Increased generation of dendritic cells from myeloid progenitors in autoimmune-prone nonobese diabetic mice

Aberrant dendritic cell (DC) development and function may contribute to autoimmune disease susceptibility. To address this hypothesis at the level of myeloid lineage-derived DC we compared the development of DC from bone marrow progenitors in vitro and DC populations in vivo in autoimmune diabetes-prone nonbese diabetic (NOD) mice, recombinant congenic nonbese diabetes-resistant (NOR) mice, and unrelated BALB/c and C57BL/6 (BL/6) mice. In GM-CSF/IL-4-supplemented bone marrow cultures, DC developed in significantly greater numbers from NOD than from NOR, BALB/c, and BL/6 mice. Likewise, DC developed in greater numbers from sorted (lineage(-)IL-7Ralpha(-)SCA-1(-)c-kit(+)) NOD myeloid progenitors in either GM-CSF/IL-4 or GM-CSF/stem cell factor (SCF)/TNF-alpha. [H-3]TdR incorporation indicated that the increased generation of NOD DC was due to higher levels of myeloid progenitor proliferation. Generation of DC with the early-acting hematopoietic growth factor, flt3 ligand, revealed that while the increased DC-generative capacity of myeloid-committed progenitors was restricted to NOD cells, early lineage-uncommitted progenitors from both NOD and NOR had increased DC-gencrative capacity relative to BALB/c and BL/6. Consistent with these findings, NOD and NOR mice had increased numbers of DC in blood and thymus and NOD had an increased proportion of the putative myeloid DC (CD11c(+)CD11b(+)) subset within spleen. These findings demonstrate that diabetes-prone NOD mice exhibit a myeloid lineage-specific increase in DC generative capacity relative to diabetes-resistant recombinant congenic NOR mice. We propose that an imbalance favoring development of DC from myeloid-committed progenitors predisposes to autoimmune disease in NOD mice.

Persistence of recipient lymphocytes in NOD mice after irradiation and bone marrow transplantation

The non-obese diabetic (NOD) mouse is a unique and invaluable model of autoimmune disease, in particular type I diabetes. Bone marrow transplantation as a therapy for type I diabetes has been explored in NOD mice. NOD mice require higher doses of conditioning irradiation for successful allogeneic bone marrow transplantation, suggesting that NOD hematopoietic cells are radioresistant compared to those of other mouse strains. However, studies of hematopoietic reconstitution in NOD mice are hampered by the lack of mice bearing a suitable cell-surface marker that would allow transferred cells or their progeny to be distinguished. In order to monitor hematopoietic reconstitution in NOD mice we generated congenic NOD mice that carry the alternative allelic form of the pan-leukocyte alloantigen CD45. Following irradiation and congenic bone marrow transplantation, we found that the myeloid lineage was rapidly reconstituted by cells of donor origin but substantial numbers of recipient T lymphocytes persisted even after supra-lethal irradiation. This indicates that radiation resistance in the NOD hematopoietic compartment is a property primarily of mature T lymphocytes. (C) 2004 Elsevier Ltd. All rights reserved.

ICT AND PRODUCTIVITY IN DEVELOPING COUNTRIES: NEW FIRM-LEVEL EVIDENCE FROM BRAZIL AND INDIA

This paper uses a unique new data set on manufacturing firms in Brazil and India to estimate production functions, augmented by information and communications technology (ICT). We find a strong positive association between ICT capital and productivity in both countries that is robust to several different specification tests. The paper also breaks new ground when using the Indian data to investigate the effect of the institutional and policy environment on ICT capital investment and productivity. We find that poorer infrastructure quality and labor market policy are associated with lower levels of ICT adoption, while poorer infrastructure is also associated with lower returns to investment.

Sequence analysis, chromosomal distribution and long-range organization show that rapid turnover of new and old pBuM satellite DNA repeats leads to different patterns of variation in seven species of the Drosophila buzzatii cluster

We aimed to study patterns of variation and factors influencing the evolutionary dynamics of a satellite DNA, pBuM, in all seven Drosophila species from the buzzatii cluster (repleta group). We analyzed 117 alpha pBuM-1 (monomer length 190 bp) and 119 composite alpha/beta (370 bp) pBuM-2 repeats and determined the chromosome location and long-range organization on DNA fibers of major sequence variants. Such combined methodologies in the study of satDNAs have been used in very few organisms. In most species, concerted evolution is linked to high copy number of pBuM repeats. Species presenting low-abundance and scattered distributed pBuM repeats did not undergo concerted evolution and maintained part of the ancestral inter-repeat variability. The alpha and alpha/beta repeats colocalized in heterochromatic regions and were distributed on multiple chromosomes, with notable differences between species. High-resolution FISH revealed array sizes of a few kilobases to over 0.7 Mb and mutual arrangements of alpha and alpha/beta repeats along the same DNA fibers, but with considerable changes in the amount of each variant across species. From sequence, chromosomal and phylogenetic data, we could infer that homogenization and amplification events involved both new and ancestral pBuM variants. Altogether, the data on the structure and organization of the pBuM satDNA give insights into genome evolution including mechanisms that contribute to concerted evolution and diversification.

Fms-like tyrosine kinase 3 ligand administration overcomes a genetically determined dendritic cell deficiency in NOD mice and protects against diabetes development

A dendritic cell (DC) imbalance with a marked deficiency in CD4(-)8(+) DC occurs in non-obese diabetic (NOD) mice, a model of human autoimmune diabetes mellitus. Using a NOD congenic mouse strain, we find that this CD4(-)8(+) DC deficiency is associated with a gene segment on chromosome 4, which also encompasses non-MHC diabetes susceptibility loci. Treatment of NOD mice with fms-like tyrosine kinase 3 ligand (FL) enhances the level of CD4(-)8(+) DC, temporarily reversing the DC subtype imbalance. At the same time, fms-like tryosine kinase 3 ligand treatment blocks early stages of the diabetogenic process and with appropriately timed administration can completely prevent diabetes development. This points to a possible clinical use of FL to prevent autoimmune disease.

Social and psychiatric influences on urban-rural differentials in Australian suicide

The purpose of this study was to investigate urban-rural differentials in Australian suicide rates, and to examine influences that previously have remained largely speculative. Suicide rates for males (all ages and young adults) were significantly higher in rural areas compared to urban areas. Urban-rural suicide rate differences in males were rendered nonsignificant after adjustment for migrant and area socioeconomic status. Adjusting for mental disorder prevalence, in addition to migrant status, reduced the excess suicide risk in rural areas; the excess was reduced further with addition of mental health service utilization. The implications of this study are that socioeconomic circumstances in rural populations contribute to higher male suicide rates compared to urban areas, but these conditions may be partly mediated by mental disorder prevalence and mental health service utilization.

Mental health and socio-economic variations in Australian suicide

This paper investigates the relationship between suicide rates and prevalence of mental disorder and suicide attempts, across socio-economic status (SES) groups based on area of residence. Australian suicide data (1996-1998) were analysed in conjunction with area-based prevalences of mental disorder derived from the National Survey of Mental Health and Well-Being (1997). Poisson regression models of suicide risk included age, quintile of area-based SES, urban-rural residence, and country of birth (COB), with males and females analysed separately. Analysis focussed on the association between suicide and prevalences of (ICD-10) affective disorders, anxiety disorders, substance use disorders and suicide attempts by SES group. Prevalences of other psychiatric symptomatology, substance use problems, health service utilisation, stressful life-events and personality were also investigated. Significant increasing gradients were evident from high to low SES groups for prevalences of affective disorders, anxiety disorders (females only), and substance use disorders (males only); sub-threshold drug and alcohol problems and depression; and suicide attempts and suicide (males only). Prevalences of mental disorder, other sub-threshold mental health items and suicide attempts were significantly associated with suicide, but in most cases associations were reduced in magnitude and became statistically non-significant after adjustment for COB, urban-rural residence, and SES. For male suicide the relative risk (RR) in the lowest SES group compared to the highest was 1.40 (95% CI 1.29-1.52, p < 0.001) for all ages, and 1.46 (95% CI 1.27-1.67, p < 0.001) for male youth (20-34 years). This relationship was not substantially modified in males when regression models included prevalences of affective disorders, and other selected mental health variables and demographic factors. From a population perspective, SES remained significantly associated with suicide after controlling for the prevalence of mental disorders and other psychiatric symptomatology. Mental conditions and previous suicidal behaviour may play an intermediary role between SES and suicide, but this study suggests that an independent relationship between suicide and SES also exists. (c) 2005 Elsevier Ltd. All rights reserved.

Cognate CD4(+) help elicited by resting DC does not impair CD8(+) T-cell tolerance induction

No abstract

Can a N-2-fixing Gluconacetobacter diazotrophicus association with sugarcane be achieved?

Several published studies claim that high rates of N-2 fixation occur in sugarcane and sorghum, and have ascribed this result to infection by the bacterium Gluconacetobacter diazotrophicus, abetted by arbuscular mycorrhizal infection ( Glomus clarum). These results have not been confirmed within Australia. In this study, G. diazotrophicus was detected in stalks of field-grown sugarcane in Australia ( based on phenotypic tests, and a PCR test using species-specific primers developed to amplify a fragment of the G. diazotrophicus 16S rRNA gene). Isolates were nitrogenase positive ( acetylene reduction assay) in vitro. However, in glasshouse trials involving inoculation of sugarcane setts with G. diazotrophicus, co-inoculation with mycorrhizae, and plant growth under low N status, recovery of bacteria from maturing plants was variable. At 165 days from planting, no appreciable N-2-fixation, as assessed by dry weight increment, N budget, or N-15 ratio, of either an Australian or a Brazilian cultivar of sugarcane, or a sorghum cultivar, was achieved. We conclude that a N-2-fixing sugarcane - G. diazotrophicus association is not easily achievable, being primarily limited by a lack of infection.

Structural shifts of aldehyde dehydrogenase enzymes were instrumental for the early evolution of retinoid-dependent axial patterning in metazoans

Aldehyde dehydrogenases (ALDHs) catabolize toxic aldehydes and process the vitamin A-derived retinaldehyde into retinoic acid (RA), a small diffusible molecule and a pivotal chordate morphogen. In this study, we combine phylogenetic, structural, genomic, and developmental gene expression analyses to examine the evolutionary origins of ALDH substrate preference. Structural modeling reveals that processing of small aldehydes, such as acetaldehyde, by ALDH2, versus large aldehydes, including retinaldehyde, by ALDH1A is associated with small versus large substrate entry channels (SECs), respectively. Moreover, we show that metazoan ALDH1s and ALDH2s are members of a single ALDH1/2 clade and that during evolution, eukaryote ALDH1/2s often switched between large and small SECs after gene duplication, transforming constricted channels into wide opened ones and vice versa. Ancestral sequence reconstructions suggest that during the evolutionary emergence of RA signaling, the ancestral, narrow-channeled metazoan ALDH1/2 gave rise to large ALDH1 channels capable of accommodating bulky aldehydes, such as retinaldehyde, supporting the view that retinoid-dependent signaling arose from ancestral cellular detoxification mechanisms. Our analyses also indicate that, on a more restricted evolutionary scale, ALDH1 duplicates from invertebrate chordates (amphioxus and ascidian tunicates) underwent switches to smaller and narrower SECs. When combined with alterations in gene expression, these switches led to neofunctionalization from ALDH1-like roles in embryonic patterning to systemic, ALDH2-like roles, suggesting functional shifts from signaling to detoxification.

Online monitoring of pulse pressure variation to guide fluid therapy after cardiac surgery

BACKGROUND: The arterial pulse pressure variation induced by mechanical ventilation (Delta PP) has been shown to be a predictor of fluid responsiveness. Until now, Delta PP has had to be calculated offline (from a computer recording or a paper printing of the arterial pressure curve), or to be derived from specific cardiac output monitors, limiting the widespread use of this parameter. Recently, a method has been developed for the automatic calculation and real-time monitoring of Delta PP using standard bedside monitors. Whether this method is to predict reliable predictor of fluid responsiveness remains to be determined. METHODS: We conducted a prospective clinical study in 59 mechanically ventilated patients in the postoperative period of cardiac surgery. Patients studied were considered at low risk for complications related to fluid administration (pulmonary artery occlusion pressure <20 mm Hg, left ventricular ejection fraction >= 40%). All patients were instrumented with an arterial line and a pulmonary artery catheter. Cardiac filling pressures and cardiac output were measured before and after intravascular fluid administration (20 mL/kg of lactated Ringer`s solution over 20 min), whereas Delta PP was automatically calculated and continuously monitored. RESULTS: Fluid administration increased cardiac output by at least 15% in 39 patients (66% = responders). Before fluid administration, responders and nonresponders were comparable with regard to right atrial and pulmonary artery occlusion pressures. In contrast, Delta PP was significantly greater in responders than in nonresponders, (17% +/- 3% vs 9% +/- 2%, P < 0.001). The Delta PP cut-off value of 12% allowed identification of responders with a sensitivity of 97% and a specificity of 95%. CONCLUSION: Automatic real-time monitoring of Delta PP is possible using a standard bedside rnonitor and was found to be a reliable method to predict fluid responsiveness after cardiac surgery. Additional studies are needed to determine if this technique can be used to avoid the complications of fluid administration in high-risk patients.