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EBioMedicine May 2024Neurofilament light (NfL) has previously been highlighted as a potential biomarker for Huntington's Disease (HD) using cross-sectional analyses. Our study aim was to...
BACKGROUND
Neurofilament light (NfL) has previously been highlighted as a potential biomarker for Huntington's Disease (HD) using cross-sectional analyses. Our study aim was to investigate how longitudinal trajectories of plasma NfL relate to HD disease stage.
METHODS
108 participants [78 individuals with the HD mutation, and 30 healthy controls (HC)] were included in this study. Individuals with the HD mutation were categorised separately by both HD-Integrated Staging System (HD-ISS) (Study 1) and PIN score-Approximated Staging System (PASS) (Study 2) criteria. Plasma NfL trajectories were examined using Mixed Linear Modeling (MLM); associations with symptom presentation were assessed using Spearman's rho correlations.
FINDINGS
The MLM coefficients for disease stage (HD-ISS β = 32.73, p < 0.0001; PASS β = 33.00, p < 0.0001) and disease stage∗time (HD-ISS β = 7.85, p = 0.004; PASS β = 6.58, p = 0.0047) suggest these are significant contributors to plasma NfL levels. In addition, the plasma NfL rate of change varied significantly across time (HD-ISS β = 3.14, p = 0.04; PASS β = 2.94, p = 0.050). The annualised rate of change was 8.32% for HC; 10.55%, 12.75% and 15.62% for HD-ISS Stage ≤1, Stage 2, and Stage 3, respectively; and 12.13%, 10.46%, 10.33%, 17.52%, for PASS Stage 0, Stage 1, Stage 2, and Stage 3, respectively. Plasma NfL levels correlated with the Symbol Digit Modalities Test (SDMT) in HD-ISS Stage ≤1, and both SDMT and Total Motor Score in Stage 3 (ps < 0.01).
INTERPRETATION
Our findings suggest that plasma NfL levels increase linearly across earlier disease stages, correlating with the cognitive SDMT measure. Thereafter, an increase or surge in plasma NfL levels, paired with correlations with both cognitive and motor measures, suggest a late acceleration in clinical and pathological progression.
FUNDING
NIH (NS111655); the UCSD HDSA CoE; the UCSD ADRC (NIH-NIA P30 AG062429).
PubMed: 38815362
DOI: 10.1016/j.ebiom.2024.105173 -
Acta Pharmaceutica (Zagreb, Croatia) Jun 2024Remifentanil is an ultra-short-acting synthetic opioid-class analgesic which might be increasingly used "off-label" as pain management during labour. Side effects in...
Remifentanil is an ultra-short-acting synthetic opioid-class analgesic which might be increasingly used "off-label" as pain management during labour. Side effects in parturients during labour, and in the infant at birth are of particular concern, especially respiratory depression which is concentration-dependent, and can occur at levels as low as 3-5 ng mL. The safety of such use, particularly in newborns due to remifentanil placental transfer, has not been fully demonstrated yet, partly due to the lack of a suitable non-invasive analytical method. The aim of our work was to develop a sensitive method to monitor the levels of remifentanil in neonates by a non-invasive sampling of umbi lical cord blood to support efficacy and safety trials. The presented LC-MS method is sensitive enough to reliably quantify remifentanil in just 20 µL of blood at only 0.3 ng mL. The dried blood spot sample preparation included solvent extraction with subsequent solid-phase extraction. The method was validated in terms of accuracy, precision, recovery, matrix effect, and stability, and was successfully applied to a small pilot study. The estimated arterial blood concentrations at the time of delivery ranged from 0.2 to 0.3, and up to 0.9 ng mL in neonatal, and maternal samples, respectively.
Topics: Remifentanil; Humans; Tandem Mass Spectrometry; Infant, Newborn; Dried Blood Spot Testing; Analgesics, Opioid; Female; Fetal Blood; Chromatography, Liquid; Pregnancy; Piperidines; Pilot Projects; Reproducibility of Results; Solid Phase Extraction
PubMed: 38815198
DOI: 10.2478/acph-2024-0010 -
PloS One 2024The push towards research commercialisation at universities has highlighted the importance of intellectual property (IP) policies in fostering innovation and guiding and... (Comparative Study)
Comparative Study
The push towards research commercialisation at universities has highlighted the importance of intellectual property (IP) policies in fostering innovation and guiding and managing research commercialisation activities. This paper undertakes a content analysis of intellectual property policies of all (37) Australian public universities, focusing on policy objectives, definition of IP, ownership of IP created by different creators, and distribution of net commercialisation revenues. It is found that all universities assert ownership over staff-created IP, particularly when related to employment or utilisation of university resources. For students, policies tend to balance their rights with university interests, with nuanced approaches for different types of student participation, but the focus of most policies was on postgraduate students engaging in research activities. While some policies had clear arrangements for IP created by visitors and affiliates and Indigenous cultural and intellectual property (ICIP), about a quarter of policies did not specify arrangements for these groups. Revenue sharing arrangements vary but generally award something between a third to a half of net revenue to creators, to both acknowledge their contribution and incentivise further innovation. Policies included a broad spectrum of objectives, from protecting and commercialising IP to fostering innovation and societal benefit, reflecting varying strategies across the higher education sector. Policies could benefit from further clarity in certain areas such as the rights of students or other creator groups. Research is needed to assess the effectiveness of these policies and their influence on innovation and commercialisation activities.
Topics: Intellectual Property; Universities; Australia; Humans; Ownership; Students; Policy
PubMed: 38814965
DOI: 10.1371/journal.pone.0304647 -
PloS One 2024Untargeted metabolomics investigations have characterized metabolic disturbances associated with various diseases in domestic cats. However, the pre-analytic stability...
Untargeted metabolomics investigations have characterized metabolic disturbances associated with various diseases in domestic cats. However, the pre-analytic stability of serum metabolites in the species is unknown. Our objective was to compare serum metabolomes from healthy cats stored at -20°C for up to 12 months to samples stored at -80°C. Serum samples from 8 adult, healthy cats were stored at -20°C for 6 months, -20°C for 12 months, or -80°C for 12 months. Untargeted liquid chromatography-mass spectrometry was used to generate serum metabolite profiles containing relative abundances of 733 serum metabolites that were compared among storage conditions. Unsupervised analysis with principal component analysis and hierarchical clustering of Euclidian distances revealed separation of samples from individual cats regardless of storage condition. Linear mixed-effects models identified 75 metabolites that differed significantly among storage conditions. Intraclass correlation analysis (ICC) classified most serum metabolites as having excellent (ICC ≥ 0.9; 33%) or moderate (ICC 0.75-0.89; 33%) stability, whereas 13% had poor stability (ICC < 0.5). Biochemicals that varied significantly among storage conditions and classified with poor stability included glutathione metabolites, amino acids, gamma-glutamyl amino acids, and polyunsaturated fatty acids. The benzoate; glycine, serine and threonine; tryptophan; chemical (xenobiotics); acetylated peptide, and primary bile acid sub pathways were enriched among highly stable metabolites, whereas the monohydroxy fatty acid, polyunsaturated fatty, and monoacylglycerol sub-pathways were enriched among unstable metabolites. Our findings suggest that serum metabolome profiles are representative of the cat of origin, regardless of storage condition. However, changes in specific serum metabolites, especially glutathione, gamma-glutamyl amino acid, and fatty acid metabolites were consistent with increased sample oxidation during storage at -20°C compared with -80°C. By investigating the pre-analytic stability of serum metabolites, this investigation provides valuable insights that could aid other investigators in planning and interpreting studies of serum metabolomes in cats.
Topics: Animals; Cats; Metabolomics; Metabolome; Male; Female; Chromatography, Liquid; Mass Spectrometry; Amino Acids
PubMed: 38814947
DOI: 10.1371/journal.pone.0303500 -
Psychiatrike = Psychiatriki May 2024According to international experience, the conditions for the successful outcome of a psychiatric reform are the following: (a) Existence of political will (supporting a...
According to international experience, the conditions for the successful outcome of a psychiatric reform are the following: (a) Existence of political will (supporting a national plan with assessment, monitoring, and corrective intervention procedures for structural dysfunctions, etc.). (b) Strong mental health leadership (executive expertise and skills that advance the public health agenda). (c) Challenging the dominance of the biomedical model in therapeutic practice through the promotion of holistic care practices, evidence-based innovative actions, collaborative care, the promotion of recovery culture, and the and the use of innovative digital tools. (d) Ensuring necessary resources over time, so that resources from the transition of the asylum model to a model of sectorial community mental health services "follow" the patient. (e) Strengthening the participation of service recipients and their families in decision-making processes and evaluation of care quality. (f) Practices based on ethical principles (value-based practice) and not only on the always necessary documentation (evidence-based practice).1- 4 Convergent evidence from the "ex post" evaluation of the implementation of the national plan Psychargos 2000-20095 and from the recent rapid assessment of the psychiatric reform by the Ministry of Health and the WHO Athens office (SWOT analysis)6 indicates "serious fragmentation of services, an uncoordinated system that often results in inappropriate service provision, a lack of epidemiological studies and studies concerning the local needs of specific populations, uneven development of services between different regions of the country, a large number of specialized professionals with significant deficits in community psychiatry expertise, a lack of personnel in supportive roles, significant gaps in specialized services (for individuals with autism spectrum disorders, intellectual disabilities, eating disorders, old and new addictions, and community forensic psychiatry services)". We would also like to highlight lack of coordination and collaboration among different mental health service systems (public primary and secondary service providers, NGOs, municipal services, mental health services of the armed forces, private sector), complete absence of systematic evaluation and monitoring (lack of quality of care indicators, clinical outcomes, epidemiological profile of each service), lack of quality assurance mechanisms and clinical management systems, insufficient number of beds mainly for acute cases, unclear protocols for discharge issuance and ensuring continuity of care, deficient budget for Mental Health in relation to the overall healthcare expenditure (currently 3.3%), and finally, one of the highest rates of involuntary hospitalizations in Europe, which is linked to serious issues concerning the protection of the rights of service users. After the pandemic and the emergence of the silent but expected mental health pandemic, WHO, EU, and the Greek Ministry of Health emphasized the need to adopt a public mental health agenda with an emphasis on community psychiatry in order to address both the old structural dysfunctions and inadequacies of psychiatric reform (regulation 815/1984, Leros I-Leros II plan, Psychargos A & B, incomplete implementation of laws 2071/1992 & 2716/1999, incomplete deinstitutionalization of the remaining psychiatric hospitals). However, it is time to reflect that it is not possible to talk today about the need to update and implement a new national plan to upgrade mental health in the country without answering basic questions, both old and new, about the wider context of its implementation. The transformation of the deficient psychiatric care in the country cannot be completed without the urgent restructuring of the National Health System7 and the reform of the Greek welfare state itself, which is also characterized by irrationality, inequalities, bureaucratic inefficiency, and fragmentation.8 As we should have learned from the bankruptcy and the prolonged economic, social, and cultural crisis in our country, reforms usually pay off in the long term, while the time horizon of the applied policies is narrow and usually reaching the next election. The fact is that in any reform effort, including psychiatry, the political system does not demonstrate the ability to promote transparency, evaluation, stable rules of regulation, reference to a universally applicable legal and institutional framework, the limitation of clientelism and guild resistances. From this point of view, it is necessary to give meaning in the context of Greek psychiatric reform to the professional burnout of the National Health System workers, the lack of motivation and vision, the intrusion into the NGO space by new entities without any connection to the culture of psychiatry reform, the guild resistances of all relevant specialties, the selective use of psychotherapeutic techniques, as trends of discrediting the relief of social and psychological suffering in the field of public mental health. There is an urgent need to understand new pathologies (narcissistic disorders, new forms of addiction, eating disorders, "pathology of emptiness", adolescent delinquency and suicide, psychosomatic manifestations due to high stress, pathology of fluid social ties, deficient socialization of young people "outside of their algorithms") through a solid and coherent analysis of the toxic postmodernity culture. In addition to the social determinants of mental health,9 it is necessary in clinical work to also assess the psychological factors, such as uncertainty, conflict, loss of control, and incomplete information, that burden human health.10 In order to reduce the gap between declarations and real life, there is an urgent need to overcome the blind spots of psychiatric reform in the country by establishing internal and external evaluation processes, training young professionals in holistic care and community networking and communication skills, retraining leaders for organizational change, and strengthening the participation of service users in the context of deepening democracy in mental health. As mental health professionals, the object of our work in the community should be the reconstruction of meaning and the fragile or non-existent social bond in subjects who have been cut off from any possible production of meaning and participation in their history. Why should our therapeutic responses be stereotypically repetitive in the face of these complex, radical changes in the meta-context and the new demands of our patients? After all, as the philosopher Ernst Bloch puts it, utopia is "that which does not exist yet.".
PubMed: 38814270
DOI: 10.22365/jpsych.2024.009 -
Microbiology Spectrum May 2024is the leading cause of bacterial sexually transmitted infections in the USA and of preventable blindness worldwide. This obligate intracellular pathogen replicates...
is the leading cause of bacterial sexually transmitted infections in the USA and of preventable blindness worldwide. This obligate intracellular pathogen replicates within a membrane-bound inclusion, but how it acquires nutrients from the host while avoiding detection by the innate immune system is incompletely understood. accomplishes this in part through the translocation of a unique set of effectors into the inclusion membrane, the lusion membrane proteins (Incs). Incs are ideally positioned at the host-pathogen interface to reprogram host signaling by redirecting proteins or organelles to the inclusion. Using a combination of co-affinity purification, immunofluorescence confocal imaging, and proteomics, we characterize the interaction between an early-expressed Inc of unknown function, Tri1, and tumor necrosis factor receptor-associated factor 7 (TRAF7). TRAF7 is a multi-domain protein with a RING finger ubiquitin ligase domain and a C-terminal WD40 domain. TRAF7 regulates several innate immune signaling pathways associated with infection and is mutated in a subset of tumors. We demonstrate that Tri1 and TRAF7 specifically interact during infection and that TRAF7 is recruited to the inclusion. We further show that the predicted coiled-coil domain of Tri1 is necessary to interact with the TRAF7 WD40 domain. Finally, we demonstrate that Tri1 displaces the native TRAF7 binding partners, mitogen-activated protein kinase kinase kinase 2 (MEKK2), and MEKK3. Together, our results suggest that by displacing TRAF7 native binding partners, Tri1 has the capacity to alter TRAF7 signaling during infection.IMPORTANCE is the leading cause of bacterial sexually transmitted infections in the USA and preventable blindness worldwide. Although easily treated with antibiotics, the vast majority of infections are asymptomatic and therefore go untreated, leading to infertility and blindness. This obligate intracellular pathogen evades the immune response, which contributes to these outcomes. Here, we characterize the interaction between a -secreted effector, Tri1, and a host protein involved in innate immune signaling, TRAF7. We identified host proteins that bind to TRAF7 and demonstrated that Tri1 can displace these proteins upon binding to TRAF7. Remarkably, the region of TRAF7 to which these host proteins bind is often mutated in a subset of human tumors. Our work suggests a mechanism by which Tri1 may alter TRAF7 signaling and has implications not only in the pathogenesis of infections but also in understanding the role of TRAF7 in cancer.
PubMed: 38814079
DOI: 10.1128/spectrum.00453-24 -
Arteriosclerosis, Thrombosis, and... May 2024Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging...
BACKGROUND
Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear.
METHODS
We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples.
RESULTS
Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF.
CONCLUSIONS
Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.
PubMed: 38813697
DOI: 10.1161/ATVBAHA.123.320270 -
Acta Biochimica Et Biophysica Sinica May 2024Chikungunya virus (CHIKV) is a neglected arthropod-borne and anthropogenic alphavirus. Over the past two decades, the CHIKV distribution has undergone significant...
Chikungunya virus (CHIKV) is a neglected arthropod-borne and anthropogenic alphavirus. Over the past two decades, the CHIKV distribution has undergone significant changes worldwide, from the original tropics and subtropics regions to temperate regions, which has attracted global attention. However, the interactions between CHIKV and its host remain insufficiently understood, which dampens the need for the development of an anti-CHIKV strategy. In this study, on the basis of the optimal overexpression of non-structural protein 4 (nsP4), we explore host interactions of CHIKV nsP4 using mass spectrometry-based protein-protein interaction approaches. The results reveal that some cellular proteins that interact with nsP4 are enriched in the ubiquitin-proteasome pathway. Specifically, the scaffold protein receptor for activated C kinase 1 (RACK1) is identified as a novel host interactor and regulator of CHIKV nsP4. The inhibition of the interaction between RACK1 and nsP4 by harringtonolide results in the reduction of nsP4, which is caused by the promotion of degradation but not the inhibition of nsP4 translation. Furthermore, the decrease in nsP4 triggered by the RACK1 inhibitor can be reversed by the proteasome inhibitor MG132, suggesting that RACK1 can protect nsP4 from degradation through the ubiquitin-proteasome pathway. This study reveals a novel mechanism by which the host factor RACK1 regulates CHIKV nsP4, which could be a potential target for developing drugs against CHIKV.
PubMed: 38813597
DOI: 10.3724/abbs.2024073 -
Turkish Journal of Medical Sciences 2023Titanium dioxide nanoparticles are widely used in a variety of products, including sunscreens, paints, and ceramics. However, their increasing use has raised concerns...
BACKGROUND/AIM
Titanium dioxide nanoparticles are widely used in a variety of products, including sunscreens, paints, and ceramics. However, their increasing use has raised concerns about their potential health risks. Titanium dioxide nanoparticles have been shown to have the ability to enter the bloodstream and accumulate in various tissues, reaching the fetus via the placenta. The aim of this study was to investigate the cytotoxic effects of titanium dioxide nanoparticles on a human embryonic lung cell line (HEL 299/An1) and the formation of oxidative DNA damage.
MATERIALS AND METHODS
The cytotoxic effects of brookite-based titanium dioxide nanoparticles (<100 nm) were assessed using the 3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay for 24 and 48 h. Cell titanium levels were determined using inductively coupled plasma mass spectrometry. Oxidative DNA damage was assessed by measuring the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) as a biomarker.
RESULTS
Titanium dioxide nanoparticles caused dose-dependent cytotoxicity in HEL 299/An1 cells. The IC values were 25.93 μM and 0.054 μM after 24 h and 48 h of exposure, respectively. Cell titanium levels were found to be 25,967 ppb after 24 h and 210,353 ppb after 48 h (p < 0.01). 8-OHdG was detected at 32.96 ng/mL after 24 h of exposure and 17.89 ng/mL after 48 h of exposure.
CONCLUSION
In our study, it was shown that titanium nanoparticles caused dose-dependent cytotoxicity and oxidative DNA damage in human embryonic lung cells. The nanoparticles also accumulated in cells and were taken up in higher amounts after 48 h of exposure. These findings suggest that titanium dioxide nanoparticles may pose a health risk, especially for pregnant women who may not be aware of their pregnancy. Therefore, it is important to take preventive measures to reduce exposure to these nanoparticles.
Topics: Titanium; Humans; DNA Damage; Cell Line; Lung; Oxidative Stress; Nanoparticles; 8-Hydroxy-2'-Deoxyguanosine; Cell Survival; Metal Nanoparticles
PubMed: 38813501
DOI: 10.55730/1300-0144.5733 -
Turkish Journal of Medical Sciences 2023Neuropathic pain (NP) is a type of chronic pain usually caused by damage to the somatosensory system. Bioactive antioxidant compounds, such as curcumin and ginger, are...
BACKGROUND/AIM
Neuropathic pain (NP) is a type of chronic pain usually caused by damage to the somatosensory system. Bioactive antioxidant compounds, such as curcumin and ginger, are widely preferred in the treatment of NP. However, the ingredient-based mechanism that underlies their pain-relieving activity remains unknown. The aim of this study was to investigate the therapeutic effects of trans-[6]-Shogaol and [6]-Gingerol active ingredients of the Roscoe extract on the spinal cord and cortex in the neuroinflammatory pathway in rats with experimental sciatic nerve injury.
MATERIALS AND METHODS
Forty-six volatile phenolic components were identified in ginger samples using gas chromatography-mass spectrometry analysis. Thirty 3-month-old male 250-300 g Wistar Albino rats were divided into three groups as (i) sham, (ii) chronic constriction injury (CCI), and (iii) CCI+ginger. NP was induced using the CCI model. A ginger extract treatment enriched with trans-[6]-shogaol and [6]-gingerol active ingredients was administered by gavage at 200 mg/kg/day for 7 days. On the 14th day of the experiment, locomotor activity was evaluated in open field and hyperalgesia in tail flick tests.
RESULTS
In behavioural experiments, a significant decrease was observed in the CCI group compared to the sham group, while a significant increase was observed in the CCI+ginger group compared to the CCI group (p < 0.05). In the spinal cord and cortex tissues, there was a significant increase in the TNF-α, IL-1β, and IL-18 neuroinflammation results of the CCI group compared to the sham group, while there was a significant decrease in the CCI+ginger group compared to the CCI group.
CONCLUSION
In this study, ginger treatment was shown to have a therapeutic effect on neuroinflammation against sciatic nerve damage.
Topics: Animals; Fatty Alcohols; Catechols; Neuralgia; Rats; Male; Rats, Wistar; Zingiber officinale; Disease Models, Animal; Cytokines; Plant Extracts; Sciatic Nerve; Spinal Cord
PubMed: 38813490
DOI: 10.55730/1300-0144.5728