Nail-patella-like renal disease masquerading as Fabry disease on kidney biopsy: a case report

BACKGROUND: Genetic changes in the LIM homeobox transcription factor 1 beta (LMX1B) have been associated with focal segmental glomerulosclerosis (FSGS) without the extra-renal or ultrastructural manifestations of Nail-patella syndrome (NPS) known as Nail-patella-like renal disease (NPLRD). Fabry disease (FD) is an X-linked lysosomal disease caused by the deficiency of alpha-galactosidase A. The classic form of the disease is characterized by acroparesthesia, angiokeratomas, cornea verticillata, hypertrophic cardiomyopathy, strokes, and chronic kidney disease. Podocyte myelin bodies on ultrastructural examination of kidney tissue are very characteristic of FD; however some medications and other conditions may mimic this finding. CASE PRESENTATION: Here, we report on a female patient with chronic kidney disease (CKD), positive family history for kidney disease and kidney biopsy showing a FSGS lesion and presence of focal myelin figures within podocytes concerning for FD. However, genetic testing for FD was negative. After comprehensive clinical, biochemical, and genetic evaluation, including whole exome and RNA sequencing, she was ultimately diagnosed with NPLRD. CONCLUSIONS: This case illustrates the difficulties of diagnosing atypical forms of rare Mendelian kidney diseases and the role of a multidisciplinary team in an individualized medicine clinic setting in combination with state-of-the-art sequencing technologies to reach a definitive diagnosis

Similar neural pathways link psychological stress and brain-age in health and multiple sclerosis

Clinical and neuroscientific studies suggest a link between psychological stress and reduced brain health in health and neurological disease but it is unclear whether mediating pathways are similar. Consequently, we applied an arterial-spin-labeling MRI stress task in 42 healthy persons and 56 with multiple sclerosis, and investigated regional neural stress responses, associations between functional connectivity of stress-responsive regions and the brain-age prediction error, a highly sensitive machine learning brain health biomarker, and regional brain-age constituents in both groups. Stress responsivity did not differ between groups. Although elevated brain-age prediction errors indicated worse brain health in patients, anterior insula–occipital cortex (healthy persons: occipital pole; patients: fusiform gyrus) functional connectivity correlated with brain-age prediction errors in both groups. Finally, also gray matter contributed similarly to regional brain-age across groups. These findings might suggest a common stress–brain health pathway whose impact is amplified in multiple sclerosis by disease-specific vulnerability factors

Understanding the chronology and occupation dynamics of oversized pit houses in the southern Brazilian highlands

A long held view about the occupation of southern proto-Je pit house villages of the southern Brazilian highlands is that these sites represent cycles of long-term abandonment and reoccupation. However, this assumption is based on an insufficient number of radiocarbon dates for individual pit houses. To address this problem, we conducted a programme of comprehensive AMS radiocarbon dating and Bayesian modelling at the deeply stratified oversized pit Houe 1, Baggio 1 site (Cal. A.D. 1395-1650), Campo Belo do Sul, Santa Catarina, Brazil. The straigraphy of House 1 revealed an unparalleled sequence of twelve well preserved floors evidencing a major change in occupation dynamics including five completely burnt collapsed roofs. The results of the radiocarbon dating allowed us to understand for the first time the occupation dynamics of an oversized pit house in the southern Brazilian highlands. The Bayesian model demonstrates that House 1 was occupied for over two centuries with no evidence of major periods of abandonment, calling into question previous models of long-term abandonment. In addition, the House 1 sequence allowed us to tie transformations in ceramic style and lithic technology to an absolute chronology. Finally, we can provide new evidence that the emergence of oversized domestic structures is a relatively recent phenomenon among the southern proto-Je. As monumental pit houses start to be bulit, small pit houses continue to be inhabited, evidencing emerging disparities in domestic architecture after AD 1000. Our research shows the importance of programmes of intensive dating of individual structures to understand occupation dynamcis and site permanence, and challenges long held assumptions that the southern Brazilian highlands were home to marginal cultures in the context of lowland South America

Constraining New Physics with a Positive or Negative Signal of Neutrino-less Double Beta Decay

We investigate numerically how accurately one could constrain the strengths of different short-range contributions to neutrino-less double beta decay in effective field theory. Depending on the outcome of near-future experiments yielding information on the neutrino masses, the corresponding bounds or estimates can be stronger or weaker. A particularly interesting case, resulting in strong bounds, would be a positive signal of neutrino-less double beta decay that is consistent with complementary information from neutrino oscillation experiments, kinematical determinations of the neutrino mass, and measurements of the sum of light neutrino masses from cosmological observations. The keys to more robust bounds are improvements of the knowledge of the nuclear physics involved and a better experimental accuracy.Comment: 23 pages, 3 figures. Minor changes. Matches version published in JHE

Focal adhesion kinase contributes to proliferative potential of ErbB2 mammary tumour cells but is dispensable for ErbB2 mammary tumour induction in vivo

INTRODUCTION: Activation of focal adhesion kinase (FAK) is hypothesized to play an important role in the pathogenesis of human breast cancer. METHODS: To directly evaluate the role of FAK in mammary tumour progression, we have used a conditional FAK mouse model and mouse mammary tumour virus (MMTV)-driven Cre recombinase strain to inactivate FAK in the mammary epithelium of a transgenic mouse model of ErbB2 breast cancer. RESULTS: Although mammary epithelial disruption of FAK in this model resulted in both a delay in onset and a decrease in the number of neoplastic lesions, mammary tumours occurred in 100% of virgin female mice. All of the tumours and derived metastases that developed were proficient for FAK due to the absence of Cre recombinase expression. The hyperplastic epithelia where Cre-mediated recombination of FAK could be detected exhibited a profound proliferative defect. Consistent with these observations, disruption of FAK in established tumour cells resulted in reduced tumour growth that was associated with impaired proliferation. To avoid the selection for FAK-proficient ErbB2 tumour epithelia through escape of Cre-mediated recombination, we next intercrossed the FAK conditional mice with a separate MMTV-driven ErbB2 strain that co-expressed ErbB2 and Cre recombinase on the same transcriptional unit. CONCLUSIONS: While a delay in tumour induction was noted, FAK-deficient tumours arose in 100% of female animals indicating that FAK is dispensable for ErbB2 tumour initiation. In addition, the FAK-null ErbB2 tumours retained their metastatic potential. We further demonstrated that the FAK-related Pyk2 kinase is still expressed in these tumours and is associated with its downstream regulator p130Cas. These observations indicate that Pyk2 can functionally substitute for FAK in ErbB2 mammary tumour progression

Cardiometabolic dysregulation and cognitive decline: potential role of depressive symptoms

INTRODUCTION: BACKGROUND: Previous studies have examined associations of cardiometabolic factors with depression and cognition separately. AIMS: To determine if depressive symptoms mediate the association between cardiometabolic factors and cognitive decline in two community studies. METHOD: Data for the analyses were drawn from the Rotterdam Study, the Netherlands (n = 2940) and the Whitehall II study, UK (n = 4469). RESULTS: Mediation analyses suggested a direct association between cardiometabolic factors and cognitive decline and an indirect association through depression: poorer cardiometabolic status at time 1 was associated with a higher level of depressive symptoms at time 2 (standardised regression coefficient 0.07 and 0.06, respectively), which, in turn, was associated with greater cognitive decline between time 2 and time 3 (standardised regression coefficient of −0.15 and −0.41, respectively). CONCLUSIONS: Evidence from two independent cohort studies suggest an association between cardiometabolic dysregulation and cognitive decline and that depressive symptoms tend to precede this declin

Lessons Learned from Creating a Mobile Version of an Educational Board Game to Increase Situational Awareness

This paper reports on an iterative design process for a serious game, which aims to raise situational awareness among different stakeholders in a logistics value chain by introducing multi-user role-playing games. It does so in several phases: After introducing the field of logistics as a problem domain for an educational challenge, it firstly describes the design of an educational board game for the field of disruption handling in logistics processes. Secondly, it de-scribes how the board game can be realized in an open-source mobile serious games platform and identifies lessons learned based on advantages and issues found. Thirdly, it derives requirements for a re-design of the mobile game and finally draws conclusions.SALOM

Effectively incorporating selected multimedia content into medical publications

Until fairly recently, medical publications have been handicapped by being restricted to non-electronic formats, effectively preventing the dissemination of complex audiovisual and three-dimensional data. However, authors and readers could significantly profit from advances in electronic publishing that permit the inclusion of multimedia content directly into an article. For the first time, the de facto gold standard for scientific publishing, the portable document format (PDF), is used here as a platform to embed a video and an audio sequence of patient data into a publication. Fully interactive three-dimensional models of a face and a schematic representation of a human brain are also part of this publication. We discuss the potential of this approach and its impact on the communication of scientific medical data, particularly with regard to electronic and open access publications. Finally, we emphasise how medical teaching can benefit from this new tool and comment on the future of medical publishing

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al