The Segregation Distorter (SD) complex and the accumulation of deleterious genes in laboratory strains of Drosophila melanogaster

Segregation Distorter (SD) associated with the second chromosome of D. melanogaster is found in nature at equilibrium frequencies lower than 5%. We report extremely high frequencies of SD (30–50%) in two selected strains, established in 1976, and show it to be responsible for the accumulation of deleterious genes in chromosome II. Samples of chromosomes extracted over a 4-year period were characterized with respect to distortion, sensitivity, lethality, sterility, and inversions. SD chromosomes were inversion-free as they have been shown to be in the Mediterranean area. The cosmopolitan inversion In(2L)t was found associated with SD ⁺ chromosomes. Lines polymorphic for SD have accumulated linked lethal and female-sterile genes approaching a near balanced system. It is proposed that deleterious genes linked in coupling to SD were accumulated by the balancing effect of distortion, while drift and restricted recombination account for the accumulation of deleterious genes linked in repulsion by a mechanism similar to Muller's ratchet. Our results should not be viewed as a particular case as SD chromosomes associated with detrimental genes and inversions are present in almost all populations around the world. The system could evolve in the way we describe whenever equilibrium conditions are broken down in small populations and lead to an increase in SD frequency.     

Search for Babesia bovis vaccine candidates

Babesia bovis is a tick-borne apicomplexan pathogen that remains an important constrain for the development of cattle industries worldwide. Effective control can be achieved by vaccination with live attenuated forms of the parasite, but they have several drawbacks and thus the development of alternative subunit vaccines, either based in recombinant versions of full size proteins or in recombinant or synthetic peptides containing combinations of protective B-cell and T-cell epitopes is needed. Our current strategies for the identification of vaccine candidate antigens include the identification of functionally relevant antigens, bioinformatics, and comparative genomics using the recently sequenced B. bovis genome. These led us to the functional and immunological characterization of members of the VMSA gene family, a group of well conserved putative cysteine and serine proteases, and to the definition of a surface exposed B-cell epitope present in the Merozoite Surface Antigen-2c. Work in progress is focused in defining additional epitopes, and to determine whether they are neutralization-sensitive. These approaches might unravel useful vaccine candidates for B. bovis, and will increase our understanding of the pathogenicity mechanisms of these and related hemoparasites.     

Treadmill running starting 3 months after orchidectomy restores femoral bone mass in rats

The present study was designed to provide data on the effects on femoral bone of endurance training starting only 3 months after orchidectomy in rats. A total of 70 Wistar male rats were used at 8 weeks of age. On day 0 of the experiment, 10 rats were killed by cervical dislocation to be used as first controls. Among the 60 other animals, half was surgically castrated (CX) or sham operated (SH). On day 90, 10 CX and 10 SH were killed and used as intermediary controls (ICX and ISH). Among the other 20 CX and 20 SH, 10 within each group (CXE, SHE) were selected for treadmill running (60% maximal oxygen uptake, 1 h x day(-1), 5 days x week(-1) for 12 weeks). The 20 other rats were used as sedentary controls (CXR, SHR) and killed (as runners) on day 180. On day 90 femoral bone density (BMD) and mineral content (BMC) were lower in ICX than in ISH. On day 180 total femoral BMD was lower in CXR than in CXE. Simultaneously metaphyseal femoral BMD was lower in CXR than in CXE, SHR or SHE. Furthermore, at that time, no significant difference concerning BMD and BMC was observed between SHR and CXE. This would indicate that treadmill running starting only 3 months after orchidectomy is able to restore BMD and BMC to control values, mainly by inhibiting bone resorption (as shown by decreased urinary deoxypyridinoline excretion in CXE) without decreasing osteoblastic activity (evaluated by plasma osteocalcin concentration).     

Efficacy of Selective PDE4D Negative Allosteric Modulators in the Object Retrieval Task in Female Cynomolgus Monkeys (Macaca fascicularis)

Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.     

Hospitalized children with 2009 pandemic influenza A (H1N1): comparison to seasonal influenza and risk factors for admission to the ICU

Background

Limited data are available describing the clinical presentation and risk factors for admission to the intensive care unit for children with 2009 H1N1 infection.

Methods

We conducted a retrospective chart review of all hospitalized children with 2009 influenza A (H1N1) and 2008–09 seasonal influenza at The Children''s Hospital, Denver, Colorado.

Results

Of the 307 children identified with 2009 H1N1 infections, the median age was 6 years, 61% were male, and 66% had underlying medical conditions. Eighty children (26%) were admitted to the ICU. Thirty-two (40%) of the ICU patients required intubation and 17 (53%) of the intubated patients developed acute respiratory distress syndrome (ARDS). Four patients required extracorporeal membrane oxygenation. Eight (3%) of the hospitalized children died. Admission to the ICU was significantly associated with older age and underlying neurological condition. Compared to the 90 children admitted during the 2008–09 season, children admitted with 2009 H1N1 influenza were significantly older, had a shorter length of hospitalization, more use of antivirals, and a higher incidence of ARDS.

Conclusions

Compared to the 2008–09 season, hospitalized children with 2009 H1N1 influenza were much older and had more severe respiratory disease. Among children hospitalized with 2009 H1N1 influenza, risk factors for admission to the ICU included older age and having an underlying neurological condition. Children under the age of 2 hospitalized with 2009 H1N1 influenza were significantly less likely to require ICU care compared to older hospitalized children.     

A comprehensive study of oxidative stress and antioxidant status in preeclampsia and normal pregnancy

Oxidative stress has been increasingly postulated as a major contributor to endothelial dysfunction in preeclampsia (PE), although evidence supporting this hypothesis remains inconsistent. This study aimed to analyze in depth the potential role of oxidative stress as a mechanism underlying endothelial damage in PE and the pregnant woman's susceptibility to the disease. To this end, indicative markers of lipoperoxidation and protein oxidation and changes in antioxidant defense systems were measured in blood samples from 53 women with PE and 30 healthy pregnant controls. Results, analyzed in relation to disease severity, showed PE women, compared with women with normal pregnancy, to have: (1) significantly enhanced antioxidant enzyme SOD and GPx activities in erythrocytes; (2) similar plasma alpha-tocopherol levels and significantly increased alpha-tocopherol/lipids in both mild and severe PE; (3) significantly decreased plasma vitamin C and protein thiol levels; (4) similar erythrocyte glutathione content, total plasma antioxidant capacity, and whole plasma oxidizability values; (5) significantly elevated plasma total lipid hydroperoxides, the major initial reaction products of lipid peroxidation, in severe PE; (6) no intracellular or extracellular increases in any of the secondary end-products of lipid peroxidation, malondialdehyde or lipoperoxides; (7) similar oxidative damage to proteins quantified by plasma carbonyl levels, immunoblot analysis, and advanced oxidation protein products assessment; and (8) significantly elevated and severity-related soluble vascular cell adhesion molecule-1 serum levels reflecting endothelial dysfunction. No correlations were found among plasma levels of circulating adhesion molecules with regard to lipid and protein oxidation markers. Globally, these data reflect mild oxidative stress in blood of preeclamptic women, as oxidative processes seem to be counteracted by the physiologic activation of antioxidant enzymes and by the high plasma vitamin E levels that would prevent further oxidative damage. These results do not permit us to conclude that oxidative stress might be a pathogenetically relevant process causally contributing to the disease.