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The Journal of Nutritional Biochemistry May 2024Arginine (ARG)/Citrulline (CIT) deficiency is associated with increased sepsis severity after infection. Supplementation of CIT to susceptible populations with ARG/CIT...
BACKGROUND
Arginine (ARG)/Citrulline (CIT) deficiency is associated with increased sepsis severity after infection. Supplementation of CIT to susceptible populations with ARG/CIT deficiency such as preterm newborns with suspected infection might prevent sepsis, via maintaining immune and vascular function.
METHODS
Caesarean-delivered, parenterally nourished preterm pigs were treated with CIT (1g/kg) via oral or continuous intravenous supplementation, then inoculated with live Staphylococcus epidermidis and clinically monitored for 14h. Blood, liver, and spleen samples were collected for analysis. In vitro cord blood stimulation was done to explore how CIT and ARG affect premature blood cell responses.
RESULTS
After infection, oral CIT supplementation led to higher mortality, increased blood bacterial load, and systemic and hepatic inflammation. Intravenous CIT administration showed increased inflammation and bacterial burdens without significantly affecting mortality. Liver transcriptomics and data from in vitro blood stimulation indicated that CIT induces systemic immunosuppression in preterm newborns, which may impair resistance response to bacteria at the early stage of infection, subsequently causing later uncontrollable inflammation and tissue damage.
CONCLUSION
The early stage of CIT supplementation exacerbates sepsis severity in infected preterm pigs, likely via inducing systemic immunosuppression.
PubMed: 38825026
DOI: 10.1016/j.jnutbio.2024.109674 -
Journal of Neuroinflammation Jun 2024T cells play an important role in the acquired immune response, with regulatory T cells (Tregs) serving as key players in immune tolerance. Tregs are found in...
T cells play an important role in the acquired immune response, with regulatory T cells (Tregs) serving as key players in immune tolerance. Tregs are found in nonlymphoid and damaged tissues and are referred to as "tissue Tregs". They have tissue-specific characteristics and contribute to immunomodulation, homeostasis, and tissue repair through interactions with tissue cells. However, important determinants of Treg tissue specificity, such as antigen specificity, tissue environment, and pathology, remain unclear. In this study, we analyzed Tregs in the central nervous system of mice with ischemic stroke and experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The gene expression pattern of brain Tregs in the EAE model was more similar to that of ischemic stroke Tregs in the brain than to that of spinal cord Tregs. In addition, most T-cell receptors (TCRs) with high clonality were present in both the brain and spinal cord. Furthermore, Gata3 and Rorc Tregs expressed TCRs recognizing MOG in the spinal cord, suggesting a tissue environment conducive to Rorc expression. Tissue-specific chemokine/chemokine receptor interactions in the spinal cord and brain influenced Treg localization. Finally, spinal cord- or brain-derived Tregs had greater anti-inflammatory capacities in EAE mice, respectively. Taken together, these findings suggest that the tissue environment, rather than pathogenesis or antigen specificity, is the primary determinant of the tissue-specific properties of Tregs. These findings may contribute to the development of novel therapies to suppress inflammation through tissue-specific Treg regulation.
Topics: Animals; T-Lymphocytes, Regulatory; Mice; Encephalomyelitis, Autoimmune, Experimental; Spinal Cord; Brain; Mice, Inbred C57BL; Female; Disease Models, Animal
PubMed: 38824594
DOI: 10.1186/s12974-024-03144-1 -
BMC Nephrology Jun 2024This study examines medication adherence among kidney transplant patients at St. Paul's Hospital Millennium Medical College (SPHMMC) in Addis Ababa, Ethiopia, focusing...
BACKGROUND
This study examines medication adherence among kidney transplant patients at St. Paul's Hospital Millennium Medical College (SPHMMC) in Addis Ababa, Ethiopia, focusing on the level of adherence and associated factors to immunosuppressant medicines.
METHODS AND MATERIALS
A cross-sectional study was conducted on 270 patients from October 2021 to January 2022 using a structured questionnaire analyzed with SPSS version 26. The prevalence of medication adherence was computed, and a binary logistic regression was fitted to estimate the association. Medication adherence level measurement in post-kidney transplant patients was assessed using the Simplified Medication Adherence Questionnaire (SMAQ) and Basel Adherence Assessment Scale in Immunosuppressants (BAASIS). A 95% confidence interval and p-value < 0.05 were used for statistical significance.
RESULTS
The study found that 71.5% of kidney transplant patients were male, with a median age of 37 and a mean duration of 3.55 years. Medication adherence in post-kidney transplant patients was 81.9%. Post-transplant duration above 5 years and missing follow-up visits more than two times was associated with a 92.6% and 91.2% in medication non-adherence rate respectively. Additionally, forgetfulness was associated with a 90.6%, non-adherence level compared to drug unavailability and financial reasons.
CONCLUSION AND RECOMMENDATION
The study indicates that our patients exhibit higher medication adherence than WHO-measured levels, suggesting the need for healthcare providers to strengthen their intervention, especially for those above 5 years post-kidney transplant. The reason for increased adherence could be explained by the health education program about the medication name, dosing, frequency of ingestion and adverse effects of the drug, and effects of non-adherence.
Topics: Humans; Kidney Transplantation; Male; Ethiopia; Medication Adherence; Female; Adult; Cross-Sectional Studies; Hospitals, Teaching; Immunosuppressive Agents; Middle Aged; Young Adult; Surveys and Questionnaires
PubMed: 38824513
DOI: 10.1186/s12882-024-03620-z -
Scientific Reports Jun 2024Vascularized composite allotransplantations are complex procedures with substantial functional impact on patients. Extended preservation of VCAs is of major importance...
Vascularized composite allotransplantations are complex procedures with substantial functional impact on patients. Extended preservation of VCAs is of major importance in advancing this field. It would result in improved donor-recipient matching as well as the potential for ex vivo manipulation with gene and cell therapies. Moreover, it would make logistically feasible immune tolerance induction protocols through mixed chimerism. Supercooling techniques have shown promising results in multi-day liver preservation. It consists of reaching sub-zero temperatures while preventing ice formation within the graft by using various cryoprotective agents. By drastically decreasing the cell metabolism and need for oxygen and nutrients, supercooling allows extended preservation and recovery with lower ischemia-reperfusion injuries. This study is the first to demonstrate the supercooling of a large animal model of VCA. Porcine hindlimbs underwent 48 h of preservation at - 5 °C followed by recovery and normothermic machine perfusion assessment, with no issues in ice formation and favorable levels of injury markers. Our findings provide valuable preliminary results, suggesting a promising future for extended VCA preservation.
Topics: Animals; Swine; Hindlimb; Organ Preservation; Cryopreservation; Reperfusion Injury; Cryoprotective Agents
PubMed: 38824189
DOI: 10.1038/s41598-024-63041-8 -
Peripheral apoptosis and limited clonal deletion during physiologic murine B lymphocyte development.Nature Communications Jun 2024Self-reactive and polyreactive B cells generated during B cell development are silenced by either apoptosis, clonal deletion, receptor editing or anergy to avoid...
Self-reactive and polyreactive B cells generated during B cell development are silenced by either apoptosis, clonal deletion, receptor editing or anergy to avoid autoimmunity. The specific contribution of apoptosis to normal B cell development and self-tolerance is incompletely understood. Here, we quantify self-reactivity, polyreactivity and apoptosis during physiologic B lymphocyte development. Self-reactivity and polyreactivity are most abundant in early immature B cells and diminish significantly during maturation within the bone marrow. Minimal apoptosis still occurs at this site, however B cell receptors cloned from apoptotic B cells show comparable self-reactivity to that of viable cells. Apoptosis increases dramatically only following immature B cells leaving the bone marrow sinusoids, but above 90% of cloned apoptotic transitional B cells are not self-reactive/polyreactive. Our data suggests that an apoptosis-independent mechanism, such as receptor editing, removes most self-reactive B cells in the bone marrow. Mechanistically, lack of survival signaling rather than clonal deletion appears to be the underpinning cause of apoptosis in most transitional B cells in the periphery.
Topics: Animals; Apoptosis; Clonal Deletion; B-Lymphocytes; Mice; Mice, Inbred C57BL; Receptors, Antigen, B-Cell; Cell Differentiation; Bone Marrow; Female; Precursor Cells, B-Lymphoid
PubMed: 38824171
DOI: 10.1038/s41467-024-49062-x -
International Journal of Infectious... May 2024Nontuberculous mycobacteria (NTM) bone and joint infections (BJIs) are uncommon. We evaluated the characteristics of BJIs and identified differences according to immune...
Clinical Features and Treatment Outcomes of Bone and Joint Nontuberculous Mycobacterial Infections According to Immune Status: a 9-year Retrospective Observational Cohort.
OBJECTIVES
Nontuberculous mycobacteria (NTM) bone and joint infections (BJIs) are uncommon. We evaluated the characteristics of BJIs and identified differences according to immune status.
METHODS
We performed a multicenter retrospective study in France involving patients with documented NTM BJI over a 9-year period. We collected the clinical and microbiological characteristics, management, and clinical outcomes of the patients.
RESULTS
Ninety-five patients were included, of whom 50.5% (48/95) were immunosuppressed. Tenosynovitis was more frequent in the immunocompetent group, and native arthritis more common in the immunosuppressed group. M. marinum and M. abscessus complex were significantly more frequent in the immunocompetent group, and M. avium and M. xenopi were significantly more frequent in the immunosuppressed group. The combination of antibiotherapy with surgery tended to be more frequent in the immunocompetent than the immunosuppressed group (63.8% (30/47) vs 47.8% (22/46), respectively); of the latter, 45.7% (21/46) received antimicrobial therapy alone, a higher frequency than in the immunocompetent group (23.4%, 11/47). The median duration of antimicrobial treatment was similar in the two groups (11 months). Mortality was significantly higher in the immunosuppressed group.
CONCLUSIONS
Although the clinical presentations and the NTM species involved in BJI differed according to immune status, most recovered completely after treatment.
PubMed: 38823623
DOI: 10.1016/j.ijid.2024.107122 -
Chest May 2024Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Limited evidence is available on the most effective diagnostic approaches,...
BACKGROUND
Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Limited evidence is available on the most effective diagnostic approaches, management strategies, and long-term outcomes for CAP in patients who have undergone solid organ transplantation.
RESEARCH QUESTION
What is the acute and long-term morbidity and mortality after CAP in organ transplant recipients?
STUDY DESIGN AND METHODS
We retrospectively analysed hospitalisations for CAP in solid organ recipients at the largest German transplant centre. The study included patients admitted between 1 January 2010 and 31 May 2021. The reported outcomes are in-hospital and 1-year mortality, risk of cardiovascular events during hospitalisation and at one year, admission to the intensive care unit, and risk of pneumonia with P. aeruginosa. Multivariable binary logistic regression using stepwise forward selection was performed to determine predictive factors for pneumonia with P. aeruginosa.
RESULTS
We analysed data from 403 hospitalisations of 333 solid organ recipients. In over 60% of cases, patients had multiple comorbidities, with cardiovascular and chronic kidney disease being the most prevalent. More than half of the patients required oxygen supplementation after admission. In-hospital mortality (13.2%) and the death rate at one year post-event (24.6%) were higher than data reported from immunocompetent patients. We also observed high rates of acute cardiovascular events and events occurring one year after admission. Early blood cultures and bronchoscopy in the first 24 hours significantly increased the odds of establishing an aetiology. In our low-resistance setting, the burden of antimicrobial resistance was driven by bacteria from chronically colonised patients, mostly lung transplant recipients.
INTERPRETATION
This comprehensive analysis highlights the high morbidity associated with CAP after transplantation. It also emphasises the need for prospective multicenter studies to guide evidence-based practices and improve outcomes for these vulnerable patients.
PubMed: 38823578
DOI: 10.1016/j.chest.2024.05.005 -
Biomedicine & Pharmacotherapy =... May 2024In contemporary times, tumors have emerged as the primary cause of mortality in the global population. Ongoing research has shed light on the significance of... (Review)
Review
In contemporary times, tumors have emerged as the primary cause of mortality in the global population. Ongoing research has shed light on the significance of neurotransmitters in the regulation of tumors. It has been established that neurotransmitters play a pivotal role in tumor cell angiogenesis by triggering the transformation of stromal cells into tumor cells, modulating receptors on tumor stem cells, and even inducing immunosuppression. These actions ultimately foster the proliferation and metastasis of tumor cells. Several major neurotransmitters have been found to exert modulatory effects on tumor cells, including the ability to restrict emergency hematopoiesis and bind to receptors on the postsynaptic membrane, thereby inhibiting malignant progression. The abnormal secretion of neurotransmitters is closely associated with tumor progression, suggesting that focusing on neurotransmitters may yield unexpected breakthroughs in tumor therapy. This article presents an analysis and outlook on the potential of targeting neurotransmitters in tumor therapy.
PubMed: 38823279
DOI: 10.1016/j.biopha.2024.116844 -
Journal of Infection and Public Health May 2024In spite of major effectiveness, a residual risk after COVID-19 primary vaccination was identified, in particular, for vulnerable individuals of advanced age or with...
BACKGROUND
In spite of major effectiveness, a residual risk after COVID-19 primary vaccination was identified, in particular, for vulnerable individuals of advanced age or with comorbidities. Less is known about the Omicron period in people protected by a booster dose. We aimed to identify the characteristics associated with severe COVID-19 during the Omicron period in a population that had received a booster dose in France and to compare differences with the previous periods of the pandemic.
METHODS
This study was carried out using the French national COVID-19 vaccination database (VAC-SI) coupled with the National Health Data System (SNDS). Individuals aged 12 years or over who received at least one booster dose were identified. Associations between socio-demographic and clinical characteristics and the risk of COVID-19 hospitalisation occurring at least 14 days after receiving a third dose of vaccine during the period of Omicron predominance, i.e., from 1 January 2022 to 10 November 2022, were assessed using Cox proportional hazard models adjusted for age, sex, time since booster dose and vaccination schedule. Analyses were performed overall and by sub-period of circulation of the strains BA.1, BA.2, and BA.4/BA.5, defined as periods where the main sub-variant accounted for more than 80 % of genotyped samples.
FINDINGS
In total, 35,640,387 individuals received a booster dose (mean follow-up of 291 days) and 73,989 were hospitalised for COVID-19 during the total period. Older age (aHR 20.5 95 % CI [19.6-21.5] for 90 years of age or older versus 45-54 years of age), being male (aHR 1.52 [1.50-1.55]), and social deprivation (aHR 1.33 [1.30-1.37] for the most deprived areas versus the least deprived) were associated with an increased risk of hospitalisation for COVID-19. Most of the chronic diseases considered were also positively associated with a residual risk, in particular, cystic fibrosis (aHR 9.83 [7.68-12.56]), active lung cancer (aHR 3.26 [3.06-3.47]), chronic dialysis (aHR 3.79 [3.49-4.11]), psychological and neurodegenerative diseases (more markedly than during the periods of circulation of the alpha and delta variants), and organ transplantation. The use of immunosuppressants was also associated with an increased risk (aHR 2.24 [2.14-2.35], including oral corticosteroids aHR (2.58 [2.50-2.67]).
CONCLUSION
Despite an effective booster and a generally less virulent circulating variant, a residual risk of severe COVID-19 still exists in vulnerable populations, especially those with neurological disorders.
PubMed: 38823086
DOI: 10.1016/j.jiph.2024.05.007 -
Experimental Hematology & Oncology May 2024Gallbladder cancer (GBC) is the most common and lethal malignancy of the biliary tract that lacks effective therapy. In many GBC cases, infiltration into adjacent organs...
BACKGROUND
Gallbladder cancer (GBC) is the most common and lethal malignancy of the biliary tract that lacks effective therapy. In many GBC cases, infiltration into adjacent organs or distant metastasis happened long before the diagnosis, especially the direct liver invasion, which is the most common and unfavorable way of spreading.
METHODS
Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), proteomics, and multiplexed immunohistochemistry (mIHC) were performed on GBC across multiple tumor stages to characterize the tumor microenvironment (TME), focusing specifically on the preferential enrichment of neutrophils in GBC liver invasion (GBC-LI).
RESULTS
Multi-model Analysis reveals the immunosuppressive TME of GBC-LI that was characterized by the enrichment of neutrophils at the invasive front. We identified the context-dependent transcriptional states of neutrophils, with the Tumor-Modifying state being associated with oxidized low-density lipoprotein (oxLDL) metabolism. In vitro assays showed that the direct cell-cell contact between GBC cells and neutrophils led to the drastic increase in oxLDL uptake of neutrophils, which was primarily mediated by the elevated OLR1 on neutrophils. The oxLDL-absorbing neutrophils displayed a higher potential to promote tumor invasion while demonstrating lower cancer cytotoxicity. Finally, we identified a neutrophil-promoting niche at the invasive front of GBC-LI that constituted of KRT17 GBC cells, neutrophils, and surrounding fibroblasts, which may help cultivate the oxLDL-absorbing neutrophils.
CONCLUSIONS
Our study reveals the existence of a subset of pro-tumoral neutrophils with a unique ability to absorb oxLDL via OLR1, a phenomenon induced through cell-cell contact with KRT17 GBC cells in GBC-LI.
PubMed: 38822440
DOI: 10.1186/s40164-024-00521-7