Automated Detection and Segmentation of Brain Metastases in Malignant Melanoma: Evaluation of a Dedicated Deep Learning Model.

BACKGROUND AND PURPOSE: Malignant melanoma is an aggressive skin cancer in which brain metastases are common. Our aim was to establish and evaluate a deep learning model for fully automated detection and segmentation of brain metastases in patients with malignant melanoma using clinical routine MR imaging. MATERIALS AND METHODS: Sixty-nine patients with melanoma with a total of 135 brain metastases at initial diagnosis and available multiparametric MR imaging datasets (T1-/T2-weighted, T1-weighted gadolinium contrast-enhanced, FLAIR) were included. A previously established deep learning model architecture (3D convolutional neural network; DeepMedic) simultaneously operating on the aforementioned MR images was trained on a cohort of 55 patients with 103 metastases using 5-fold cross-validation. The efficacy of the deep learning model was evaluated using an independent test set consisting of 14 patients with 32 metastases. Manual segmentations of metastases in a voxelwise manner (T1-weighted gadolinium contrast-enhanced imaging) performed by 2 radiologists in consensus served as the ground truth. RESULTS: After training, the deep learning model detected 28 of 32 brain metastases (mean volume, 1.0 [SD, 2.4] cm3) in the test cohort correctly (sensitivity of 88%), while false-positive findings of 0.71 per scan were observed. Compared with the ground truth, automated segmentations achieved a median Dice similarity coefficient of 0.75. CONCLUSIONS: Deep learning-based automated detection and segmentation of brain metastases in malignant melanoma yields high detection and segmentation accuracy with false-positive findings of <1 per scan.

In vitro antimicrobial and antimycobacterial activity and HPLC-DAD screening of phenolics from Chenopodium ambrosioides L

Abstract The main objective of this study was to demonstrate the antimicrobial potential of the crude extract and fractions of Chenopodium ambrosioides L., popularly known as Santa-Maria herb, against microorganisms of clinical interest by the microdilution technique, and also to show the chromatographic profile of the phenolic compounds in the species. The Phytochemical screening revealed the presence of cardiotonic, anthraquinone, alkaloids, tannins and flavonoids. The analysis by HPLC-DAD revealed the presence of rutin in the crude extract (12.5 ± 0.20 mg/g), ethyl acetate (16.5 ± 0.37 mg/g) and n-butanol (8.85 ± 0.11 mg/g), whereas quercetin and chrysin were quantified in chloroform fraction (1.95 ± 0.04 and 1.04 ± 0.01 mg/g), respectively. The most promising results were obtained with the ethyl acetate fraction, which inhibited a greater number of microorganisms and presented the lowest values of MIC against Staphylococcus aureus and Enterococcus faecalis (MIC = 0.42 mg/mL), Pseudomonas aeruginosa (MIC = 34.37 mg/mL), Paenibacillus apiarus (MIC = 4.29 mg/mL) and Paenibacillus thiaminolyticus (MIC = 4.29 mg/mL). Considering mycobacterial inhibition, the best results were obtained by chloroform fraction against M. tuberculosis, M. smegmatis, and M. avium (MIC ranging from 156.25 to 625 µg/mL). This study proves, in part, that the popular use of C. ambrosioides L. can be an effective and sustainable alternative for the prevention and treatment of diseases caused by various infectious agents.

In vitro antimicrobial and antimycobacterial activity and HPLC-DAD screening of phenolics from Chenopodium ambrosioides L.

The main objective of this study was to demonstrate the antimicrobial potential of the crude extract and fractions of Chenopodium ambrosioides L., popularly known as Santa-Maria herb, against microorganisms of clinical interest by the microdilution technique, and also to show the chromatographic profile of the phenolic compounds in the species. The Phytochemical screening revealed the presence of cardiotonic, anthraquinone, alkaloids, tannins and flavonoids. The analysis by HPLC-DAD revealed the presence of rutin in the crude extract (12.5±0.20mg/g), ethyl acetate (16.5±0.37mg/g) and n-butanol (8.85±0.11mg/g), whereas quercetin and chrysin were quantified in chloroform fraction (1.95±0.04 and 1.04±0.01mg/g), respectively. The most promising results were obtained with the ethyl acetate fraction, which inhibited a greater number of microorganisms and presented the lowest values of MIC against Staphylococcus aureus and Enterococcus faecalis (MIC=0.42mg/mL), Pseudomonas aeruginosa (MIC=34.37mg/mL), Paenibacillus apiarus (MIC=4.29mg/mL) and Paenibacillus thiaminolyticus (MIC=4.29mg/mL). Considering mycobacterial inhibition, the best results were obtained by chloroform fraction against M. tuberculosis, M. smegmatis, and M. avium (MIC ranging from 156.25 to 625µg/mL). This study proves, in part, that the popular use of C. ambrosioides L. can be an effective and sustainable alternative for the prevention and treatment of diseases caused by various infectious agents.

In vitro growth-inhibitory effect of Brazilian plants extracts against Paenibacillus larvae and toxicity in bees.

American foulbrood (AFB) is a serious worldwide spreading disease in bees caused by Paenibacillus larvae. Plants extracts are known to decrease or inhibit the growth of these bacteria. The purpose of this study was to evaluate the antimicrobial activity of Calendula. officinalis, Cariniana domestica, and Nasturtium officinale extracts against the P. larvae and to evaluate the toxicity of the extracts in bees. In vitro activity against P. larvae of the extracts was evaluated by micro dilution method and the minimal inhibitory concentrations (MICs) were also determined. The concentrations used in the toxicity test were established based on the MIC values and by the spraying application method. The P. larvae was susceptible to the evaluated crude extract of C. officinalis and N. officinale. To C. domestica, only the ethyl acetate (EtAc) fraction and n-butanol (BuOH) fractions had activity against P. larvae. Toxicity analysis in bees showed no toxicity for N. officinale crude extract and for C. domestica BuOH fraction during 15 days of treatment, however, some deaths of bees occurred during the first three days of treatment with C. officinalis and C. domestica EtAc fraction. The results with these species were firstly described and showed that N. officinale crude extract and C. domestica BuOH fraction both presented not toxic effects in the concentration tested by the spraying application method, and can be a useful alternative for treatment or prevention of AFB.

Scutia buxifolia Reissek essential oil: in vitro antioxidant and antimicrobial activities.

The volatile oil from the stem bark of Scutia buxifolia (Rhamnaceae) has been obtained by hydrodistillation and analyzed by GC-MS. Twenty-one components were identified representing 99.93 % of the total oil composition, spathulenol (35.87%), ß-cubebene (17.26%), germacrene D (6.43%), linalool (5.19%), carvacrol (4.05%) were the main components of S. buxifolia essential oil. Antioxidant and antimicrobial properties of the essential oil were evaluated by free radical scavenging (DPPH) assay and micro broth dilution method, respectively. S. buxifolia essential oil presented interesting radical scavenging activity (IC50 = 15.03 ± 0.11 µg/mL). The antibacterial assay showed that S. buxifolia stem bark essential oil was moderately active against the Staphylococcus aureus and Micrococcus sp. (MIC = 500 µg/mL) and Escherichia coli (250 µg/mL). To the best of our knowledge, this is the first study on the composition, antioxidant and antimicrobial activities of essential oil from the S. buxifolia collected from Brazil.

Phytochemical analysis and antioxidant capacity of Tabernaemontana catharinensis A. DC. Fruits and branches.

The antioxidant capacity of the crude extract and fractions of Tabernaemontana catharinensis fruits and branches, was evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and the content of polyphenols, flavonoids, alkaloids and condensed tannins were determined by the spectrophotometric method. The ethyl acetate fraction of the fruits and the n-butanol fraction of the branches showed IC50 of 181.82 µg/mL and 78.19 µg/mL, respectively. All fractions were analyzed by high performance liquid chromatography (HPLC), in the branches were quantified chlorogenic acid in the chloroform (8.96 mg/g), ethyl acetate (4.31 mg/g) and n-butanol (3.33 mg/g) fractions; caffeic acid in the ethyl acetate (5.24 mg/g) and n-butanol (1.81 mg/g); gallic acid (0.52 mg/g) in the n-butanol. In the fruits, chlorogenic acid in the chloroform (1.67 mg/g); rutin in the ethyl acetate (3.45 mg/g) and n-butanol (8.98 mg/g) fractions. The present study showed that these quantified compounds can contribute to antioxidant capacity which was higher in the branches than in the fruits.

[Enrolment of intensive care patients in clinical studies. Ethical, legal and organizational problems from an interdisciplinary point of view]. / Der Einschluss von Intensivpatienten in klinische Studien. Ethische, rechtliche und organisatorische Probleme aus interdisziplinärer Sicht.

Nowadays, most patients in hospital die in the intensive care unit from sepsis and multiple organ failure. Clinical research in this critically ill and vulnerable patient population bears a lot of ethical and legal problems; however, it remains a must in order to develop evidence-based diagnostic and therapeutic strategies for life-threatening diseases with special respect to limited health care resources. With regard to the Declaration of Helsinki, good clinical practice guidelines (GCP) from the European Medicines Agency (EMA) and the German medical drug law (AMG) this article discusses ethical and legal aspects of patient inclusion for clinical trials as well as incentives for appropriate patient recruitment from an interdisciplinary point of view.

The German Mouse Clinic: a platform for systemic phenotype analysis of mouse models.

The German Mouse Clinic (GMC) is a large scale phenotyping center where mouse mutant lines are analyzed in a standardized and comprehensive way. The result is an almost complete picture of the phenotype of a mouse mutant line--a systemic view. At the GMC, expert scientists from various fields of mouse research work in close cooperation with clinicians side by side at one location. The phenotype screens comprise the following areas: allergy, behavior, clinical chemistry, cardiovascular analyses, dysmorphology, bone and cartilage, energy metabolism, eye and vision, host-pathogen interactions, immunology, lung function, molecular phenotyping, neurology, nociception, steroid metabolism, and pathology. The German Mouse Clinic is an open access platform that offers a collaboration-based phenotyping to the scientific community (www.mouseclinic.de). More than 80 mutant lines have been analyzed in a primary screen for 320 parameters, and for 95% of the mutant lines we have found new or additional phenotypes that were not associated with the mouse line before. Our data contributed to the association of mutant mouse lines to the corresponding human disease. In addition, the systemic phenotype analysis accounts for pleiotropic gene functions and refines previous phenotypic characterizations. This is an important basis for the analysis of underlying disease mechanisms. We are currently setting up a platform that will include environmental challenge tests to decipher genome-environmental interactions in the areas nutrition, exercise, air, stress and infection with different standardized experiments. This will help us to identify genetic predispositions as susceptibility factors for environmental influences.

The simplified reference tissue model for SPECT/PET brain receptor studies. Interpretation of its parameters.

AIM: The SRTM (simplified reference tissue model) of brain receptor imaging assumes that the time activity curve in the receptor-rich region of interest can be fitted satisfactorily by the 1-tissue compartment model. This assumption has been formulated by a rather restrictive constraint on the rate constants. Empirically, the SRTM might well describe also tracers which do not fulfil this constraint, such as [(11)C]raclopride, for example. However, this has not been justified rigorously. METHODS: The requirements for the SRTM to be applicable are analyzed in detail. RESULTS: The SRTM is applicable under a less restrictive constraint than described previously. The interpretation of the SRTM parameters R(1) and k(2) in physiological terms depends on the constraint, while the interpretation of BP(ND) does not. CONCLUSION: Correct interpretation of the results of the SRTM is tracer specific. In particular, the parameter R(1), which in case of compliance with the original constraint might be used to detect perfusion and/or extraction effects, might not be appropriate for this purpose in case of raclopride-like tracers.

Refining animal models in fracture research: seeking consensus in optimising both animal welfare and scientific validity for appropriate biomedical use.

BACKGROUND: In an attempt to establish some consensus on the proper use and design of experimental animal models in musculoskeletal research, AOVET (the veterinary specialty group of the AO Foundation) in concert with the AO Research Institute (ARI), and the European Academy for the Study of Scientific and Technological Advance, convened a group of musculoskeletal researchers, veterinarians, legal experts, and ethicists to discuss, in a frank and open forum, the use of animals in musculoskeletal research. METHODS: The group narrowed the field to fracture research. The consensus opinion resulting from this workshop can be summarized as follows: RESULTS & CONCLUSION: Anaesthesia and pain management protocols for research animals should follow standard protocols applied in clinical work for the species involved. This will improve morbidity and mortality outcomes. A database should be established to facilitate selection of anaesthesia and pain management protocols for specific experimental surgical procedures and adopted as an International Standard (IS) according to animal species selected. A list of 10 golden rules and requirements for conduction of animal experiments in musculoskeletal research was drawn up comprising 1) Intelligent study designs to receive appropriate answers; 2) Minimal complication rates (5 to max. 10%); 3) Defined end-points for both welfare and scientific outputs analogous to quality assessment (QA) audit of protocols in GLP studies; 4) Sufficient details for materials and methods applied; 5) Potentially confounding variables (genetic background, seasonal, hormonal, size, histological, and biomechanical differences); 6) Post-operative management with emphasis on analgesia and follow-up examinations; 7) Study protocols to satisfy criteria established for a "justified animal study"; 8) Surgical expertise to conduct surgery on animals; 9) Pilot studies as a critical part of model validation and powering of the definitive study design; 10) Criteria for funding agencies to include requirements related to animal experiments as part of the overall scientific proposal review protocols. Such agencies are also encouraged to seriously consider and adopt the recommendations described here when awarding funds for specific projects. Specific new requirements and mandates related both to improving the welfare and scientific rigour of animal-based research models are urgently needed as part of international harmonization of standards.

Decreased factor XIII activity during severe Henoch-Schoenlein purpura -- does it play a role?

BACKGROUND: In patients with Henoch-Schoenlein purpura (HSP), particularly with severe gastrointestinal symptoms, an associated decrease of plasma factor XIII has been observed. PATIENT: The authors report a case of HSP in a boy and describe the development of factor XIII activities throughout the course of the disease. Every relapse of severe gastrointestinal manifestation was associated with a decrease of factor XIII. No improvement was seen after treatment with prednisone. The symptoms resolved each time factor XIII concentrate was administered. With the return of factor XIII to normal values eight weeks after admission abdominal symptoms ceased. CONCLUSION: The documented course supports the hypothesis that factor XIII activity correlates well with the severity of abdominal symptoms. Measuring factor XIII activity helps to identify those patients with severe gastrointestinal manifestation who may benefit from substitution therapy.

The renin-angiotensin system in transgenic rats.

Transgenic animals are used to study the function, regulation and in vivo expression of genes. The effects of the genes of the renin-angiotensin system on blood pressure regulation and hypertension were invested in transgenic rats. The role of the renin-angiotensin system in the development of the cardiovascular hypertrophy or hypertensive renal damage was analysed, as well as its interaction with other hormonal systems, i.e., adrenal steroids. The development of a transgenic rat strain carrying the mouse REN-2 gene has provided a new model of hypertension with systolic blood pressure values of 200 mmHg. This model is characterised by low active plasma renin, hyperproreninaemia and high expression of renin in the adrenal gland and other external tissues. Transgenic rats with the human components of the renin-angiotensin system expressed the human renin and angiotensinogen proteins which interacted species-specifically in transgenic rats. These transgenic models demonstrate the feasibility of studying the function of candidate hypertension genes in transgenic animals. In the future, further refinements in transgene construction, mutation, and modification can be tested in such transgenic animal models.

Fluid mechanics of the stagnation point flow chamber and its platelet deposition.

The interaction of flow and thrombus generation often is a crucial question for the engineer working in the field of artificial organs. However, this interaction is only incompletely known, and quantitative data under well-defined experimental conditions are especially rare. These can be attained with the stagnation point flow chamber. This flow model applies platelet-rich plasma (PRP) as fluid. Its flow conditions are assessed with the help of computational fluid mechanics. In addition, the concept of the boundary layer is introduced, which permits assessment of the platelet flow along the wall. The results of the experiment indicate that platelets are deposited at a defined shear rate.

Transgenic animals as models for human disease.

Since its first description in 1981 (1), transgenic technology has greatly influenced the focus and direction pace of biomedical research. Introduction of foreign DNA into the genome of animals by microinjection into fertilized oocytes is now used in almost every field of research spanning from oncology, immunology and neurology to cardiovascular medicine. The ability to integrate genes in the germline and their successful expression in the host provides an opportunity to study the role of a certain gene in the initiation and propagation of disease. Transgenic methodology serves as the link between molecular biology, introducing in vitro a defined genetic modification and whole animal physiology, with the resulting in vivo alteration of body function. This potential has been exploited to study the pathophysiological role of human genes. Transgenic animals have been used to study aspects of tumor development, immune regulation, cardiovascular development and atherosclerosis. These studies have provided new insights into the genetic origin of certain diseases and have improved our understanding of pathological processes on the cellular level. As a future goal, these studies may also serve the development of new diagnostic tools or novel therapeutic strategies such as gene therapy.

Appearance of poststenotic jets in MRI: dependence on flow velocity and on imaging parameters.

A flow model was used to study the appearance of poststenotic jets in MRI. Jets in CuSO4-doped water and bovine blood were imaged by spin-echo (SE) and fast-field-echo (FFE) pulse sequences at different degrees of stenosis and various flow rates. On flow-compensated FFE images, the jets were characterized by signal void if the mean flow velocity within the stenosis exceeded a limit, which was independent of the degree of the stenosis and the type of the fluid. On SE images and on FFE images without flow compensation, signal void occurred at significantly lower flow velocity. The extension of the poststenotic signal void on flow-compensated FFE images was increased by either reduction of the pixel diameter or by prolongation of the echo time. However, it was independent of the orientation of the imaging plane relative to the direction of flow. The results have an impact on attempts to use signal void for the assessment of turbulent jets with MRI.

[Measurement of noise levels in MR tomography at 1.5 Tesla]. / Messungen zur Geräuschbelastung in der MR-Tomographie bei 1,5 Tesla.

The noise levels at the isocentrum of an MR apparatus with a field strength of 1.5 Tesla was measured during various sequences. The rapid switching of the gradients exerts effects on the gradient coils, which result in the development of noise as from a loudspeaker. Measurements were carried out using gradients of 3 and 9.3 mT/m with head and body coils and a variety of sequences. The noise level depended largely on the type of sequence and, under extreme conditions, may attain 96 dB. Because of the short exposure times, we do not consider it necessary to use any form of protection. During the examination of patients with damaged hearing, some protection may be advisable.

[Poststenotic flow in MRT: phantom measurements using spin-echo and gradient-echo sequences]. / Poststenotischer Fluss in der MRT: Phantommessungen mit Spin-Echo- und Gradienten-Echo-Sequenzen.

A flow model was used to study the appearance of poststenotic flow on spin-echo (SE) and fast-field-echo (FFE) images. On SE-images, extensive signal void distal to the stenosis was observed even with low flow velocities. FFE-sequences with short echo time and flow-compensated gradients demonstrated poststenotic loss of signal intensity only with high flow velocities. On FFE-images, the poststenotic signal loss increased with the severity of the stenosis, if total flow across the stenosis was maintained. The lower limit of the mean flow velocity within the stenosis, for which signal void was observed, appeared essentially independent of the degree of the stenosis. The results demonstrate the capability of flow-compensated FFE-sequences to assess poststenotic turbulent flow.