We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

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In Alzheimer's disease (AD), neurofibrillary tangles spread from the entorhinal cortex to the limbic system, then to neocortical areas, according to the Braak's stages. Olfaction is impaired in early stages of AD. The aim of this study was to describe the pathology of the cortical olfactory centres in relation to Braak's stages determining the earliest site of pathology. We examined 15 control and 15 AD cases. The primary olfactory cortices were involved in more advanced Braak's stages, while olfactory bulbs were damaged in very early (i.e. Braak's stage 0 or 1) stages. These results are supporting the fact that olfaction might be an early marker in AD and argues against the hypothesis that AD pathology is spreading through the olfactory system.

Impaired olfaction, hyposmia or anosmia are part of the clinical phenotype in neurodegenerative disorders including Alzheimer's disease (AD). It has been proposed that the most severely affected areas are interconnected with the central olfactory system in contrast to the relative sparing of other sensory areas which lack olfactory connections. The pathology of the first synaptic relay in the olfactory pathway, the olfactory bulb (OB), has been studied in AD, but the results have been inconsistent. In order to define more fully the pathology of the OB, we analysed 15 AD and 15 control cases, using amyloid and tau immunohistochemistry on serial sections. This study demonstrates for the first time that all layers of the OB are severely affected in AD and in normal ageing. The principal effector cells of the OB, the mitral cells, developed neurofibrillary tangles (NFTs) both in AD and in controls. All the cases, with the exception of two of the controls, contained NFTs. Amyloid immunoreactivity was detected in diffuse, primitive, classical and compact deposits in AD, while five control cases contained mainly diffuse deposits. We did not find a correlation between amyloid deposition and NFT formation. Among the control cases, two contained neither amyloid nor NFTs, eight had NFTs but no amyloid and only five had both NFTs and amyloid. All the AD cases had NFT and amyloid deposition. Our data suggest that the earlier pathology in the OB is NFT formation and more than ten NFTs/section is compatible with 93.3% diagnostic accuracy for AD.

In early-stage breast cancer, the primary treatment option for most women is breast-conserving surgery (BCS). There is a clear need for more accurate techniques to assess resection margins intraoperatively, because on average 20% of patients require further surgery to achieve clear margins. Cerenkov luminescence imaging (CLI) combines optical and molecular imaging by detecting light emitted by 18 F-FDG. Its high-resolution and small size imaging equipment make CLI a promising technology for intraoperative margin assessment. A first-in-human study was conducted to evaluate the feasibility of 18 F-FDG CLI for intraoperative assessment of tumor margins in BCS. Methods: Twenty-two patients with invasive breast cancer received 18 F-FDG (5 MBq/kg) 45-60 min before surgery. Sentinel lymph node biopsy was performed using an increased 99m Tc-nanocolloid activity of 150 MBq to facilitate nodal detection against the g-probe background signal (cross-talk) from 18 F-FDG. The cross-talk and 99m Tc dose required was evaluated in 2 lead-in studies. Immediately after excision, specimens were imaged intraoperatively in an investigational CLI system. The first 10 patients were used to optimize the imaging protocol; the remaining 12 patients were included in the analysis dataset. Cerenkov luminescence images from incised BCS specimens were analyzed postoperatively by 2 surgeons blinded to the histopathology results, and mean radiance and margin distance were measured. The agreement between margin distance on CLI and histopathology was assessed. Radiation doses to staff were measured. Results: Ten of the 12 patients had an elevated tumor radiance on CLI. Mean radiance and tumor-to-background ratio were 560 6 160 photons/s/cm 2 /sr and 2.41 6 0.54, respectively. All 15 assessable margins were clear on CLI and histopathology. The agreement in margin distance and interrater agreement was good (k 5 0.81 and 0.912, respectively). Sentinel lymph nodes were successfully detected in all patients. The radiation dose to staff was low; surgeons received a mean dose of 34 6 15 mSv per procedure. Conclusion: Intraoperative 18 F-FDG CLI is a promising, low-risk technique for intraoperative assessment of tumor margins in BCS. A randomized controlled trial will evaluate the impact of this technique on reexcision rates. In early-stage breast cancer, the primary treatment option for most women is breast-conserving surgery (BCS) by wide local excision (WLE) of the tumor. WLE often fails to achieve clear surgical margins, and on average 20% of patients who undergo BCS will require repeated surgery to achieve clear margins (1) (although this may vary because there is no global agreement of the definition of clear margins). Reoperations potentially have several negative consequences including delayed commencement of adjuvant therapy, worse cosmesis, increased patient anxiety, and costs (2,3).There have been several attempts to assess surgical margins intraoperatively to reduce breast cancer reoperation rates after WLE (1). Techniques evaluated to date in...

PurposeIndications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion.MethodsThe panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology.ResultsConsensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference.ConclusionsIn case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.Electronic supplementary materialThe online version of this article (10.1007/s10549-018-4937-1) contains supplementary material, which is available to authorized users.

Using the emerging technique of peripheral nerve ultrasonography, multiple focal nerve swellings corresponding to sites of existing conduction blocks have been described in demyelinating polyneuropathies. We report two cases of multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). In the first, multiple focal nerve enlargements were detected by ultrasound at sites of previous conduction blocks, well after complete clinical and electrophysiological resolution. In the second case, existing proximal conduction blocks could be localized by ultrasound. Our cases highlight the importance of nerve ultrasound in identifying conduction blocks and demonstrate that ultrasonographic morphological changes may outlast functional recovery in demyelinating neuropathies.

In recent decades, imaging devices have become indispensable tools in the basic sciences, in preclinical research and in modern drug development. The rapidly evolving high-resolution in vivo imaging technologies provide a unique opportunity for studying biological processes of living organisms in real time on a molecular level. State of the art small-animal imaging modalities provide non-invasive images rich in quantitative anatomical and functional information, which renders longitudinal studies possible allowing precise monitoring of disease progression and response to therapy in models of different diseases. The number of animals in a scientific investigation can be substantially reduced using imaging techniques, which is in full compliance with the ethical endeavours for the 3R (reduction, refinement, replacement) policies formulated by Russell and Burch; furthermore, biological variability can be alleviated, as each animal serves as its own control. The most suitable and commonly used imaging modalities for in vivo small-animal imaging are optical imaging (OI), ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and finally the methods of nuclear medicine: positron emission tomography (PET) and single photon emission computed tomography (SPECT).