Improving hybrid image and structure-based deformable image registration for large internal deformations.

Objective.Deformable image registration (DIR) is a widely used technique in radiotherapy. Complex deformations, resulting from large anatomical changes, are a regular challenge. DIR algorithms generally seek a balance between capturing large deformations and preserving a smooth deformation vector field (DVF). We propose a novel structure-based term that can enhance the registration efficacy while ensuring a smooth DVF.Approach.The proposed novel similarity metric for controlling structures was introduced as a new term into a commercially available algorithm. Its performance was compared to the original algorithm using a dataset of 46 patients who received pelvic re-irradiation, many of which exhibited complex deformations.Main results.The mean Dice Similarity Coefficient (DSC) under the improved algorithm was 0.96, 0.94, 0.76, and 0.91 for bladder, rectum, colon, and bone respectively, compared to 0.69, 0.89, 0.62, and 0.88 for the original algorithm. The improvement was more pronounced for complex deformations.Significance.With this work, we have demonstrated that the proposed term is able to improve registration accuracy for complex cases while maintaining realistic deformations.

Intra-fractional per-beam adaptive workflow to mitigate the need for a rotating gantry during MRI-guided proton therapy.

The integration of real-time magnetic resonance imaging (MRI) guidance and proton therapy would potentially improve the proton dose steering capability by reducing daily uncertainties due to anatomical variations. The use of a fixed beamline coupled with an axial patient couch rotation would greatly simplify the proton delivery with MRI guidance. Nonetheless, it is mandatory to assure that the plan quality is not deteriorated by the anatomical deformations due to patient rotation. In this work, an in-house tool allowing for intra-fractional per-beam adaptation of intensity-modulated proton plans (BeamAdapt) was implemented through features available in RayStation. A set of three MRIs was acquired for two healthy volunteers (V1,V2): (1) no rotation/static, (2) rotation to the right and (3) left.V1was rotated by 15°, to simulate a clinical pediatric abdominal case andV2by 45°, to simulate an extreme patient rotation case. For each volunteer, a total of four intensity-modulated pencil beam scanning plans were optimized on the static MRI using virtual abdominal targets and two-three posterior-oblique beams. Beam angles were defined according to the angulations on the rotated MRIs. With BeamAdapt, each original plan was initially converted into separate plans with one beam per plan. In an iterative order, individual beam doses were non-rigidly deformed to the rotated anatomies and re-optimized accounting for the consequent deformations and the beam doses delivered so far. For evaluation, the final accumulated dose distribution was propagated back to the static MRI. Planned and adapted dose distributions were compared by computing relative differences between dose-volume histogram metrics. Absolute target dose differences were on average below 1% and organs-at-risk mean dose differences were below 3%. With BeamAdapt, not only intra-fractional per-beam proton plan adaptation coupled with axial patient rotation is possible but also the need for a rotating gantry during MRI guidance might be mitigated.

Single bunch X-ray pulses on demand from a multi-bunch synchrotron radiation source.

Synchrotron radiation facilities routinely operate in a multi-bunch regime, but applications relying on time-of-flight schemes require single bunch operation. Here we show that pulse picking by resonant excitation in a storage ring creates in addition to the multi-bunch operation a distinct and separable single bunch soft X-ray source. It has variable polarization, a photon flux of up to 10(7)-10(9) ph s(-1)/0.1%BW at purity values of 10(4)-10(2) and a repetition rate of 1.25 MHz. The quasi-resonant excitation of incoherent betatron oscillations of electrons allows horizontal pulse separation at variable (also circular) polarization accessible for both, regular 30 ps pulses and ultrashort pulses of 2-3 ps duration. Combined with a new generation of angularly resolving electron spectrometers this creates unique opportunities for time-resolved photoemission studies as confirmed by time-of-flight spectra. Our pulse picking scheme is particularly suited for surface physics at diffraction-limited light sources promising ultimate spectral resolution.

Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy.

Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC.

Large tunable Rashba spin splitting of a two-dimensional electron gas in Bi2Se3.

We report a Rashba spin splitting of a two-dimensional electron gas in the topological insulator Bi(2)Se(3) from angle-resolved photoemission spectroscopy. We further demonstrate its electrostatic control, and show that spin splittings can be achieved which are at least an order-of-magnitude larger than in other semiconductors. Together these results show promise for the miniaturization of spintronic devices to the nanoscale and their operation at room temperature.

Succinate independently stimulates full platelet activation via cAMP and phosphoinositide 3-kinase-ß signaling.

BACKGROUND: The citric cycle intermediate succinate has recently been identified as a ligand for the G-protein-coupled receptor (GPCR) SUCNR1. We have previously found that this receptor is one of the most highly expressed GPCRs in human platelets. OBJECTIVE: The aim of this study was to investigate the role of SUCNR1 in platelet aggregation and to explore the signaling pathways of this receptor in platelets. METHODS AND RESULTS: Using real-time-PCR, we demonstrated that SUCNR1 is expressed in human platelets at a level corresponding to that of the P2Y(1) receptor. Light transmission aggregation experiments showed dose-dependent aggregation induced by succinate, reaching a maximum response at 0.5 mM. The effect of succinate on platelet aggregation was confirmed with flow cytometry, showing increased surface expression of activated glycoprotein IIb-IIIa and P-selectin. Intracellular SUCNR1 signaling was found to result in decreased cAMP levels, Akt phosphorylation mediated by phosphoinositide 3-kinase-ß activation, and receptor desensitization. Furthermore, succinate-induced platelet aggregation was demonstrated to depend on Src, generation of thromboxane A(2), and ATP release. Platelet SUCNR1 is subject to desensitization through both homologous and heterologous mechanisms. In addition, the P2Y(12) receptor inhibitor ticagrelor completely prevented platelet aggregation induced by succinate. CONCLUSIONS: Our experiments show that succinate induces full aggregation of human platelets via SUCNR1. Succinate-induced platelet aggregation depends on thromboxane A(2) generation, ATP release, and P2Y(12) activation.

The diagnostic accuracy of dual-view digital mammography, single-view breast tomosynthesis and a dual-view combination of breast tomosynthesis and digital mammography in a free-response observer performance study.

The purpose of the present study was to compare the diagnostic accuracy of dual-view digital mammography (DM), single-view breast tomosynthesis (BT) and BT combined with the opposite DM view. Patients with subtle lesions were selected to undergo BT examinations. Two radiologists who are non-participants in the study and have experience in using DM and BT determined the locations and extents of lesions in the images. Five expert mammographers interpreted the cases using the free-response paradigm. The task was to mark and rate clinically reportable findings suspicious for malignancy and clinically relevant benign findings. The marks were scored with reference to the outlined regions into lesion localization or non-lesion localization, and analysed by the jackknife alternative free-response receiver operating characteristic method. The analysis yielded statistically significant differences between the combined modality and dual-view DM (p < 0.05). No differences were found between single-view BT and dual-view DM or between single-view BT and the combined modality.

Predictors for outcome after vacuum assisted closure therapy of peri-vascular surgical site infections in the groin.

OBJECTIVES: To assess outcomes (wound healing, amputation and mortality) after vacuum assisted closure (VAC) therapy of peri-vascular surgical site infections in the groin after arterial surgery. DESIGN: Retrospective study. MATERIALS: Thirty-three groins received VAC therapy between August 2004 and December 2006 at Vascular Centre, Malmö University Hospital. METHODS: Following surgical revision, VAC therapy was applied in the groin at a continuous topical negative pressure of 125 mmHg. The median follow up time was 16 months. RESULTS: Median age was 75 years. Twenty-three (70%) cases underwent surgery for lower limb ischaemia. Intestinal flora was present in 88% of the wound cultures. Median duration of VAC therapy was 20 days and 27 (82%) wounds healed within 55 days. One serious VAC associated bleeding and three late false femoral artery aneurysms were reported. The median cost of VAC treatment was 2.7% of the in-hospital costs. Synthetic vascular graft infection (n=21) was associated with adverse infection-related events (n=9; p=0.012). Non-healing wounds were associated with amputation (p=0.005) and death (p<0.001). CONCLUSIONS: VAC treated synthetic vascular graft infections in the groin were at a greater risk of developing infection-related complications. Non-healing surgical site infections after VAC therapy were associated with amputation and death.

Synchrotron radiation study of chloromethane clusters: effects of polarizability and dipole moment on core level chemical shifts.

Free neutral chloromethane clusters have been produced by adiabatic expansion and investigated by means of photoelectron spectroscopy. By studying the differences between the cluster binding energy shifts at the Cl 2p and C 1s thresholds we have shown that antiparallel packing is the dominant local structure of the clusters. This geometry is induced by the polar character of the constituent molecules, and it accords with the structures of chloromethane solids and dimers. Furthermore, results obtained from the analysis of the outer valence levels of the clusters support the suggested local structure. The roles of the polarizability and of the dipole moment of the constituent molecules in the cluster binding energy shifts are discussed in comparison with a recent investigation of bromomethane clusters.

Postcollision interaction in noble gas clusters: observation of differences in surface and bulk line shapes.

The surface and bulk components of the x-ray photoelectron spectra of free noble gas clusters are shown to display differences in the influence of postcollision interaction between the photoelectron and the Auger electron on the spectral line shape; the bulk component is observed to be less affected than the surface and atomic parts of the spectra. A model for postcollision interaction in nonmetallic solids and clusters is also provided which takes the polarization screening into account. Core-level photoelectron spectra of Ar, Kr, and Xe have been recorded to verify the dependence of the postcollision interaction effect on the polarizability of the sample.

Anatomical mismatch of the pulmonary autograft in the aortic root may be the cause of early aortic insufficiency after the Ross procedure.

OBJECTIVE: Early aortic insufficiency can be a problem after the Ross procedure. Anatomical mismatch and an inexact surgical technique may lead to distortion of the normal pulmonary valve geometry and subsequent incorrect leaflet coaptation and valve insufficiency. In this study, we assessed the efficacy of changing and improving the surgical technique to minimize the early pulmonary autograft valve failure. The modifications and the strategy are discussed. METHODS: From January 1995 to February 1999, a total of 77 adults underwent the Ross procedure for aortic valve replacement at Sahlgrenska University Hospital. The operative technique used was full free-standing aortic root replacement with a pulmonary autograft in all cases. In the first 24 cases, the diameter of the pulmonary roots was seldom measured, eye-balling was used to exclude anatomical mismatch due to a dilated aortic root, and only one attempt of correction was made, which failed. In the other 53 cases, the technique was improved by: (1) reducing the aortic anulus diameter in cases with moderate dilatation; (2) excluding cases with severe dilatation of the aortic annulus; (3) adjusting the diameter of the sinotubular junction of the aorta to the diameter of the sinotubular junction of the pulmonary artery; (4). reimplanting the left ostium in the autograft, and (5) changing the proximal anastomosis technique. RESULTS: In this study, we had an early aortic incompetence of grade 2 in eight patients among the first 24 patients. In the other 53 patients, postoperative echocardiography at 1 week revealed aortic insufficiency of grade 2 in two patients. CONCLUSIONS: Aortic insufficiency after the Ross procedure can be minimized by patient selection, intraoperative correction of anatomical mismatch and improved surgical technique.

Protein adsorption to oligo(ethylene glycol) self-assembled monolayers: experiments with fibrinogen, heparinized plasma, and serum.

Low protein adsorption is believed advantageous for blood-contacting materials and ethylene glycols (EG)-based polymeric compounds are often attached to surfaces for this purpose. In the present study, the adsorption of fibrinogen, serum, and plasma were studied by ellipsometry on a series of well-defined oligo(EG) terminated alkane-thiols self-assembled on gold. The layers were prepared with compounds of the general structure HS-(CH2)15-CONH-EGn, where n = 2, 4, and 6. Methoxy-terminated tri(EG) undecanethiol and hydroxyl-terminated hexadecanethiol self-assembled monolayers (SAMs) were used as references. The results clearly demonstrate that the adsorption depends on the experimental conditions with small amounts of fibrinogen adsorbing from a single protein solution, but larger amounts of proteins from serum and plasma. The adsorption of fibrinogen and blood plasma decreased with an increasing number of EG repeats and was temperature-dependent. Significantly less serum adsorbed to methoxy tri(EG) than to hexa(EG) and more proteins remained on the latter surface after incubation in a sodium dodecyl sulfate (SDS) solution, indicating a looser protein binding to the methoxy-terminated surface. All surfaces adsorbed complement factor 3 (C3) from serum and plasma, although no surface-mediated complement activation was observed. The present study points to the importance of a careful choice of the protein model system before general statements regarding the protein repellant properties of potential surfaces can be made.

The importance of grade 2 ischemic mitral regurgitation in coronary artery bypass grafting.

OBJECTIVE: To study if grade 2 ischemic mitral regurgitation (MR) influences outcome after coronary artery bypass grafting (CABG). METHODS: Results of all CABG patients with grade 2/4 ischemic MR operated during 1995--1998 (n = 89) were compared with all CABG patients without MR (n = 4709) during the same period. To further evaluate patients with grade 2 ischemic MR, a case-control study focusing on functional status was performed. Control patients without MR (n = 89) were matched for age, gender and left ventricular ejection fraction. All patients were interviewed regarding angina symptoms and functional status. RESULTS: Survival according to Kaplan--Meier at 1 and 3 years were inferior in the MR group compared to all CABG patients (91 vs 96% and 84 vs 92%, respectively (P = 0.0017). However, MR patients were older (68 +/- 9 vs 65 +/- 9 years (mean +/- SD), P = 0.008) and had an inferior preoperative left ventricular ejection fraction (42 +/- 14 vs 58 +/- 14%, P < 0.0001). In the case-control study, New York Heart Association (NYHA) class and Higgins' risk score differed preoperatively between the MR group and controls. Neither 30-day mortality (4,5% in both groups) nor survival at 1 (91 vs 93%) and 3 years (84 vs 88%) differed significantly. NYHA class and angina class (Canadian Cardiovascular Society, CCS) improved similarly in both groups. Postoperatively, 62% of the patients in the MR group had reduced, 36% unchanged and 2% increased MR. CONCLUSIONS: CABG on patients with grade 2 ischemic MR reduces angina pectoris and improves functional status to the same extent as in CABG patients without MR. Postoperative morbidity and mortality do not differ significantly between the groups. Grade of MR is reduced or unchanged after CABG in patients with grade 2 ischemic MR. The study supports an operative strategy where grade 2 ischemic mitral regurgitation is treated by CABG alone but the result do not exclude that there might be individual patients that would benefit from a valvular or annular procedure in combination with CABG. How these patients should be identified remains unclear.

Synthesis of a series of oligo(ethylene glycol)-terminated alkanethiol amides designed to address structure and stability of biosensing interfaces.

A strategy for the synthesis of a series of closely related oligo(ethylene glycol)-terminated alkanethiol amides (principally HS(CH(2))(m)CONH(CH(2)CH(2)O)(n)H; m = 2, 5, 11, 15, n = 1, 2, 4, 6, 8, 10, 12) and analogous esters has been developed. These compounds were made to study the structure and stability of self-assembled monolayers (SAMs) on gold in the prospect of designing new biosensing interfaces. For this purpose, monodisperse heterofunctional oligo(ethylene glycols) with up to 12 units were prepared. Selective monoacylation of the symmetrical tetra- and hexa(ethylene glycol) diols as their mesylates with the use of silver(I) oxide was performed. The synthetic approach was based on carbodiimide couplings of various oligo(ethylene glycol) derivatives to omega-(acetylthio) carboxylic acids via a terminal amino or hydroxyl function. SAM structures on gold were studied with respect to thickness, wettability (water contact angles approximately 30 degrees ), and conformation. A good fit was obtained for the relation between monolayer thickness (d) and the number of units in the oligo(ethylene glycol) chain (n): d = 2.8n + 21.8 (A). Interestingly, the corresponding infrared spectroscopy analysis showed a dramatic change in conformation of the oligomeric chains from all-trans (n = 4) to helical (n > or = 6) conformation. A crystalline helical structure was observed in the SAMs for n > 6.

[A case report. Endometriosis caused colonic ileus, ureteral obstruction and hypertension]. / Fallbeskrivning. Endometrios orsakade kolonileus, uretärobstruktion och hypertoni.

Laparoscopy and palpation offer only a rough estimate of the extent of endometriosis. Consequently, endometriosis involving the bowels and urinary tract is under-diagnosed. Bowel obstruction and retroperitoneal endometriosis with obstruction of the ureter are uncommon conditions, but awareness of them is important. Ureteric obstruction develops slowly from periureteral fibrosis and often results in an asymptomatic hydronephrosis, loss of renal function and hypertension. Although renography is the first line of choice in investigation of the upper urinary tract in cases of suspected ureteric obstruction, ultrasound of the kidneys may be useful in the hands of the experienced gynecologist as a screening tool at consultation. The rationale for this recommendation is that ureteric obstruction and hydronephrosis often occur simultaneously. We present a case with bowel obstruction mimicking sigmoid carcinoma, ureteric obstruction and hypertension, caused by endometriosis, where the diagnostic difficulties are illustrated. Collaboration between gynecologist and urologist is essential in selected cases of endometriosis.

[Policy document. Catheter-based diagnosis and treatment of coronary diseases]. / Policydokument. Kateterburen diagnostik och behandling av kranskärlssjukdom.

Diagnostic coronary angiography and percutaneous coronary interventions (PCI) are rapidly developing fields. In-house thoracic surgery backup is no longer a prerequisite for PCI. The demand for physicians trained in interventional cardiology has created a need to formalise such education. The Swedish societies of cardiology and thoracic radiology have agreed on a policy document establishing the details of this education. It is the responsibility of the tutor to decide when the pupil has achieved adequate skills.

Mammalian alcohol dehydrogenase - functional and structural implications.

Mammalian alcohol dehydrogenase (ADH) constitutes a complex system with different forms and extensive multiplicity (ADH1-ADH6) that catalyze the oxidation and reduction of a wide variety of alcohols and aldehydes. The ADH1 enzymes, the classical liver forms, are involved in several metabolic pathways beside the oxidation of ethanol, e.g. norepinephrine, dopamine, serotonin and bile acid metabolism. This class is also able to further oxidize aldehydes into the corresponding carboxylic acids, i.e. dismutation. ADH2, can be divided into two subgroups, one group consisting of the human enzyme together with a rabbit form and another consisting of the rodent forms. The rodent enzymes almost lack ethanol-oxidizing capacity in contrast to the human form, indicating that rodents are poor model systems for human ethanol metabolism. ADH3 (identical to glutathione-dependent formaldehyde dehydrogenase) is clearly the ancestral ADH form and S-hydroxymethylglutathione is the main physiological substrate, but the enzyme can still oxidize ethanol at high concentrations. ADH4 is solely extrahepatically expressed and is probably involved in first pass metabolism of ethanol beside its role in retinol metabolism. The higher classes, ADH5 and ADH6, have been poorly investigated and their substrate repertoire is unknown. The entire ADH system can be seen as a general detoxifying system for alcohols and aldehydes without generating toxic radicals in contrast to the cytochrome P450 system.

L-NAME-induced dispersion of melanosomes in melanophores activates PKC, MEK and ERK1.

Melanosome movement represents a good model of cytoskeleton-mediated transport of organelles in eukaryotic cells. We recently observed that inhibiting nitric oxide synthase (NOS) with Nomega-nitro-L-arginine methyl ester (L-NAME) induced dispersion in melanophores pre-aggregated with melatonin. Activation of cyclic adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA) or calcium-dependent protein kinase (PKC) is known to cause dispersion. Also, PKC and NO have been shown to regulate the mitogen/extracellular signal-regulated kinase (MEK)-ERK pathway. Accordingly, our objective was to further characterize the signaling pathway of L-NAME-induced dispersion. We found that the dispersion was decreased by staurosporine and PD98059, which respectively inhibit PKC and MEK, but not by the PKA inhibitor H89. Furthermore, Western blotting revealed that ERK1 kinase was phosphorylated in L-NAME-dispersed melanophores. L-NAME also caused dispersion in latrunculin-B-treated cells, suggesting that this effect is not due to inhibition of the melatonin signaling pathway. Summarizing, we observed that PKC and MEK inhibitors decreased the L-NAME-induced dispersion, which caused phosphorylation of ERK1. Our results also suggest that NO is a negative regulator of phosphorylations that leads to organelle transport.

Melatonin-induced organelle movement in melanophores is coupled to tyrosine phosphorylation of a high molecular weight protein.

Melanophores, brown to black pigment cells from, for example, Xenopus laevis, contain mobile melanin filled organelles, and are well suited for studies on organelle movement. The intracellular regulation of the movement seems to be controlled by serine and threonine phosphorylations and dephosphorylations. Melatonin induces aggregation of the melanosomes to the cell centre through a G(i/o)-protein-coupled receptor, Mel1c, which leads to an inhibition of PKA and a stimulation of PP2A. However, this study shows that the melatonin-induced aggregation of melanosomes is also accompanied by tyrosine phosphorylation of a protein with a molecular weight of approximately 280 kDa. Cells pre-incubated with genistein, an inhibitor of tyrosine phosphorylations, showed inhibited melanosome movement after melatonin stimulation, and a lower degree of tyrosine phosphorylation of the approximately 280 kDa protein. The adenylyl cyclase activator forskolin, and the G(i/o) protein inhibitor pertussis toxin, also inhibited tyrosine phosphorylation of the approximately 280 kDa protein. The results indicate that melatonin stimulation generates tyrosine phosphorylation of a high molecular weight protein, an event that seems to be essential for melanosome aggregation.

Changes in beta(2)-adrenoceptor expression and in adenylyl cyclase and phosphodiesterase activity in human uterine leiomyomas.

Uterine leiomyoma is a very common benign tumour with unclear pathophysiology in adult women. In the present study we have investigated the expression level of alpha(2)- and beta(2)-adrenoceptors, and the adenylyl cyclase and phosphodiesterase activity in leiomyoma tissue compared with adjacent myometrium. Our results show that the alpha(2)/beta(2)-adrenoceptor ratio is increased in leiomyoma, due to a significant decrease in beta(2)-adrenoceptor expression. These changes were not due to an increased innervation, as the tumour tissue was completely devoid of nerve fibres. Moreover, the adenylyl cyclase activity of leiomyoma membranes was found to be approximately 50% lower, whereas the phosphodiesterase activity was significantly increased (by approximately 100%). We found that stimulating an increase in intracellular cyclic AMP, by adenylyl cyclase activity through beta(2)-adrenoceptors (isoprenaline), by direct enzyme activation (forskolin), or by inhibition of phosphodiesterase activity (papaverine), potently blocked both protein and DNA synthesis in cultured leiomyoma smooth muscle cells. Our results imply the adrenoceptors might be involved in, or a consequence of, leiomyoma growth. The results also suggest a new interesting approach for leiomyoma pharmacotherapy.