Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Gender, space, and the location changes of jobs and people: a spatial simultaneous equations analysis.

This article summarizes a spatial econometric analysis of local population and employment growth in the Netherlands, with specific reference to impacts of gender and space. The simultaneous equations model used distinguishes between population- and gender-specific employment groups, and includes autoregressive and cross-regressive spatial lags to detect relations both within and among these groups. Spatial weights matrices reflecting different bands of travel times are used to calculate the spatial lags and to gauge the spatial nature of these relations. The empirical results show that although population­employment interaction is more localized for women's employment, no gender difference exists in the direction of interaction. Employment growth for both men and women is more influenced by population growth than vice versa. The interaction within employment groups is even more important than population growth. Women's, and especially men's, local employment growth mostly benefits from the same employment growth in neighboring locations. Finally, interaction between these groups is practically absent, although men's employment growth may have a negative impact on women's employment growth within small geographic areas. In summary, the results confirm the crucial roles of gender and space, and offer important insights into possible relations within and among subgroups of jobs and people.

Genetic dissection of complex traits in yeast: insights from studies of gene expression and other phenotypes in the BYxRM cross.

The genetic basis of many phenotypes of biological and medical interest, including susceptibility to common human diseases, is complex, involving multiple genes that interact with one another and the environment. Despite decades of effort, we possess neither a full grasp of the general rules that govern complex trait genetics nor a detailed understanding of the genetic basis of specific complex traits. We have used a cross between two yeast strains, BY and RM, to systematically investigate the genetic complexity underlying differences in global gene expression and other traits. The number and diversity of traits dissected to the locus, gene, and nucleotide levels in the BYxRM cross make it arguably the most extensively characterized system with regard to causal effects of genetic variation on phenotype. We summarize the insights obtained to date into the genetics of complex traits in yeast, with an emphasis on the BYxRM cross. We then highlight the central outstanding questions about the genetics of complex traits and discuss how to answer them using yeast as a model system.

Oral vaccination and multivalent vaccine against Pseudomonas aeruginosa keratitis.

Active immunization against Pseudomonas aeruginosa keratitis and systemic disease in mice was studied. In the first series of experiments, monovalent vaccine, administered orally or intraperitoneally, protected against subsequent corneal and intraperitoneal challenge with the homologous strain of P. aeruginosa; however, oral administration of vaccine elicited less protection than intraperitoneal administration. After both routes, protection was observed at 11 and 32 days post-vaccination, but it was greater at 11 days. In the second series of experiments, multivalent vaccine administered intraperitoneally protected against corneal challenge with 56 to 78 percent of 18 strains.

Experimental Pseudomonas aeruginosa Infection of the Mouse Cornea.

Pseudomonas aeruginosa infection of human cornea is rare but serious. The work of previous investigators using experimental infection primarily of rabbit cornea resulted in successful therapy for 10 to 50% of clinical cases. The advantage of using the mouse is demonstrated. The methods we adapted for characterizing the untreated experimental infection included: incising the cornea to enable establishing the infection; corneal examination with a steroscopic microscope; grading corneal pathology; qualitative and quantitative monitoring of the infecting bacteria by culturing and staining sectioned and dissected tissues. The characteristics of the tissue pathology, host response, and infection were similar to those reported for other animals and man. Corneal pathology was frequently nearly maximal 1 day after infection; host response involved a progression of events of long duration; pathology persisted well beyond the period of bacterial infection. The infection was essentially noncommunicable, and invasiveness was limited to the tissues of the incised eye. The results show the possibility of tests for invasiveness of clinical isolates and for screening for therapeutic and prophylactic measures.