MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation.

Acute Graft-versus-host disease (GVHD) is a major immunological complication after allogeneic hematopoietic cell transplantation and a better understanding of the molecular regulation of the disease could help to develop novel targeted therapies. Here we found that a G/C polymorphism within the human microRNA-146a (miR-146a) gene of transplant recipients, which causes reduced miR-146a levels, was strongly associated with the risk of developing severe acute GVHD (n=289). In mice, deficiency of miR-146a in the hematopoietic system or transfer of recipient-type miR-146a-/- dendritic cells (DCs) enhanced GVHD, while miR-146a mimic-transfected DCs ameliorated disease. Mechanistically, lack of miR-146a enhanced JAK2-STAT1 pathway activity, which led to higher expression of class II-transactivator (CIITA) and consecutively increased MHCII-levels on DCs. Inhibition of JAK1/2 or CIITA knockdown in DCs prevented miR-146a-/- DC-induced GVHD exacerbation. Consistent with our findings in mice, patients with the miR-146a polymorphism rs2910164 in hematopoietic cells displayed higher MHCII levels on monocytes, which could be targeted by JAK1/2 inhibition. Our findings indicate that the miR-146a polymorphism rs2910164 identifies patients at high risk for GVHD before allo-HCT. Functionally we show that miR-146a acts as a central regulator of recipient-type DC activation during GVHD by dampening the pro-inflammatory JAK-STAT/CIITA/MHCII axis, which provides a scientific rationale for early JAK1/2 inhibition in selected patients.

Use of intravenous tigecycline in patients with severe Clostridium difficile infection: a retrospective observational cohort study.

There are only a limited number of antimicrobials for treating severe Clostridium difficile infection (sCDI). Tigecycline shows significant in vitro effect against C. difficile and is approved for management of complicated intra-abdominal infections. Our aim was to analyse the efficacy of tigecycline compared with standard therapy (oral vancomycin plus intravenous metronidazole) in adults treated for sCDI. A retrospective cohort study of such patients hospitalized at our department from January 2014 to December 2015 was performed. Patients receiving tigecycline monotherapy were compared with patients treated with standard therapy alone. Diagnosis and severity of CDI were determined according to guidelines of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Primary outcome was clinical recovery, secondary outcomes were in-hospital and 90-day all-cause mortality and relapse, colectomy, and complication rates. Of the 359 patients hospitalized for sCDI, 90 (25.0%) were included, 45 in each group. Patients treated with tigecycline had significantly better outcomes of clinical cure (34/45, 75.6% vs. 24/45, 53.3%; p 0.02), less complicated disease course (13/45, 28.9% vs. 24/45, 53.3%; p 0.02), and less CDI sepsis (7/45, 15.6% vs. 18/45, 40.0%; p 0.009) compared with patients receiving standard therapy. Tigecycline usage was not associated with adverse drug reactions or need for colectomy. Rates of ileus, toxic megacolon, mortality, and relapse were similar between the two groups. Favourable outcomes suggest that tigecycline might be considered as a potential candidate for therapeutic use in cases of sCDI refractory to standard treatment.

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels.

Acute graft-versus-host disease (GvHD) limits the applicability of allogeneic hematopoietic cell transplantation for the treatment of leukemia. GvHD occurs as a consequence of multiple activating events in antigen-presenting cells (APCs) and T cells (Tcs). Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase involved in multiple signaling events of immune cells. Therefore, we hypothesized that Syk may be a promising target to inhibit GvHD, which involves activation of different immune cell populations. In vivo expansion of luciferase(+) donor Tcs in mice developing GvHD was reduced by treatment with the Syk inhibitor Fostamatinib, which led to increased survival and reduced histologically confirmed GvHD severity. Importantly, in vivo and in vitro cytotoxicity against leukemia target cells and anti-murine cytomegalovirus immune responses were not impacted by Fostamatinib. In APCs Syk inhibition reduced the expression of costimulatory molecules and disrupted cytoskeletal organization with consecutive APC migratory defects in vitro and in vivo while phagocytic activity remained intact. On the basis of these immunomodulatory effects on different cell populations, we conclude that Syk targeting in alloantigen-activated Tcs and APCs with pharmacologic inhibitors, already applied successfully in anti-lymphoma therapy, has clinical potential to reduce GvHD, especially as anti-leukemia and anti-viral immunity were preserved.

Beating of coupled ultraviolet light modes in zinc oxide nanoresonators.

Periodic spatial intensity modulations of near-band-gap luminescence light at 3.36 eV photon energy are reported in nanometer-sized resonators of single zinc oxide nanorods. These modulations are observed when the luminescence light, due to excitonic recombination, is excited by a focused low-energy electron beam scanned along the rods. The acceleration energy of only 2 keV allows for a spatial resolution of a few ten nanometers. Numerical calculations based on the theory of dielectric cylindrical waveguides are performed identifying the intensity modulations as beating patterns of coupled TE01 and TM01 modes in the nanoresonator.

Characterization of ryanodine receptors in rat colonic epithelium.

AIM: Functional evidence suggests the presence of two types of intracellular Ca(2+) channels responsible for the release of Ca(2+) from Ca(2+)-stores, i.e. inositol-1,4,5-trisphosphate (IP(3)R) and ryanodine receptors (RyR), in rat colonic epithelium. Generally, three ryanodine receptor isoforms (RyR1-RyR3) are known; however, the type of RyR at this epithelium is unknown and was the focus of the present study. METHODS: RyRs were characterized by molecular biological and immunohistochemical methods in the rat colon. RESULTS: A transcript of RyR1 was found in mRNA from colonic crypts. In contrast, RyR2 and RyR3 were found in their corresponding reference tissues, but not in the cDNA from colonic crypts suggesting a predominant expression of the RyR1 isoform in this epithelium. In order to characterize the subcellular localization of RyR1, immunohistochemical experiments were performed. They showed that RyR1 is present in the lamina epithelialis mucosae and smooth muscle cells and is distributed equally along the whole crypt axis with no difference between surface and crypt cells. A double staining with IP(3)R3, the dominant cytoplasmic isoform of IP3Rs in this epithelium, revealed that there is only little colocalization of the two receptor subtypes within the epithelial cells. Furthermore, the epithelium is equipped with the enzyme CD38 responsible for the production of cyclic adenosine diphosphate ribose, the physiological agonist of RyR. RyRs are known to be activated by changes in the redox state. The oxidant, monochloramine evoked a ruthenium red-sensitive Ca(2+) release all over the crypt axis. This release was unaffected by prior stimulation of IP(3) receptors with ATP (and vice versa). CONCLUSION: The present data suggest a functional separation of IP(3)- and ryanodine receptor-carrying Ca(2+) stores in the colonic epithelium.

Analysis of Ir in Köfelsit rocks by inductively coupled plasma-sector-field mass spectrometry (ICP-SFMS).

Three different analytical strategies have been evaluated for the quantification of Ir in geological samples. Glassy rock samples from Köfels and reference material WGB-1 were analyzed directly by inductively coupled plasma sector field mass spectrometry (ICP-SFMS) at mass resolution 400 using membrane desolvation and at mass resolution 9500 without membrane desolvation. Matrix separation by anion-exchange pre-concentration was also investigated. The ultrasonic nebulizer USN6000AT+ (Cetac Technologies, Omaha, NE, USA) incorporating a membrane desolvation unit was used as the sample-introduction system. Sample preparation involved complete microwave-assisted acid digestion of the silicate matrix with HNO3-HCl-HF. The results obtained by the three methods of quantification were in good agreement, showing that oxide-type interferences were effectively eliminated solely by membrane desolvation. The limits of detection were 6 pg g for low resolution measurement with use of the membrane, 15 pg g(-1) at a mass resolution of 9500, and 59 pg g(-1) for the ion-exchange procedure. The ultimate precision obtained for the Köfelsit Ir data was, however, compromised by the small sample intake (0.3 g), because of the inhomogeneous distribution of Ir in geological samples.

[Adult-onset Kawasaki syndrome in the differential diagnosis of liver disease]. / Felnóttkori Kawasaki-szindróma a májbetegségek differenciáldiagnózisában.

The authors present a case of an adult with Kawasaki syndrome, who, due to jaundice, enlarged liver and abnormal liver function tests, was admitted the hospital with the suspicion of liver disease. The symptoms of Kawasaki syndrome appeared during the first nine days of the hospital stay. The authors emphasise, that liver function tests are frequently abnormal in adults presenting with this clinical entity, therefore Kawasaki syndrome should be taken into consideration in the differential diagnosis of liver diseases.

[Successful treatment of acute ethylene glycol poisoning with plasmapheresis]. / Plazmaferézissel sikeresen kezelt akut etilén-glikol mérgezés esete.

The authors show the differential diagnostics, therapy and patomechanism of the ethylene glycol intoxication in connection with review of their young patient became acute paraparetical in consequence of the intoxication. In the therapy of the ethylene glycol intoxication, instead of the traditionally proved hemodialysis their patients was treated with great efficiency with plasmapheresis. The authors show the patomechanism of a patient came with atypical Guillain-Barré-Syndrome. In the hinterground of an acute paraparesis was an ethylene glycol intoxication identified. In the therapy of this intoxication their patients was treated with great efficiency with plasmapheresis instead of the traditionally proved haemodialysis. They touch upon the possibility of monitoring with gas chromatography of the patients plasmapheretised, and call attention the easy check of the sodium fluorescein content of the antifreeze additive therefore the rapid recognition of the intoxicated status.

Value of surveillance cultures in a bone marrow transplantation unit.

Because of the increased risk of infection with the associated diagnostic and therapeutic problems in bone marrow transplantation (BMT) patients, the usefulness of surveillance cultures (SC) at the BMT department of the National Institute of Haematology, Blood Transfusion, Transplantation and Immunology, Budapest, was reviewed. Between January 1992 and May 1995, 26 BMT operations were performed; 13 patients had 23 febrile espisodes. In 12 of these episodes infection was clinically documented; however, SC of these patients yielded bacteria identical with those in the blood culture in only two episodes (1 and 6 days before their blood cultures became positive, respectively). Out of a total of 1187 samples from these patients, potentially pathogenic bacteria were isolated from 145 SC and 43 blood cultures (drawn on 31 different days). Suppression of the gastrointestinal flora could be achieved by the department's decontamination regimen; however, overgrowth by gram-positive organisms (mainly coagulase-negative staphylococci) occurred in the intestine and at other body sites. On the basis of these results, SC are of limited value in predicting infection or identifying the causative organisms of fever. On the other hand, SC are useful in confirming the efficiency of suppression of the body flora by antimicrobial agents. Specific treatment was based on suitably sampled materials, and close contact between physicians, infectious disease specialists and microbiologists was essential.

[Successful meropenem therapy of recurrent multiple brain abscess]. / Recidiváló multiplex agytályog sikeres kezelése meropenemmel.

Authors describe the history of a 37-year-old man suffering from multiple purulent brain abscess. The multiple brain abscess evolved primarily from a gluteal abscess to the lung, and secondarily from the lung to the brain by hematogenous spreading of the bacteria. The identification of the pathogene/s was unsuccessful despite numerous bacteriological examination. Despite many regimens of empiric antibacterial therapy the brain abscesses progressed, neurologic state of the patient deteriorated. At long last, the patient was given chloramphenicol. After that, he had no more fever, his consciousness cleared, no more epileptic convulsion occurred and the cell number of the cerebrospinal fluid became normal. The patient was thought to be cured and was sent home. Two months later fever occurred again and it was accompanied by excrutiating headache, increasing disorientation, so the patient was admitted to the hospital. The occurrence of a new brain abscess and purulent meningitis indicated the relapse of the disease. It was again unsuccessful to identify the pathogene/s therefore the authors treated the patient with many empiric antibiotic regimen, all of which-including chloramphenicol too--proved to be uneffective. As all the therapeutic regimens usually used in the treatment of purulent brain abscess were uneffective--including the combinations which have the widest antibacterial spectrum, authors gave meropenem as ultimum refugium. Some days later the fever came to an end, his consciousness cleared, the brain pressure and the cerebrospinal fluid became normal. The patient had no serious complaints in the course of the four years follow up, his residual neurologic symptoms regressed. On the base of this case history, authors suppose that meropenem--which has already proved to have a very wide antibacterial spectrum and to be very effective in the therapy of many kinds of serious bacterial infections--could also become a promising new therapeutic alternative in the treatment of purulent brain abscess.

[Opportunistic systemic mycoses]. / Opportunista szisztémás mycosisok.

Systemic fungal infections can be primary or opportunistic. The mycoses caused by opportunistic pathogens become increasingly more important. These infections are mainly caused by Candida species, Aspergillus species, Cryptococcus neoformans, Mucor etc. The predisposing factors to these diseases are numerous: neutropenia, organ transplantation, use of steroids, broad spectrum antibiotics, antineoplastic chemotherapy, parenteral nutrition, prolonged intravenous infusions, extensive surgery etc. Mortality is high because many fungal infection are difficult to diagnose, especially in their early, more treatable stages. Considerable progress in treating these infections has been achieved. Systemic fungal infections, however, continue to present major problems, including clinical resistance, microbial resistance, emergence of new pathogens and involvement of more susceptible patients. The purpose of this paper is to review the recent progress and current problems in diagnosis, treatment and prevention of opportunistic systemic fungal infections.

[Hypereosinophilia syndrome of unknown origin]. / Az ismerethen eredetü hypereosinophiliás syndroma.

The authors describe the case of a 19-year-old man with hypereosinophilic syndrome. At first the clinical picture suggested a localized eosinophilic gastrointestinal disease which rapidly progressed to the fatal disseminated form. The spectrum of hypereosinophilic syndrome is discussed and current thoughts on diagnosis, pathology and treatment presented.

Activity of intracellular antibiotics.

We have studied the intracellular bioactivity of several antimicrobial agents against two strains of Staphylococcus aureus, a pathogen sequestrated in phagolysosomes, using peripheral blood neutrophils from human volunteers. This was compared to the activity of cell-associated drugs also measured in vitro. Several discrepancies (high cellular association, low bioactivity) were observed (coumermycin, glycopeptides, erythromycin and clindamycin) which can be due to the binding of the drug to a particular cellular organelle, to intracellular metabolization or inactivation, to unfavourable conditions in the phagolysosome (pH drop), or to a toxic effect of the drug on the functions of the neutrophil. Addition of the antibiotic during ingestion was frequently associated with better neutrophil-dependent killing through several potential mechanisms: coingestion of the antibiotic with the inoculum, modification of opsonization, release of activating substances and fragilization of the microorganism to oxygen-dependent or -independent killing mechanisms.

Hybrid ferromagnetic-semiconductor structure.

Ultrahigh-vacuum growth techniques are now being used to grow single-crystal films of magnetic materials. These growth procedures, carried out in the same molecular beam epitaxy systems commonly used for the growth of semiconductor films, have yielded a variety of new materials and structures that may prove useful for integrated electronics and integrated optical device applications. Examples are given for growth on GaAs and ZnSe, including magnetic sandwiches and patterned structures.

[Imported food poisoning caused by fish toxins (ciguatoxin)]. / Importált alimentaris intoxicatio halméreggel (ciguatoxin).

Various types of fish-poisoning mainly occur in tropical areas. Saxitoxin, tetrodotoxin, scombrotoxin and clupeotoxin are heat labile while ciguatoxin, in contrast, is heat stable thus it may be the source of severe poisoning even in case of thorough cooking and baking. In December 1987 a mass alimentary poisoning occurred following ingestion of fish meat in a group returning from Cuba. The most severe case was admitted to our department with symptoms of extended paresis. Diagnosis of ciguatoxin poisoning was established based upon the history, clinical features and laboratory results. Nowadays exotic, remote "Fish-poisoning" cases have to be taken into consideration even in our country.

[Isolation of Corynebacterium JK from the blood of neutropenic patients with septic diseases]. / Corynebacterium JK isolálása neutropéniás szeptikus betegek véréböl.

The authors report on the isolation of Corynebacterium JK from the blood of two neutropenic patients with hematological malignancy. In Hungary this paper is the first to discuss the microbiology of the organism and clinical manifestations of the group JK Coryneform infection. The clinical significance of this organism in the nosocomial infections of compromised patients and the association of the infection with the use of plastic devices has been emphasized. The sensitivity of the multiresistant coryneform bacterium to vancomycin may help to make the microbiological diagnosis and to select the drug for therapy.

[Granulomatous hepatitis in cytomegalovirus infection]. / Granulomatosus hepatitis cytomegalovírus fertözésben.

Authors report the serologically verified CMV hepatitis of a 35-year old man whose hepatic alteration appeared in the form of a granulomatous hepatitis. On this account the characteristics of granulomatous hepatitis cases published so far in the literature are surveyed.