The growing utility of microbial genome sequences (Meeting Report)

© 2000 GenomeBiology.comA report from the Genome Biology session of the 4th annual conference on microbial genomes, Virginia, February 12-15, 2000

Magnetic resonance imaging protocols for paediatric neuroradiology

Increasingly, radiologists are encouraged to have protocols for all imaging studies and to include imaging guidelines in care pathways set up by the referring clinicians. This is particularly advantageous in MRI where magnet time is limited and a radiologist’s review of each patient’s images often results in additional sequences and longer scanning times without the advantage of improvement in diagnostic ability. The difficulties of imaging small children and the challenges presented to the radiologist as the brain develops are discussed. We present our protocols for imaging the brain and spine of children based on 20 years experience of paediatric neurological MRI. The protocols are adapted to suit children under the age of 2 years, small body parts and paediatric clinical scenarios

Spatial distribution of podoconiosis in relation to environmental factors in Ethiopia: a historical review

BACKGROUND An up-to-date and reliable map of podoconiosis is needed to design geographically targeted and cost-effective intervention in Ethiopia. Identifying the ecological correlates of the distribution of podoconiosis is the first step for distribution and risk maps. The objective of this study was to investigate the spatial distribution and ecological correlates of podoconiosis using historical and contemporary survey data. METHODS Data on the observed prevalence of podoconiosis were abstracted from published and unpublished literature into a standardized database, according to strict inclusion and exclusion criteria. In total, 10 studies conducted between 1969 and 2012 were included, and data were available for 401,674 individuals older than 15 years of age from 229 locations. A range of high resolution environmental factors were investigated to determine their association with podoconiosis prevalence, using logistic regression. RESULTS The prevalence of podoconiosis in Ethiopia was estimated at 3.4% (95% CI 3.3%-3.4%) with marked regional variation. We identified significant associations between mean annual Land Surface Temperature (LST), mean annual precipitation, topography of the land and fine soil texture and high prevalence of podoconiosis. The derived maps indicate both widespread occurrence of podoconiosis and a marked variability in prevalence of podoconiosis, with prevalence typically highest at altitudes >1500 m above sea level (masl), with >1500 mm annual rainfall and mean annual LST of 19-21°C. No (or very little) podoconiosis occurred at altitudes 24°C. CONCLUSION Podoconiosis remains a public health problem in Ethiopia over considerable areas of the country, but exhibits marked geographical variation associated in part with key environmental factors. This is work in progress and the results presented here will be refined in future work

Long term time variability of cosmic rays and possible relevance to the development of life on Earth

An analysis is made of the manner in which the cosmic ray intensity at Earth has varied over its existence and its possible relevance to both the origin and the evolution of life. Much of the analysis relates to the 'high energy' cosmic rays ($E>10^{14}eV;=0.1PeV$) and their variability due to the changing proximity of the solar system to supernova remnants which are generally believed to be responsible for most cosmic rays up to PeV energies. It is pointed out that, on a statistical basis, there will have been considerable variations in the likely 100 My between the Earth's biosphere reaching reasonable stability and the onset of very elementary life. Interestingly, there is the increasingly strong possibility that PeV cosmic rays are responsible for the initiation of terrestrial lightning strokes and the possibility arises of considerable increases in the frequency of lightnings and thereby the formation of some of the complex molecules which are the 'building blocks of life'. Attention is also given to the well known generation of the oxides of nitrogen by lightning strokes which are poisonous to animal life but helpful to plant growth; here, too, the violent swings of cosmic ray intensities may have had relevance to evolutionary changes. A particular variant of the cosmic ray acceleration model, put forward by us, predicts an increase in lightning rate in the past and this has been sought in Korean historical records. Finally, the time dependence of the overall cosmic ray intensity, which manifests itself mainly at sub-10 GeV energies, has been examined. The relevance of cosmic rays to the 'global electrical circuit' points to the importance of this concept.Comment: 18 pages, 5 figures, accepted by 'Surveys in Geophysics

Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival.

BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). DESIGN, SETTING, AND PARTICIPANTS: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. RESULTS AND LIMITATIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16) than noncarriers. CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. PATIENT SUMMARY: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa

Multi-centre reproducibility of diffusion MRI parameters for clinical sequences in the brain.

The purpose of this work was to assess the reproducibility of diffusion imaging, and in particular the apparent diffusion coefficient (ADC), intra-voxel incoherent motion (IVIM) parameters and diffusion tensor imaging (DTI) parameters, across multiple centres using clinically available protocols with limited harmonization between sequences. An ice-water phantom and nine healthy volunteers were scanned across fives centres on eight scanners (four Siemens 1.5T, four Philips 3T). The mean ADC, IVIM parameters (diffusion coefficient D and perfusion fraction f) and DTI parameters (mean diffusivity MD and fractional anisotropy FA), were measured in grey matter, white matter and specific brain sub-regions. A mixed effect model was used to measure the intra- and inter-scanner coefficient of variation (CV) for each of the five parameters. ADC, D, MD and FA had a good intra- and inter-scanner reproducibility in both grey and white matter, with a CV ranging between 1% and 7.4%; mean 2.6%. Other brain regions also showed high levels of reproducibility except for small structures such as the choroid plexus. The IVIM parameter f had a higher intra-scanner CV of 8.4% and inter-scanner CV of 24.8%. No major difference in the inter-scanner CV for ADC, D, MD and FA was observed when analysing the 1.5T and 3T scanners separately. ADC, D, MD and FA all showed good intra-scanner reproducibility, with the inter-scanner reproducibility being comparable or faring slightly worse, suggesting that using data from multiple scanners does not have an adverse effect compared with using data from the same scanner. The IVIM parameter f had a poorer inter-scanner CV when scanners of different field strengths were combined, and the parameter was also affected by the scan acquisition resolution. This study shows that the majority of diffusion MRI derived parameters are robust across 1.5T and 3T scanners and suitable for use in multi-centre clinical studies and trials

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

In order to elucidate the relative importance of oestrogen receptor (ER)α, ERβ and an ERβ variant (ERβ2/βcx) in the response of breast cancers to tamoxifen, tumour levels of each receptor were assessed in 36 patients before and after 3 months of neoadjuvant treatment with tamoxifen (20 mg daily). All patients were postmenopausal women presenting with large ERα-positive breast cancers. Clinical response to treatment was assessed by tumour volume changes as determined from sequential ultrasounds and pathological response by comparison of the tumour morphology before and after treatment. Of 33 cases, 23 (70%) were classified as having a clinical response and 16 (48%) as having a response pathologically. All tumours stained positively for ERα and ERβ and 15 out of 33 (45%) for ERβ2/βcx. There were no significant differences in quantitative expression of any receptor between tumours that subsequently responded and that did not, whether response was assessed clinically or pathologically. Tamoxifen treatment was associated with a decrease in ERα, but an increase was the most frequent change (17 out of 33) in ERβ, and no consistent change was evident in staining of the ERβ2/βcx variant. In summary, ERβ1 and ERβ2/βcx variant protein are detected in ERα-positive breast tumours but their expression is not associated with a response to tamoxifen. Differential changes in ERα and ERβ were seen with treatment

Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host

Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and “synthetic” SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV