Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6

Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.     

Importance of factors determining the effective lifetime of a mass, long-lasting, insecticidal net distribution: a sensitivity analysis

Background

Long-lasting insecticidal nets (LLINs) reduce malaria transmission by protecting individuals from infectious bites, and by reducing mosquito survival. In recent years, millions of LLINs have been distributed across sub-Saharan Africa (SSA). Over time, LLINs decay physically and chemically and are destroyed, making repeated interventions necessary to prevent a resurgence of malaria. Because its effects on transmission are important (more so than the effects of individual protection), estimates of the lifetime of mass distribution rounds should be based on the effective length of epidemiological protection.

Methods

Simulation models, parameterised using available field data, were used to analyse how the distribution's effective lifetime depends on the transmission setting and on LLIN characteristics. Factors considered were the pre-intervention transmission level, initial coverage, net attrition, and both physical and chemical decay. An ensemble of 14 stochastic individual-based model variants for malaria in humans was used, combined with a deterministic model for malaria in mosquitoes.

Results

The effective lifetime was most sensitive to the pre-intervention transmission level, with a lifetime of almost 10 years at an entomological inoculation rate of two infectious bites per adult per annum (ibpapa), but of little more than 2 years at 256 ibpapa. The LLIN attrition rate and the insecticide decay rate were the next most important parameters. The lifetime was surprisingly insensitive to physical decay parameters, but this could change as physical integrity gains importance with the emergence and spread of pyrethroid resistance.

Conclusions

The strong dependency of the effective lifetime on the pre-intervention transmission level indicated that the required distribution frequency may vary more with the local entomological situation than with LLIN quality or the characteristics of the distribution system. This highlights the need for malaria monitoring both before and during intervention programmes, particularly since there are likely to be strong variations between years and over short distances. The majority of SSA's population falls into exposure categories where the lifetime is relatively long, but because exposure estimates are highly uncertain, it is necessary to consider subsequent interventions before the end of the expected effective lifetime based on an imprecise transmission measure.     

Biocontrol proteomics: development of an in situ interaction model and a protein extraction method for a proteomic study of the inhibiting mechanisms of Pichia anomala against Botrytis cinerea

The biocontrol by Pichia anomala strain Kh6 (Hansen) Kurtzman (Saccharomycetales: Endomycetaceae) has been extensively studied using microbial, biochemical and molecular approaches. However, due to the complexity of the interaction process, the inhibition mechanism remains uncharacterized. An objective study based on proteomic techniques could allow to increase our knowledge. Studying modes of action requires conditions as close as possible to natural infection in order to take into account interactions between organisms implicating a more complex protein extraction procedure. In the present study, we developed an in situ model allowing the interaction between apple, antagonist and pathogen and maintaining the antagonist inhibitory effect while limiting the contaminations by the apple components. Moreover, we set up an extraction protocol compatible with our in situ conditions and suitable for 2D analysis. Nine protocols, which differed in cell lysis or protein precipitation procedures, were compared on the basis of the protein yield, 1D gel quality and 2D gel quality.     

Intestinal colonization by enteroaggregative Escherichia coli supports long-term bacteriophage replication in mice

Bacteriophages have been known to be present in the gut for many years, but studies of relationships between these viruses and their hosts in the intestine are still in their infancy. We isolated three bacteriophages specific for an enteroaggregative O104:H4 Escherichia coli (EAEC) strain responsible for diarrhoeal diseases in humans. We studied the replication of these bacteriophages in vitro and in vivo in a mouse model of gut colonization. Each bacteriophage was able to replicate in vitro in both aerobic and anaerobic conditions. Each bacteriophage individually reduced biofilms formed on plastic pegs and a cocktail of the three bacteriophages was found to be more efficient. The cocktail was also able to infect bacterial aggregates formed on the surface of epithelial cells. In the mouse intestine, bacteriophages replicated for at least 3 weeks, provided the host was present, with no change in host levels in the faeces. This model of stable and continuous viral replication provides opportunities for studying the long-term coevolution of virulent bacteriophages with their hosts within a mammalian polymicrobial ecosystem.     

First detection, isolation and molecular characterization of infectious salmon anaemia virus associated with clinical disease in farmed Atlantic salmon (Salmo salar) in Chile

Background  

Several forms of progressive retinal atrophy (PRA) segregate in more than 100 breeds of dog with each PRA segregating in one or a few breeds. This breed specificity may be accounted for by founder effects and genetic drift, which have reduced the genetic heterogeneity of each breed, thereby facilitating the identification of causal mutations. We report here a new form of PRA segregating in the Border Collie breed. The clinical signs, including the loss of night vision and a progressive loss of day vision, resulting in complete blindness, occur at the age of three to four years and may be detected earlier through systematic ocular fundus examination and electroretinography (ERG).     

Wine biotechnology in South Africa: towards a systems approach to wine science

The wine industry in South Africa is over three centuries old and over the last decade has reemerged as a significant competitor in world wine markets. The Institute for Wine Biotechnology (IWBT) was established in partnership with the Department of Viticulture and Oenology at Stellenbosch University to foster basic fundamental research in the wine sciences leading to applications in the broader wine and grapevine industries. This review focuses on the different research programmes of the Institute (grapevine, yeast and bacteria biotechnology programmes, and chemical-analytical research), commercialisation activities (SunBio) and new initiatives to integrate the various research disciplines. An important focus of future research is the Wine Science Research Niche Area programme, which connects the different research thrusts of the IWBT and of several research partners in viticulture, oenology, food science and chemistry. This 'Functional Wine-omics' programme uses a systems biology approach to wine-related organisms. The data generated within the programme will be integrated with other data sets from viticulture, oenology, analytical chemistry and the sensory sciences through chemometrics and other statistical tools. The aim of the programme is to model aspects of the wine making process, from the vineyard to the finished product.     

Altered Dopamine Receptor and Dopamine Transporter Binding and Tyrosine Hydroxylase mRNA Expression Following Perinatal NMDA Receptor Blockade

This study examined how perinatal phencyclidine (PCP) treatment would affect dopamine D2 receptor and dopamine transporter (DAT) binding at different stages after treatment cessation. Female rat pups received injections of PCP (10 mg/kg, s.c.) or saline on postnatal day (PN)7, 9 and 11. D2 receptor and transporter binding was examined at four time-points (PN12, 18, 32 and 96) following injections. PCP treatment altered D2 receptor binding throughout development, with a final end-point of 22-33% decreased binding at adulthood in the nucleus accumbens and caudate putamen (P < 0.01), accompanied by a small but significant increase in DAT binding in the caudate putamen. Tyrosine hydroxylase mRNA expression was also significantly increased by 25% (P < 0.05) in the ventral tegmental area of adult rats, suggesting that this model may produce a long-term increase in dopamine output. This study demonstrates that early insult to the brain from NMDA receptor hypofunction alters the dopaminergic system at different stages of development.     

Autoantibodies in cryptogenic fibrosing alveolitis

The pathogenesis of cryptogenic fibrosing alveolitis (CFA) involves injury, an immune/inflammatory response and fibrosis. The cause of the injury is unknown, but the identification of serum autoantibodies makes an autoimmune aetiology attractive. The core study on which this commentary is based used novel cloning and serum screening technologies in order to identify new public and private autoantibodies in sera from 12 patients with CFA. Largely negative conclusions were drawn from that study. However, we suggest that the prevalence of autoantibodies may have been underestimated, that the study was timely and that this approach is worth pursuing further.