Evolution and medicine - The central role of anatomy.

In medicine, there is an increasing number of publications that deal with or at least consider an evolutionary background. In zoology or comparative anatomy, work on evolutionary developments is taking on an ever-greater role in parallel. The pre-clinical (or pre-medical) phase in medical studies would be able to form a bridge between these related and yet so distant subjects but is currently completely evolution-free. This means that there is no consideration of the evolution of the healthy human being as a prerequisite for a systematic study of the evolutionary background in medicine. In this work the view is expressed that anatomy should be given a central, framework-giving and integrating role, which should urgently be actively pursued.

(Re-) Defining evolutionary medicine.

The applicability of evolutionary biology principles to diseases has been largely questioned by the medical field. While Evolutionary Medicine (EM) developed in part to lessen this gap, EM is an independent field from both evolution and medicine, whose continued narrowing of topics as a consequence of its reductionist approach, in addition to its focus to introduce itself at a late stage in medical education, has led to its continued resistance toward implementation. In turn, this has had a profound and lasting impact on the awareness of evolution in medicine among physicians. For both the evolutionary and medical communities to reach a common perspective and obtain a greater frame-work of medical thought, a comprehensive view of the evolution of the healthy human being needs to be introduced as a starting point during the premedical curriculum. Here, we present our views on the ongoing challenges that have caused the continued division between the evolutionary fields and medicine, and provide solutions to help bridge the gap for an interdisciplinary field of evolution in medicine.

Assessment of the additional clinical potential of X-ray dark-field imaging for breast cancer in a preclinical setup.

BACKGROUND: Mammography can identify calcifications up to 50-100 µm in size as a surrogate parameter for breast cancer or ductal carcinoma in situ (DCIS). Microcalcifications measuring <50 µm are also associated with breast cancer or DCIS and are frequently not detected on mammography, although they can be detected with dark-field imaging. This study examined whether additional breast examination using X-ray dark-field imaging can increase the detection rate of calcifications. Advances in knowledge: (1) evaluation of additional modality of breast imaging; (2) specific evaluation of breast calcifications.Implications for patient care: the addition of X-ray dark-field imaging to conventional mammography could detect additional calcifications. METHODS: Talbot-Lau X-ray phase-contrast imaging and X-ray dark-field imaging were used to acquire images of breast specimens. The radiation dosage with the technique is comparable with conventional mammography. Three X-ray gratings with periods of 5-10 µm between the X-ray tube and the flat-panel detector provide three different images in a single sequence: the conventional attenuation image, differential phase image, and dark-field image. The images were read by radiologists. Radiological findings were marked and examined pathologically. The results were described in a descriptive manner. RESULTS: A total of 81 breast specimens were investigated with the two methods; 199 significant structures were processed pathologically, consisting of 123 benign and 76 malignant lesions (DCIS or invasive breast cancer). X-ray dark-field imaging identified 15 additional histologically confirmed carcinoma lesions that were visible but not declared suspicious on digital mammography alone. Another four malignant lesions that were not visible on mammography were exclusively detected with X-ray dark-field imaging. CONCLUSIONS: Adding X-ray dark-field imaging to digital mammography increases the detection rate for breast cancer and DCIS associated lesions with micrometer-sized calcifications.The use of X-ray dark-field imaging may be able to provide more accurate and detailed radiological classification of suspicious breast lesions.Adding X-ray dark-field imaging to mammography may be able to increase the detection rate and improve preoperative planning in deciding between mastectomy or breast-conserving therapy, particularly in patients with invasive lobular breast cancer.

Discrimination analysis of breast calcifications using x-ray dark-field radiography.

BACKGROUND: X-ray dark-field radiography could enhance mammography by providing more information on imaged tissue and microcalcifications. The dark field signal is a measure of small angle scattering and can thus provide additional information on the imaged materials. This information can be useful for material distinction of calcifications and the diagnosis of breast cancer by classifying benign and malign association of these calcifications. METHODS: For this study, institutional review board approval was obtained. We present the evaluation of images acquired with interferometric grating-based x-ray imaging of 323 microcalcifications (166 malign and 157 benign associated) in freshly dissected breast tissue and compare the results to the information extracted in follow-up pathological evaluation. The number of imaged calcifications is sufficiently higher than in similar previous studies. Fourteen calcification properties were extracted from the digital images and used as predictors in three different models common in discrimination analysis namely a simple threshold model, a naive Bayes model and a linear regression model, which classify the calcifications as associated with a benign or suspicious finding. Three of these fourteen predictors have been newly defined in this work and are independent from the tissue background surrounding the microcalcifications. Using these predictors no background correction is needed, as in previous works in this field. The new predictors are the length of the first and second principle component of the absorption and dark-field data, as well as the angle between the first principle component and the dark-field axis. We called these predictors data length, data width, and data orientation. RESULTS: In fourfold cross-validation malignancy of the imaged tissue was predicted. Models that take only classical absorption predictors into account reached a sensitivity of 53.3% at a specificity of 81.1%. For a combination of predictors that also include dark field information, a sensitivity of 63.2% and specificity of 80.8% were obtained. The included dark field information consisted of the newly introduced parameters, data orientation and data width. CONCLUSIONS: While remaining at a similar specificity, the sensitivity, with which a trained model was able to distinguish malign from benign associated calcifications, was increased by 10% on including dark-field information. This suggests grating-based x-ray imaging as a promising clinical imaging method in the field of mammography.

Talbot-Lau x-ray phase-contrast setup for fast scanning of large samples.

Compared to conventional attenuation x-ray radiographic imaging, the x-ray Talbot-Lau technique provides further information about the scattering and the refractive properties of the object in the beam path. Hence, this additional information should improve the diagnostic process concerning medical applications and non-destructive testing. Nevertheless, until now, due to grating fabrication process, Talbot-Lau imaging suffers from small grating sizes (70 mm diameter). This leads to long acquisition times for imaging large objects. Stitching the gratings is one solution. Another one consists of scanning Talbot-Lau setups. In this publication, we present a compact and very fast scanning setup which enables imaging of large samples. With this setup a maximal scanning velocity of 71.7 mm/s is possible. A resolution of 4.1 lines/mm can be achieved. No complex alignment procedures are necessary while the field of view comprises 17.5 × 150 cm2. An improved reconstruction algorithm concerning the scanning approach, which increases robustness with respect to mechanical instabilities, has been developed and is presented. The resolution of the setup in dependence of the scanning velocity is evaluated. The setup imaging qualities are demonstrated using a human knee ex-vivo as an example for a high absorbing human sample.

Exploration of different x-ray Talbot-Lau setups for dark-field lung imaging examined in a porcine lung.

X-ray dark-field imaging is a promising technique for lung diagnosis. Due to the alveolar structure of lung tissue, a higher contrast is obtained by the dark-field image compared to the attenuation image. Animal studies indicate an enhancement regarding the detection of lung diseases in early stages. In this publication, we focus on the influence of different Talbot-Lau interferometer specifications while maintaining the x-ray source, sample magnification and detector system. By imaging the same porcine lung with three different grating sets, we analyze the contrast-to-noise ratio of the obtained dark-field images with respect to visibility and correlation length. We demonstrate that relatively large grating periods of the phase and of the analyzer grating are sufficient for high quality lung imaging at reasonable dose levels.

Single-shot Talbot-Lau x-ray dark-field imaging of a porcine lung applying the moiré imaging approach.

Talbot-Lau x-ray imaging provides additionally to the conventional attenuation image, two further images: the differential phase-contrast image which is especially sensitive to differences in refractive properties and the dark-field image which is showing the x-ray scattering properties of the object. Thus, in the dark-field image sub-pixeled object information can be observed. As it has been shown in recent studies, this is of special interest for lung imaging. Changes in the alveoli structure, which are in the size of one detector pixel, can be seen in the dark-field images. A fast acquisition process is crucial to avoid motion artifacts due to heartbeat and breathing of the patient. Using moiré imaging the images can be acquired with a single-shot exposure. Nevertheless, the spatial resolution is reduced compared to the phase-stepping acquisition. We evaluate the results of both imaging techniques towards their feasibility in clinical routine. Furthermore, we analyse the influence of artificial linear object movement on the image quality, in order to simulate the heartbeat of a patient.

Insulin-like signaling within and beyond metazoans.

Insulin signaling is pivotal in controlling animals' lifespan and responses to environmental changes and, when altered, it may lead to pathogenic states. Despite its importance and relevance for biomedical research, insulin's mechanism of action and the full range of its pathophysiological effects remain incompletely understood. Likewise, the evolutionary origin of insulin and its associated signaling components are unclear. Notwithstanding the common view that insulin signaling originated within metazoans, experimental evidence from non-metazoans suggest a more widespread distribution across eukaryotes. Here, we summarize this evidence. Furthermore, we put forward an evolutionary account that reconciles seemingly contradictory results in the literature.

Implementation of a Talbot-Lau interferometer in a clinical-like c-arm setup: A feasibility study.

X-ray grating-based phase-contrast imaging has raised interest regarding a variety of potential clinical applications, whereas the method is feasible using a medical x-ray tube. Yet, the transition towards a clinical setup remains challenging due to the requirement of mechanical robustness of the interferometer and high demands applying to medical equipment in clinical use. We demonstrate the successful implementation of a Talbot-Lau interferometer in an interventional c-arm setup. The consequence of vibrations induced by the rotating anode of the tube is discussed and the prototype is shown to provide a visibility of 21.4% at a tube voltage of 60 kV despite the vibrations. Regarding clinical application, the prototype is mainly set back due to the limited size of the field of view covering an area of 17 mm × 46 mm. A c-arm offers the possibility to change the optical axis according to the requirements of the medical examination. We provide a method to correct for artifacts that result from the angulation of the c-arm. Finally, the images of a series of measurements with the c-arm in different angulated positions are shown. Thereby, it is sufficient to perform a single reference measurement in parking position that is valid for the complete series despite angulation.

[Dietary Recommendations in Metabolic Vascular Syndrome]. / Ernährungsempfehlungen beim metabolisch-vaskulären Syndrom.

Cardiovascular disease is the number one cause of death globally. Poor diet constitutes a key factor in the initiation and progression of cardiovascular disease and has become the leading risk factor for disability and death worldwide. Therefore, addressing suboptimal nutrition is of key prognostic relevance in primary and secondary prevention of metabolic vascular syndrome.Metabolic vascular syndrome is a multidimensional network of acquired cardiometabolic risk factors closely related to insulin resistance (IR) and concomitant hyperinsulinemia. IR, being the underlying cause of metabolic vascular syndrome and certain types of cancer, should attract the attention of every clinician. As changes in lipoprotein metabolism are one of the earliest indicators of metabolic dysfunction, a relevant biomarker for identifying individuals with IR is the TAG/HDL-C ratio.IR - and concomitant metabolic vascular risk - can be effectively treated by lifestyle intervention. If IR is present, dietary carbohydrate restriction has consistently been shown to be superior to dietary fat restriction in reversing metabolic dysfunction. The beneficial effects of carbohydrate restricted diets on metabolic vascular risk are independent of BMI - diet quality therefore confers patient benefit beyond weight reduction.The effect of single nutrients on isolated lipid surrogate markers such as LDL-C does not capture their global effect on metabolic vascular risk.Targeting IR with a low glycemic load, real food diet will reduce overall energy density and will improve all risk factors of metabolic vascular syndrome. In particular, replacing refined carbohydrates with healthy fats in the context of a Mediterranean style-, low carbohydrate and calorie-unrestricted dietary pattern has been shown to significantly reduce burden of metabolic vascular disease.

Improved reconstruction of phase-stepping data for Talbot-Lau x-ray imaging.

Grating-based Talbot-Lau x-ray interferometry is a popular method for measuring absorption, phase shift, and small-angle scattering. The standard acquisition method for this modality is phase stepping, where the Talbot pattern is reconstructed from multiple images acquired at different grating positions. We review the implicit assumptions in phase-stepping reconstruction, and find that the assumptions of perfectly known grating positions and homoscedastic noise variance are violated in some scenarios. Additionally, we investigate a recently reported estimation bias in the visibility and dark-field signal. To adapt the phase-stepping reconstruction to these findings, we propose three improvements to the reconstruction. These improvements are (a) to use prior knowledge to compute more accurate grating positions to reduce moiré artifacts, (b) to utilize noise variance information to reduce dark-field and phase noise in high-visibility acquisitions, and (c) to perform correction of an estimation bias in the interferometer visibility, leading to more quantitative dark-field imaging in acquisitions with a low signal-to-noise ratio. We demonstrate the benefit of our methods on simulated data, as well as on images acquired with a Talbot-Lau interferometer.

Talbot-Lau X-ray phase contrast for tiling-based acquisitions without reference scanning.

PURPOSE: Grating-based Talbot-Lau interferometers are a popular choice for phase-contrast X-ray acquisitions. Here, an air reference scan has to be acquired prior to an object scan. This particularly complicates acquisition of large objects: large objects are tiled into multiple scans due to the small field of view of current gratings. However, phase reference drifts occurring between these scans may require to repeatedly move the object in and out of the X-ray beam to update the reference information. METHODS: We developed an image processing technique that completely removes the need for phase reference scans in tiled acquisitions. We estimate the reference from object scans using a tailored iterated robust regression, using a novel efficient optimizer. RESULTS: Our evaluation indicates that the estimated reference is not only close to the acquired reference but also improves the final image quality. We hypothesize that this is because we mitigate errors that are introduced when actually acquiring the reference phase. CONCLUSION: Phase-contrast imaging of larger objects may benefit from computational estimation of phase reference data due to reduced scanning complexity and improved image quality.

A beam hardening and dispersion correction for x-ray dark-field radiography.

PURPOSE: X-ray dark-field imaging promises information on the small angle scattering properties even of large samples. However, the dark-field image is correlated with the object's attenuation and phase-shift if a polychromatic x-ray spectrum is used. A method to remove part of these correlations is proposed. METHODS: The experimental setup for image acquisition was modeled in a wave-field simulation to quantify the dark-field signals originating solely from a material's attenuation and phase-shift. A calibration matrix was simulated for ICRU46 breast tissue. Using the simulated data, a dark-field image of a human mastectomy sample was corrected for the finger print of attenuation- and phase-image. RESULTS: Comparing the simulated, attenuation-based dark-field values to a phantom measurement, a good agreement was found. Applying the proposed method to mammographic dark-field data, a reduction of the dark-field background and anatomical noise was achieved. The contrast between microcalcifications and their surrounding background was increased. CONCLUSIONS: The authors show that the influence of and dispersion can be quantified by simulation and, thus, measured image data can be corrected. The simulation allows to determine the corresponding dark-field artifacts for a wide range of setup parameters, like tube-voltage and filtration. The application of the proposed method to mammographic dark-field data shows an increase in contrast compared to the original image, which might simplify a further image-based diagnosis.

Energy weighted x-ray dark-field imaging.

The dark-field image obtained in grating-based x-ray phase-contrast imaging can provide information about the objects' microstructures on a scale smaller than the pixel size even with low geometric magnification. In this publication we demonstrate that the dark-field image quality can be enhanced with an energy-resolving pixel detector. Energy-resolved x-ray dark-field images were acquired with a 16-energy-channel photon-counting pixel detector with a 1 mm thick CdTe sensor in a Talbot-Lau x-ray interferometer. A method for contrast-noise-ratio (CNR) enhancement is proposed and validated experimentally. In measurements, a CNR improvement by a factor of 1.14 was obtained. This is equivalent to a possible radiation dose reduction of 23%.

Grating-based x-ray phase-contrast imaging with a multi energy-channel photon-counting pixel detector.

We have carried out grating-based x-ray differential phase-contrast measurements with a hybrid pixel detector in 16 energy channels simultaneously. A method for combining the energy resolved phase-contrast images based on energy weighting is presented. An improvement in contrast-to-noise ratio by 58.2% with respect to an emulated integrating detector could be observed in the final image. The same image quality could thus be achieved with this detector and with energy weighting at 60.0% reduced dose compared to an integrating detector. The benefit of the method depends on the object, spectrum, interferometer design and the detector efficiency.

Increasing the darkfield contrast-to-noise ratio using a deconvolution-based information retrieval algorithm in X-ray grating-based phase-contrast imaging.

A novel information retrieval algorithm for X-ray grating-based phase-contrast imaging based on the deconvolution of the object and the reference phase stepping curve (PSC) as proposed by Modregger et al. was investigated in this paper. We applied the method for the first time on data obtained with a polychromatic spectrum and compared the results to those, received by applying the commonly used method, based on a Fourier analysis. We confirmed the expectation, that both methods deliver the same results for the absorption and the differential phase image. For the darkfield image, a mean contrast-to-noise ratio (CNR) increase by a factor of 1.17 using the new method was found. Furthermore, the dose saving potential was estimated for the deconvolution method experimentally. It is found, that for the conventional method a dose which is higher by a factor of 1.66 is needed to obtain a similar CNR value compared to the novel method. A further analysis of the data revealed, that the improvement in CNR and dose efficiency is due to the superior background noise properties of the deconvolution method, but at the cost of comparability between measurements at different applied dose values, as the mean value becomes dependent on the photon statistics used.

Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy.

The introduction of highly active antiretroviral therapy (HAART) has significantly decreased morbidity and mortality among patients infected with HIV-1. However, HIV-1 can acquire resistance against all currently available antiretroviral drugs targeting viral reverse transcriptase, protease, and gp41. Moreover, in a growing number of patients, the development of multidrug-resistant viruses compromises HAART efficacy and limits therapeutic options. Therefore, it is an ongoing task to develop new drugs and to identify new targets for antiretroviral therapy. Here, we identified the guanylhydrazone CNI-1493 as an efficient inhibitor of human deoxyhypusine synthase (DHS). By inhibiting DHS, this compound suppresses hypusine formation and, thereby, activation of eukaryotic initiation factor 5A (eIF-5A), a cellular cofactor of the HIV-1 Rev regulatory protein. We demonstrate that inhibition of DHS by CNI-1493 or RNA interference efficiently suppressed the retroviral replication cycle in cell culture and primary cells. We show that CNI-1493 inhibits replication of macrophage- and T cell-tropic laboratory strains, clinical isolates, and viral strains with high-level resistance to inhibitors of viral protease and reverse transcriptase. Moreover, no measurable drug-induced adverse effects on cell cycle transition, apoptosis, and general cytotoxicity were observed. Therefore, human DHS represents a novel and promising drug target for the development of advanced antiretroviral therapies, particularly for the inhibition of multidrug-resistant viruses.