Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function

Ubiquilin 1 (UBQLN1) is involved in the ubiquitination machinery, which has been implicated in Alzheimer's disease (AD) as well as Parkinson's disease (PD). A polymorphism in the gene encoding for UBQLN1 has been previously associated with a higher risk of AD. We studied the role of the SNP rs12344615 on the UBQLN 1 gene in AD, PD and cognitive function in a population-based study, the Rotterdam Study, and a family-based study embedded in the genetic research in isolated population (GRIP) program. The Rotterdam Study includes 549 patients with AD and 157 patients with PD. The GRIP program includes a series of 123 patients with AD and a study of 1049 persons who are characterized for cognitive function. Data were analysed using logistic and multiple regression analysis. We found no significant difference in risk of AD or PD by the UBQLN1 SNP rs12344615 in our overall and stratified analyses in the Rotterdam Study. In our family-based study, we did not find evidence for linkage of AD to the region including the UBQLN1 gene. In the family-based study we also failed to detect an effect of this polymorphism on cognitive function. Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function.     

Infant feeding and infant health in American Samoa

This study examines the association between infant feeding patterns and health for 6,267 Samoan children born between 1976 and 1982, and represented in the Well Baby Clinic records at the LBJ Tropical Medical Center, American Samoa. The visits to the clinic were aggregated by trimester of age during the first year of life. For each trimester, the principal source of milk was determined, and the children were categorized as breast-fed if they were taking only breast milk, bottle-fed if they were getting no breast milk, or mixed-fed if they were getting both breast milk and milk from other sources. Symptoms and complaints noted in the records were assigned to ICD categories. Associations between source of milk and disease category were analyzed. The Samoan infants were found to be quite healthy for a tropical developing population, as evidenced by both growth in weight and length, as well as by frequency of illnesses. The most common specific disease category, aside from miscellaneous symptoms, was ICD 8, respiratory problems. Gastrointestinal diseases were rare for a developing area. There was an association between source of milk and illness (yes/no) for both the second and third trimesters. In both cases breast-fed infants were healthier than the mixed-fed infants, and during the second trimester the contrast was significant with bottle-fed infants also. When examined by ICD category, breast-fed infants tended to be less likely to have problems in any of the categories, but the only significant differences were between mixed-fed (lower prevalence) and bottle-fed infants during the first trimester for ICD 3, primarily nutritional problems; and for breast-fed (lower prevalence) and mixed-fed infants for ICD 9, digestive problems. These findings highlight the need for additional household work to delineate associations with the growth and health of Samoan infants.     

Interferon-gamma levels in nasopharyngeal secretions of infants with respiratory syncytial virus and other respiratory viral infections

Respiratory syncytial virus (RSV) infection, one of the most common causes of hospitalization of children in developed countries, has been implicated as a cause of asthma. We aimed to characterize the cytokine profile in nasopharyngeal aspirates (NPAs) taken from infants during upper respiratory tract infection to investigate whether RSV induced a unique immune response as compared with other viruses. Additionally, we sought to determine whether this profile was influenced by the infants' atopic status. A prospective birth cohort of babies at high risk of atopy was recruited. Ratios of a T-helper 1 (Th1) cytokine, interferon gamma (IFN-gamma) and a T-helper 2 (Th2)-like cytokine, interleukin-10 (IL-10), in NPAs were determined during episodes of respiratory tract infections in the first year. The viral aetiology of the respiratory tract infections was determined using polymerase chain reaction (PCR), culture and immunofluorescence. Atopic status was ascertained at 1 year of age using skin prick tests. Participants were recruited antenatally and subsequently followed in the community. Sixty babies with one or both parents atopic were enrolled into the study. IFN-gamma : IL-10 ratios in NPAs during upper respiratory tract infections and their correlation with viral aetiology and atopic status were the main outcome measures. The mean IFN-gamma : IL-10 ratio was significantly lower (due to lower IFN-gamma) during RSV infections than during infections with other viruses (P = 0.035). The cytokine ratio, however, did not differ between infants with or without wheeze during URTIs (P = 0.44), or between infants who were atopic or non-atopic (P = 0.49). This study suggests that RSV is associated with lower IFN-gamma production in young babies, regardless of their atopic status, compared to upper respiratory tract infections where either another virus is detected or where no viral identification is made.     

Can Only Partial T-Cell Depletion of the Graft before Hematopoietic Stem Cell Transplantation Mitigate Graft-versus-Host Disease While Preserving a Graft-versus-Leukemia Reaction? A Prospective Phase II Study

The study comprised 37 consecutive patients who underwent transplantation with a Campath-1H in vitro T cell-depleted granulocyte colony-stimulating factor-mobilized peripheral blood stem cell graft from an HLA-identical sibling, followed 24 hours later by an unmanipulated graft. Acute graft-versus-host disease (GVHD) was limited to grade I to II, whereas chronic graft-versus-host disease occurred in 9 patients, mostly (n = 7) with limited disease. Molecular relapses (8 chronic myeloid leukemia [CML] and 1 non-Hodgkin lymphoma) that occurred not earlier than the sixth month after transplantation were treated with donor lymphocyte infusion (DLI), which induced complete remission in all but 1 CML patient with persistent very low BCR-ABL molecular levels. With a median follow-up of 54 months (range, 29-84 months), the actuarial 5-year overall survival, disease-free survival, and transplant-related mortality are 78% (95% confidence interval [CI], 52%-88%), 78% (95% CI, 52%-86%), and 6% (95% CI, 1.5%-32%), respectively. All CML patients are alive and free of disease. The results of this prospective, nonrandomized study show that incomplete T-cell depletion in vitro with Campath-1H (in combination with DLI for molecular relapses in CML) may decrease the incidence of GVHD and transplant-related mortality with no adverse effect on disease-free survival. The described method decreases the number of T cells to an extent that severe GVHD is prevented while relapse is postponed to a time when the patient can be treated with DLI without severe side effects.     

Identification of two new Pmp22 mouse mutants using large-scale mutagenesis and a novel rapid mapping strategy

Mouse mutants have a key role in discerning mammalian gene function and modelling human disease; however, at present mutants exist for only 1-2% of all mouse genes. In order to address this phenotype gap, we have embarked on a genome-wide, phenotype-driven, large-scale N-ethyl-N--nitrosourea (ENU) mutagenesis screen for dominant mutations of clinical and pharmacological interest in the mouse. Here we describe the identification of two similar neurological phenotypes and determination of the underlying mutations using a novel rapid mapping strategy incorporating speed back-crosses and high throughput genotyping. Two mutant mice were identified with marked resting tremor and further characterized using the SHIRPA behavioural and functional assessment protocol. Back-cross animals were generated using in vitro fertilization and genome scans performed utilizing DNA pools derived from multiple mutant mice. Both mutants were mapped to a region on chromosome 11 containing the peripheral myelin protein 22 gene (Pmp22). Sequence analysis revealed novel point mutations in Pmp22 in both lines. The first mutation, H12R, alters the same amino acid as in the severe human peripheral neuropathy Dejerine Sottas syndrome and Y153TER in the other mutant truncates the Pmp22 protein by seven amino acids. Histological analysis of both lines revealed hypo-myelination of peripheral nerves. This is the first report of the generation of a clinically relevant neurological mutant and its rapid genetic characterization from a large-scale mutagenesis screen for dominant phenotypes in the mouse, and validates the use of large-scale screens to generate desired clinical phenotypes in mice.     

Improved protection conferred by vaccination with a recombinant vaccinia virus that incorporates a foreign antigen into the extracellular enveloped virion

Recombinant poxviruses have shown promise as vaccine vectors. We hypothesized that improved cellular immune responses could be developed to a foreign antigen by incorporating it as part of the extracellular enveloped virion (EEV). We therefore constructed a recombinant vaccinia virus that replaced the cytoplasmic domain of the B5R protein with a test antigen, HIV-1 Gag. Mice immunized with the virus expressing Gag fused to B5R had significantly better primary CD4 T-cell responses than recombinant virus expressing HIV-Gag from the TK-locus. The CD8 T-cell responses were less different between the two groups. Importantly, although we saw differences in the immune response to the test antigen, the vaccinia virus-specific immune responses were similar with both constructs. When groups of vaccinated mice were challenged 30 days later with a recombinant Listeria monocytogenes that expresses HIV-Gag, mice inoculated with the virus that expresses the B5R-Gag fusion protein had lower colony counts of Listeria in the liver and spleen than mice vaccinated with the standard recombinant. Thus, vaccinia virus expressing foreign antigen incorporated into EEV may be a better vaccine strategy than standard recombinant vaccinia virus.     

Mycotic infections of brain

Six cases of mycotic infectation of the brain are presented. All the patients were in the age group ranging from 18 years to 38 years. the duration of clinical symptoms varied from 6 days to 7 months. Computerized tomographic visualization of brain revealed a mass lesion in all. Operative findings were suggestive of tumour in 3 cases. All the patients were non-immunocompromised. There was history of previous ear infection and sinusitis in one case. Histopathological examination of biopsy tissue showed dichotomously branching septate fungal hyphae highlighted by special stains like methanamin silver and PAS in all cases.     

Deciphering the impaired cytokine cascades in chronic leg ulcers (review)

Chronic leg ulcers are typically wounds that do not heal at a normal rate. Impaired healing appears to be due to primary microvascular changes and it is aggravated by ongoing bacteria-driven vasculitis. The various cytokines identified in experimental wounds are also present in leg ulcers. VEGF is strongly implicated as a promoter of blood vessel growth in patients with venous disease. In addition, there is good evidence of increased expression of bFGF, TGF-beta1, and PDGF in lipodermatosclerosis. All of these growth factors are involved in wound healing. Upregulated TGF-beta1 is probably one of the main causes of the fibrosis observed in lipodermatosclerosis. In leg ulcers, cytokines appear to be trapped in the perivascular fibrinoid deposits. It is not the nature and amount of cytokines that are inadequate in leg ulcers, but rather their spatial distribution. Dermal dendrocytes (DD) are resident factor XIIIa-enriched macrophages. They likely play a role in tissue repair when boosted adequately. New therapies aiming at helping the release of cytokines by DD apparently promote and improve the healing phase.     

IL-7 receptor is present on human microvascular endothelial cells

Interleukin-7 (IL-7) is a pleiotropic, non-redundant cytokine crucial for development of B and T lymphocytes. The cellular response to IL-7 is triggered by binding of the cytokine to its receptor, IL-7R. Until now the expression of the receptor was evidenced only in lymphoid and myeloid cell lineages. The receptor consists of two chains: IL-7 specific alpha chain (CD127) and the common gamma(c) chain (CD132) which is a component of several other cytokine receptors: IL-2, IL-4, IL-9 and IL-15. The former observation that exogenous IL-7 is biologically active towards murine endothelial cell lines from secondary lymphoid organs was the starting point of our studies. This observation has prompted us to search for the presence of IL-7 receptor in human microvascular endothelial cells. We used in our studies a set of human endothelial cell lines established from various organs. Our results demonstrate the presence of IL-7R in human microvascular endothelial cells, mainly in the mesenteric but also in the peripheral and to a lesser extent, in the mucosa-associated lymph node endothelial cells. On the basis of the RT-PCR reaction, molecular weight estimated in Western blot and IL-7 binding activity the identified endothelial IL-7 receptor was identical to the lymphocyte-type IL7-R.     

Monkeypox virus and insights into its immunomodulatory proteins

Summary: Monkeypox is a disease that is endemic in Central and Western Africa. However, in 2003, there was an outbreak in the United States, representing the first documented monkeypox cases in the Western hemisphere. Although monkeypox virus is less fatal and not as transmissible as variola virus, the causative agent of smallpox, there is concern that monkeypox virus could become a more efficient human pathogen. The reason for this may lie in the virus' genetic makeup, ecological changes, changes in host behavior, and the fact that with the eradication of variola virus, routine smallpox vaccination is no longer carried out. In this review, we focus on the viral proteins that are predicted to modulate the host immune response and compare the genome of monkeypox virus with the genomes of variola virus and the vaccinia virus, the orthopoxvirus that represented the smallpox vaccine. There are differences found in several of these immune-modulating genes including genes that express proteins that affect cytokines such as interleukin-1, tumor necrosis factor, and interferon. There are also differences in genes that code for virulence factors and host range proteins. Genetic differences likely also explain the differences in virulence between two strains of monkeypox virus found in two different regions of Africa. In the current setting of limited smallpox vaccination and little orthopoxvirus immunity in parts of the world, monkeypox could become a more efficient human pathogen under the right circumstances.