MAPK/ERK2 phosphorylates ERG at serine 283 in leukemic cells and promotes stem cell signatures and cell proliferation.

Aberrant ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) expression drives leukemic transformation in mice and high expression is associated with poor patient outcomes in acute myeloid leukemia (AML) and T-acute lymphoblastic leukemia (T-ALL). Protein phosphorylation regulates the activity of many ETS factors but little is known about ERG in leukemic cells. To characterize ERG phosphorylation in leukemic cells, we applied liquid chromatography coupled tandem mass spectrometry and identified five phosphorylated serines on endogenous ERG in T-ALL and AML cells. S283 was distinct as it was abundantly phosphorylated in leukemic cells but not in healthy hematopoietic stem and progenitor cells (HSPCs). Overexpression of a phosphoactive mutant (S283D) increased expansion and clonogenicity of primary HSPCs over and above wild-type ERG. Using a custom antibody, we screened a panel of primary leukemic xenografts and showed that ERG S283 phosphorylation was mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling and in turn regulated expression of components of this pathway. S283 phosphorylation facilitates ERG enrichment and transactivation at the ERG +85 HSPC enhancer that is active in AML and T-ALL with poor prognosis. Taken together, we have identified a specific post-translational modification in leukemic cells that promotes progenitor proliferation and is a potential target to modulate ERG-driven transcriptional programs in leukemia.

Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias.

High expression of the ETS family transcription factor ERG is associated with poor clinical outcome in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL). In murine models, high ERG expression induces both T-ALL and AML. However, no study to date has defined the effect of high ERG expression on primary human hematopoietic cells. In the present study, human CD34+ cells were transduced with retroviral vectors to elevate ERG gene expression to levels detected in high ERG AML. RNA sequencing was performed on purified populations of transduced cells to define the effects of high ERG on gene expression in human CD34+ cells. Integration of the genome-wide expression data with other data sets revealed that high ERG drives an expression signature that shares features of normal hematopoietic stem cells, high ERG AMLs, early T-cell precursor-ALLs and leukemic stem cell signatures associated with poor clinical outcome. Functional assays linked this gene expression profile to enhanced progenitor cell expansion. These results support a model whereby a stem cell gene expression network driven by high ERG in human cells enhances the expansion of the progenitor pool, providing opportunity for the acquisition and propagation of mutations and the development of leukemia.

Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia.

LMO1 is a transcriptional regulator and a T-acute lymphoblastic leukaemia (T-ALL) oncogene. Although first identified in association with a chromosomal translocation in T-ALL, the ectopic expression of LMO1 occurs far more frequently in the absence of any known mutation involving its locus. Given that LMO1 is barely expressed in any haematopoietic lineage, and activation of transcriptional drivers in leukaemic cells is not well described, we investigated the regulation of this gene in normal haematopoietic and leukaemic cells. We show that LMO1 has two promoters that drive reporter gene expression in transgenic mice to neural tissues known to express endogenous LMO1. The LMO1 promoters display bivalent histone marks in multiple blood lineages including T-cells, and a 3' flanking region at LMO1 +57 contains a transcriptional enhancer that is active in developing blood cells in transgenic mouse embryos. The LMO1 promoters become activated in T-ALL together with the 3' enhancer, which is bound in primary T-ALL cells by SCL/TAL1 and GATA3. Taken together, our results show that LMO1 is poised for expression in normal progenitors, where activation of SCL/TAL1 together with a breakdown of epigenetic repression of LMO1 regulatory elements induces ectopic LMO1 expression that contributes to the development and maintenance of T-ALL.

[Salmonella bacteremia]. / Salmonela bakteriemije.

INTRODUCTION: Non-typhi salmonellae are invasive bacteria, which can, in certain conditions, get into the blood stream, and course bacteriemia or localized infections in different organ systems. Incidence of salmonella bacteriemia varied in different studies between 5.2-13.7%. The incidence is higher in patients younger than 1 year and the elderly. Among different serotypes, the most invasive are Salmonella typhimurium, Salmonella choleraesuis and Salmonella Virchow. The aim of our study was to determine the incidence of salmonella bacteriemia among patients hospitalized at the Clinic of Infectious Diseases Novi Sad during 1991-1998, and to point to certain risk factors for salmonella bacteriemia. RESULTS: During 1991-1998, 1309 patients were hospitalized with the diagnosis of Salmonella gastroenteritis. 12 patients (0.99%) had positive blood culture. The average age of salmonella bacteriemia patients was 17 (1-54 year), but 50% of them were younger than 10. 4/12 patients (33.33%) had positive stool and blood culture, but in 8/12 (66.66%) only positive blood culture had been established. The main serotype was Salmonella enteritidis (83.33%) and after that Salmonella Virchow (16.66%). In more than 50% of patients there was at least one risk factor responsible for dissemination: sideropenic anemia (25%), cerebral palsy (8.33%) and chronic cardiac disease (8.33%). Average duration of fever was 13.16 days and diarrhea 8.83. All patients presented with hepatosplenomegaly. One patient had a localized salmonella infection (periappendicular abscess) and she had undergone successful surgery. All our patients had been under cephalosporins of the third generation for 2 weeks and they recovered completely without sequelae. CONCLUSIONS: A relatively low incidence of salmonella bacteriemia (0.99%) in our patients can be explained with small number of children younger than 1 year and patients older than 70 years of age in whom bacteriemia is most common. Positive blood culture doesn't mean obligatory positive stool culture. Routine laboratory analyses are relatively nonspecific for the diagnosis of generalized infection. Cephalosporins of the third generation are considered to be the drug of choice in treatment of salmonella bacteriemia.

[Manifestations of visceral and ocular symptoms of toxocariasis in a 6-year-old boy]. / Pojava visceralne i okularne klinicke slike toksokarijaze kod sestogodisnjeg decaka.

In the past 10 years we have examined 137 cases of toxocariasis, predominantly in children. Three cases were with unilateral ocular involvement. The article reviews a 6-year-old boy with left side strabismus and granulomatous chorioretinitis. Laboratory examinations revealed blood eosinophylia 24% and IgG against Toxocara canis larvae in titer 1:320 by indirect immunofluorescent assay. In epidemiologic anamnesis we concluded that about 4, 5-year-long geophagia was the source of infection.

[Neurotrichinosis]. / Neurotrihineloza.

INTRODUCTION: Trichinellosis is an anthropozoonosis caused by Trichinella spiralis. Central nervous system complications can occur during the course of this disease. This paper presents a case of neurotrichinellosis, assayed by using indirect immunofluorescence test. CASE REVIEW: A patient aged 30, was admitted to the Clinic on the fifth day after onset of the disease, which was gradual, starting with flu-like symptoms. Two days before admittance, the diseased became somnolent, disconcerted and disoriented. On admission, the patient was highly febrile (39 degrees C), dehydrated, with eyelid edema. Right hemiparesis was present. The disease was confirmed by indirect immunofluorescence test, showing an increase of trichinella antibody titre (1:20, 1:160 and 1:640). The cerebrospinal fluid was cytobiochemically normal. Electroencephalographic findings exhibited a moderate cerebral dysfunction. Multifocal unspecific changes were established by magnetic tomography. The diseased was treated by mebendazole and prednisolone. The course of the disease was favourable and the patient was cured without sequelae. DISCUSSION: Recognition and diagnosis of Trichinellosis are complicated due to its polymorphid symptomatology. In the case reviewed, the disease started with clinical features of flu-like symptoms and febrile gastroenteritis. According to some authors, central nervous system manifestations occurred in 10-15% of the diseased. CONCLUSION: When examining clinically manifested encephalitis, Trichinelosis should be taken into consideration as a cause of the disease.

[Leishmaniasis: case report]. / Lejsmanioza: prikaz slucaja.

INTRODUCTION: Leishmaniasis is a chronic parasitic disease of the reticuloendothelial system which is manifested by gradual onset, unspecific disorders and can take a form of visceral, cutaneous or mucocutaneous leishmaniasis. The aim of the study is to present the patient who was treated for visceral leishmaniasis at the Clinic for Infectious Diseases in Novi Sad. CASE REPORT: A patient, 22 years old, had been admitted at the Clinic one month after the beginning of the disease with gradual onset malaise, fatigue, loss of appetite, intermittent temperature and night sweating. A few days before the admittance to the hospital, dark colour of urine and the pain under the left rib occurred. On admission, the patient had been afebrile, dehydrated, intoxicated, he had subicteric sclerae with enlarged liver and extremely enlarged spleen. Laboratory findings revealed anemia, leucopenia, and increased level of gamma globulins. Hypercellularity of the bone marrow with cells of all degrees of maturity had been determined by sternal puncture. We have epidemiologically obtained information about the bites of a mosquito from the Phlebotomus genus at the Adriatic coastal region, two years and two months ago. The diagnosis had been confirmed by the formol-gel test and by the indirect hemaglutination test. Leishmaniae donovani had been found in the bone marrow punctate. TREATMENT: The patient had been treated by appropriate doses of N-methyl-glucamine-antimonate (Glucantime), during three weeks, after which he was cured. During the one-year follow-up period normalization of laboratory findings as well as liver and spleen ultrasonographic findings occurred. CONCLUSION: Because of gradual onset and polymorphic troubles during the beginning of leishmaniasis, many diseases can be taken into account for diagnostic differentiation. From this study it is obvious that even the possibility of such a disease must be considered, despite the fact that it is rare in our region, because fatal outcome is avoidable only by the timely diagnosis and therapy.

[Eosinophilia in trichinosis]. / Eozinofilija u trihinelozi.

This study included 90 patients with trichinosis treated at the Clinic for Infectious and Dermatovenereology Diseases in Novi Sad for a year. In patients with mild clinical picture the lowest values of eosinophils was 0.08% (Xmin = 0.08), the highest 0.80% (Xmax = 0.80) and mean value 0.37% (x = 0.37). In patients with mild to severe clinical picture the lowest number of eosinophils was 0.02% (Xmin -0.02), the highest value 0.81% (Xmax = 0.81) and mean value 0.36% (x = 0.36). In severe cases of trichinosis eosinophilia was evident in 0.14% (Xmin = 0.14), the highest value 0.70% (Xmax = 0.70), while the mean value was 0.39% (x = 0.39). Most patients (46.14% with mild clinical picture, 32.82% with mild to severe clinical picture and 40% with severe clinical picture) had values of eosinophilia between 0.26% and 0.40%. By the follow-up of total number of eosinophils it has been established that most patients (71.80% with mild 75% with mild to severe and 60% with severe clinical picture), had values between 0.50 x 10(9)/l and 6.00 x 10(9)/l. In ten patients values of eosinophils were extremely high-10.00 x 10(9)/l. Extremely high eosinophilia-29.16 x 10(9)/l was recorded in a patient with a mild to severe clinical picture. It has been established that on the basis of percentile eosinophilia or total number of peripheral blood eosinophils severity of clinical picture cannot be assessed (x2 = 0.852 and x2 = 2.452).

[Clinical characteristics of trichinosis]. / Klinicke karakteristike trihineloze.

91 patients with trichinosis were treated at the Clinic of Infectious and Dermatovenereology Diseases in Novi Sad during a one-year period. In 64% of patients the onset was intestinal, while in 36% it was invasive. Diarrhea (in 28.89%) and abdominal pain (in 22.22%) are the most common symptoms of the intestinal stage. Nausea, vomiting and opstipation are less common. The main symptoms of the invasive stage are myalgia (65.54%), high temperature and eyelid edema (57.78%). Facial edema (38.89%), general weakness (24.44%), conjunctivitis (15.56%) and rash (8.89%) are somewhat less common. Heavy sweating, headache, nervousness, psychic instability and fast forgetting occur in a small number of treated patients. Myocarditis and encephalitis occurred in 3.33% of patients. There were 43.33% of patients with mild clinical picture, 40% with mild-to-severe and 16.66% with severe clinical picture. 54.44% of patients were males and 45.56% were females, and it can be said that sex did not influence the severeness of the clinical picture. The youngest patient was 5 years of age, the oldest 72. Most patients were 21-50 years of age but we did not establish statistical importance between clinical picture severeness in regard to age. The shortest period of incubation was 5 days, the longest 40 days. Average incubation period was 18.05 days (x = 18.05). Studying period of incubation and severeness of the clinical picture we established the following (x2 = 28.535). The shorter the incubation period, the severer the disease.

[Hemorrhagic fever with renal syndrome in Vojvodina]. / Hemoragijska groznica s bubreznim sindromom u Vojvodini.

This paper presents 4 serologically confirmed cases of hemorrhagic fever with kidney syndrome. The objective of this study was to point to occurrence of unexpected hemorrhagic fever with kidney syndrome, to different clinical pictures and differential-diagnostic difficulties as well as to therapeutic procedures of serious cases. The disease had a sudden onset with general signs of infection in all our patients. 3 out of 4 patients had had a dominant symptomatology in regard to gastrointestinal tract, whereas signs of acute renal insufficiency appeared later. In 3 patients there was a complete recovery without consequences, while one female patient died on the twelfth day of the disease.

[Therapy of salmonella gastroenterocolitis]. / Terapija salmoneloznog gastroenterokolitisa.

At the Clinic for infectious and dermatovenerologic diseases in Novi Sad a prospective randomized, simple, blind investigation of differently organized treatments of salmonellal gastroenterocolitis (symptomatic therapies, ampicillin, co-trimoxazole and ciprofloxacine) was carried out. It was established that there is no statistically significant difference in the length of febrile states in any of the compared therapeutic groups. However, ciprofloxacine significantly shortens diarrhea and excretion of germs comparing with other therapeutic treatments.

[Occurrence of Salmonella infection in diarrheal syndromes: the most common types and clinical patterns]. / Ucestalost salmoneloznih infekcija u dijarealnom sindromu: najcesci tipovi i klinicki oblici.

Diarrhoeic syndrome is one of the most commonly found acute infectious diseases, with different etiologies. Our study comprised 396 patients with acute diarrhoeic syndrome. Salmonella infection was confirmed in 26.26% of the cases. Most commonly found was S. enteritidis (54.8%), S. hada, S. Typhi murium and S. virchow. Febrile gastroenterocolitis was the most frequent clinical pattern of salmonella infection (58.6%); dysenteric type of the diseases was present in 17% of patients, while only one case (0.9%), of salmonella fever with two positive hemocultures was observed. Most severe forms of the disease were caused by S. enteritidis, in 10% of the patients and S. virchow (0.9%). There was one lethal outcome (0.9%), while in the remainder of the patients the outcome was favorable. Remarkably severe clinical patterns were observed in children under 5 and in adults over 56 years.

[Sensorineural impairment in the inner ear in epidemic parotitis]. / Senzorineuralno ostecenje unutrasnjeg uva u toku epidemicnog parotitisa.

During morbilli and mumps, classical forms of acquired deafness develop in childhood. The aim of the study was to investigate effects of mumps virus on cochlear function. Of 237 examined patients 71 had parotitis and 166 meningitis-meningoencephalitis. Audiometric analyses were carried out at the beginning of the treatment and after 6 months. Hearing loss above 30 dB was found in 109 patients (45.99%). Mild hearing impairment of sensorineural type was registered in the majority of patients, while total one-sided hearing loss was found in 2.53% of subjects. No correlation between clinical manifestations of parotitis or meningoencephalitis and hearing loss was found. Cytochemical liquor levels did not influence the development of hearing loss. 6 months later a recovery followed mainly in patients with mild impairments.

[The role of Epstein-Barr viruses as etiologic agents in the mononucleosis syndrome]. / Uloga Epstein-Barrovog virusa kao etioloskog cinioca u mononukleoznom sindromu.

Mononucleosis syndrome represents a number of symptoms with different etiology and pathogenicity with similar clinical features. The aim of the study was to investigate etiologic structure of mononucleosis syndrome, effects of etiologic factors and age on the severity of clinical features, clinical forms of the disease, complications and the outcome. The investigation was conducted in 46 patients treated at the Clinic who had been diagnosed as having mononucleosis syndrome. EBV-IM was confirmed in 43%, adenoviral IM in 13%, while in 44% of the patients etiology of the disease was not established. In both groups more severe forms were present in patients over 16 years of age, but more frequently in EBV-IM than in other patients with mononucleosis syndrome (40% vs 19.23%). Complications in the form of acute hepatitis were found only in patients with EBV-IM in 20% of the cases, mean age 17 years. We are of the opinion that EBV is a significant etiologic agent in mononucleosis syndrome, that the disease is more severe in older patients who also develop complications. The outcome for all the patients was favorable.

[Abdominal typhus today]. / Trbusni tifus danas.

Abdominal typhus is all the rearer disease among acute infectious diseases in Vojvodina. In the last ten years (1981-1990) 16 patients with abdominal typhus were treated at the Department of Infectious Diseases in Novi Sad, mostly young individuals from 6 to 30 years of age (13 patients). Positive epidemiologic features were found in 13 patients. In 80% of the cases the source of infection was outside Vojvodina. They usually were admitted at the Department on the first and second week of the disease (11 patients), and 3 patients were admitted on the third week. None of the patients was suspected of having abdominal typhus at the time of admittance. Delayed hospitalization and unrecognized abdominal typhus were most likely due to the atypical onset and course of the disease. Atypical features in the clinical picture occurred in all the patients with a sudden onset of the disease. The abrupt temperature elevation in 50% of the patients was followed by shivering, fever and shaking. Hepatosplenomegaly was found in 12 patients, abdominal meteorism in 10, typical typhus tongue in none. Typhus state was not found in any of the patients. Normal leucocyte count was found in 7 patients, positive Widal's agglutination reaction in 13, coproculture in 8 and hemoculture in 15 patients. The atypical clinical picture was the result of early administration of broad-spectrum antibiotics before the established etiology of the febrile state.

[Pneumococcal meningitis from 1974 to 1984]. / Meningitis pneumococcica u periodu 1974-1984. godine.

We examined a group of 22 patients presented with the acute infective meningeal syndrome. Lumbar punction confirmed diagnosed purulent meningitis--meningoencephalitis, and bacteriologic liquor culture identified Streptococcus pneumoniae as a cause of the disease. Patients were mostly aged over 30. Clinical picture revealed signs of general infection and the meningeal syndrome. The severity of the disease was assessed on the basis of apparent signs of general infection, state of consciousness and endotoxic shock symptoms. Severe consciousness disorders were present in 16 (72.72%) patients. In our patients possible pneumococcus infection foci were: sinusitis, otitis media, pneumonia, mastoiditis and adnexitis. Lethal outcome occurred in 5 (22.72%) patients. In the therapy we used penicillin, chloramphenicol and ampicillin along with corticosteroid administration.

[Typhoid fever--case report]. / Tifusna groznica--prikaz slucaja.

The paper describes a case treated at the Department of Infective Diseases in Novi Sad admitted during the remittance of typhoid fever. The course of the disease was atypical. Epidemiological and clinical features resembled those found in malaria but laboratory findings gave the true diagnosis. We found the case interesting because the diseased patient moved around a lot, making contacts with many people. Fortunately, contact diseases never happened to occur.

[Mumps infection and disorders of glucose tolerance]. / Mumps infekcija i poremecaji glikozne tolerancije.

In the last few years there is a more frequent appearance of papers which suggest the viral etiology of juvenile diabetes mellitus, where the mumps virus is primarily pointed to as the etiological factor. Since there is a high incidence of diabetes in our Province as well as the presence of an epidemic appearance of mumps infections, we were of the opinion that there was good reason for us to study the influence of mumps infection on glucose tolerance. With our research we have proved that mumps leads to the disturbances of carbohydrate metabolism and this is the case not only in the acute stage of infection but also in the course of a two-year follow-up, and they develop as a consequence of the direct influence of the virus on the beta cells of the pancreas. Glucose tolerance disturbances were not in correlation with the changes on the exocrine part of the pancreas neither in the acute stage nor in reconvalescence. Hereditary factors also didn't influence the more frequent appearance of these disturbances in persons with a hereditary disease, which was confirmed statistically also (X2 = 0.67). By research we have proved that disturbances which take the course of the "slow virus infection" type also occur and that they are statistically more significant (X2 = 22.31) in relation to the glucose tolerance disturbances which develop due to a direct activity of the mumps virus.