabilitation intervention was identified as crucial for improving patient outcomes. The timing of tracheostomy was identified as a high-risk factor for failure to wean from mechanical ventilation.
PubMed: 38873585
DOI: 10.3389/fped.2024.1413094 -
Frontiers in Neurology 2024Severe acute respiratory syndrome corona virus 2 (SARS CoV-2) is the cause of Corona virus disease 2019 (COVID-19), which turned into a pandemic in late 2019 and early...
Severe acute respiratory syndrome corona virus 2 (SARS CoV-2) is the cause of Corona virus disease 2019 (COVID-19), which turned into a pandemic in late 2019 and early 2020. SARS CoV-2 causes endothelial cell destruction and swelling, microthrombosis, constriction of capillaries, and malfunction of pericytes, all of which are detrimental to capillary integrity, angiogenesis, and healing processes. Cytokine storming has been connected to COVID-19 disease. Hypoxemia and tissue hypoxia may arise from impaired oxygen diffusion exchange in the lungs due to capillary damage and congestion. This personal view will look at how inflammation and capillary damage affect blood and tissue oxygenation, cognitive function, and the duration and intensity of COVID-19 disease. The general effects of microvascular injury, hypoxia, and capillary damage caused by COVID-19 in key organs are also covered in this point of view. Once initiated, this vicious cycle leads to diminished capillary function, which exacerbates inflammation and tissue damage, and increased inflammation due to hypoxia. Brain damage may result from low oxygen levels and high cytokines in brain tissue. In this paper we give a summary in this direction with focus on the role of the neuropeptide Substance P. On the basis of this, we discuss selected approaches to the question: "How Substance P is involved in the etiology of the COVID-19 and how results of our research could improve the prevention or therapy of corona? Thereby pointing out the role of Substance P in the post-corona syndrome and providing novel concepts for therapy and prevention.
PubMed: 38872816
DOI: 10.3389/fneur.2024.1370454 -
Vascular Pharmacology Jun 2024Capillaries are the smallest blood vessels (<10 μm in diameter) in the body and their walls are lined by endothelial cells. These microvessels play a crucial role in... (Review)
Review
Capillaries are the smallest blood vessels (<10 μm in diameter) in the body and their walls are lined by endothelial cells. These microvessels play a crucial role in nutrient and gas exchange between blood and tissues. Capillary endothelial cells also produce vasoactive molecules and initiate the electrical signals that underlie functional hyperemia and neurovascular coupling. Accordingly, capillary function and density are critical for all cell types to match blood flow to cellular activity. This begins with the process of angiogenesis, when new capillary blood vessels emerge from pre-existing vessels, and ends with rarefaction, the loss of these microvascular structures. This review explores the mechanisms behind these processes, emphasizing their roles in various microvascular diseases and their impact on surrounding cells in health and disease. We discuss recent work on the mechanisms controlling endothelial cell proliferation, migration, and tube formation that underlie angiogenesis under physiological and pathological conditions. The mechanisms underlying functional and anatomical rarefaction and the role of pericytes in this process are also discussed. Based on this work, a model is proposed in which the balance of angiogenic and rarefaction signaling pathways in a particular tissue match microvascular density to the metabolic demands of the surrounding cells. This negative feedback loop becomes disrupted during microvascular rarefaction: angiogenic mechanisms are blunted, reactive oxygen species accumulate, capillary function declines and eventually, capillaries disappear. This, we propose, forms the foundation of the reciprocal relationship between vascular density, blood flow, and metabolic needs and functionality of nearby cells.
PubMed: 38857638
DOI: 10.1016/j.vph.2024.107393