High risk for unbalanced segregation of some reciprocal translocations: A large pedigree containing distal 4q trisomy from t(4;7)(q28;p22)

We report on a familial t(4;7)(q28;p22) with 2:2 adjacent‐1 unbalanced segregation producing duplication of 4q28→qter in multiple offspring. Within the large four‐generation pedigree, a carrier had a reproductive outcome that was approximately equal for 1) the balanced translocation, 2) normal chromosomes, and 3) viable 4q trisomy or pregnancy loss. The three individuals with chromosomal confirmation of trisomy 4q28→qter (comprising approximately 1.8% of the haploid autosomal length) had similar mental and developmental retardation, hypotonia, restricted speech, seizures, and facial anomalies but no cardiac, renal, or skeletal anomalies. It is suggested that these latter severe malformations, associated with the classic 4q2 to 3 group of anomalies, were from an imbalance outside 4q28→qter and were not necessarily related to the relatively large size of the trisomic segment. Multiple different chromosomes are reported to be rearranged with 4q in the production of distal 4q trisomy. The incidence of 4q rearrangement remains unexplained, but once it is present in a family, viability of a large trisomy in 4q seems to explain the number of affected individuals reported. © 2001 Wiley‐Liss, Inc.     

Attenuated poxvirus expressing three immunodominant CMV antigens as a vaccine strategy for CMV infection.

BACKGROUND: Human cytomegalovirus (CMV) infection is an important risk factor in the post-transplant (Tx) recovery phase for both hematopoietic stem cell Tx (HSCT) and solid organ Tx (SOT) recipients. CMV infection may be prevented or controlled by simultaneously inducing both CMV-specific neutralizing antibody (nAb) and cellular immunity. Soluble (s) UL55 (surface glycoprotein), UL83 (tegument protein) and UL123/e4 (nuclear protein) are immunodominant in eliciting both CMV nAb and cellular immunity. An attenuated poxvirus, modified vaccinia Ankara (MVA) was selected to develop this vaccine strategy in Tx recipients, because of its clinical safety record, large foreign gene capacity, and capability to activate strong humoral and cellular immune responses against recombinant antigens. OBJECTIVES: A subunit vaccine that targets multiple CMV antigens will be used to gain maximal coverage and protective function against CMV infection. rMVA simultaneously expressing sUL55, UL83 and UL123/e4 will be generated, and humoral and cellular immunity it elicits will be characterized, after murine immunization and in vitro to amplify clinical recall responses. STUDY DESIGN: rMVA will be constructed in two steps using UL123/e4-pLW22 followed by sUL55-UL83-pLW51 transfer plasmids. Western blots will be used to characterize expression levels of each antigen. Primary immunity will be evaluated in mouse models, while recall responses to the virally expressed CMV antigens will be assessed in human peripheral blood. RESULTS: We generated CMV-MVA via homologous recombination, and demonstrated high expression levels of sUL55, UL83 and UL123/e4 by Western blot. CMV-MVA immunization potently induced both humoral and cellular immunity to sUL55, UL83 and UL123 after murine immunization, and cellular immunity to UL83 and UL123 by in vitro amplification of T cell recall responses in human PBMC. CONCLUSIONS: rMVA promotes high level expression of three immunodominant CMV antigens, which is reflected in results of immunization studies in which high titers of UL55-specific antibodies and CD4+ T-help are detected, as well as high levels of UL83-specific and moderate levels of UL123-specific CD8+ CTL.     

Assessment of Antibody Response Elicited by a 7-valent Pneumococcal Conjugate Vaccine in Pediatric Human Immunodeficiency Virus Infection

We investigated antibody responses against pneumococci of serotypes 6B, 14, and 23F in 56 children and adolescents with perinatal human immunodeficiency virus (HIV) infection who were vaccinated with 7-valent pneumococcal conjugate vaccine. Overall immune responses differed greatly between serotypes. Correlation coefficients between immunoglobulin G (IgG) measured by enzyme-linked immunosorbent assay (ELISA) and functional antibodies measured by a flow cytometry opsonophagocytosis assay (OPA) varied with serotype and time points studied. After 3 months of administering a second PCV7 dose we got the highest correlation (with significant r values of 0.754, 0.414, and 0.593 for serotypes 6B, 14, and 23F, respectively) but no significant increase in IgG concentration and OPA titers compared to the first dose. We defined a responder to a serotype included in the vaccine with two criteria: frequency of at least twofold OPA and ELISA increases for each serotype and frequency of conversion from negative to positive OPA levels. Responders varied from 43.9% to 46.3%, 28.5% to 50.0%, and 38.0% to 50.0% for serotypes 6B, 14, and 23F, respectively, depending on the response criterion. The present research highlights the importance of demonstrating vaccine immunogenicity with suitable immunological endpoints in immunocompromised patients and also the need to define how much antibody is required for protection from different serotypes, since immunogenicity differed significantly between serotypes.     

Outbreak of infection with hepatitis A virus (HAV) associated with a foodhandler and confirmed by sequence analysis reveals a new HAV genotype IB variant

An outbreak of infection with hepatitis A virus associated with a foodhandler and involving 26 subjects occurred in Southern Italy. Sequence analysis of the VP3-VP1 and VP1-P2A junctions confirmed that the outbreak was due to a point source and allowed the identification of a new genotype IB variant. This report confirms the usefulness of sequence-based molecular fingerprinting during outbreaks.     

Impaired Recovery of CD4+ Cell Counts Following Highly Active Antiretroviral Therapy in Drug-Naïve Patients Coinfected with Human Immunodeficiency Virus and Hepatitis C Virus

Coinfection with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) is highly prevalent in southern Europe. However, there are few and contradictory data about the effect of HCV carriage on the response to highly active antiretroviral therapy (HAART). In this study, the recovery of CD4+ T cells following HAART among antiretroviral-naïve patients seropositive for HIV with and without HCV coinfection was investigated. Two hundred one HIV-infected patients without previous exposure to antiretroviral drugs were included in the study. HCV coinfection was detected in 123 (61%) patients. The time to recover 200 CD4+ cells/µl was longer in the HCV-positive group (P<0.001). In a Cox model, HCV infection and lack of persistent HIV viremia (defined as <200 copies/ml) were associated with the time to recover 200 CD4+ cells/µl. The mean increase in CD4+ cell counts was lower in the HCV-positive group during the first year of therapy. HIV/HCV-coinfected patients naïve for antiretroviral therapy show a delayed recovery of CD4+ cell counts after starting HAART.     

Memory T-cell competition for bone marrow seeding

The presence in the bone marrow of memory CD8 T cells is well recognized. However, it is still largely unclear how T-cell migration from the lymphoid periphery to the bone marrow is regulated. In the present report, we show that antigen-specific CD4 T cells, as well as antigen-specific CD8 T cells, localize to the bone marrow of immunized mice, and are sustained there over long periods of time. To investigate the rules governing T-cell migration to the bone marrow, we generated chimeric mice in which the lymphoid periphery contained two genetically or phenotypically distinct groups of T cells, one of which was identical to the host. We then examined whether a distinct type of T cell had an advantage over the others in the colonization of bone marrow. Our results show that whereas ICAM1 and CD18 molecules are both involved in homing to lymph nodes, neither is crucial for T-cell bone marrow colonization. We also observed that memory-phenotype CD44high T cells, but not virgin-type CD44-/low T cells, preferentially home to the bone marrow upon adoptive transfer to normal young mice, but not to thymectomized old recipients where an existing memory T-cell pool precludes their free access. Thus, T-cell colonization of the bone marrow uses distinct molecules from those implicated in lymph node homing, and is regulated both by the properties of the T cell and by the competitive efficacy of other T cells inhabiting the same, saturable niche. This implies that the homing potential of an individual lymphocyte is not merely an intrinsic property of the cell, but rather a property of the lymphoid system taken as a whole.     

Osteomyelitis caused by Enterobacter cancerogenus infection following a traumatic injury: case report and review of the literature

We report a case of osteomyelitis caused by Enterobacter cancerogenus resistant to aminopenicillins in a 56-year-old male who had a motorcycle accident and suffered from multiple bone fractures with abundant environmental exposure. E. cancerogenus has rarely been associated with human infections, and its clinical significance remains unclear.     

Validation of a pXO2-A PCR assay to explore diversity among Italian isolates of Bacillus anthracis strains closely related to the live, attenuated Carbosap vaccine

Several circulating Bacillus anthracis strains isolated in Italy and belonging to the A1.a cluster, genotype 3 (A1.a-3) are genotypically indistinguishable from Carbosap, a live attenuated vaccine strain, containing both pXO1 and pXO2 plasmids. The genotype was assessed by using eight-locus multilocus variable-number tandem repeat analysis. We describe here the use of a ninth locus able to explore variability among strains that have the same genotype. It is important to be able to genotype the wild isolate of B. anthracis strains from outbreaks of anthrax in areas where Carbosap vaccination of cattle and sheep is common practice. A total of 27 representative field strains isolated in Italy and four vaccinal strains, namely, Carbosap, Sterne, Pasteur I, and Pasteur II, were characterized by a ninth marker, called pXO2-A. Twenty-three field strains were genotype 3 and therefore identical to Carbosap. The marker was in the pXO2 plasmid and is based on the polymorphism of the already-known VX2-3 locus. Detection was obtained by PCR with fluorescence-labeled forward primers in order to produce appropriate fragments for capillary electrophoresis with an ABI 310 genetic analyzer. Genetic relationships showed heterogeneity in all of the examined samples. Interestingly, with respect to genotype 3, samples grouped into eight different subtypes, A to H, and the subtype G, had only two samples indistinguishable from Carbosap. The results of the present study confirm the validity of a hierarchical progressive protocol for discrimination among closely related isolates.     

Renal-hepatic-pancreatic dysplasia: an autosomal recessive malformation.

We report two brothers with a cystic malformation of the kidneys, liver, and pancreas. In both cases the malformation was fatal and the children died shortly after birth. The pathological findings, consisting of multicystic dysplastic kidneys, dilated and dysgenetic bile ducts, dilated pancreatic ducts, and polysplenia, correspond to those reported by Ivemark as renal-hepatic-pancreatic dysplasia. Many polymalformation syndromes include cystic affectation of these three organs, so this syndrome could be an isolated entity or a final common pathway of response of these organs to a variety of developmental disturbances, which could also include splenic abnormalities. We propose an autosomal recessive pattern of inheritance for renal-hepatic-pancreatic dysplasia.