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Frontiers in Immunology 2024Encephalitozoon hellem (E. hellem) infection is a zoonotic disease, rarely observed in individuals, causing various clinical manifestations including diarrhea,...
BACKGROUND
Encephalitozoon hellem (E. hellem) infection is a zoonotic disease, rarely observed in individuals, causing various clinical manifestations including diarrhea, keratoconjunctivitis, cystitis, etc. E. hellem infection after hematopoietic stem-cell transplantation (HSCT) is a rare, serious complication.
CASE PRESENTATION
Herein, we present a case of E. hellem infection developing during HLA-haploidentical HSCT in a 9-year-old boy who suffered from aplastic anemia. On 15 days after HSCT, the patient developed recurrent and prolonged fever, diarrhea and hematuria. It is challenging to differentiate whether the symptoms mentioned in this case are caused by graft-versus-host disease (GVHD) or a specific infection. Based on the result of metagenomic next-generation sequencing (mNGS) and clinical observation, the patient was diagnosed as E. hellem infection, and received albendazole and decreased the immunosuppressive treatment. Finally, he had recovered.
CONCLUSION
We should pay attention to the uncommon disease caused by the E. hellem infection after HSCT, especially in cases with immune reconstitution unrecovered. Among those rare infection, mNGS can be performed for better understanding the source of infection and targeted therapy, which can benefit the patients.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Male; Child; Transplantation, Haploidentical; Anemia, Aplastic; Albendazole; Graft vs Host Disease; Transplantation, Homologous
PubMed: 38863712
DOI: 10.3389/fimmu.2024.1396260 -
International Journal of Nanomedicine 2024Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a...
PURPOSE
Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability.
METHODS
The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments.
RESULTS
DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively.
CONCLUSION
SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism.
Topics: Animals; Liposomes; Biological Availability; Caco-2 Cells; Humans; Administration, Oral; Artemisinins; Intestinal Absorption; Male; Tissue Distribution; Particle Size; Mice; Lymphatic System; Rats, Sprague-Dawley; Rats; Biomimetic Materials; Intestinal Mucosa
PubMed: 38859952
DOI: 10.2147/IJN.S462374 -
Journal of Korean Medical Science Jun 2024Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the...
Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per μL of blood (p/μL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/μL. However, at follow-up, parasite density increased to 7,630 p/μL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria.
Topics: Humans; Malaria, Falciparum; Ghana; Antimalarials; Middle Aged; Male; Plasmodium falciparum; Proguanil; Atovaquone; Travel; Artemisinins; Artesunate; Parasitemia; Doxycycline; Drug Combinations; Treatment Failure; Artemether, Lumefantrine Drug Combination
PubMed: 38859743
DOI: 10.3346/jkms.2024.39.e186 -
Malaria Journal Jun 2024Plasmodium vivax malaria is a leading cause of morbidity in Ethiopia. The first-line treatment for P. vivax is chloroquine (CQ) and primaquine (PQ), but there have been...
BACKGROUND
Plasmodium vivax malaria is a leading cause of morbidity in Ethiopia. The first-line treatment for P. vivax is chloroquine (CQ) and primaquine (PQ), but there have been local reports of CQ resistance. A clinical study was conducted to determine the efficacy of CQ for the treatment of P. vivax malaria in southern Ethiopia.
METHODS
In 2021, patients with P. vivax mono-infection and uncomplicated malaria were enrolled and treated with 25 mg/kg CQ for 3 consecutive days. Patients were followed for 28 days according to WHO guidelines. The data were analysed using per-protocol (PP) and Kaplan‒Meier (K‒M) analyses to estimate the risk of recurrent P. vivax parasitaemia on day 28.
RESULTS
A total of 88 patients were enrolled, 78 (88.6%) of whom completed the 28 days of follow-up. Overall, 76 (97.4%) patients had adequate clinical and parasitological responses, and two patients had late parasitological failures. The initial therapeutic response was rapid, with 100% clearance of asexual parasitaemia within 48 h.
CONCLUSION
Despite previous reports of declining chloroquine efficacy against P. vivax, CQ retains high therapeutic efficacy in southern Ethiopia, supporting the current national treatment guidelines. Ongoing clinical monitoring of CQ efficacy supported by advanced molecular methods is warranted to inform national surveillance and ensure optimal treatment guidelines.
Topics: Malaria, Vivax; Chloroquine; Ethiopia; Humans; Antimalarials; Male; Adult; Female; Adolescent; Young Adult; Child; Middle Aged; Child, Preschool; Plasmodium vivax; Treatment Outcome; Aged; Parasitemia
PubMed: 38858696
DOI: 10.1186/s12936-024-05009-7 -
Redox Biology Aug 2024Elevated lactate levels are a significant biomarker of sepsis and are positively associated with sepsis-related mortality. Sepsis-associated lung injury (ALI) is a...
Elevated lactate levels are a significant biomarker of sepsis and are positively associated with sepsis-related mortality. Sepsis-associated lung injury (ALI) is a leading cause of poor prognosis in clinical patients. However, the underlying mechanisms of lactate's involvement in sepsis-associated ALI remain unclear. In this study, we demonstrate that lactate regulates N6-methyladenosine (m6A) modification levels by facilitating p300-mediated H3K18la binding to the METTL3 promoter site. The METTL3-mediated m6A modification is enriched in ACSL4, and its mRNA stability is regulated through a YTHDC1-dependent pathway. Furthermore, short-term lactate stimulation upregulates ACSL4, which promotes mitochondria-associated ferroptosis. Inhibition of METTL3 through knockdown or targeted inhibition effectively suppresses septic hyper-lactate-induced ferroptosis in alveolar epithelial cells and mitigates lung injury in septic mice. Our findings suggest that lactate induces ferroptosis via the GPR81/H3K18la/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated ALI. These results reveal a histone lactylation-driven mechanism inducing ferroptosis through METTL3-mediated m6A modification. Targeting METTL3 represents a promising therapeutic strategy for patients with sepsis-associated ALI.
Topics: Ferroptosis; Methyltransferases; Animals; Sepsis; Mice; Humans; Coenzyme A Ligases; Adenosine; Lung Injury; Acute Lung Injury; Male; Disease Models, Animal; Lactic Acid
PubMed: 38852200
DOI: 10.1016/j.redox.2024.103194 -
Cardiovascular Toxicology Jul 2024Antiviral therapies for treatment of COVID-19 may be associated with significant proarrhythmic potential. In the present study, the potential cardiotoxic side effects of... (Comparative Study)
Comparative Study
Antiviral therapies for treatment of COVID-19 may be associated with significant proarrhythmic potential. In the present study, the potential cardiotoxic side effects of these therapies were evaluated using a Langendorff model of the isolated rabbit heart. 51 hearts of female rabbits were retrogradely perfused, employing a Langendorff-setup. Eight catheters were placed endo- and epicardially to perform an electrophysiology study, thus obtaining cycle length-dependent action potential duration at 90% of repolarization (APD), QT intervals and dispersion of repolarization. After generating baseline data, the hearts were assigned to four groups: In group 1 (HXC), hearts were treated with 1 µM hydroxychloroquine. Thereafter, 3 µM hydroxychloroquine were infused additionally. Group 2 (HXC + AZI) was perfused with 3 µM hydroxychloroquine followed by 150 µM azithromycin. In group 3 (LOP) the hearts were perfused with 3 µM lopinavir followed by 5 µM and 10 µM lopinavir. Group 4 (REM) was perfused with 1 µM remdesivir followed by 5 µM and 10 µM remdesivir. Hydroxychloroquine- and azithromycin-based therapies have a significant proarrhythmic potential mediated by action potential prolongation and an increase in dispersion. Lopinavir and remdesivir showed overall significantly less pronounced changes in electrophysiology. In accordance with the reported bradycardic events under remdesivir, it significantly reduced the rate of the ventricular escape rhythm.
Topics: Animals; Rabbits; Female; Antiviral Agents; Isolated Heart Preparation; Action Potentials; COVID-19 Drug Treatment; Hydroxychloroquine; Arrhythmias, Cardiac; Cardiotoxicity; Alanine; Heart Rate; Adenosine Monophosphate; Heart
PubMed: 38851664
DOI: 10.1007/s12012-024-09872-3 -
Biology Direct Jun 2024The molecular mechanisms of osteosarcoma (OS) are complex. In this study, we focused on the functions of melanoma cell adhesion molecule (MCAM), methyltransferase 3...
BACKGROUND
The molecular mechanisms of osteosarcoma (OS) are complex. In this study, we focused on the functions of melanoma cell adhesion molecule (MCAM), methyltransferase 3 (METTL3) and insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) in OS development.
METHODS
qRT-PCR assay and western blot assay were performed to determine mRNA and protein expression of MCAM, METTL3, IGF2BP1 and YY1. MTT assay and colony formation assay were conducted to assess cell proliferation. Cell apoptosis, invasion and migration were evaluated by flow cytometry analysis, transwell assay and wound-healing assay, respectively. Methylated RNA Immunoprecipitation (MeRIP), dual-luciferase reporter, Co-IP, RIP and ChIP assays were performed to analyze the relationships of MCAM, METTL3, IGF2BP1 and YY1. The functions of METTL3 and MCAM in tumor growth were explored through in vivo experiments.
RESULTS
MCAM was upregulated in OS, and MCAM overexpression promoted OS cell growth, invasion and migration and inhibited apoptosis. METTL3 and IGF2BP1 were demonstrated to mediate the m6A methylation of MCAM. Functionally, METTL3 or IGF2BP1 silencing inhibited OS cell progression, while MCAM overexpression ameliorated the effects. Transcription factor YY1 promoted the transcription level of METTL3 and regulated METTL3 expression in OS cells. Additionally, METTL3 deficiency suppressed tumor growth in vivo, while MCAM overexpression abated the effect.
CONCLUSION
YY1/METTL3/IGF2BP1/MCAM axis aggravated OS development, which might provide novel therapy targets for OS.
Topics: Osteosarcoma; Methyltransferases; Humans; RNA-Binding Proteins; Adenosine; Cell Line, Tumor; Animals; Mice; Cell Proliferation; Bone Neoplasms; Disease Progression; Mice, Nude; Apoptosis; Cell Movement; Gene Expression Regulation, Neoplastic
PubMed: 38849910
DOI: 10.1186/s13062-024-00486-x -
Nature Communications Jun 2024N-methyladenosine (mA) plays critical roles in regulating mRNA metabolism. However, comprehensive mA methylomes in different plant tissues with single-base precision...
N-methyladenosine (mA) plays critical roles in regulating mRNA metabolism. However, comprehensive mA methylomes in different plant tissues with single-base precision have yet to be reported. Here, we present transcriptome-wide mA maps at single-base resolution in different tissues of rice and Arabidopsis using mA-SAC-seq. Our analysis uncovers a total of 205,691 mA sites distributed across 22,574 genes in rice, and 188,282 mA sites across 19,984 genes in Arabidopsis. The evolutionarily conserved mA sites in rice and Arabidopsis ortholog gene pairs are involved in controlling tissue development, photosynthesis and stress response. We observe an overall mRNA stabilization effect by 3' UTR mA sites in certain plant tissues. Like in mammals, a positive correlation between the mA level and the length of internal exons is also observed in plant mRNA, except for the last exon. Our data suggest an active mA deposition process occurring near the stop codon in plant mRNA. In addition, the MTA-installed plant mRNA mA sites correlate with both translation promotion and translation suppression, depicting a more complicated regulatory picture. Our results therefore provide in-depth resources for relating single-base resolution mA sites with functions in plants and uncover a suppression-activation model controlling mA biogenesis across species.
Topics: Oryza; Arabidopsis; Adenosine; Gene Expression Regulation, Plant; RNA, Messenger; Transcriptome; RNA, Plant; 3' Untranslated Regions; Gene Expression Profiling; RNA Stability; Exons; Codon, Terminator
PubMed: 38849358
DOI: 10.1038/s41467-024-48941-7 -
PLoS Neglected Tropical Diseases Jun 2024Ocular toxoplasmosis (OT) is the most common cause of infectious uveitis worldwide, including Thailand. This study describes the clinical presentation, visual acuity...
Clinical characteristics, visual acuity outcomes, and factors associated with loss of vision among patients with active ocular toxoplasmosis: A retrospective study in a Thai tertiary center.
BACKGROUND
Ocular toxoplasmosis (OT) is the most common cause of infectious uveitis worldwide, including Thailand. This study describes the clinical presentation, visual acuity (VA) outcomes, and factors associated with VA loss in patients with active OT following antiparasitic treatment.
METHODOLOGY/PRINCIPAL FINDINGS
A retrospective chart review of patients with active OT treated with antiparasitic drugs between 2010 and 2020 was performed. Outcome measures included clinical characteristics, interval VA, and predictive factors associated with loss of VA ≤ 20/50 at 6 months post-treatment. Ninety-two patients (95 eyes) were enrolled. The median follow-up time was 10.9 months (IQR 4.9-31.8 months). The median age at presentation was 35.9 years, 51% were male, and 92.4% had unilateral OT. Eleven patients (12%) were immunocompromised (HIV infection, eight patients; receiving immunosuppressive agents, three patients). Patients mainly presented with primary retinitis without previous scar (62%), posterior pole lesion (56%), and lesion size of ≤ 2-disc area (75%). Immunocompromised patients showed a significantly larger size of retinitis than immunocompetent patients. Oral trimethoprim/sulfamethoxazole monotherapy was the primary short-term antiparasitic drug prescribed (85%). At the final visit, 21% of all affected eyes suffered VA ≤ 20/200. The cumulative incidence of recurrent OT at three years was 33.9% (95% CI, 19.7%-54.2%). Immunocompromised patients [adjusted odds ratio (aOR) 4.9, p = 0.041], macular lesion (aOR 5.4, p = 0.032), and initial VA ≤ 20/200 (aOR 9.1, p = 0.014) were predictive of having VA ≤ 20/50 at 6 months post-treatment.
CONCLUSIONS
Ocular toxoplasmosis mainly presents as unilateral primary retinitis within the posterior pole. Severe VA loss was observed in one-fifth of eyes following treatment with lesion resolution. Immunocompromised patients, eyes with macular lesions, and poor initial VA were associated with poor VA outcomes.
Topics: Humans; Toxoplasmosis, Ocular; Male; Retrospective Studies; Adult; Female; Thailand; Visual Acuity; Middle Aged; Tertiary Care Centers; Young Adult; Immunocompromised Host; Antiparasitic Agents; Trimethoprim, Sulfamethoxazole Drug Combination; Adolescent; Treatment Outcome; Southeast Asian People
PubMed: 38843299
DOI: 10.1371/journal.pntd.0012232 -
Malaria Journal Jun 2024Neonatal malaria is defined as the detection of asexual stages of Plasmodium species in the cord blood within the first 28 days of life. It can be congenital or...
BACKGROUND
Neonatal malaria is defined as the detection of asexual stages of Plasmodium species in the cord blood within the first 28 days of life. It can be congenital or acquired through mosquito bites or blood transfusions. Neonates are generally considered to be relatively protected due to the multiple innate and acquired physiological protective effects present in neonates. However, in areas where malaria is endemic, the prevalence of malaria in neonates is high. The predominant clinical feature of malaria in neonates is fever. Other clinical manifestations of neonatal malaria include respiratory distress, pallor and anaemia, hepatomegaly, refusal to feed, jaundice and diarrhoea. Atypical presentations without fever can lead to inaccurate diagnosis and contribute to neonatal morbidity and mortality. Neonates from endemic areas with any of the above symptoms should be screened for malaria.
CASE PRESENTATION
We present a series of three cases of neonatal Plasmodium falciparum malaria that presented atypically without febrile episodes and were diagnosed and managed at Mizan-Tepi University Teaching Hospital between July and September 2023. The first patient presented with vomiting, refusal to feed, pallor, severe anaemia, and splenomegaly. The second patient presented with an inconsolable cry, failure to pass feces, abdominal distention, and anaemia. The third patient presented with vomiting and anaemia. All patients received a 7-day course of intravenous artesunate; the first patient also received a blood transfusion. All patients recovered and were discharged.
CONCLUSIONS
Partial immunity resulting from repeated malaria infections in endemic regions may result in the transfer of high levels of maternal Immunoglobulin G (IgG) antibodies through the placenta and can produce different atypical clinical presentations. In malaria-endemic areas, neonates presenting with any of the presenting signs and symptoms of malaria, including afebrile presentation, require malaria screening to avoid delays in diagnosis.
Topics: Humans; Infant, Newborn; Malaria, Falciparum; Female; Male; Ethiopia; Plasmodium falciparum; Antimalarials; Artesunate
PubMed: 38840266
DOI: 10.1186/s12936-024-04987-y