AIPvariant causing familial prolactinoma

Pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene are increasingly recognised as a cause of familial isolated pituitary adenoma. AIP-associated tumours are most commonly growth hormone (GH) producing. In our cohort of 175 AIP mutation positive patients representing 93 kindreds, 139 (79%) have GH excess, 19 have prolactinoma (17 familial and 2 sporadic cases) and out of the 17 clinically non-functioning tumours 4 were subsequently operated and found to be GH or GH & prolactin immunopositive adenoma. Here we report a family with an AIP variant, in which multiple family members are affected by prolactinoma, but none with GH excess. To our knowledge this is the first reported family with an AIP pathogenic variant to be affected solely by prolactinoma. These data suggest that prolactinoma families represent a small subset of AIP mutation positive kindreds, and similar to young-onset sporadic prolactinomas, AIP screening would be indicated

Postural assessment of patients with non-conventional knee endoprosthesis

Objective:To investigate the correlation between the sagittal and frontal alignment and possible postural asymmetries found in patients submitted to total knee stent placement for osteosarcoma.Methods:Twenty two individuals were divided into two groups according to tumor location: femur group (13 patients) and tibia group (nine patients), who were evaluated through postural analysis software (SAPO).Results:No statistically significant difference was found between groups, supporting previous result showing that both groups present the same postural asymmetries.Conclusion:We conclude that both groups have the same postural imbalances, especially the knee of the affected limb that presents hyperextension and center of gravity shifted anteriorly and laterally to the non-affected limb, indicating changes in weight bearing and influencing the gait pattern and balance. Level of Evidence II, Prospective Comparative Study.Universidade Federal de São Paulo (UNIFESP) Instituto de Oncologia PediátricaUNIFESP, Instituto de Oncologia PediátricaSciEL

O18O and C18O observations of rho Oph A

Observations of the (N_J=1_1-1_0) ground state transition of O_2 with the Odin satellite resulted in a about 5 sigma detection toward the dense core rho Oph A. At the frequency of the line, 119 GHz, the Odin telescope has a beam width of 10', larger than the size of the dense core, so that the precise nature of the emitting source and its exact location and extent are unknown. The current investigation is intended to remedy this. Telluric absorption makes ground based O_2 observations essentially impossible and observations had to be done from space. mm-wave telescopes on space platforms were necessarily small, which resulted in large, several arcminutes wide, beam patterns. Although the Earth's atmosphere is entirely opaque to low-lying O_2 transitions, it allows ground based observations of the much rarer O18O in favourable conditions and at much higher angular resolution with larger telescopes. In addition, rho Oph A exhibits both multiple radial velocity systems and considerable velocity gradients. Extensive mapping of the region in the proxy C18O (J=3-2) line can be expected to help identify the O_2 source on the basis of its line shape and Doppler velocity. Line opacities were determined from observations of optically thin 13C18O (J=3-2) at selected positions. During several observing periods, two C18O intensity maxima in rho Oph A were searched for in the 16O18O (2_1-0_1) line at 234 GHz with the 12m APEX telescope. Our observations resulted in an upper limit on the integrated O18O intensity of < 0.01 K km/s (3 sigma) into the 26.5" beam. We conclude that the source of observed O_2 emission is most likely confined to the central regions of the rho Oph A cloud. In this limited area, implied O_2 abundances could thus be higher than previously reported, by up to two orders of magnitude.Comment: 7 pages, 6 figures (5 colour), Astronomy & Astrophysic

Was Sinn Féin dying? A quantitative post-mortem of the party's decline and the emergence of Fianna Fáil

This article calls for a reappraisal of the consensus surrounding the split within Sinn Féin in 1926 that led to the foundation of Fianna Fáil. It demonstrates that quantitative factors cited to demonstrate Sinn Féin’s “terminal” decline – finances, cumann numbers, and election results – and to explain de Valera’s decision to leave Sinn Féin and establish a rival republican organisation, Fianna Fáil, do not provide sufficient objective grounds to explain the republican leader’s actions. This article demonstrates that Sinn Féin’s election results during the period in question (1923-1926) were encouraging and the decline in finances and cumann numbers can be explained by the fact that the base year used to compare progress was 1923, an election year. Moreover, this article compares the performance of Sinn Féin to the first five years of Fianna Fáil (1926-1931) to show that what has been interpreted as terminal decline can also be attributed to normal inter-election lulls in party activity. Correspondingly, subjective factors – e.g. personal rivalries, differences in ideology, organisational style and levels of patience in terms of achieving political power – were most likely the determining factors rather than organisational decline

Combination of indoor residual spraying with long-lasting insecticide-treated nets for malaria control in Zambezia, Mozambique: a cluster randomised trial and cost-effectiveness study protocol.

Background: Most of the reduction in malaria prevalence seen in Africa since 2000 has been attributed to vector control interventions. Yet increases in the distribution and intensity of insecticide resistance and higher costs of newer insecticides pose a challenge to sustaining these gains. Thus, endemic countries face challenging decisions regarding the choice of vector control interventions. Methods: A cluster randomised trial is being carried out in Mopeia District in the Zambezia Province of Mozambique, where malaria prevalence in children under 5 is high (68% in 2015), despite continuous and campaign distribution of long-lasting insecticide-treated nets (LLINs). Study arm 1 will continue to use the standard, LLIN-based National Malaria Control Programme vector control strategy (LLINs only), while study arm 2 will receive indoor residual spraying (IRS) once a year for 2 years with a microencapsulated formulation of pirimiphos-methyl (Actellic 300 CS), in addition to the standard LLIN strategy (LLINs+IRS). Prior to the 2016 IRS implementation (the first of two IRS campaigns in this study), 146 clusters were defined and stratified per number of households. Clusters were then randomised 1:1 into the two study arms. The public health impact and cost-effectiveness of IRS intervention will be evaluated over 2 years using multiple methods: (1) monthly active malaria case detection in a cohort of 1548 total children aged 6-59 months; (2) enhanced passive surveillance at health facilities and with community health workers; (3) annual cross-sectional surveys; and (4) entomological surveillance. Prospective microcosting of the intervention and provider and societal costs will be conducted. Insecticide resistance status pattern and changes in local Anopheline populations will be included as important supportive outcomes. Discussion: By evaluating the public health impact and cost-effectiveness of IRS with a non-pyrethroid insecticide in a high-transmission setting with high LLIN ownership, it is expected that this study will provide programmatic and policy-relevant data to guide national and global vector control strategies. Trial registration number: NCT02910934

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

&lt;p&gt;Background - Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.&lt;/p&gt; &lt;p&gt;Methods - We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.&lt;/p&gt; &lt;p&gt;Findings - We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p&#60;5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort.&lt;/p&gt; &lt;p&gt;Interpretation - Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.&lt;/p&gt

Proteomics as a quality control tool of pharmaceutical probiotic bacterial lysate products

Probiotic bacteria have a wide range of applications in veterinary and human therapeutics. Inactivated probiotics are complex samples and quality control (QC) should measure as many molecular features as possible. Capillary electrophoresis coupled to mass spectrometry (CE/MS) has been used as a multidimensional and high throughput method for the identification and validation of biomarkers of disease in complex biological samples such as biofluids. In this study we evaluate the suitability of CE/MS to measure the consistency of different lots of the probiotic formulation Pro-Symbioflor which is a bacterial lysate of heat-inactivated Escherichia coli and Enterococcus faecalis. Over 5000 peptides were detected by CE/MS in 5 different lots of the bacterial lysate and in a sample of culture medium. 71 to 75% of the total peptide content was identical in all lots. This percentage increased to 87–89% when allowing the absence of a peptide in one of the 5 samples. These results, based on over 2000 peptides, suggest high similarity of the 5 different lots. Sequence analysis identified peptides of both E. coli and E. faecalis and peptides originating from the culture medium, thus confirming the presence of the strains in the formulation. Ontology analysis suggested that the majority of the peptides identified for E. coli originated from the cell membrane or the fimbrium, while peptides identified for E. faecalis were enriched for peptides originating from the cytoplasm. The bacterial lysate peptides as a whole are recognised as highly conserved molecular patterns by the innate immune system as microbe associated molecular pattern (MAMP). Sequence analysis also identified the presence of soybean, yeast and casein protein fragments that are part of the formulation of the culture medium. In conclusion CE/MS seems an appropriate QC tool to analyze complex biological products such as inactivated probiotic formulations and allows determining the similarity between lots