ABSTRACT
Chronic kidney disease of unknown aetiology (CKDu) reported in Sri Lanka and other countries is a mysterious and serious disease. Recently, we reported a high seroprevalence of antibodies to a hantavirus antigen among CKDu patients in Girandurukotte, Badulla district, Sri Lanka. However, the type of hantavirus with which the residents were infected was not determined. In this study, a total of 89 seropositive sera were examined to identify their serotypes using an indirect immunofluorescent antibody assay, a truncated-N-protein-based enzyme-linked immunosorbent assay, and a cross-neutralization test. These results indicated that the residents in this area were frequently infected with Thailand orthohantavirus or an antigenically related virus.
Subject(s)
Bunyaviridae Infections/virology , Bunyaviridae/classification , Bunyaviridae/isolation & purification , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/virology , Bunyaviridae Infections/epidemiology , Humans , Renal Insufficiency, Chronic/blood , Sri LankaABSTRACT
Conservation of the local genetic variation and evolutionary integrity of economically and ecologically important trees is a key aspect of studies involving forest genetics, and a population demographic history of the target species provides valuable information for this purpose. Here, the genetic structure of 48 populations of Betula maximowicziana was assessed using 12 expressed sequence tag-simple sequence repeat (EST-SSR) markers. Genetic diversity was lower in northern populations than southern ones and structure analysis revealed three groups: northern and southern clusters and an admixed group. Eleven more genomic-SSR loci were added and the demographic history of these three groups was inferred by approximate Bayesian computation (ABC). The ABC revealed that a simple split scenario was much more likely than isolation with admixture, suggesting that the admixture-like structure detected in this species was due to ancestral polymorphisms. The ABC analysis suggested that the population growth and divergence of the three groups occurred 96 800 (95% CI, 20 500-599 000) and 28 300 (95% CI, 8700-98 400) years ago, respectively. We need to be aware of several sources of uncertainty in the inference such as assumptions about the generation time, overlapping of generations, confidence intervals of the estimated parameters and the assumed model in the ABC. However, the results of the ABC together with the model-based maps of reconstructed past species distribution and palaeoecological data suggested that the modern genetic structure of B. maximowicziana originated prior to the last glacial maximum (LGM) and that some populations survived in the northern range even during the LGM.
Subject(s)
Betula/genetics , Biological Evolution , Genetic Variation , Genetics, Population , Bayes Theorem , Conservation of Natural Resources , DNA, Plant/genetics , Expressed Sequence Tags , Japan , Microsatellite Repeats , Models, Genetic , Sequence Analysis, DNAABSTRACT
BACKGROUND: This study compared natural root caries lesions with artificial root caries lesions prepared with one of the two demineralising solutions. METHODS: Twelve natural root caries lesions on upper incisors and 24 artificial root lesions were prepared on sound root surfaces using 50 mM acetic acid, 1.5 mM CaCl2 , 0.9 mM KH2 PO4 at pH 5.0 or 80 mL/L Noverite K-702 polyacrylate solution, 500 mg/L hydroxyapatite, 0.1 mol/L lactic acid at pH 4.8 (n = 12/group) for 96 hours. Lesions were scanned using micro-CT. Inciso-gingival oriented images were analysed and mineral density calculated at 7.5 µm increments from the surface to 225-µm deep. Sectioned lesions were analysed by Knoop microhardness up to 250 µm from the lesion surface. Data were analysed by the Dunn's test with Bonferroni correction. RESULTS: Natural and artificial lesion mean mineral densities were not statistically different (P > 0.05). Mineral density from the surface to 75 µm was greater in natural lesions and from 150 to 225 µm was greater in artificial lesions (P < 0.05). Microhardness values were statistically higher in artificial lesions (P < 0.05); no difference was found among artificial lesions produced by the two solutions (P > 0.05). Mineral density and microhardness of natural and artificial root caries are different from each other. A greater mineralized surface layer existed on natural lesions.
Subject(s)
Dental Caries , Root Caries , Humans , Root Caries/diagnostic imaging , X-Ray Microtomography , Minerals , Dental Caries/diagnostic imaging , Tooth Remineralization/methodsABSTRACT
The ecology and geographical distribution of disease vectors are major determinants of spatial and temporal variations in the transmission dynamics of vector-borne pathogens. However, there are limited studies on the ecology of vectors that contribute to the natural transmission of most vector-borne pathogens. Avian Plasmodium parasites are multihost mosquito-borne pathogens transmitted by multiple mosquito species, which might regulate the diversity and persistence of these parasites. From 2007 to 2010, we conducted entomological surveys at Sakata wetland in central Japan, to investigate temporal variation in mosquito occurrence and prevalence of avian Plasmodium lineages in the mosquito populations. A polymerase chain reaction (PCR)-based method was used to detect Plasmodium parasites and identify the blood sources of mosquitoes. Culex inatomii and C. pipiens pallens represented 60.0% and 34.8% of 11 mosquito species collected, respectively. Our results showed that the two dominant mosquito species most likely serve as principal vectors of avian Plasmodium parasites during June, which coincides with the breeding season of bird species nesting in the wetland reed beds. Fourteen animal species were identified as blood sources of mosquitoes, with the oriental reed warbler (Acrocephalus orientalis) being the commonest blood source. Although there was significant temporal variation in the occurrence of mosquitoes and prevalence of Plasmodium lineages in the mosquitoes, the dominant Plasmodium lineages shared by the two dominant mosquito species were consistently found at the same time during transmission seasons. Because vector competence cannot be confirmed solely by PCR approaches, experimental demonstration is required to provide definitive evidence of transmission suggested in this study.
Subject(s)
Culex/parasitology , Insect Vectors/parasitology , Plasmodium/genetics , Songbirds/parasitology , Animals , DNA, Protozoan/genetics , Female , Japan , Malaria, Avian/parasitology , Malaria, Avian/transmission , Molecular Sequence Data , Plasmodium/isolation & purification , Seasons , WetlandsABSTRACT
Acoustic telemetry and microchemical analysis of otolith strontium-calcium ratios were used to evaluate how exotic brown trout Salmo trutta have responded to Japanese riverine environments of south-western Hokkaido by observing their migratory patterns. The existence of anadromous S. trutta was also verified. Most S. trutta caught in rivers for otolith analysis were freshwater residents (95·6%), whereas those caught in the sea were mainly smolts (91·3%), which had just migrated from rivers during spring. Anadromous S. trutta (n = 6) were captured in rivers and in the sea, confirming the existence of mature pre- and post-spawning fish. According to telemetry results, both mature and immature S. trutta used the river in winter, and their estimated sea-run timings showed individual differences. Through the combination of these two methods, migratory patterns on various spatio-temporal scales were observed. This first documentation of the presence of both male and female anadromous S. trutta in the same region within Japan indicated the risk of further colonization of exotic S. trutta via oceanic migration.
Subject(s)
Animal Migration , Otolithic Membrane/chemistry , Telemetry , Trout/physiology , Acoustics , Animal Identification Systems , Animals , Calcium/analysis , Female , Fresh Water , Introduced Species , Japan , Male , Seawater , Strontium/analysisABSTRACT
The detection of electron antineutrinos produced by natural radioactivity in the Earth could yield important geophysical information. The Kamioka liquid scintillator antineutrino detector (KamLAND) has the sensitivity to detect electron antineutrinos produced by the decay of 238U and 232Th within the Earth. Earth composition models suggest that the radiogenic power from these isotope decays is 16 TW, approximately half of the total measured heat dissipation rate from the Earth. Here we present results from a search for geoneutrinos with KamLAND. Assuming a Th/U mass concentration ratio of 3.9, the 90 per cent confidence interval for the total number of geoneutrinos detected is 4.5 to 54.2. This result is consistent with the central value of 19 predicted by geophysical models. Although our present data have limited statistical power, they nevertheless provide by direct means an upper limit (60 TW) for the radiogenic power of U and Th in the Earth, a quantity that is currently poorly constrained.
ABSTRACT
Heterogeneity in the transmission of mosquito-borne pathogens is determined largely by distribution patterns of mosquito bites among wild animal populations. Although mosquitoes are crucial for transmission of avian malaria parasites, little is known about the ecology of natural vectors. We examined bloodmeal and parasite incidence in Culex pipiens pallens by a polymerase chain reaction (PCR)-based procedure to determine how the feeding pattern of mosquitoes govern transmission dynamics of avian malaria parasites in Japanese wild birds. We collected 881 unfed and 486 blood-fed Cx. pipiens pallens resting on vegetation in a park in Tokyo. The mosquitoes were separated into abdomen and thorax prior to PCR screening. Abdomens of unfed mosquitoes were combined into 95 pools. From these, we amplified Plasmodium DNA in 32 (33.7%) pools. Among blood-fed mosquitoes, 371 individuals were screened for blood-sources and Plasmodium parasites. Plasmodium DNA was amplified from mosquitoes fed on 6 of 13 avian species identified as blood-sources. Ten Plasmodium lineages were identified on the basis of 478 bp of the cytochrome b gene, with 0.2-10% sequence divergence. The three commonest Plasmodium lineages (CXPIP09, SGS1 and PADOM02) were detected in both the abdomens and thoraxes of mosquitoes, strongly suggesting transmission of these lineages. Jungle crow (Corvus macrorhynchos) served as a natural host for the three commonest Plasmodium lineages and made up 63.8% of blood-sources. As a significant increase in feeding of vector mosquitoes on jungle crows coincided with their breeding season, jungle crows were considered to be the primary reservoir of Plasmodium transmission in this study.
Subject(s)
Birds/parasitology , Culex/physiology , Culex/pathogenicity , Feeding Behavior/physiology , Insect Vectors/physiology , Insect Vectors/pathogenicity , Malaria, Avian/transmission , Animals , SeasonsABSTRACT
The Hayabusa2 spacecraft investigated the small asteroid Ryugu, which has a rubble-pile structure. We describe an impact experiment on Ryugu using Hayabusa2's Small Carry-on Impactor. The impact produced an artificial crater with a diameter >10 meters, which has a semicircular shape, an elevated rim, and a central pit. Images of the impact and resulting ejecta were recorded by the Deployable CAMera 3 for >8 minutes, showing the growth of an ejecta curtain (the outer edge of the ejecta) and deposition of ejecta onto the surface. The ejecta curtain was asymmetric and heterogeneous and it never fully detached from the surface. The crater formed in the gravity-dominated regime; in other words, crater growth was limited by gravity not surface strength. We discuss implications for Ryugu's surface age.
ABSTRACT
AIMS: The aim of this study was to report the results of custom-made endoprostheses with extracortical plates plus or minus a short, intramedullary stem aimed at preserving the physis after resection of bone sarcomas in children. PATIENTS AND METHODS: Between 2007 and 2017, 18 children aged less than 16 years old who underwent resection of bone sarcomas, leaving ≤ 5 cm of bone from the physis, and reconstruction with a custom-made endoprosthesis were reviewed. Median follow-up was 67 months (interquartile range 45 to 91). The tumours were located in the femur in 11 patients, proximal humerus in six, and proximal tibia in one. RESULTS: The five-year overall survival rate was 78%. No patient developed local recurrence. The five-year implant survival rate was 79%. In all, 11 patients (61%) developed a complication. Seven patients (39%) required further surgery to treat the complications. Implant failures occurred in three patients (17%) including one patient with aseptic loosening and two patients with implant or periprosthetic fracture. The preserved physis continued to grow at mean 3.3 cm (0 to 14). The mean Musculoskeletal Society score was 88% (67% to 97%). CONCLUSION: Custom-made endoprostheses that aim to preserve the physis are a safe and effective option for preserving physeal growth, limb length, and joint function with an acceptable rate of complications. Cite this article: Bone Joint J 2019;101-B:1144-1150.
Subject(s)
Bone Neoplasms/surgery , Growth Plate/surgery , Osteosarcoma/surgery , Prostheses and Implants , Adolescent , Child , Female , Femur/surgery , Fracture Fixation, Intramedullary , Humans , Humerus/surgery , Limb Salvage/methods , Male , Prosthesis Design , Prosthesis Failure , Prosthesis Implantation/instrumentation , Plastic Surgery Procedures/instrumentation , Recovery of Function , Reoperation , Tibia/surgeryABSTRACT
AIMS: The aim of this study was to determine the risk of local recurrence and survival in patients with osteosarcoma based on the proximity of the tumour to the major vessels. PATIENTS AND METHODS: A total of 226 patients with high-grade non-metastatic osteosarcoma in the limbs were investigated. Median age at diagnosis was 15 years (4 to 67) with the ratio of male to female patients being 1.5:1. The most common site of the tumour was the femur (n = 103) followed by tibia (n = 66). The vascular proximity was categorized based on the preoperative MRI after neoadjuvant chemotherapy into four types: type 1 > 5 mm; type 2 ≤ 5 mm, > 0 mm; type 3 attached; type 4 surrounded. RESULTS: Limb salvage rate based on the proximity type was 92%, 88%, 51%, and 0% for types 1 to 4, respectively, and the overall survival at five years was 82%, 77%, 57%, and 67%, respectively (p < 0.001). Local recurrence rate in patients with limb-salvage surgery was 7%, 8%, and 22% for the types 1 to 3, respectively (p = 0.041), and local recurrence at the perivascular area was observed in 1% and 4% for type 2 and 3, respectively. The mean microscopic margin to the major vessels was 6.9 mm, 3.0 mm, and 1.4 mm for types 1 to 3, respectively. In type 3, local recurrence-free survival with limb salvage was significantly poorer compared with amputation (p = 0.025), while the latter offered no overall survival benefit. In this group of patients, factors such as good response to chemotherapy or limited vascular attachment to less than half circumference or longitudinal 10 mm reduced the risk of local recurrence. CONCLUSION: The proximity of osteosarcoma to major blood vessels is a poor prognostic factor for local control and survival. Amputation offers better local control for tumours attached to the blood vessels but does not improve survival. Limb salvage surgery offers similar local control if the tumour attachment to blood vessels is limited. Cite this article: Bone Joint J 2019;101-B:1024-1031.
Subject(s)
Blood Vessels/diagnostic imaging , Femoral Neoplasms/surgery , Magnetic Resonance Imaging , Neoplasm Recurrence, Local/etiology , Osteosarcoma/surgery , Preoperative Care/methods , Tibia , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Femoral Neoplasms/diagnostic imaging , Femoral Neoplasms/mortality , Femoral Neoplasms/pathology , Follow-Up Studies , Humans , Limb Salvage , Male , Middle Aged , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/mortality , Osteosarcoma/diagnostic imaging , Osteosarcoma/mortality , Osteosarcoma/pathology , Prognosis , Retrospective Studies , Risk Assessment , Survival Analysis , Tibia/diagnostic imaging , Tibia/pathology , Tibia/surgery , Young AdultABSTRACT
The near-Earth asteroid (162173) Ryugu is a 900-m-diameter dark object expected to contain primordial material from the solar nebula. The Mobile Asteroid Surface Scout (MASCOT) landed on Ryugu's surface on 3 October 2018. We present images from the MASCOT camera (MASCam) taken during the descent and while on the surface. The surface is covered by decimeter- to meter-sized rocks, with no deposits of fine-grained material. Rocks appear either bright, with smooth faces and sharp edges, or dark, with a cauliflower-like, crumbly surface. Close-up images of a rock of the latter type reveal a dark matrix with small, bright, spectrally different inclusions, implying that it did not experience extensive aqueous alteration. The inclusions appear similar to those in carbonaceous chondrite meteorites.
ABSTRACT
Unilateral (left eye) optic nerve hypoplasia was detected in a six-month-old male Beagle dog. Vision testing indicated that the left eye had poor vision and testing the pupillary light reflex showed the left eye to have an absence of the afferent pathway of the reflex but it had a normal efferent pathway. Ophthalmoscopy revealed a small-sized optic disc, winding retinal artery and dilated retinal vasculature in the left globe. Electroretinography showed no abnormal findings even in the left globe. Histopathologically, the left optic nerve was markedly hypoplastic and was composed of sparse neural elements and a moderate amount of connective and glial tissues. In the retina of the left globe, the nerve fibre layer and the ganglion cell layer were reduced in thickness, although a small number of ganglion cells were still present. There were no abnormal findings detected in the right globe and the right optic nerve. The brain appeared normal macroscopically.
Subject(s)
Dog Diseases/pathology , Optic Nerve Diseases/veterinary , Animals , Dog Diseases/diagnosis , Dogs , Electroretinography/veterinary , Fatal Outcome , Male , Ophthalmoscopy/veterinary , Optic Nerve Diseases/diagnosis , Optic Nerve Diseases/pathologyABSTRACT
Recent progress of chicken genome projects has revealed that bird ZW and mammalian XY sex chromosomes were derived from different autosomal pairs of the common ancestor; however, the evolutionary relationship between bird and reptilian sex chromosomes is still unclear. The Chinese soft-shelled turtle (Pelodiscus sinensis) exhibits genetic sex determination, but no distinguishable (heteromorphic) sex chromosomes have been identified. In order to investigate this further, we performed molecular cytogenetic analyses of this species, and thereby identified ZZ/ZW-type micro-sex chromosomes. In addition, we cloned reptile homologues of chicken Z-linked genes from three reptilian species, the Chinese soft-shelled turtle and the Japanese four-striped rat snake (Elaphe quadrivirgata), which have heteromorphic sex chromosomes, and the Siam crocodile (Crocodylus siamensis), which exhibits temperature-dependent sex determination and lacks sex chromosomes. We then mapped them to chromosomes of each species using FISH. The linkage of the genes has been highly conserved in all species: the chicken Z chromosome corresponded to the turtle chromosome 6q, snake chromosome 2p and crocodile chromosome 3. The order of the genes was identical among the three species. The absence of homology between the bird Z chromosome and the snake and turtle Z sex chromosomes suggests that the origin of the sex chromosomes and the causative genes of sex determination are different between birds and reptiles.
Subject(s)
Chickens/genetics , Evolution, Molecular , Physical Chromosome Mapping , Reptiles/genetics , Sex Chromosomes/genetics , Animals , Base Sequence , Cells, Cultured , Cloning, Molecular , DNA, Complementary/genetics , Female , Karyotyping , Male , Metaphase/genetics , RNA, Ribosomal/genetics , Sequence Homology, Nucleic AcidABSTRACT
We treated a 62-year-old male who had previously undergone a mitral valve plasty and aorto-coronary bypass. One year after the operation, he underwent pacemaker implantation for atrial fibrillation. Two months following implantation, the pacemaker generator was exposed due to a methicillin-resistant Staphylococcus aureus (MRSA) infection. We selected a new catheter route from the right saphenous vein, and implanted a generator under the fascia of the external oblique abdominal muscle. Thereafter, the pacemaker is functioning without trouble and there is no evidence of infection.
Subject(s)
Pacemaker, Artificial , Prosthesis-Related Infections/etiology , Atrial Fibrillation/therapy , Device Removal , Humans , Inguinal Canal , Male , Methicillin Resistance , Middle Aged , Staphylococcal Infections/etiologyABSTRACT
Japanese encephalitis virus (JEV) is the most frequent cause of mosquito-borne encephalitis in Asian countries. Several culicine species are potential vectors. The primary JEV vectors feed mainly on cows (a dead-end host for JEV), pigs (an amplifying host), and, occasionally, humans (a dead-end host). It is essential to determine blood-feeding patterns to understand the transmission cycle of the disease. Here we review blood-feeding characteristics of the primary JEV vectors Culex tritaeniorhynchus, Culex vishnui, and Culex gelidus based on experimental works and field surveys conducted in Asian countries. Several studies showed that these JEV vectors have an innate preference for cows; however, the former two species often showed higher rates of blood-feeding on pigs than on cows, probably because pigs are more abundant than cows. On the other hand, the latter species Cx. gelidus fed mostly on cows. Thus, the first two species showed higher plasticity to compromise host availability than the last. By reviewing the available articles and based on our relevant studies, it may be deduced that JEV transmission cannot be reduced by zooprophylaxis. We emphasize the need of keeping cows away from the human residences to dampen the human risk of JEV. These primary JEV vector species exhibit pre-biting resting. The adaptive significance of this behavior remains to be unexplored, but it may have a function to avoid defensive attack of host animals. Application of recent quantitative analysis of gene expression in this phase may enable us to come up with novel vector control strategies.
Subject(s)
Culex/physiology , Encephalitis Virus, Japanese/physiology , Encephalitis, Japanese/transmission , Mosquito Vectors/physiology , Animals , Cattle , Culex/virology , Encephalitis, Japanese/virology , Feeding Behavior , Humans , Mosquito Vectors/virologyABSTRACT
BACKGROUND: Patients with critical aortic stenosis, a heavily calcified aorta, and a small aortic annulus are at an increasing risk of complications during a conventional aortic valve replacement (AVR) procedure. Insertion of an apicoaortic conduit (AAC) can be an alternative to AVR in such situations. This study is a review of our experiences with AAC in elderly patients with acquired aortic stenosis. METHOD: From 2001 to 2005, 7 elderly patients (mean age of 81 : range 74 to 87) underwent an AAC insertion for severe symptomatic aortic stenosis with a small aortic annulus (mean annulus size 17.9 mm). Preoperatively, all were symptomatic, with 4 rated as New York Heart Association (NYHA) functional class IV, 2 as class III, and 1 as class II. In addition, 3 patients had severe congestive heart failure with mechanical ventilation and received a high dose administration of catecholamine, and 1 had undergone coronary artery bypass grafting (CABG) previously. RESULT: The AAC insertions were performed under a cardiopulmonary bypass through a left thoracotomy in 6 patients, while 1 patient underwent the procedure without a cardiopulmonary bypass. Distal anastomoses were performed in the descending thoracic aorta with a partial occluding clamp. A composite woven Dacron conduit with a stented biological valve was used in 2 cases, and a woven Dacron conduit with a stentless bioprosthesis was used in 5. Two patients underwent a concomitant CABG. There was 1 hospital death due to obstructive ileus 4 months after the operation. One patient who had been in a shock state preoperatively had hypoxic encephalopathy due to inoperative severe hypotension. Postoperative echocardiography showed relief of the left ventricle-aortic gradient in all patients. After a mean follow-up period of 22 months, there was no late death, while 3 patients were readmitted due to congestive heart failure. Further, 1 of the patients was rated as NYHA class I, 1 as class II, and 2 as class III. CONCLUSION: An AAC procedure was found to be an acceptable alternative for elderly patients who had a high-risk of complications with the standard procedure.
Subject(s)
Aortic Valve Stenosis/surgery , Aortic Valve/surgery , Blood Vessel Prosthesis Implantation/methods , Aged , Aged, 80 and over , Bioprosthesis , Cardiopulmonary Bypass , Female , Heart Valve Prosthesis , Heart Valve Prosthesis Implantation/methods , Humans , Male , Prognosis , Retrospective Studies , StentsABSTRACT
Free energy calculations were carried out on a series of exosite-binding inhibitors of thrombin. These inhibitors are based on the C-terminal fragment of hirudin and have the sequence Phe-Glu-Glu-IleH59-Pro-Glu-Glu-Tyr- Leu, where the superscript over Ile indicates its relative position in the natural sequence of hirudin. In this study, the effect of replacing IleH59 with ten other non-polar amino acids was examined. Three preferred interaction sites for methyl/methylene groups for the various XaaH59 side-chains in the complex were identified from conformational search calculations. The corresponding thermodynamic changes were determined using a combination of systematic search and energy minimization in a manner that locates the local minima in the system and in the process simultaneously builds up the partition function. The free energy, internal energy and entropic contributions are readily calculated from the partition function. Very good agreement in the resulting relative binding free energies was obtained between theory and experiment. The calculations allowed us to dissect out the enthalpic, entropic and solvation contributions to delta delta G. The contribution from desolvation was found to be relatively weak. The binding of these non-polar side-chains to thrombin is found to be driven mainly by favorable protein-ligand interactions rather than by the desire for non-polar groups to be desolvated. We also find that the configurational entropy contributes about 0.48 kcal/mol (0.81 kappa T) in average for each torsional angle "frozen" in binding.
Subject(s)
Hirudins/chemistry , Peptide Fragments/chemistry , Thrombin/antagonists & inhibitors , Algorithms , Amino Acid Sequence , Binding Sites , Drug Stability , Hirudins/genetics , Hirudins/pharmacology , Humans , In Vitro Techniques , Models, Chemical , Models, Molecular , Molecular Sequence Data , Molecular Structure , Peptide Fragments/genetics , Peptide Fragments/pharmacology , Protein Conformation , Solvents , ThermodynamicsABSTRACT
Streptococcus milleri was isolated in pure culture from the pericardial fluid of a 42-year-old man with pulmonary tuberculosis. Pericardiectomy had to be done to cure the pericarditis.
Subject(s)
Pericarditis, Constrictive/etiology , Streptococcal Infections , Adult , Antibodies, Bacterial/analysis , Dental Caries/microbiology , Humans , Male , Pericarditis, Constrictive/immunology , Streptococcal Infections/immunology , Streptococcus/immunology , Streptococcus/isolation & purification , SuppurationABSTRACT
The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.