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Heliyon Jun 2024Colchicine is a common therapeutic agent for inflammatory conditions such as gout, yet its narrow therapeutic range frequently results in cases of overdose and...
BACKGROUND
Colchicine is a common therapeutic agent for inflammatory conditions such as gout, yet its narrow therapeutic range frequently results in cases of overdose and subsequent poisoning. Acute colchicine poisoning can be difficult to identify due to its nonspecific clinical manifestations, posing a diagnostic challenge for emergency physicians without a clear history of colchicine ingestion.
CASE PRESENTATION
This report describes a tragic case of acute colchicine poisoning that resulted in three familial homicides. The patients presented with fever, abdominal pain, and diarrhea, which rapidly escalated to shock during their emergency department visits. Laboratory tests revealed a marked leukocytosis, mild elevation in procalcitonin (PCT), significantly elevated creatine kinase (CK) and CK-MB levels, and liver function abnormalities. Despite treatment with carbapenem antibiotics and aggressive fluid resuscitation, the patients' condition deteriorated, marked by a progressive decline in leukocytes and neutrophils. Initially misdiagnosed as septic shock, the ineffectiveness of the standard treatment protocols led to a fatal outcome for all three individuals.
CONCLUSION
Emergency physicians should consider acute colchicine poisoning as a differential diagnosis in patients presenting with shock and the following clinical indicators: (1) pronounced increase in peripheral leukocytes with a disproportionate rise in neutrophils; (2) discordance between the level of serum procalcitonin and the severity of presumed septic shock; (3) early increase in serum creatine kinase (CK) and CK-MB; (4) poor response to antibiotics and resuscitative efforts, accompanied by a continuous decrease in white blood cells and neutrophils. This case underscores the critical need for awareness of colchicine toxicity in the emergency setting, particularly when the clinical presentation mimics septic shock but fails to respond to standard treatments.
PubMed: 38947441
DOI: 10.1016/j.heliyon.2024.e32407 -
Frontiers in Immunology 2024Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple...
Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple functions in cell adhesion, cell migration, and protection from complement attack. We studied the role of sialoglycans on T cells in a mouse model with a T cell-specific deletion of cytidine monophosphate-sialic acid synthase (CMAS), the enzyme that is crucial for the synthesis of sialoglycans. These mice showed a T-cell deficiency in peripheral lymphoid organs. Many T cells with an undeleted allele were found in the periphery, suggesting that they escaped the Cre-mediated deletion. The remaining peripheral T cells of T cell-specific KO mice had a memory-like phenotype. Additional depletion of the complement factor C3 could not rescue the phenotype, showing that the T-cell defect was not caused by a host complement activity. -deficient T cells showed a high level of activated caspase 3, indicating an ongoing apoptosis. In bone marrow chimeric cellular transfer experiments, we observed a strong competitive disadvantage of -deficient T cells compared to wild-type T cells. These results show that sialoglycans on the surface of T cells are crucial for T-cell survival and maintenance. This function has not been recognized before and is similar to the function of sialoglycans on B cells.
Topics: Animals; Mice; Mice, Knockout; T-Lymphocytes; Sialic Acids; Cell Survival; Mice, Inbred C57BL; Apoptosis; Complement C3; Mixed Function Oxygenases
PubMed: 38947328
DOI: 10.3389/fimmu.2024.1359494 -
Frontiers in Immunology 2024Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from...
Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression.
BACKGROUND
Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression.
METHODS
Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following heme treatment was also examined.
RESULTS
Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response.
CONCLUSIONS
Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.
Topics: Humans; Heme; Burns; Male; Adult; Female; Middle Aged; Cytokines; Wounds and Injuries; Young Adult; Aged; THP-1 Cells; Leukocytes, Mononuclear; Biomarkers; Lipopolysaccharides; Heme Oxygenase-1
PubMed: 38947312
DOI: 10.3389/fimmu.2024.1416820 -
Frontiers in Medicine 2024Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus, often causing pain or numbness in the patient's limbs and even leading...
BACKGROUND
Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus, often causing pain or numbness in the patient's limbs and even leading to amputation and death. Elderly patients with DPN usually have higher morbidity and more severe results. Acupuncture has been widely used as an effective treatment for DPN in China. However, the efficacy of acupuncture in the treatment of DPN remains unclear. In this review, we aimed to explore the impact of acupuncture in alleviating symptoms of DPN.
METHOD AND ANALYSIS
Six databases were searched from inception to October 2023. We searched Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and three Chinese databases, namely China National Knowledge Infrastructure (CNKI), SinoMed, and Wanfang. All randomized controlled trials related to the effect of acupuncture on DPN will be included. There was no restriction in language or publication year. The primary outcome is the response rate. The secondary outcomes are the Toronto clinical scoring system (TCSS), nerve conduction velocities (NCVs), and blood glucose before and after the treatment. Two researchers will be responsible for the selection of study, data extraction, and assessment of study quality independently. RevMan V5.1.0 software will be used to assess the risk of bias and generate data.
RESULTS
We searched 4518 studies, among which 9 RCTs were considered eligible. Overall, acupuncture treatment had a higher response rate than controls (relative risk (RR), -2.87 [95% confidence interval (CI), -5.27 to -0.48], = 0.02) and significantly alleviated the symptoms of DPN patients, reduced their blood glucose levels, and improved their NCVs compared to the control group. This study will provide a high-quality synthesis of current available evidence for the clinical treatment of DPN with this therapy.
CONCLUSION
The results suggested that acupuncture might be effective in improving symptoms of DPN in elderly patients. Owing to the overall low quality of the literature included, we need more large-sample, high-quality, and low-bias studies to prove it.
PubMed: 38947240
DOI: 10.3389/fmed.2024.1339747 -
Journal of Veterinary Research Jun 2024The main adaptive immune cells are T and B lymphocytes and they play key roles in the induction of immune responses against canine mammary tumours. Investigating these...
INTRODUCTION
The main adaptive immune cells are T and B lymphocytes and they play key roles in the induction of immune responses against canine mammary tumours. Investigating these cell subpopulations may lead to more precise diagnosis of these malignancies.
MATERIAL AND METHODS
The percentages of CD3, CD4 and CD8 T cells and of CD21 B cells in the peripheral blood of bitches with malignant mammary tumours were compared with those in the blood of healthy animals. The phenotypic features of peripheral blood leukocytes were evaluated by flow cytometry.
RESULTS
There was a significant difference in the mean percentages of CD3 lymphocytes between healthy (66.7%) and metastatic dogs (46.1%), and between tumour-bearing non-metastatic (66.6%) and metastatic dogs. There was also a significant difference in CD4 T helper cell percentages between healthy dogs (40.4%) and dogs with metastases (23.2%), and between the latter and dogs without them (35.5%). In the case of CD21 lymphocyte subsets, a significant difference was noted between healthy animals (10.9%) and those with metastases (20.1%), and between the latter and patients without metastases (8.5%). There were also significant differences in CD3/CD21 ratios between the group with metastases (3.0), the healthy group (7.8), and the group without metastases (8.5). Similarly, a significant difference was noted in CD4/CD8 ratios between animals with metastases (1.4), bitches in the control group (2.2), and dogs without metastases (1.9).
CONCLUSION
Peripheral blood leukocyte phenotypic characteristics are putative novel biomarkers. These findings may be useful in future studies improving mammary tumour diagnostic procedures, especially in metastasis detection.
PubMed: 38947156
DOI: 10.2478/jvetres-2024-0035 -
The Yale Journal of Biology and Medicine Jun 2024Nodal regions, areas of intensive contact between Schwann cells and axons, may be exceptionally vulnerable to diabetes-induced changes because they are exposed to and...
Nodal regions, areas of intensive contact between Schwann cells and axons, may be exceptionally vulnerable to diabetes-induced changes because they are exposed to and impacted by the metabolic implications of diabetes. Insulin receptors, glucose transporters, Na and K channels, and mitochondria are abundant in nodes, all of which have been linked to the development and progression of Diabetic Peripheral Neuropathy (DPN) and Type 1 Diabetes Mellitus (T1DM)-associated cognitive impairment. Our study aimed to evaluate if the administration of (NS) and (CA) prevented diabetes-associated nervous system deficits in hyperglycemic mice. We developed T1DM mice through Streptozotocin (STZ) injections and validated the elevations in blood glucose levels. NS and CA were administered immediately upon the induction of diabetes. Behavioral analysis, histopathological evaluations, and assessment of molecular biomarkers (NR2A, MPZ, NfL) were performed to assess neuropathy and cognitive impairment. Improvements in memory, myelin loss, and the expression of synaptic proteins, even with the retention of hyperglycemia, were evident in the mice who were given a dose of herbal products upon the detection of hyperglycemia. NS was more beneficial in preventing memory impairments, demyelination, and synaptic dysfunction. The findings indicate that including these herbs in the diets of diabetic as well as pre-diabetic patients can reduce complications associated with T1DM, notably diabetic peripheral neuropathy and cognitive deficits associated with T1DM.
Topics: Animals; Diabetic Neuropathies; Nigella sativa; Mice; Cognitive Dysfunction; Male; Diabetes Mellitus, Experimental; Plant Extracts; Plants, Medicinal; Senna Plant
PubMed: 38947105
DOI: 10.59249/UQLO8012 -
MedRxiv : the Preprint Server For... Jun 2024Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by...
BACKGROUND
Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs.
METHODS
We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation.
RESULTS
Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir.
CONCLUSIONS
Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.
PubMed: 38947072
DOI: 10.1101/2024.02.16.24302713 -
Research Square Jun 2024Background DNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity or asthma endotypes...
Background DNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity or asthma endotypes are less well-defined. Objective To examine how DNA methylomic patterns differ among adults with asthma based on asthma severity and airway inflammation. Methods Peripheral blood T cells from 35 adults with asthma in Beijing, China were serially collected over time (130 samples total) and analyzed for global DNA methylation using the Illumina MethylationEPIC Array. Differential methylation was compared among subjects with varying airway inflammation and severity, as measured by fraction of exhaled nitric oxide, forced expiratory volume in one second (FEV1), and Asthma Control Test (ACT) scores. Results Significant differences in DNA methylation were noted among subjects with different degrees of airway inflammation and asthma severity. These differences in DNA methylation were annotated to genes that were enriched in pathways related to asthma or T cell function and included gene ontology categories related to MHC class II assembly, T cell activation, interleukin (IL)-1, and IL-12. Genes related to P450 drug metabolism, glutathione metabolism, and developmental pathways were also differentially methylated in comparisons between subjects with high vs low FEV1 and ACT. Notable genes that were differentially methylated based on asthma severity included , several members of the family, , , , and several genes downstream of the and signaling pathway. Conclusion These findings demonstrate how adults with asthma of varying severity possess differences in peripheral blood T cell DNA methylation that contribute to the phenotype and severity of their overall disease.
PubMed: 38946998
DOI: 10.21203/rs.3.rs-4476948/v1 -
BME Frontiers 2024: We have developed a baroreceptor-inspired microneedle skin patch for pressure-controlled drug release. : This design is inspired by the skin baroreceptors, which are...
: We have developed a baroreceptor-inspired microneedle skin patch for pressure-controlled drug release. : This design is inspired by the skin baroreceptors, which are mechanosensitive elements of the peripheral nervous system. We adopt the finger touching to trigger the electric stimulation, ensuring a fast-response and user-friendly administration with potentially minimal off-target effects. : Chronic skin diseases bring about large, recurrent skin damage and often require convenient and timely transdermal treatment. Traditional methods lack spatiotemporal controllable dosage, leaving a risk of skin irritation or drug resistance issues. : The patch consists of drug-containing microneedles and stretchable electrode array. The electrode array, integrated with the piezoconductive switch and flexible battery, provides a mild electric current only at the spot that is pressed. Drugs in microneedles will then flow along the current into the skin tissues. The stretchable feature also provides the mechanical robustness and electric stability of the device on large skin area. : This device delivers Cy3 dye in pig skin with spatiotemporally controlled dosage, showing ~8 times higher fluorescence intensity than the passive delivery. We also deliver insulin and observe the reduction of the blood glucose level in the mouse model upon pressing. Compared with passive delivery without pressing, the dosage of drugs released by the simulation is 2.83 times higher. : This baroreceptor-inspired microneedle skin patch acts as a good example of the biomimicking microneedle device in the precise control of the drug release profile at the spatiotemporal resolution.
PubMed: 38946867
DOI: 10.34133/bmef.0044 -
World Journal of Clinical Oncology Jun 2024Myeloproliferative neoplasms (MPNs) occur due to the abnormal proliferation of one or more terminal myeloid cell lines in peripheral blood. Subjects suffering from MPNs... (Review)
Review
Myeloproliferative neoplasms (MPNs) occur due to the abnormal proliferation of one or more terminal myeloid cell lines in peripheral blood. Subjects suffering from MPNs display a high burden of cardiovascular risk factors, and thrombotic events are often the cause of death in this population of patients. Herein, we provide a brief overview of dyslipidemia and metabolic syndrome and their epidemiology in MPNs and examine the common molecular mechanisms between dyslipidemia, metabolic syndrome, and MPNs, with a special focus on cardiovascular risk, atherosclerosis, and thrombotic events. Furthermore, we investigate the impact of dyslipidemia and metabolic syndrome on the occurrence and survival of thrombosis in MPN patients, as well as the management of dyslipidemia in MPNs, and the impact of MPN treatment on serum lipid concentrations, particularly as side/adverse effects reported in the context of clinical trials.
PubMed: 38946827
DOI: 10.5306/wjco.v15.i6.717