Gastric transit and small intestinal transit time and motility assessed by a magnet tracking system

<p>Abstract</p> <p>Background</p> <p>Tracking an ingested magnet by the Magnet Tracking System MTS-1 (Motilis, Lausanne, Switzerland) is an easy and minimally-invasive method to assess gastrointestinal transit. The aim was to test the validity of MTS-1 for assessment of gastric transit time and small intestinal transit time, and to illustrate transit patterns detected by the system.</p> <p>Methods</p> <p>A small magnet was ingested and tracked by an external matrix of 16 magnetic field sensors (4 × 4) giving a position defined by 5 coordinates (position: <b>x, y, z, and angle: θ, ϕ)</b>. Eight healthy subjects were each investigated three times: (1) with a small magnet mounted on a capsule endoscope (PillCam); (2) with the magnet alone and the small intestine in the fasting state; and (3) with the magnet alone and the small intestine in the postprandial state.</p> <p>Results</p> <p>Experiment (1) showed good agreement and no systematic differences between MTS-1 and capsule endoscopy when assessing gastric transit (median difference 1 min; range: 0-6 min) and small intestinal transit time (median difference 0.5 min; range: 0-52 min). Comparing experiments (1) and (2) there were no systematic differences in gastric transit or small intestinal transit when using the magnet-PillCam unit and the much smaller magnetic pill. In experiments (2) and (3), short bursts of very fast movements lasting less than 5% of the time accounted for more than half the distance covered during the first two hours in the small intestine, irrespective of whether the small intestine was in the fasting or postprandial state. The mean contraction frequency in the small intestine was significantly lower in the fasting state than in the postprandial state (9.90 min^-1vs. 10.53 min^-1) (p = 0.03).</p> <p>Conclusion</p> <p>MTS-1 is reliable for determination of gastric transit and small intestinal transit time. It is possible to distinguish between the mean contraction frequency of small intestine in the fasting state and in the postprandial state.</p

Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy

<p>Abstract</p> <p>Background</p> <p>P53 mutations are an adverse prognostic factor in esophageal cancer. P53 and KRas mutations are involved in chemo-radioresistance. Circulating anti-p53 or anti-KRas antibodies are associated with gene mutations. We studied whether anti-p53 or anti-KRas auto-antibodies were prognostic factors for response to chemoradiotherapy (CRT) or survival in esophageal carcinoma.</p> <p>Methods</p> <p>Serum p53 and KRas antibodies (abs) were measured using an ELISA method in 97 consecutive patients treated at Saint Louis University Hospital between 1999 and 2002 with CRT for esophageal carcinoma (squamous cell carcinoma (SCCE) 57 patients, adenocarcinoma (ACE) 27 patients). Patient and tumor characteristics, response to treatment and the follow-up status of 84 patients were retrospectively collected. The association between antibodies and patient characteristics was studied. Univariate and multivariate survival analyses were conducted.</p> <p>Results</p> <p>Twenty-four patients (28%) had anti-p53 abs. Abs were found predominantly in SCCE (p = 0.003). Anti-p53 abs were associated with a shorter overall survival in the univariate analysis (HR 1.8 [1.03-2.9], p = 0.04). In the multivariate analysis, independent prognostic factors for overall and progression-free survival were an objective response to CRT, the CRT strategy (alone or combined with surgery [preoperative]) and anti-p53 abs. None of the long-term survivors had p53 abs. KRas abs were found in 19 patients (23%, no difference according to the histological type). There was no significant association between anti-KRas abs and survival neither in the univariate nor in the multivariate analysis. Neither anti-p53 nor anti-KRas abs were associated with response to CRT.</p> <p>Conclusions</p> <p>Anti-p53 abs are an independent prognostic factor for esophageal cancer patients treated with CRT. Individualized therapeutic approaches should be evaluated in this population.</p

Physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumors

<p>Abstract</p> <p>Background</p> <p>The existence of large pores in the blood-tumor barrier (BTB) of malignant solid tumor microvasculature makes the blood-tumor barrier more permeable to macromolecules than the endothelial barrier of most normal tissue microvasculature. The BTB of malignant solid tumors growing outside the brain, in peripheral tissues, is more permeable than that of similar tumors growing inside the brain. This has been previously attributed to the larger anatomic sizes of the pores within the BTB of peripheral tumors. Since in the physiological state <it>in vivo </it>a fibrous glycocalyx layer coats the pores of the BTB, it is possible that the effective physiologic pore size in the BTB of brain tumors and peripheral tumors is similar. If this were the case, then the higher permeability of the BTB of peripheral tumor would be attributable to the presence of a greater number of pores in the BTB of peripheral tumors. In this study, we probed <it>in vivo </it>the upper limit of pore size in the BTB of rodent malignant gliomas grown inside the brain, the orthotopic site, as well as outside the brain in temporalis skeletal muscle, the ectopic site.</p> <p>Methods</p> <p>Generation 5 (G5) through generation 8 (G8) polyamidoamine dendrimers were labeled with gadolinium (Gd)-diethyltriaminepentaacetic acid, an anionic MRI contrast agent. The respective Gd-dendrimer generations were visualized <it>in vitro </it>by scanning transmission electron microscopy. Following intravenous infusion of the respective Gd-dendrimer generations (Gd-G5, N = 6; Gd-G6, N = 6; Gd-G7, N = 5; Gd-G8, N = 5) the blood and tumor tissue pharmacokinetics of the Gd-dendrimer generations were visualized <it>in vivo </it>over 600 to 700 minutes by dynamic contrast-enhanced MRI. One additional animal was imaged in each Gd-dendrimer generation group for 175 minutes under continuous anesthesia for the creation of voxel-by-voxel Gd concentration maps.</p> <p>Results</p> <p>The estimated diameters of Gd-G7 dendrimers were 11 ± 1 nm and those of Gd-G8 dendrimers were 13 ± 1 nm. The BTB of ectopic RG-2 gliomas was more permeable than the BTB of orthotopic RG-2 gliomas to all Gd-dendrimer generations except for Gd-G8. The BTB of both ectopic RG-2 gliomas and orthotopic RG-2 gliomas was not permeable to Gd-G8 dendrimers.</p> <p>Conclusion</p> <p>The physiologic upper limit of pore size in the BTB of malignant solid tumor microvasculature is approximately 12 nanometers. In the physiologic state <it>in vivo </it>the luminal fibrous glycocalyx of the BTB of malignant brain tumor and peripheral tumors is the primary impediment to the effective transvascular transport of particles across the BTB of malignant solid tumor microvasculature independent of tumor host site. The higher permeability of malignant peripheral tumor microvasculature to macromolecules smaller than approximately 12 nm in diameter is attributable to the presence of a greater number of pores underlying the glycocalyx of the BTB of malignant peripheral tumor microvasculature.</p

Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

<p>Abstract</p> <p>Background</p> <p>Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells.</p> <p>Methods</p> <p>Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured <it>in vivo </it>with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed <it>ex vivo </it>with fluorescence imaging.</p> <p>Results</p> <p>We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells.</p> <p>Conclusion</p> <p>The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.</p

In Vivo Methods to Study Uptake of Nanoparticles into the Brain

Several in vivo techniques have been developed to study and measure the uptake of CNS compounds into the brain. With these techniques, various parameters can be determined after drug administration, including the blood-to-brain influx constant (Kin), the permeability-surface area (PS) product, and the brain uptake index (BUI). These techniques have been mostly used for drugs that are expected to enter the brain via transmembrane diffusion or by carrier-mediated transcytosis. Drugs that have limitations in entering the brain via such pathways have been encapsulated in nanoparticles (based on lipids or synthetic polymers) to enhance brain uptake. Nanoparticles are different from CNS compounds in size, composition and uptake mechanisms. This has led to different methods and approaches to study brain uptake in vivo. Here we discuss the techniques generally used to measure nanoparticle uptake in addition to the techniques used for CNS compounds. Techniques include visualization methods, behavioral tests, and quantitative methods

Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors

Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof

Use of Extended Characteristics of Locomotion and Feeding Behavior for Automated Identification of Lame Dairy Cows.

This study was carried out to detect differences in locomotion and feeding behavior in lame (group L; n = 41; gait score ≥ 2.5) and non-lame (group C; n = 12; gait score ≤ 2) multiparous Holstein cows in a cross-sectional study design. A model for automatic lameness detection was created, using data from accelerometers attached to the hind limbs and noseband sensors attached to the head. Each cow's gait was videotaped and scored on a 5-point scale before and after a period of 3 consecutive days of behavioral data recording. The mean value of 3 independent experienced observers was taken as a definite gait score and considered to be the gold standard. For statistical analysis, data from the noseband sensor and one of two accelerometers per cow (randomly selected) of 2 out of 3 randomly selected days was used. For comparison between group L and group C, the T-test, the Aspin-Welch Test and the Wilcoxon Test were used. The sensitivity and specificity for lameness detection was determined with logistic regression and ROC-analysis. Group L compared to group C had significantly lower eating and ruminating time, fewer eating chews, ruminating chews and ruminating boluses, longer lying time and lying bout duration, lower standing time, fewer standing and walking bouts, fewer, slower and shorter strides and a lower walking speed. The model considering the number of standing bouts and walking speed was the best predictor of cows being lame with a sensitivity of 90.2% and specificity of 91.7%. Sensitivity and specificity of the lameness detection model were considered to be very high, even without the use of halter data. It was concluded that under the conditions of the study farm, accelerometer data were suitable for accurately distinguishing between lame and non-lame dairy cows, even in cases of slight lameness with a gait score of 2.5

Does altered emotional regulation modify visual attention among injured athletes

Swanik, Charles B.Context: Growing evidence suggests both orthopedic and mild traumatic brain injuries (mTBI), such as concussions, may be related to underlying neuropsychological factors potentially affecting sport performance. The ability of a person to visually assess their physical surroundings, fixate on relevant cues and make expedient decisions, can potentially affect the way an individual reacts to certain situations. Within athletics, this visual attention may influence emotional regulation and alter responses that shift a person’s focus, thus affecting decision-making. Past injuries are strong predictors for athletes who tend to get hurt repeatedly, despite physical rehabilitation, and the cause may be due to neuroplastic changes in the brain that affect their attention to images in their visual field and emotional regulation, such as arousal, anxiety and fear. This sequence of events may explain the high incidence of re-injury related to errors in coordination or judgment. Objective: The purpose of this study was to examine the interactions between visual attention, emotional regulation, and injury history/severity among athletes. Design: Post-test only control group design. Participants: 38 NCAA DI student-athletes and club sport athletes (males n=6, females n=32) from the University of Delaware between the ages of 18-30, were recruited into two groups, previously injured (n=29) and healthy controls (n=9). Methods: Each participant completed the Nordic Musculoskeletal Questionnaire (NMEQ-E), Concussion History Questionnaire, Competitive State Anxiety Inventory-2 (CSAI-2), and Extended Sheehan Disability Scale to assess injury history, psychological state, and current physical state. Participants then viewed and rated 30 IAPS images based on valance, arousal, and fear. Visual attention was measured using eye tracking instrumentation (Pupil Labs), which captured pupil dilation, eye fixations/duration and blinks. Statistical Analysis: A two (group) by three (neutral, fear, injury images) analysis of variance (ANOVA, p<0.05) was used to determine if there was a difference between injured and control groups for anxiety, levels of fear, pupil dilation, blinks, number of image fixations, and duration of image fixation among the different types of images. A one-way ANOVA was used to compare group differences in anxiety (CSAI-2). An alpha level of .05 was set a priori to represent statistical significance. An independent t-test was used to assess all dependent variables against both injured and control groups as well as to assess severity (surgery/season ending injury) and frequency (days out of activity) within the control group. Chi square analysis was used when necessary when dependent variables were binary. Results: Individuals with one injury or greater, including season ending injuries and/or surgery, reported significant more total days out and total number of injuries when compared to the control group (p<0.05). The experimental group had a significantly larger pupil diameter when viewing pictures, however the control group reported a greater number of blinks during picture viewing. The experimental group had significantly higher arousal and fear scores (p<0.05), in addition to higher cognitive and somatic anxiety score, and lower self-confidence. The control group had significantly higher valance scores. Tukey post hoc tests showed several significant differences between picture types among the visual attention and emotional regulation variables, but no significant interactions were found between groups. Athletes with more severe injuries also had greater disability, arousal and fear, anxiety, and both fixation number and pupil diameter scores, but lower self-confidence. Conclusion: In aim one, athletes with a history of injuries present with different visual attention characteristics based on pupil diameter, fixation duration and blinks, as well as increased arousal, anxiety and current disability. In aim two, injury severity was also linked to differences in visual attention and emotion regulation. Clinicians and researcher should explore future studies and/or intervention strategies to ameliorate these characteristics, with the aspiration of minimizing the phenomena of recurring injury and disability among athletes.University of Delaware, Department of Kinesiology and Applied PhysiologyM.S

Magnetic pill tracking: a novel non-invasive tool for investigation of human digestive motility.

A new minimally invasive technique allowing for anatomical mapping and motility studies along the entire human digestive system is presented. The technique is based on continuous tracking of a small magnet progressing through the digestive tract. The coordinates of the magnet are calculated from signals recorded by 16 magnetic field sensors located over the abdomen. The magnet position, orientation and trajectory are displayed in real time. Ten young healthy volunteers were followed during 34 h. The technique was well tolerated and no complication was encountered. The information obtained was 3-D configuration of the digestive tract and dynamics of the magnet displacement (velocity, transit time, length estimation, rhythms). In the same individual, repeated examination gave very reproducible results. The anatomical and physiological information obtained corresponded well to data from current methods and imaging. This simple, minimally invasive technique permits examination of the entire digestive tract and is suitable for both research and clinical studies. In combination with other methods, it may represent a useful tool for studies of GI motility with respect to normal and pathological conditions