Are the orthostatic fluid shifts to the calves augmented in autonomic failure?

In autonomic failure (AF), blood pressure (BP) falls upon standing which is commonly ascribed to defective vasoconstriction and excessive pooling. Observations on the amount of pooling in AF are contradictory. We evaluated pooling using strain-gauge plethysmography (SGP) during head-up tilt (HUT) with a parachute harness fixed to the tilt table to avoid muscle tension in the lower limbs and thus to maximise pooling. 23 healthy subjects and 12 patients with AF were tilted for 5 min. BP and calf volume changes, as measured by SGP, were measured continuously. Multiple regression analysis was used to examine the effect of AF on orthostatic fluid shifts after adjustment for potential confounders. Patients did not differ from controls with respect to the increase of calf volume after 5 min HUT. The acute (0-1 min) and the prolonged (1-5 min) phases of calf volume responses to HUT were also similar between patients and controls. No correlation was found between the degree of orthostatic hypotension and the orthostatic calf volume change in AF. In one patient an additional measurement was made before rising from bed in the early morning demonstrating a greater albeit small increase of calf volume upon HUT. Orthostatic fluid shifts at the level of the calf in AF are not augmented during the course of the day despite marked hypotension. However, a small increase of pooling may be expected when the patient first gets out of bed in the morning probably due to the absence of oedema.Paroxysmal Cerebral Disorder

Mutation supply and the repeatability of selection for antibiotic resistance

Whether evolution can be predicted is a key question in evolutionary biology. Here we set out to better understand the repeatability of evolution. We explored experimentally the effect of mutation supply and the strength of selective pressure on the repeatability of selection from standing genetic variation. Different sizes of mutant libraries of an antibiotic resistance gene, TEM-1 $\beta$-lactamase in Escherichia coli, were subjected to different antibiotic concentrations. We determined whether populations went extinct or survived, and sequenced the TEM gene of the surviving populations. The distribution of mutations per allele in our mutant libraries- generated by error-prone PCR- followed a Poisson distribution. Extinction patterns could be explained by a simple stochastic model that assumed the sampling of beneficial mutations was key for survival. In most surviving populations, alleles containing at least one known large-effect beneficial mutation were present. These genotype data also support a model which only invokes sampling effects to describe the occurrence of alleles containing large-effect driver mutations. Hence, evolution is largely predictable given cursory knowledge of mutational fitness effects, the mutation rate and population size. There were no clear trends in the repeatability of selected mutants when we considered all mutations present. However, when only known large-effect mutations were considered, the outcome of selection is less repeatable for large libraries, in contrast to expectations. Furthermore, we show experimentally that alleles carrying multiple mutations selected from large libraries confer higher resistance levels relative to alleles with only a known large-effect mutation, suggesting that the scarcity of high-resistance alleles carrying multiple mutations may contribute to the decrease in repeatability at large library sizes.Comment: 31pages, 9 figure

NARCIS:onderzoekinformatie en onderzoeksresultaten onder één dak

NARCIS, acroniem voor National Academic Research and Collaborations Information Systems, is een geheel nieuwe informatiedienst. NARCIS is een portal voor onderzoekinformatie in brede zin, waarin zowel toegang tot de beschrijvingen van onderzoek wordt geboden als toegang tot de resultaten van onderzoek. NARCIS, mede gerealiseerd dankzij een subsidie van DARE, biedt meer informatie dan DAREnet, dat alleen de repositories ontsluit. NARCIS omvat ook informatie over onderzoekers, programma’s, projecten en onderzoeksinstellingen. NARCIS gebruikt RSS-feeds als attenderingstool. Vernieuwing van informatie-uitwisseling is gerealiseerd door de ontwikkeling van een schema voor de uitwisseling van informatie tussen NWODelfi, KNAW en de METISsen. Deze oplossing leidt tevens tot beperking van de administratieve lastendruk. Voor de geautomatiseerde ontsluiting van de binnen NARCIS beschikbare records wordt gebruikt gemaakt van Collexis

Integrating cross-frequency and within band functional networks in resting-state MEG: A multi-layer network approach

Neuronal oscillations exist across a broad frequency spectrum, and are thought to provide a mechanism of interaction between spatially separated brain regions. Since ongoing mental activity necessitates the simultaneous formation of multiple networks, it seems likely that the brain employs interactions within multiple frequency bands, as well as cross-frequency coupling, to support such networks. Here, we propose a multi-layer network framework that elucidates this pan-spectral picture of network interactions. Our network consists of multiple layers (frequency-band specific networks) that influence each other via inter-layer (cross-frequency) coupling. Applying this model to MEG resting-state data and using envelope correlations as connectivity metric, we demonstrate strong dependency between within layer structure and inter-layer coupling, indicating that networks obtained in different frequency bands do not act as independent entities. More specifically, our results suggest that frequency band specific networks are characterised by a common structure seen across all layers, superimposed by layer specific connectivity, and inter-layer coupling is most strongly associated with this common mode. Finally, using a biophysical model, we demonstrate that there are two regimes of multi-layer network behaviour; one in which different layers are independent and a second in which they operate highly dependent. Results suggest that the healthy human brain operates at the transition point between these regimes, allowing for integration and segregation between layers. Overall, our observations show that a complete picture of global brain network connectivity requires integration of connectivity patterns across the full frequency spectrum

On the feasibility of automatically selecting similar patients in highly individualized radiotherapy dose reconstruction for historic data of pediatric cancer survivors

Purpose: The aim of this study is to establish the first step toward a novel and highly individualized three-dimensional (3D) dose distribution reconstruction method, based on CT scans and organ delineations of recently treated patients. Specifically, the feasibility of automatically selecting the CT scan of a recently treated childhood cancer patient who is similar to a given historically treated child who suffered from Wilms' tumor is assessed.Methods: A cohort of 37 recently treated children between 2- and 6-yr old are considered. Five potential notions of ground-truth similarity are proposed, each focusing on different anatomical aspects. These notions are automatically computed from CT scans of the abdomen and 3D organ delineations (liver, spleen, spinal cord, external body contour). The first is based on deformable image registration, the second on the Dice similarity coefficient, the third on the Hausdorff distance, the fourth on pairwise organ distances, and the last is computed by means of the overlap volume histogram. The relationship between typically available features of historically treated patients and the proposed ground-truth notions of similarity is studied by adopting state-of-the-art machine learning techniques, including random forest. Also, the feasibility of automatically selecting the most similar patient is assessed by comparing ground-truth rankings of similarity with predicted rankings.Results: Similarities (mainly) based on the external abdomen shape and on the pairwise organ distances are highly correlated (Pearson rp ≥ 0.70) and are successfully modeled with random forests based on historically recorded features (pseudo-R2 ≥ 0.69). In contrast, similarities based on the shape of internal organs cannot be modeled. For the similarities that random forest can reliably model, an estimation of feature relevance indicates that abdominal diameters and weight are the most important. Experiments on automatically selecting similar patients lead to coarse, yet quite robust results: the most similar patient is retrieved only 22% of the times, however, the error in worst-case scenarios is limited, with the fourth most similar patient being retrieved.Conclusions: Results demonstrate that automatically selecting similar patients is feasible when focusing on the shape of the external abdomen and on the position of internal organs. Moreover, whereas the common practice in phantom-based dose reconstruction is to select a representative phantom using age, height, and weight as discriminant factors for any treatment scenario, our analysis on abdominal tumor treatment for children shows that the most relevant features are weight and the anterior-posterior and left-right abdominal diameters

Diaphragm and abdominal organ motion during radiotherapy:a comprehensive multicenter study in 189 children

Background: For accurate thoracic and abdominal radiotherapy, inter- and intrafractional geometrical uncertainties need to be considered to enable accurate margin sizes. We aim to quantify interfractional diaphragm and abdominal organ position variations, and intrafractional diaphragm motion in a large multicenter cohort of pediatric cancer patients (&lt; 18 years). We investigated the correlation of interfractional position variations and intrafractional motion with age, and with general anesthesia (GA). Methods: In 189 children (mean age 8.1; range 0.4–17.9 years) from six institutes, interfractional position variation of both hemidiaphragms, spleen, liver, left and right kidneys was quantified using a two-step registration. CBCTs were registered to the reference CT relative to the bony anatomy, followed by organ registration. We calculated the group mean, systematic and random errors (standard deviations Σ and σ, respectively) in cranial-caudal (CC), left-right and anterior-posterior directions. Intrafractional right hemidiaphragm motion was quantified using CBCTs on which the breathing amplitude, defined as the difference between end-inspiration and end-expiration peaks, was assessed (N = 79). We investigated correlations with age (Spearman’s ρ), and differences in motion between patients treated with and without GA (N = 75; all &lt; 5.5 years). Results: Interfractional group means were largest in CC direction and varied widely between patients, with largest variations in the right hemidiaphragm (range -13.0–17.5 mm). Interfractional group mean of the left kidney showed a borderline significant correlation with age (p = 0.047; ρ = 0.17). Intrafractional right hemidiaphragm motion in patients ≥ 5.5 years (mean 10.3 mm) was significantly larger compared to patients &lt; 5.5 years treated without GA (mean 8.3 mm) (p = 0.02), with smaller Σ and σ values. We found a significant correlation between breathing amplitude and age (p &lt; 0.001; ρ = 0.43). Interfractional right hemidiaphragm position variations were significantly smaller in patients &lt; 5.5 years treated with GA than without GA (p = 0.004), but intrafractional motion showed no significant difference. Conclusion: In this large multicenter cohort of children undergoing thoracic and abdominal radiotherapy, we found that interfractional position variation does not depend on age, but the use of GA in patients &lt; 5.5 years showed smaller systematic and random errors. Furthermore, our results showed that breathing amplitude increases with age. Moreover, variations between patients advocate the need for a patient-specific margin approach.</p

A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty

__Background:__ The likelihood of restenosis is a major limitation of coronary angioplasty. We studied whether hirudin, a highly selective inhibitor of thrombin with irreversible effects, would prevent restenosis after angioplasty. We compared two regimens of recombinant hirudin with heparin. __Methods:__ We randomly assigned 1141 patients with unstable angina who were scheduled for angioplasty to receive one of three treatments: (1) a bolus dose of 10,000 IU of heparin followed by an intravenous infusion of heparin for 24 hours and subcutaneous placebo twice daily for three days (382 patients), (2) a bolus dose of 40 mg of hirudin followed by an intravenous infusion of hirudin for 24 hours and subcutaneous placebo twice daily for three days (381 patients), or (3) the same hirudin regimen except that 40 mg of hirudin was given subcutaneously instead of placebo twice daily for three days (378 patients). The primary end point was event-free survival at seven months. Other end points were early cardiac events (within 96 hours), bleeding and other complications of the study treatment, and angiographic measurements of coronary diameter at six months of follow-up. __Results:__ At seven months, event-free survival was 67.3 percent in the group receiving heparin, 63.5 percent in the group receiving intravenous hirudin, and 68.0 percent in the group receiving both intravenous and subcutaneous hirudin (P=0.61). However, the administration of hirudin was associated with a significant reduction in early cardiac events, which occurred in 11.0, 7.9, and 5.6 percent of patients in the respective groups (combined relative risk with hirudin, 0.61; 95 percent confidence interval, 0.41 to 0.90; P=0.023). The mean minimal luminal diameters in the respective groups on follow-up angiography at six months were 1.54, 1.47, and 1.56 mm. __Conclusions:__ Although significantly fewer early cardiac events occurred with hirudin than with heparin, hirudin had no apparent benefit with longer-term follow-up

Relating anatomical variations and patient features with dose-reconstruction accuracy of a 3D dose-reconstruction approach using CT scans of recently-treated children

Purpose Reconstructing 3D dose distributions for pre-1990 pediatric 2D radiotherapy plans is challenging, but key to research on late adverse effects. We studied the relation between dosimetric accuracy, anatomical variation, and other patient features of a 3D dose-reconstruction approach using CT scans of recently-treated patients, rather than phantoms. Materials and methods CT-scans of 22 Wilms’ tumor patients (age:2.5-5.3yrs; n boys/girls:11/11) treated between 2004 and 2015 were included. Two clinical plans as applied to a 4-year-old boy and girl with a left-sided Wilms’ tumor served as references. Each plan was applied to the CT scans of the other 21 patients, adjusted to correct for anatomical differences as visible in digitally-reconstructed-radiographs, and the resulting dose was calculated. Deviations in reconstructed dose, with respect to the reference dose, in organs-at-risk (spinal cord, right kidney, liver, and spleen) were characterized by the mean dose error normalized by the prescribed dose (DEmean). Deviations in organs’ location relative to a reference point (\Delta O_loc) and in organs’ shape captured by the Dice coefficient (DC) were calculated. We estimated the Pearson’s correlation between DEmean, on the one hand, and O­loc, DC, gender, age, height, and weight, on the other hand. Results Average(range) DEmean values were: spinal cord:3(0-8)%; right kidney:6(0-20)%; liver:9(0-20)%; and spleen:23(0-80)%. DC and DEmean in the right kidney were moderately negatively correlated (r2=0.41). DEmean in the liver was uncorrelated with any o