A simulation model for colorectal cancer screening: potential of stool tests with various performance characteristics compared with screening colonoscopy.

OBJECTIVE: Many new stool tests intended to detect neoplastic cells or cell products are developed at present for colorectal cancer (CRC) screening. The aim of this study was to simulate a population-based screening setting to assess and compare the potential for early detection and prevention of CRC of screening based on stool tests with different sensitivity and specificity and of screening with colonoscopy as a primary screening tool. METHOD: A Markov model was developed aimed to estimate the proportion of CRC cases which are early detected or prevented due to screening as well as the number of equired stool tests and colonoscopies per early detected or prevented CRC case. Model outcomes were calculated for the offer of annual stool testing from age 55 to 74 in combination with colonoscopic follow-up of positive test results and for the offer of screening colonoscopy as a primary screening tool at ages 55 and 65. The long-lasting risk reduction of colonoscopy allowing the removal of precancerous lesions was taken into account quantitatively. RESULTS: For a variety of stool tests with different performance characteristics, the proportion of CRC cases early detected or prevented was estimated to be higher for stool testing in combination with colonoscopic follow-up of positive test results compared with screening colonoscopy assuming levels of compliance to be expected for the respective screening scheme. Optimizing performance characteristics of stool tests in terms of detecting precancerous lesions, in addition to those in terms of detecting CRC, seemed to be crucial for maximizing effectiveness of CRC screening with stool tests. CONCLUSION: Screening based on new stool tests with colonoscopic follow-up of positive test results might offer a high potential for early detection or prevention of CRC.     

Effects of an Omega-3 Supplemented,High-Protein Diet in Combination with Vibration and Resistance Exercise on Muscle Power and Inflammation in Old Adults: A Pilot Randomized Controlled Trial

Background: Inflammaging is considered to drive loss of muscle function. Omega-3 fatty acids exhibit anti-inflammatory properties. Therefore, we examined the effects of eight weeks of vibration and home-based resistance exercise combined with a whey-enriched, omega-3-supplemented diet on muscle power, inflammation and muscle biomarkers in community-dwelling old adults. Methods: Participants were randomized to either exercise (3x/week, n = 20), exercise + high-protein diet (1.2–1.5 g/kg, n = 20), or exercise + high-protein and omega-3-enriched diet (2.2 g/day, n = 21). Muscle power (watt/m²) and chair rise test (CRT) time (s) were assessed via CRT measured with mechanography. Furthermore, leg strength (kg/m²) and fasting concentrations of inflammatory (interleukin (IL-) 6, IL-10, high-mobility group box-1 (HMGB-1)) and muscle biomarkers (insulin-like growth factor (IGF-) 1, IGF-binding protein-3, myostatin) were assessed. Results: Sixty-one participants (70.6 ± 4.7 years; 47% men) completed the study. According to generalized linear mixed models, a high-protein diet improved leg strength and CRT time. Only IGF-1 increased with additional omega-3. Sex-specific analyses revealed that muscle power, IL-6, IL-6/IL-10 ratio, and HMGB-1 improved significantly in the male high-protein, omega-3-enriched group only. Conclusion: Vibration and home-based resistance exercise combined with a high-protein, omega-3-enriched diet increased muscle power and reduced inflammation in old men, but not in old women. While muscle biomarkers remained unchanged, a high-protein diet combined with exercise improved leg strength and CRT time.     

Novel Method for Three-Dimensional Facial Expression Recognition Using Self-Normalizing Neural Networks and Mobile Devices

Introduction To date, most ways to perform facial expression recognition rely on two-dimensional images, advanced approaches with three-dimensional data exist. These however demand stationary apparatuses and thus lack portability and possibilities to scale deployment. As human emotions, intent and even diseases may condense in distinct facial expressions or changes therein, the need for a portable yet capable solution is signified. Due to the superior informative value of three-dimensional data on facial morphology and because certain syndromes find expression in specific facial dysmorphisms, a solution should allow portable acquisition of true three-dimensional facial scans in real time. In this study we present a novel solution for the three-dimensional acquisition of facial geometry data and the recognition of facial expressions from it. The new technology presented here only requires the use of a smartphone or tablet with an integrated TrueDepth camera and enables real-time acquisition of the geometry and its categorization into distinct facial expressions. Material and Methods Our approach consisted of two parts: First, training data was acquired by asking a collective of 226 medical students to adopt defined facial expressions while their current facial morphology was captured by our specially developed app running on iPads, placed in front of the students. In total, the list of the facial expressions to be shown by the participants consisted of “disappointed”, “stressed”, “happy”, “sad” and “surprised”. Second, the data were used to train a self-normalizing neural network. A set of all factors describing the current facial expression at a time is referred to as “snapshot”. Results In total, over half a million snapshots were recorded in the study. Ultimately, the network achieved an overall accuracy of 80.54% after 400 epochs of training. In test, an overall accuracy of 81.15% was determined. Recall values differed by the category of a snapshot and ranged from 74.79% for “stressed” to 87.61% for “happy”. Precision showed similar results, whereas “sad” achieved the lowest value at 77.48% and “surprised” the highest at 86.87%. Conclusions With the present work it can be demonstrated that respectable results can be achieved even when using data sets with some challenges. Through various measures, already incorporated into an optimized version of our app, it is to be expected that the training results can be significantly improved and made more precise in the future. Currently a follow-up study with the new version of our app that encompasses the suggested alterations and adaptions, is being conducted. We aim to build a large and open database of facial scans not only for facial expression recognition but to perform disease recognition and to monitor diseases’ treatment progresses.     

Phytochemical screening and antiviral activity of some medicinal plants from the island Soqotra

Methanol and hot-aqueous extracts of 25 different plant species, used in Yemeni traditional medicine and growing, partly as endemic plants, on the island Soqotra have been investigated for their antiviral activity. In addition, the phytochemical identification of the main chemical constituents was performed. The extracts were assayed in two in vitro viral systems, which used influenza virus type A/MDCK cells and herpes simplex virus type 1/Vero cells, at non-cytotoxic concentrations. The herpes simplex virus type 1 showed more sensitivity than the influenza virus type A against the extracts investigated. The methanol extracts of Boswellia ameero, Boswellia elongata, Buxus hildebrandtii, Cissus hamaderohensis, Cleome socotrana, Dracaena cinnabari, Exacum affine, Jatropha unicostata and Kalanchoe farinacea showed anti-influenza virus type A activity with 50% inhibition (IC50) concentrations ranging from 0.7 to 12.5 microg/mL. In addition, 17 plants of the 25 investigated exhibited anti-HSV-1 activity. The antiviral activity of some active extracts was also observed on a molecular level.     

Functional modulation of PTH1R activation and signaling by RAMP2

Receptor-activity-modifying proteins (RAMPs) are ubiquitously expressed membrane proteins that associate with different G protein–coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R), a class B GPCR and an important modulator of mineral ion homeostasis and bone metabolism. However, it is unknown whether and how RAMP proteins may affect PTH1R function. Using different optical biosensors to measure the activation of PTH1R and its downstream signaling, we describe here that RAMP2 acts as a specific allosteric modulator of PTH1R, shifting PTH1R to a unique preactivated state that permits faster activation in a ligand-specific manner. Moreover, RAMP2 modulates PTH1R downstream signaling in an agonist-dependent manner, most notably increasing the PTH-mediated Gi3 signaling sensitivity. Additionally, RAMP2 increases both PTH- and PTHrP-triggered β-arrestin2 recruitment to PTH1R. Employing homology modeling, we describe the putative structural molecular basis underlying our functional findings. These data uncover a critical role of RAMPs in the activation and signaling of a GPCR that may provide a new venue for highly specific modulation of GPCR function and advanced drug design.

G protein–coupled receptors(GPCRs) represent the largest class of membrane-bound proteins and are involved in a multitude of biological processes (1). They are characterized by a seven-transmembrane helix structure, which undergoes a characteristic rearrangement upon binding of agonists. Agonist binding to its cognate receptor induces conformational changes in the transmembrane helices, which are transmitted to the cytosolic face of the receptors and ultimately result in receptor activation, which represents the key step of signal transduction. The combination of crystallographic and cryogenic electron microscopy studies and the employment of optical biosensors to study the reorganization of the seven transmembrane domains has allowed a detailed understanding of the general mechanisms of GPCR activation (2–5).Earlier structural studies suggest that GPCRs undergo similar conformational changes upon activation, including, most prominently, an outward movement of the transmembrane helix 6 at the cytosolic face, thereby creating a pocket to which the G protein α-subunit can couple (5). More recent studies, however, have revealed that the exact type of changes may depend on the receptor class and the specific receptor (6–8). Class- and receptor-specific differences may also exist in the interaction of receptors not only with downstream G proteins and β-arrestins but also with accessory and modulatory proteins (9).Studies of the kinetic steps that govern the structural rearrangements which underlie receptor activation (10) showed that its speed might depend on the receptor class and the specific receptor. For example, when exposed to saturating agonist concentrations, most class A GPCRs switch into the active state within tens of milliseconds. The same process takes 1 to 2 ms for a class C GPCR and may take up to a second for class B receptors (11–15). Little is known whether the activation kinetics of GPCRs can be modulated by their cellular context and whether proteins other than the receptors themselves might play a role in shaping signaling kinetics and specificity.Here, we study the parathyroid hormone 1 receptor (PTH1R), a prototypical member of class B GPCRs characterized by a large N-terminal domain that binds a major part of their cognate peptide agonists (16, 17). Compared to class A GPCRs, PTH1R activation is relatively slow and occurs in a two-step process: The initial N-terminal binding step has a time constant of ∼140 ms, followed by an interaction of the ligand with the transmembrane core, which changes into its active conformation with a time constant of ∼1 s (11, 14). Pleiotropic in its downstream coupling, PTH1R signals primarily via G_s but can also couple to G_q (18), G_12/13 (19), and G_i (20) and interacts with and signals via β-arrestins (21, 22). The two endogenous agonists, parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), trigger PTH1R activation with similar kinetics and specificity for the various intracellular pathways (23–25). However, PTH can induce prolonged signaling from intracellular sites, while PTHrP signals exclusively from the cell surface (26).PTH1R has been reported to interact with modulatory proteins of the receptor-activity-modifying protein (RAMP) family (27–29). RAMPs constitute a family of single transmembrane helix proteins with three members: RAMP1, RAMP2, and RAMP3.It is controversial whether PTH1R interacts only or preferentially with RAMP2 (28) or all three RAMPs (28, 29). In RAMP2 knock-out mice, PTH1R function is deregulated, and placental dysfunction is observed (30), suggesting a major physiological role of the PTH1R/RAMP2 interaction. Yet, the molecular mechanisms of how RAMPs may modulate the activation dynamics of PTH1R and their signaling properties remain to be elucidated.To address these questions, we develop and employ biosensors for PTH1R activation and investigate an array of downstream signaling pathways to assess the effects of RAMPs on the activation dynamics and signaling properties of PTH1R in response to its two endogenous ligands, PTH and PTHrP. We observe that RAMP2 specifically interacts with PTH1R and modulates its activation kinetics as well as signaling dynamics in an agonist-dependent manner.     

Evaluation of neurotoxicity induced by paclitaxel second-line chemotherapy

 The most important cytotoxic drugs for the treatment of ovarian cancer, platinum compounds and paclitaxel, are known to induce neurotoxicity, which is dose limiting when higher paclitaxel doses are used or platinum-pretreated patients are treated. The absolute dose of paclitaxel per course has been demonstrated to be an important risk factor for the development of neurotoxicity. The role of cumulative dose, treatment duration and infusion schedule as additional risk factors are still in debate, and are therefore evaluated in this study. This study evaluates paclitaxel induced neurotoxicity in 38 patients, most of whom had already received platinum treatment, receiving either 135 or 175 mg/m² as 3-h or 24-h infusion. Patients were compared with an age-matched control group. A detailed questionnaire and neurophysiological measurements including vibration perception threshold were used. Overall, the majority of patients (76%) developed some degree of neurotoxicity, but symptoms were usually mild or moderate with no grade 3/4 neurotoxicity observed. Age has been demonstrated to be an important risk factor for the development of neurotoxicity. Furthermore, the higher dose per course showed a significant impact on neurotoxicity, while the different infusion schedules were of minor importance. Vibration threshold perception, 2-point discrimination, a walking-the-line test, and reports of paresthesias were shown to be the most sensitive and useful parameters for neurotoxicity evaluation. Neurotoxicity is a common adverse event during paclitaxel chemotherapy in platinum-pretreated patients. A clinically useful test panel composed of a detailed history and the above three easily performed neurophysiological evaluations should be incorporated into future studies evaluating new drugs, treatment modifications, new combinations, and potential modulators of chemotherapy-induced neurotoxicity. Published online: 22 July 1999     

Acute management and outcome of multiple trauma patients with pelvic disruptions

ABSTRACT: INTRODUCTION: Data on pre-hospital and trauma room fluid management of multiple trauma patients with pelvic disruptions are rarely reported. Present trauma algorithms recommend early haemorrhage control and massive fluid resuscitation. By matching the German Pelvic Injury Register (PIR) with the TraumaRegister DGU(R) (TR) for the first time, we attempt to assess the initial fluid management for different Tile/OTA types of pelvic ring fractures. Special attention was given to the patient's post traumatic course, particularly ICU data and patient outcome. METHODS: A specific match code was applied to identify certain patients with pelvic disruptions from both PIR and TR anonymous trauma databases, admitted between 2004 and 2009. From the resulting intersection set, a retrospective analysis was done of pre-hospital and trauma room data, length of ICU stay, days of ventilation, incidence of multiple organ dysfunction syndrome (MODS), sepsis, and mortality. RESULTS: In total 402 patients were identified. Mean ISS was 25.9 points and the mean ratio of patients with ISS [greater than or equal to]16 was 85.6%. The fracture distribution was as follows: 19.7% type A, 29.4% type B, 36.6% type C, and 14.3% isolated acetabular and/or sacrum fractures. The type B/C, compared with type A fractures, were related to constantly worse vital signs that necessitated a higher volume of fluid and blood administration in the pre-hospital and/or the trauma room setting. This group of B/C fractures were also related to a significantly higher presence of concomitant injuries and related with increased ISS. This was related to increased ventilation and ICU stay, increased rate of MODS, sepsis and increased rate of mortality at least for the type C fractures. Approximately 80% of the deceased had sustained type B/C fractures. CONCLUSIONS: The present study confirms the actuality of traditional trauma algorithms with initial massive fluid resuscitation in the recent therapy of multiple trauma patients with pelvic disruptions. Low volume resuscitation seems not yet accepted in practice in managing this special patient entity. Mechanically unstable pelvic ring fractures type B/C (according Tile's/OTA classification) form a distinct entity that has to be considered notably in future trauma algorithms.