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Psychoneuroendocrinology May 2024In mammals, some physiological conditions are associated with the high brain oxytocin (OXT) system activity. These include lactation in females and mating in males and...
In mammals, some physiological conditions are associated with the high brain oxytocin (OXT) system activity. These include lactation in females and mating in males and females, both of which have been linked to reduced stress responsiveness and anxiolysis. Also, in a murine model of social fear conditioning (SFC), enhanced brain OXT signaling in lactating mice, specifically in the lateral septum (LS), was reported to underlie reduced social fear expression. Here, we studied the effects of mating in male mice on anxiety-related behaviour, social (and cued) fear expression and its extinction, and the activity of OXT neurons reflected by cFos expression and OXT release in the LS and amygdala. We further focused on the involvement of brain OXT in the mating-induced facilitation of social fear extinction. We could confirm the anxiolytic effect of mating in male mice irrespective of the occurrence of ejaculation. Further, we found that only successful mating resulting in ejaculation (Ej) facilitated social fear extinction, whereas mating without ejaculation (Ej) did not. In contrast, mating did not affect cues fear expression. Using the cellular activity markers cFos and pErk, we further identified the ventral LS (vLS) as a potential region participating in the effect of ejaculation on social fear extinction. In support, microdialysis experiments revealed a rise in OXT release within the LS, but not the amygdala, during mating. Finally, infusion of an OXT receptor antagonist into the LS before mating or into the lateral ventricle (icv) after mating demonstrated a significant role of brain OXT receptor-mediated signaling in the mating-induced facilitation of social fear extinction.
PubMed: 38788461
DOI: 10.1016/j.psyneuen.2024.107083 -
Frontiers in Endocrinology 2024The aim of this substudy (Eudra CT No:2019-001997-27)was to assess ATB availability in patients with infected diabetic foot ulcers(IDFUs)in the context of...
Does PAD and microcirculation status impact the tissue availability of intravenously administered antibiotics in patients with infected diabetic foot? Results of the DFIATIM substudy.
AIMS/HYPOTHESIS
The aim of this substudy (Eudra CT No:2019-001997-27)was to assess ATB availability in patients with infected diabetic foot ulcers(IDFUs)in the context of microcirculation and macrocirculation status.
METHODS
For this substudy, we enrolled 23 patients with IDFU. Patients were treated with boluses of amoxicillin/clavulanic acid(AMC)(12patients) or ceftazidime(CTZ)(11patients). After induction of a steady ATB state, microdialysis was performed near the IDFU. Tissue fluid samples from the foot and blood samples from peripheral blood were taken within 6 hours. ATB efficacy was the maximum serum and tissue ATB concentrations(C and C)and the percentage of time the unbound drug tissue concentration exceeds the minimum inhibitory concentration (MIC)(≥100% and ≥50%/60% fT>MIC). Vascular status was assessed by triplex ultrasound, ankle-brachial and toe-brachial index tests, occlusive plethysmography comprising two arterial flow phases, and transcutaneous oxygen pressure(TcPO).
RESULTS
Following bolus administration, the C of AMC was 91.8 ± 52.5 μgmL and the C of AMC was 7.25 ± 4.5 μgmL(<0.001). The C for CTZ was 186.8 ± 44.1 μgmL and the C of CTZ was 18.6 ± 7.4 μgmL(<0.0001). Additionally, 67% of patients treated with AMC and 55% of those treated with CTZ achieved tissue fT>MIC levels exceeding 50% and 60%, respectively. We observed positive correlations between both C and AUC and arterial flow. Specifically, the correlation coefficient for the first phase was 0.42; (=0.045), and for the second phase, it was =0.55(=0.01)and =0.5(=0.021).
CONCLUSIONS
Bactericidal activity proved satisfactory in only half to two-thirds of patients with IDFUs, an outcome that appears to correlate primarily with arterial flow.
Topics: Humans; Diabetic Foot; Microcirculation; Male; Female; Anti-Bacterial Agents; Middle Aged; Aged; Administration, Intravenous
PubMed: 38774229
DOI: 10.3389/fendo.2024.1326179 -
Brain Research May 2024Altered extracellular amino acid concentrations following concussion or mild traumatic brain injury can result in delayed neuronal damage through overactivation of NMDA...
Altered extracellular amino acid concentrations following concussion or mild traumatic brain injury can result in delayed neuronal damage through overactivation of NMDA glutamatergic receptors. However, the consequences of repeated concussions prior to complete recovery are not well understood. In this study, we utilized in vivo cerebral microdialysis and a weight-drop model to investigate the acute neurochemical response to single and repeated concussions in adult rats that were fully conscious. A microdialysis probe was inserted into the hippocampus and remained in place during impact. Primary outcomes included concentrations of glutamate, GABA, taurine, glycine, glutamine, and serine, while secondary outcomes were righting times and excitotoxic indices. Compared to sham injury, the first concussion resulted in significant increases in glutamate, GABA, taurine, and glycine levels, longer righting times, and higher excitotoxic indices. Following the second concussion, righting times were significantly longer, suggesting cumulative effects of repeated concussion while only partial increases were observed in glutamate and taurine levels. GABA and glycine levels, and excitotoxic indices were comparable to sham injury. These findings suggest that single and repeated concussions may induce acute increases in several amino acids, while repeated concussions could exacerbate neurological symptoms despite less pronounced neurochemical changes.
PubMed: 38754802
DOI: 10.1016/j.brainres.2024.148998 -
Journal of Dermatological Science Apr 2024Metabolites in biofluids can serve as biomarkers for diagnosing diseases and monitoring body conditions. Among the available biofluids, interstitial fluid (ISF) in the...
BACKGROUND
Metabolites in biofluids can serve as biomarkers for diagnosing diseases and monitoring body conditions. Among the available biofluids, interstitial fluid (ISF) in the skin has garnered considerable attention owing to its advantages, which include inability to clot, easy access to the skin, and possibility of incorporating wearable devices. However, the scientific understanding of skin ISF composition is limited.
OBJECTIVE
In this study, we aimed to compare metabolites between skin dialysate containing metabolites from the skin ISF and venous blood (plasma) samples, both collected under resting states.
METHODS
We collected forearm skin dialysate using intradermal microdialysis alongside venous blood (plasma) samples from 12 healthy young adults. We analyzed these samples using capillary electrophoresis-fourier transform mass spectrometry-based metabolomics (CE-FTMS).
RESULTS
Significant positive correlations were observed in 39 metabolites between the skin dialysate and plasma, including creatine (a mitochondrial disease biomarker), 1-methyladenosine (an early detection of cancer biomarker), and trimethylamine N-oxide (a posterior predictor of heart failure biomarker). Based on the Human Metabolome Technologies database, we identified 12 metabolites unique to forearm skin dialysate including nucleic acids, benzoate acids, fatty acids, amino acids, ascorbic acid, 3-methoxy-4-hydroxyphenylethyleneglycol (an Alzheimer's disease biomarker), and cysteic acid (an acute myocardial infarction biomarker).
CONCLUSION
We show that some venous blood biomarkers may be predicted from skin dialysate or skin ISF, and that these fluids may serve as diagnostic and monitoring tools for health and clinical conditions.
PubMed: 38740531
DOI: 10.1016/j.jdermsci.2024.04.001 -
Molecular Pain 2024It has been widely recognized that electroacupuncture (EA) inducing the release of β-endorphin represents a crucial mechanism of EA analgesia. The arcuate nucleus (ARC)...
Low-frequency electroacupuncture exerts antinociceptive effects through activation of POMC neural circuit induced endorphinergic input to the periaqueductal gray from the arcuate nucleus.
It has been widely recognized that electroacupuncture (EA) inducing the release of β-endorphin represents a crucial mechanism of EA analgesia. The arcuate nucleus (ARC) in the hypothalamus is a vital component of the endogenous opioid peptide system. Serving as an integration center, the periaqueductal gray (PAG) receives neural fiber projections from the frontal cortex, insular cortex, and ARC. However, the specific mechanisms how EA facilitates the release of β-endorphin within the ARC, eliciting analgesic effects are yet to be elucidated. In this study, we conducted in vivo and in vitro experiments by transcriptomics, microdialysis, photogenetics, chemical genetics, and calcium imaging, combined with transgenic animals. Firstly, we detected 2 Hz EA at the Zusanli (ST36) increased the level of β-endorphin and transcriptional level of proopiomelanocortin (POMC). Our transcriptomics profiling demonstrated that 2 Hz EA at the ST36 modulates the expression of c-Fos and Jun B in ARC brain nuclear cluster, and the transcriptional regulation of 2 Hz EA mainly occur in POMC neurons by Immunofluorescence staining verification. Meaning while, 2 Hz EA specifically activated the cAMP-PKA-CREB signaling pathway in ARC which mediating the c-Fos and Jun B transcription, and 2 Hz EA analgesia is dependent on the activation of cAMP-PKA-CREB signaling pathway in ARC. In order to investigate how the β-endorphin produced in ARC transfer to integration center PAG, transneuronal tracing technology was used to observe the 2 Hz EA promoted the neural projection from ARC to PAG compared to 100 Hz EA and sham mice. Inhibited PAG neurons, the transfer of β-endorphin from the ARC nucleus to the PAG nucleus through the ARC-PAG neural circuit. Furthermore, by manipulating the excitability of POMC neurons from ARC to PAG using inhibitory chemogenetics and optogenetics, we found that this inhibition significantly reduced transfer of β-endorphin from the ARC nucleus to the PAG nucleus and the effectiveness of 2 Hz EA analgesia in neurological POMC cyclization recombination enzyme (Cre) mice and C57BL/6J mice, which indicates that the transfer of β-endorphin depends on the activation of POMC neurons prefect from ARC to PAG. These findings contribute to our understanding of the neural circuitry underlying the EA pain-relieving effects and maybe provide valuable insights for optimizing EA stimulation parameters in clinical pain treatment using the in vivo dynamic visual investigating the central analgesic mechanism.
Topics: Animals; Pro-Opiomelanocortin; Periaqueductal Gray; Arcuate Nucleus of Hypothalamus; Electroacupuncture; beta-Endorphin; Male; Mice, Transgenic; Mice, Inbred C57BL; Mice; Proto-Oncogene Proteins c-fos; Neurons
PubMed: 38670551
DOI: 10.1177/17448069241254201 -
Acta Neurochirurgica Apr 2024Cerebral perfusion pressure (CPP) management in the developing child with traumatic brain injury (TBI) is challenging. The pressure reactivity index (PRx) may serve as...
BACKGROUND
Cerebral perfusion pressure (CPP) management in the developing child with traumatic brain injury (TBI) is challenging. The pressure reactivity index (PRx) may serve as marker of cerebral pressure autoregulation (CPA) and optimal CPP (CPPopt) may be assessed by identifying the CPP level with best (lowest) PRx. To evaluate the potential of CPPopt guided management in children with severe TBI, cerebral microdialysis (CMD) monitoring levels of lactate and the lactate/pyruvate ratio (LPR) (indicators of ischemia) were related to actual CPP levels, autoregulatory state (PRx) and deviations from CPPopt (ΔCPPopt).
METHODS
Retrospective study of 21 children ≤ 17 years with severe TBI who had both ICP and CMD monitoring were included. CPP, PRx, CPPopt and ΔCPPopt where calculated, dichotomized and compared with CMD lactate and lactate-pyruvate ratio.
RESULTS
Median age was 16 years (range 8-17) and median Glasgow coma scale motor score 5 (range 2-5). Both lactate (p = 0.010) and LPR (p = < 0.001) were higher when CPP ≥ 70 mmHg than when CPP < 70. When PRx ≥ 0.1 both lactate and LPR were higher than when PRx < 0.1 (p = < 0.001). LPR was lower (p = 0.012) when CPPopt ≥ 70 mmHg than when CPPopt < 70, but there were no differences in lactate levels. When ΔCPPopt > 10 both lactate (p = 0.026) and LPR (p = 0.002) were higher than when ΔCPPopt < -10.
CONCLUSIONS
Increased levels of CMD lactate and LPR in children with severe TBI appears to be related to disturbed CPA (PRx). Increased lactate and LPR also seems to be associated with actual CPP levels ≥ 70 mmHg. However, higher lactate and LPR values were also seen when actual CPP was above CPPopt. Higher CPP appears harmful when CPP is above the upper limit of pressure autoregulation. The findings indicate that CPPopt guided CPP management may have potential in pediatric TBI.
Topics: Humans; Brain Injuries, Traumatic; Child; Adolescent; Homeostasis; Female; Male; Retrospective Studies; Intracranial Pressure; Cerebrovascular Circulation; Lactic Acid; Microdialysis; Pyruvic Acid; Brain
PubMed: 38653934
DOI: 10.1007/s00701-024-06085-z -
Physiological Reports Apr 2024We assessed the combined effect of superoxide and iNOS inhibition on microvascular function in non-Hispanic Black and non-Hispanic White participants (n = 15 per...
We assessed the combined effect of superoxide and iNOS inhibition on microvascular function in non-Hispanic Black and non-Hispanic White participants (n = 15 per group). Participants were instrumented with four microdialysis fibers: (1) lactated Ringer's (control), (2) 10 μM tempol (superoxide inhibition), (3) 0.1 mM 1400 W (iNOS inhibition), (4) tempol + 1400 W. Cutaneous vasodilation was induced via local heating and NO-dependent vasodilation was quantified. At control sites, NO-dependent vasodilation was lower in non-Hispanic Black (45 ± 9% NO) relative to non-Hispanic White (79 ± 9% NO; p < 0.01; effect size, d = 3.78) participants. Tempol (62 ± 16% NO), 1400 W (78 ± 12% NO) and tempol +1400 W (80 ± 13% NO) increased NO-dependent vasodilation in non-Hispanic Black participants relative to control sites (all p < 0.01; d = 1.22, 3.05, 3.03, respectively). The effect of 1400 W (p = 0.04, d = 1.11) and tempol +1400 W (p = 0.03, d = 1.22) was greater than tempol in non-Hispanic Black participants. There was no difference between non-Hispanic Black and non-Hispanic White participants at 1400 W or tempol + 1400 W sites. These data suggest iNOS has a greater effect on NO-dependent vasodilation than superoxide in non-Hispanic Black participants.
Topics: Humans; Young Adult; Cyclic N-Oxides; Imines; Nitric Oxide; Regional Blood Flow; Skin; Spin Labels; Superoxides; Vasodilation; Black or African American; White
PubMed: 38639714
DOI: 10.14814/phy2.16021 -
Frontiers in Veterinary Science 2024This study aim to explore the application of microdialysis in pharmacokinetic (PK) and pharmacodynamic (PD) integration of cefquinome against in a porcine experimental...
This study aim to explore the application of microdialysis in pharmacokinetic (PK) and pharmacodynamic (PD) integration of cefquinome against in a porcine experimental lung infection model. The model was established via intratracheal inoculation where average bacterial counts (CFU) in the lungs of infected pigs reached 6.57 log CFU/g after 3 h. The PK profiles of unbound cefquinome in lung dialysates were determined following intramuscular injection of single doses of 0.125, 0.25, 0.5, 1, 2, and 4 mg/kg. Lung dialysate samples were collected using microdialysis at a flow rate of 1.5 μL/min until 24 h. The PD studies were conducted over 24 h based on 10 intermittent dosing regimens and total daily doses ranged from 0.25 to 4 mg/kg and dosage intervals included 12 and 24 h. The lung tissue was collected after 24 h of treatment and homogenized for bacterial counts. The relationships between PK/PD parameters derived from lung dialysates and drug efficacy were analyzed using an inhibitory sigmoid E model. The percentage of time the free drug concentration exceeded the minimum inhibitory concentration (%T > MIC) was the PK/PD index best describing the antimicrobial activity ( = 0.96) in the porcine experimental infection model. The %T > MIC values required to achieve net bacterial stasis, 1, 2 and 3 log CFU/g reductions in the lung were 22.45, 28.86, 37.62, and 56.46%, respectively. Cefquinome exhibited time-dependent characteristics against . These results provide valuable insights into the application of microdialysis in PK/PD integration model studies and optima regimen of cefquinome for the treatment of porcine respiratory diseases caused by .
PubMed: 38596468
DOI: 10.3389/fvets.2024.1390336 -
ACS Sensors Apr 2024The hormone cortisol, released as the end-product of the hypothalamic-pituitary-adrenal (HPA) axis, has a well-characterized circadian rhythm that enables an allostatic... (Review)
Review
The hormone cortisol, released as the end-product of the hypothalamic-pituitary-adrenal (HPA) axis, has a well-characterized circadian rhythm that enables an allostatic response to external stressors. When the pattern of secretion is disrupted, cortisol levels are chronically elevated, contributing to diseases such as heart attacks, strokes, mental health disorders, and diabetes. The diagnosis of chronic stress and stress related disorders depends upon accurate measurement of cortisol levels; currently, it is quantified using mass spectroscopy or immunoassay, in specialized laboratories with trained personnel. However, these methods are time-consuming, expensive and are unable to capture the dynamic biorhythm of the hormone. This critical review traces the path of cortisol detection from traditional laboratory-based methods to decentralised cortisol monitoring biosensors. A complete picture of cortisol biology and pathophysiology is provided, and the importance of precision medicine style monitoring of cortisol is highlighted. Antibody-based immunoassays still dominate the pipeline of development of point-of-care biosensors; new capture molecules such as aptamers and molecularly imprinted polymers (MIPs) combined with technologies such as microfluidics, wearable electronics, and quantum dots offer improvements to limit of detection (LoD), specificity, and a shift toward rapid or continuous measurements. While a variety of different sensors and devices have been proposed, there still exists a need to produce quantitative tests for cortisol ─ using either rapid or continuous monitoring devices that can enable a personalized medicine approach to stress management. This can be addressed by synergistic combinations of technologies that can leverage low sample volumes, relevant limit of detection and rapid testing time, to better account for cortisol's shifting biorhythm. Trends in cortisol diagnostics toward rapid and continuous monitoring of hormones are highlighted, along with insights into choice of sample matrix.
Topics: Hydrocortisone; Humans; Biosensing Techniques; Immunoassay
PubMed: 38551608
DOI: 10.1021/acssensors.3c01912 -
Methods in Molecular Biology (Clifton,... 2024Crustaceans serve as a useful, simplified model for studying peptides and neuromodulation, as they contain numerous neuropeptide homologs to mammals and enable...
Crustaceans serve as a useful, simplified model for studying peptides and neuromodulation, as they contain numerous neuropeptide homologs to mammals and enable electrophysiological studies at the single-cell and neural circuit levels. Crustaceans contain well-defined neural networks, including the stomatogastric ganglion, oesophageal ganglion, commissural ganglia, and several neuropeptide-rich organs such as the brain, pericardial organs, and sinus glands. As existing mass spectrometry (MS) methods are not readily amenable to neuropeptide studies, there is a great need for optimized sample preparation, data acquisition, and data analysis methods. Herein, we present a general workflow and detailed methods for MS-based neuropeptidomic analysis of crustacean tissue samples and circulating fluids. In conjunction with profiling, quantitation can also be performed with isotopic or isobaric labeling. Information regarding the localization patterns and changes of peptides can be studied via mass spectrometry imaging. Combining these sample preparation strategies and MS analytical techniques allows for a multi-faceted approach to obtaining deep knowledge of crustacean peptidergic signaling pathways.
Topics: Animals; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Neuropeptides; Peptides; Diagnostic Imaging; Ganglia; Mammals
PubMed: 38549019
DOI: 10.1007/978-1-0716-3646-6_14