ABSTRACT
Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy.
Subject(s)
Anemia, Diamond-Blackfan/pathology , Hematopoietic Stem Cells/pathology , Protein Serine-Threonine Kinases/metabolism , Anemia, Diamond-Blackfan/diet therapy , Anemia, Diamond-Blackfan/genetics , Animals , Benzamides/pharmacology , Benzamides/therapeutic use , Cell Differentiation/drug effects , Cell Proliferation , Cells, Cultured , Dioxoles/pharmacology , Dioxoles/therapeutic use , Disease Models, Animal , Erythropoiesis/drug effects , Erythropoiesis/genetics , Humans , Mice , Mice, Transgenic , Mutation , Primary Cell Culture , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Quinolines/pharmacology , Quinolines/therapeutic use , RNA, Small Interfering/metabolism , Ribosomal Proteins/geneticsSubject(s)
Poliomyelitis/immunology , Poliovirus Vaccine, Oral/administration & dosage , Adolescent , Adult , Antibodies, Viral/analysis , Antibody Formation , Child , Child, Preschool , Female , Humans , Infant , Italy , Male , Middle Aged , Poliomyelitis/prevention & control , Poliovirus/immunology , Rural Population , Time Factors , Urban PopulationABSTRACT
The age-prevalence of antibodies directed against the hepatitis viruses A (anti-HAV) and B (anti-HBs and anti-HBc) has been studied in an open sample of population of Turin (Italy), made up by 680 persons. Is has been shown that all three types of antibodies are present at birth, thast they progressively decrease and than again raise, from 6-10 years of age, up to 70-75%, 35% and about 40% in adults, respectively for anti-HAV, anti-HBs and anti-HBc. A further peak over 97% after 40 years for anti-HAV likely means a past higher spreading of the virus. The conclusion is drawn that, for both hepatitis A and B, the percentage of positive and the time of appearance of active humoral immunity after the loss of maternal antibodies are typical medium level of hygienic conditions. The comparison of anti-HBs and anti-HBc behaviour has shown that the latter is more frequent and at least as persistent as the former, and that it should not therefore be obligatory considered ia a marker of viral replication.
Subject(s)
Hepatitis A/epidemiology , Hepatitis B/epidemiology , Adolescent , Adult , Age Factors , Aged , Antibodies, Viral/analysis , Child , Child, Preschool , Female , Hepatitis A/immunology , Hepatitis B/immunology , Hepatitis B Antibodies/analysis , Humans , Infant , Italy , Male , Middle AgedABSTRACT
During the outbreak of rubella in Turin in 1977, 1,041 newborns, whose mother's pregnancy coincided with the epidemic, were studied for the elimination of rubella virus through inoculation in primary cultures of African green monkey kidney cells. Additional 10 embryos or fetuses of therapeutic abortion from women with rubella early in pregnancy were studied through cultivation of material of abortion and inoculation in monkey cells. Only one strain was isolated, from the placenta of an embryo whose mother suffered rubella in the 2nd month of pregnancy. The hypothesis is proposed of a particularly benignity, from a teratogenic point of view, of the virus involved in the outbreak.
Subject(s)
Antibodies, Viral/analysis , Disease Outbreaks/epidemiology , Fetal Blood/immunology , Pregnancy Complications, Infectious/epidemiology , Rubella virus/immunology , Rubella/epidemiology , Adult , Female , Fetal Diseases/epidemiology , Humans , Italy , Pregnancy , Rubella/congenitalSubject(s)
Antibodies , Toxoplasmosis/epidemiology , Adolescent , Age Factors , Antibodies/analysis , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Italy , MaleABSTRACT
During the outbreak of rubella in Turin in 1973, 110 newborns, whose mother's pregnancy clash with the epidemic, were studied for the elimination of rubella virus. 708 samples were in total examined, through inoculation in primary cultures of African green monkey kidney (and study of the possible interference with ECHO-virus type 11), and partially in RK 13 and SIRC continuous cell lines. No strain of rubella virus was isolated, and the Authors conclude that the virus involved was particularly benign from a teratogenetic point of view.
Subject(s)
Infant, Newborn, Diseases/epidemiology , Pregnancy Complications, Infectious/epidemiology , Rubella virus , Rubella/epidemiology , Adolescent , Adult , Antibodies, Viral/analysis , Female , Humans , Infant, Newborn , Italy , Male , Pregnancy , Rubella/congenitalABSTRACT
An A strain influenza virus isolated in Turin during the winter of 1974-75 was antigenetically related to the A/Port Chalmers/1/73 strain and dominant with respect to it. In addition, it was dissimilar and antigenically distant from the A/Scotland/840/74 strain.
Subject(s)
Antigens, Viral/isolation & purification , Hemagglutination, Viral , Influenza A Virus, H3N2 Subtype , Influenza A virus/immunology , Animals , Antibody Formation , Chickens , Italy , Seasons , Virus CultivationABSTRACT
Measurement of influenza A/Torino/1/75, A/MRC 11 and A/Scotland/840/74 viruses h.i. antibodies in a sample of the Turin population represented by 200 non-vaccinated adults, showed that the percentage of subjects carrying antibiodies at the minimum titre of 1/10 was respectively 83, 78,5 and 52 and respective mean titres were 1/65, 1/65 and 1/43. These results confirm the antigenic affinity between A/Torino/1/75 and A/MRC/11 strains and their diversity with respect to A/Scotland/840/74. It is emphasized that vaccines should include the Scottish variant of the influenza virus also.
Subject(s)
Immunity , Influenza A virus/immunology , Influenza, Human/immunology , Antibodies, Viral/isolation & purification , Antibody Formation , Antigens, Viral/isolation & purification , Humans , Italy , SeasonsABSTRACT
53%, and 29.8% respectively, of a sample of 500 adults living in Turin have been shown lacking of any antibody against A/Victoria/3/75 and B/Hong Kong/8/73 influenza strains; less than 20%, and 45.4% respectively, possessed antibodies at a protective level (greater than or equal to 1:40). Furthermore, the study of age distribution of immunity against A/New Jersey/76 has confirmed specific h.a.i. antibodies to be present, at a significant level, only from the sixth decade onwards.
Subject(s)
Antibodies, Viral , Influenza, Human/immunology , Adolescent , Adult , Aged , Antibodies, Viral/analysis , Child , Child, Preschool , Female , Humans , Infant , Influenza A Virus, H3N2 Subtype , Influenza A virus , Influenza, Human/epidemiology , Italy , Male , Middle Aged , OrthomyxoviridaeABSTRACT
On the basis of 1,083 cases of acute hepatitis, the radioimmunoassay has been confirmed the most sensible test for the detection of HBAg, followed by counterimmunoelectrophoresis, immunodiffusion and latex agglutination. Although the most complicated and expensive test, it is worth to be routinely employed in the acute hepatitis, both diagnostically and from a prophylactic point of view.
