Non-amyloid, ubiquitinated cytoplasmic inclusions containing TDP-43 and its C-terminal fragments are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Importantly, TDP-43 mutations are linked to sporadic and non-SOD1 familial ALS. However, TDP-43 is not the only protein in disease-associated inclusions, and whether TDP-43 misfolds or is merely sequestered by other aggregated components is unclear. Here, we report that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP-43 deposits in degenerating neurons of ALS FTLD-U patients. The C-terminal domain of TDP-43 is critical for spontaneous aggregation. Several ALS-linked TDP-43 mutations within this domain (Q331K, M337V, Q343R, N345K, R361S, and N390D) increase the number of TDP-43 aggregates and promote toxicity in vivo. Importantly, mutations that promote toxicity in vivo accelerate aggregation of pure TDP-43 in vitro. Thus, TDP-43 is intrinsically aggregation-prone, and its propensity for toxic misfolding trajectories is accentuated by specific ALS-linked mutations.TDP-43 is a ubiquitously expressed and highly conserved metazoan nuclear protein (1), which contains two RNA recognition motifs (RRMs) 3 and a glycine-rich region in its C-terminal domain (see Fig. 1A). TDP-43 function is uncertain, but it likely plays important roles in pre-mRNA splicing and transcriptional repression (2, 3). In ALS and FTLD-U, TDP-43 is depleted from the nucleus and accumulates in ubiquitinated cytoplasmic inclusions (4). These and other situations of TDP-43 pathology, including some forms of Alzheimer and Parkinson diseases, are now known as TDP-43 proteinopathies (5). Importantly, mutations in the TDP-43 gene (TARDBP) are linked to sporadic and non-SOD1 familial ALS, implying that TDP-43 abnormalities are likely one cause of disease (6 -11). However, despite this synthesis of pathology and genetics, the mechanisms by which TDP-43 might contribute to disease remain unknown and controversial (12, 13).A key unresolved question is whether TDP-43 is inherently aggregation-prone or whether TDP-43 is sequestered by other aggregated components and is merely a marker of disease (13-16). Indeed, multiple proteins aside from TDP-43 are found in Sarkosyl-insoluble fractions from FTLD-U patients (14). Moreover, deconvolution imaging reveals that TDP-43 appears to be excluded from some regions of the ubiquitinated inclusions in ALS (15).Here, we assess TDP-43 aggregation in the absence of other components. We then define which domains of TDP-43 are important for this process and determine the direct effects of several ALS-linked TDP-43 mutations on TDP-43 misfolding and toxicity. Our findings bring to light several intrinsic properties of TDP-43 and ALS-linked TDP-43 mutants that likely play important roles in the aberrant TDP-43 proteostasis (17) that contributes to the pathogenesis of ALS,...

On page 20329 in the Abstract, the sentence beginning on line 10 should read as follows: "Here, we report that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP-43 deposits in degenerating neurons of ALS and FTLD-U patients." VOLUME 281 (2006) The following "Acknowledgment" was inadvertently omitted from the manuscript: "We thank Dr. Muniswamy Madesh for critical reading of the manuscript." VOLUME 281 ( ADDITIONS AND CORRECTIONS This paper is available online at www.jbc.orgWe suggest that subscribers photocopy these corrections and insert the photocopies in the original publication at the location of the original article. Authors are urged to introduce these corrections into any reprints they distribute. Secondary (abstract) services are urged to carry notice of these corrections as prominently as they carried the original abstracts.

Telemedicine is slowly transforming the way in which healthcare is delivered and has the potential to improve access to subspecialty expertise, reduce healthcare costs, and improve the overall quality of care. While many subspecialty fields within medicine today have either experimented with or begun to implement telemedicine platforms to enable remote consultation and care, dermatology is particularly suited for this care system as skin disorders are uniquely visible to the human eye. Through teledermatology, diagnostic images of skin disorders with accompanying clinical histories can be remotely reviewed by teledermatologists by any number of modalities, such as photographic clinical images or live video teleconferencing. Diagnoses and treatment recommendations can then be rendered and implemented remotely. The evidence to date supports both its diagnostic and treatment accuracy and its cost effectiveness. Administrative, regulatory, privacy, and reimbursement policies surrounding this dynamic field continue to evolve. In this review, we examine the history, evidence, and administrative landscape surrounding teledermatology and discuss current practice guidelines and ongoing controversies.

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Children in sub-Saharan Africa continue to acquire and die from cerebral malaria, despite efforts to control or eliminate the causative agent, Plasmodium falciparum. We present a quantitative histopathological assessment of the sequestration of parasitized erythrocytes in multiple organs obtained during a prospective series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi, on pediatric patients who died from cerebral malaria and controls. After the brain, sequestration of parasites was most intense in the gastrointestinal tract, both in patients with cerebral malaria and those with parasitemia in other organs. Within cases of histologically defined cerebral malaria, which includes phenotypes termed "sequestration only" (CM1) and "sequestration with extravascular pathology" (CM2), CM1 was associated with large parasite numbers in the spleen and CM2 with intense parasite sequestration in the skin. A striking histological finding overall was the marked sequestration of parasitized erythrocytes across most organs in patients with fatal cerebral malaria, supporting the hypothesis that the disease is, in part, a result of a high level of total-body parasite sequestration.

Background: The prognostic importance of left atrial (LA) dysfunction is increasingly recognized. Magnetic Resonance Imaging (MRI) can provide excellent visualization of the left atrial wall. We aimed to study the association of LA dysfunction measured using feature-tracking MRI with incident adverse cardiovascular events among subjects with or without HF at baseline. Methods and Results: We prospectively studied 640 adults without HF (n=419), HF with preserved ejection fraction (HFpEF, n=101), or HF with reduced ejection fraction (HFrEF, n=120). We measured phasic LA function by volumetric and feature-tracking methods to derive longitudinal strain. The composite outcome of incident heart failure hospitalization or death was adjudicated over a median follow-up of 37.1 months. Measures of LA phasic function were more prominently impaired in subjects with HFrEF, than among subjects with HFpEF. In unadjusted Cox proportional hazards models, all measures of phasic LA function and volumes (maximum, minimum and diastatic) were associated with the composite outcome. However, in analyses that adjusted for clinical risk factors, heart failure status, maximum LA volume, left ventricular (LV) mass and LV ejection fraction, measures of conduit and reservoir LA function, but not booster-pump function, were associated with the composite outcome. The strongest associations were observed for conduit longitudinal strain (Standardized Hazard ratio=0.66; 95%CI=0.49–0.88, P=0.004), conduit strain rate (Standardized HR=1.59; 95%CI=1.16–2.16, P=0.0035), and reservoir strain (Standardized HR=0.68; 95%CI=0.52–0.89, P=0.0055). Conclusions: Phasic LA function measured using MRI feature-tracking is independently predictive of the risk of incident HF admission or death, even after adjusting for LA volume and LV remodeling.

Chordoma is a low-grade notochordal tumor of the skull base, mobile spine and sacrum which behaves malignantly and confers a poor prognosis despite indolent growth patterns. These tumors often present late in the disease course, tend to encapsulate adjacent neurovascular anatomy, seed resection cavities, recur locally and respond poorly to radiotherapy and conventional chemotherapy, all of which make chordomas challenging to treat. Extent of surgical resection and adequacy of surgical margins are the most important prognostic factors and thus patients with chordoma should be cared for by a highly experienced, multi-disciplinary surgical team in a quaternary center. Ongoing research into the molecular pathophysiology of chordoma has led to the discovery of several pathways that may serve as potential targets for molecular therapy, including a multitude of receptor tyrosine kinases (e.g., platelet-derived growth factor receptor [PDGFR], epidermal growth factor receptor [EGFR]), downstream cascades (e.g., phosphoinositide 3-kinase [PI3K]/protein kinase B [Akt]/mechanistic target of rapamycin [mTOR]), brachyury—a transcription factor expressed ubiquitously in chordoma but not in other tissues—and the fibroblast growth factor [FGF]/mitogen-activated protein kinase kinase [MEK]/extracellular signal-regulated kinase [ERK] pathway. In this review article, the pathophysiology, diagnosis and modern treatment paradigms of chordoma will be discussed with an emphasis on the ongoing research and advances in the field that may lead to improved outcomes for patients with this challenging disease.

CKD is associated with increased (inactive) dp-ucMGP, a vitamin K-dependent inhibitor of vascular calcification, which correlates with large artery stiffness. Further studies are needed to assess whether vitamin K2 supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffening in CKD.