Synergism/complementarity of recombinant adenoviral vectors and other vaccination platforms during induction of protective immunity against malaria

The lack of immunogenicity of most malaria antigens and the complex immune responses required for achieving protective immunity against this infectious disease have traditionally hampered the development of an efficient human malaria vaccine. The current boom in development of recombinant viral vectors and their use in prime-boost protocols that result in enhanced immune outcomes have increased the number of malaria vaccine candidates that access pre-clinical and clinical trials. In the frontline, adenoviruses and poxviruses seem to be giving the best immunization results in experimental animals and their mutual combination, or their combination with recombinant proteins (formulated in adjuvants and given in sequence or being given as protein/virus admixtures), has been shown to reach unprecedented levels of anti-malaria immunity that predictably will be somehow reproduced in the human setting. However, all this optimism was previously seen in the malaria vaccine development field without many real applicable results to date. We describe here the current state-of-the-art in the field of recombinant adenovirus research for malaria vaccine development, in particular referring to their use in combination with other immunogens in heterologous prime-boost protocols, while trying to simultaneously show our contributions and point of view on this subject

Small fiber neuropathy: a disabling and underrecognized syndrome

Purpose of review To discuss cause, clinical manifestations, diagnostics, and treatment of small fiber neuropathy (SFN). The diagnosis is difficult and can be easily missed. Recent findings SFN causes high morbidity with disabling symptoms and impact on quality of life. Patients may benefit from being diagnosed with SFN, even if no underlying cause is identified and no specific treatment is yet available. Recently, genetic mutations as a possible cause of SFN were identified. Clinical diagnostic criteria have been proposed, but no gold standard exists, and each test has its limitations. The diagnosis requires a combination of typical symptoms, abnormal neurologic findings, and absence of large fiber involvement. Clinicians should be aware of overlapping symptoms of SFN and fibromyalgia. Treatment is often difficult, even when the underlying cause is identified and appropriately treated. Usually, only symptomatic relief of complaints is available. Summary Awareness of SFN and related symptoms is of great clinical relevance. Guidelines for appropriate diagnostic workup using a stepwise approach involving a combination of tests are warranted. Even if no treatment is available, patients may benefit from timely recognition of SF

Comparison of two instruments measuring carotid-femoral pulse wave velocity: Vicorder versus SphygmoCor

Background The carotid-femoral pulse wave velocity (PWVcf) is used as an indicator of arterial stiffness. It is often measured using applanation tonometry, for instance with the SphygmoCor. In young children, this method is difficult to perform. Therefore, techniques are needed that are less dependent on patient compliance. The Vicorder device uses the oscillometric technique to measure the PWVcf and is thought to be less time consuming and less dependent on operator skills. Objective To compare the PWVcf measured by an extensively used device (SphygmoCor) and the Vicorder in adults initially. Methods Thirty-eight healthy volunteers (20 men, mean age 48 +/- 13.1 years) participated in this cross-sectional study. The PWVcf was assessed twice using the SphygmoCor and the Vicorder by a single investigator during one visit. Intra-rater reproducibility of each instrument and comparison between the two instruments were assessed by the Bland-Altman method. Results The mean difference (95% confidence interval) between repeated measurements was 0.09 (-0.20 to 0.38) m/s and 0.24 (-0.55 to 1.03) m/s, for the SphygmoCor and Vicorder, respectively. The Limits of Agreement (LoA) were -1.53 to 1.71 m/s and -4.24 to 4.72 m/s, for the SphygmoCor and Vicorder, respectively. The mean PWVcf measured by the Vicorder was 0.58 (-0.20 to 1.35) m/s higher than the PWVcf measured by the SphygmoCor. The LoA between the two instruments were -3.50 to 4.66 m/s. Conclusion The LoA of both instruments exceed a value of 1.5 m/s. The LoA of the Vicorder PWVcf measurements are considered too wide for using this technique reliably in adults or in children. J Hypertens 28: 1687-1691 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkin

Erratum to: ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density

Albert Dahan, Ann Dunne, Maarten Swartjes, Paolo L Proto, Lara Heij, Oscar Vogels, Monique van Velzen, Elise Sarton, Marieke Niesters, Martijn R Tannemaat, Anthony Cerami, and Michael Brines. (2013) ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density. Mol. Med. 19:334–45

1399 H&E-stained sentinel lymph node sections of breast cancer patients : The CAMELYON dataset

Background: The presence of lymph node metastases is one of the most important factors in breast cancer prognosis. The most common way to assess regional lymph node status is the sentinel lymph node procedure. The sentinel lymph node is the most likely lymph node to contain metastasized cancer cells and is excised, histopathologically processed, and examined by a pathologist. This tedious examination process is time-consuming and can lead to small metastases being missed. However, recent advances in whole-slide imaging and machine learning have opened an avenue for analysis of digitized lymph node sections with computer algorithms. For example, convolutional neural networks, a type of machine-learning algorithm, can be used to automatically detect cancer metastases in lymph nodes with high accuracy. To train machine-learning models, large, well-curated datasets are needed. Results: We released a dataset of 1,399 annotated whole-slide images (WSIs) of lymph nodes, both with and without metastases, in 3 terabytes of data in the context of the CAMELYON16 and CAMELYON17 Grand Challenges. Slides were collected from five medical centers to cover a broad range of image appearance and staining variations. Each WSI has a slide-level label indicating whether it contains no metastases, macro-metastases, micro-metastases, or isolated tumor cells. Furthermore, for 209 WSIs, detailed hand-drawn contours for all metastases are provided. Last, open-source software tools to visualize and interact with the data have been made available. Conclusions: A unique dataset of annotated, whole-slide digital histopathology images has been provided with high potential for re-use

Biochemical Characterization of the Transcriptional Regulator BzdR from Azoarcus sp. CIB*

The BzdR transcriptional regulator that controls the PN promoter responsible for the anaerobic catabolism of benzoate in Azoarcus sp. CIB constitutes the prototype of a new subfamily of transcriptional regulators. Here, we provide some insights about the functional-structural relationships of the BzdR protein. Analytical ultracentrifugation studies revealed that BzdR is homodimeric in solution. An electron microscopy three-dimensional reconstruction of the BzdR dimer has been obtained, and the predicted structures of the respective N- and C-terminal domains of each BzdR monomer could be fitted into such a reconstruction. Gel retardation and ultracentrifugation experiments have shown that the binding of BzdR to its cognate promoter is cooperative. Different biochemical approaches revealed that the effector molecule benzoyl-CoA induces conformational changes in BzdR without affecting its oligomeric state. The BzdR-dependent inhibition of the PN promoter and its activation in the presence of benzoyl-CoA have been established by in vitro transcription assays. The monomeric BzdR4 and BzdR5 mutant regulators revealed that dimerization of BzdR is essential for DNA binding. Remarkably, a BzdRΔL protein lacking the linker region connecting the N- and C-terminal domains of BzdR is also dimeric and behaves as a super-repressor of the PN promoter. These data suggest that the linker region of BzdR is not essential for protein dimerization, but rather it is required to transfer the conformational changes induced by the benzoyl-CoA to the DNA binding domain leading to the release of the repressor. A model of action of the BzdR regulator has been proposed