Evidence for Coexisting Shapes through Lifetime Measurements in

The lifetimes of the first excited 2^{+}, 4^{+}, and 6^{+} states in ^{98}Zr were measured with the recoil-distance Doppler shift method in an experiment performed at GANIL. Excited states in ^{98}Zr were populated using the fission reaction between a 6.2 MeV/u ^{238}U beam and a ^{9}Be target. The γ rays were detected with the EXOGAM array in correlation with the fission fragments identified by mass and atomic number in the VAMOS++ spectrometer. Our result shows a very small B(E2;2_{1}^{+}→0_{1}^{+}) value in ^{98}Zr, thereby confirming the very sudden onset of collectivity at N=60. The experimental results are compared to large-scale Monte Carlo shell model and beyond-mean-field calculations. The present results indicate the coexistence of two additional deformed shapes in this nucleus along with the spherical ground state.

Major involvement of trunk muscles in myotonic dystrophy type 1.

OBJECTIVES: The motor impairments in Myotonic Dystrophy 1 (DM1) are assumed to progress from distal toward proximal parts of the extremities in the Juvenile and Adult forms of DM1. On occasion and late in progress spine deformity is observed. In this study we have examined whether and to what extent trunk muscles are impaired in DM1, and if this impairment is correlated with the duration of the disorder, walking capacity, mobility, balance, and CTG-repeats. MATERIALS & METHODS: Manual muscle testing (MMT) of skeletal muscle strength in trunk and extremities, reassessment of the mutation size, time since first symptom, the 6 min walk test (6MWT), Rivermead mobility index (RIM) and Timed up & go (TUG) were sampled in 38 adult DM1 outpatients. RESULTS: We found significant impairment in trunk muscles. Trunk muscle strength decreased significantly with increasing mutation size (r = -0.64, P < 0.001). Reduced walking capacity, mobility and balance were significantly related to decreased trunk muscle strength. CONCLUSION: DM1 affects trunk muscle groups. The trunk impairments seem to occur relatively early in disease progression. Awareness of trunk impairments may be of importance for everyday functioning and for understanding the risk of injuries due to falls reported among DM1 patients. It may also help in identification of DM1 patients and considered outcome measure in future clinical trials.

Symptomatic and asymptomatic secondary transmission of Cryptosporidium parvum following two related outbreaks in schoolchildren.

Two related outbreaks (in 2009 and 2012) of cryptosporidiosis in Norwegian schoolchildren during a stay at a remote holiday farm provided us with a natural experiment to investigate possible secondary transmission of Cryptosporidium parvum IIa A19G1R1. After the children had returned home, clinical data and stool samples were obtained from their household contacts. Samples were investigated for the presence of Cryptosporidium oocysts by immunofluorescence antibody test. We found both asymptomatic and symptomatic infections, which are likely to have been secondary transmission. Laboratory-confirmed transmission rate was 17% [4/23, 95% confidence interval (CI) 7·0-37·1] in the 2009 outbreak, and 0% (95% CI 0-16·8) in the 2012 outbreak. Using a clinical definition, the probable secondary transmission rate in the 2012 outbreak was 8% (7/83, 95% CI 4·1-16·4). These findings highlight the importance of hygienic and public health measures during outbreaks or individual cases of cryptosporidiosis. We discuss our findings in light of previous studies reporting varying secondary transmission rates of Cryptosporidium spp.

Prognostic value of systemic inflammation-based markers in advanced pancreatic cancer.

BACKGROUND: The prognostic significance of various systemic inflammation-based markers has been explored in different cancers. These markers can be used to assist with decision-making in oncology clinics. AIM: The aim of this study was to investigate the prognostic significance of three systemic inflammation-based factors: neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and modified Glasgow Prognostic Score (mGPS) in patients with advanced pancreatic cancer. METHODS: Data were collected retrospectively for advanced pancreatic cancer patients treated between 1 January 2008 and 31 December 2012 at the Royal Perth Hospital. The ratios were dichotomised as <5 versus ≥5 for NLR and <200 versus ≥200 for PLR. Modified Glasgow Prognostic Scores were scored as: mGPS '0' = both C-reactive protein (CRP) and albumin normal, mGPS '1' = elevated CRP < 10 mg/L and mGPS '2' = both elevated CRP > 10 mg/L and albumin < 35 g/L. Univariate and multivariate analyses were carried out. RESULTS: Data were evaluable for 124 patients. Median survivals based on the three inflammation-based prognostic markers evaluated were: NLR <5 versus ≥5 = 8.5 months versus 2.6 months respectively (P = 0.0007; hazard ratio (HR) 1.81), PLR <200 versus ≥200 = 9.1 months versus 4 months respectively (P = 0.007; HR 1.64) and mGPS score 1, 2, 3 = 8.3 months, 9.6 months and 1.8 months respectively (P = 0.0004). Besides Eastern Cooperative Oncology Group performance status, NLR, PLR and mGPS were significant independent prognostic markers both on univariate as well as multivariate analysis. CONCLUSIONS: Our findings suggest that the NLR, PLR and mGPS derived from routine blood tests can be used as clinically meaningful biomarkers to stratify advanced pancreatic cancer patients into different prognostic groups.

Hospital-based antimicrobial stewardship in Denmark, Greenland and the Faroe Islands - current landscape and barriers.

OBJECTIVES: To describe the current organization and implementation of formalized, multi-disciplinary hospital-based antimicrobial stewardship (AMS) structures in Denmark, the Faroe Islands and Greenland. METHODS: A structured electronic questionnaire was sent to all trainees and specialists in clinical microbiology (N=207) and infectious diseases (N=260), as well as clinical pharmacists (N=20) and paediatricians (N=10) with expertise in infectious diseases. The survey had 30 multiple-choice, rating-scale, and open-ended questions based on an international consensus checklist for hospital AMS, adapted to a Danish context. RESULTS: Overall, 145 individual responses representing 20 hospitals were received. Nine hospitals (45%) reported a formal AMS strategy, eight (40%) a formal organizational multi-disciplinary structure and a multi-disciplinary AMS team, and six (30%) a designated professional as a leader of the AMS team. A majority of hospitals reported access to updated guidelines (80%) and regularly monitored and reported the quantity of antibiotics prescribed (70% and 65%, respectively). Only one hospital (5%) reported a dedicated, sustainable and sufficient AMS budget, three hospitals (15%) audited courses of therapy for specific agents/clinical conditions and four hospitals (20%) had a document clearly defining roles, procedures of collaboration and responsibilities for AMS. A total of 42% of all individual respondents had received formal AMS training. Main barriers were a lack of financial resources (52%), a lack of mandate from the hospital management (30%) and AMS not being a priority (18%). CONCLUSIONS: Core elements important for multi-disciplinary hospital-based AMS can be strengthened in Danish hospitals. Funding, clear mandates, prioritization from the hospital management and the implementation of multi-disciplinary AMS structures may help close the identified gaps.

Evidence for the dipole nature of the low-energy γ enhancement in 56Fe.

The γ-ray strength function of 56Fe has been measured from proton-γ coincidences for excitation energies up to ≈11 MeV. The low-energy enhancement in the γ-ray strength function, which was first discovered in the (3He,αγ)56Fe reaction, is confirmed with the (p,p'γ)56Fe experiment reported here. Angular distributions of the γ rays give for the first time evidence that the enhancement is dominated by dipole transitions.

Tumour basement membrane laminin expression predicts outcome following curative resection of pancreatic head cancer.

BACKGROUND: Although widely fragmented BMs have been associated with adverse outcome in several cancer types, comparatively little is known with respect to its effect on the prognosis of pancreatic cancer. The aim of the current study was therefore to determine the prognostic value of tumour basement membrane (BM) continuity in two anatomically closely related, however, prognostically different tumours, pancreatic head- and periampullary cancer. METHODS: Tumour BM continuity was determined by immunohistochemical staining of its two major components, laminin and collagen type IV. Associations were made with recurrence free survival (RFS), cancer-specific survival (CSS), overall survival (OS) and conventional prognostic factors. RESULTS: Fifty-nine and 61% of pancreatic head and periampullary tumours, respectively, showed limited BM laminin expression. Whereas 43% and 41% of pancreatic head and periampullary cancers, respectively, showed limited BM collagen type IV expression. Limited BM laminin was associated with poor outcome following curative resection of pancreatic head cancer (P=0.034, 0.013 and 0.017 for RFS, CSS and OS, respectively). Two and a half times as many patients with ≥ 25% BM laminin were recurrence free and alive 5 years following resection compared with those with limited BM laminin. Although staining patterns of both BM components were weakly correlated with each other, BM collagen type IV expression was not significantly associated with outcome in either tumour type. CONCLUSION: Discontinuous BMs, determined by laminin expression, are associated with poor outcome following curative resection of pancreatic head cancer.

Observation of large scissors resonance strength in actinides.

The orbital M1 scissors resonance has been measured for the first time in the quasicontinuum of actinides. Particle-γ coincidences are recorded with deuteron and (3)He-induced reactions on (232)Th. The residual nuclei (231,232,233)Th and (232,233) Pa show an unexpectedly strong integrated strength of B(M1)=11-15µ(n)(2) in the E(γ)=1.0-3.5 MeV region. The increased γ-decay probability in actinides due to scissors resonance is important for cross-section calculations for future fuel cycles of fast nuclear reactors and may also have an impact on stellar nucleosynthesis.

[Personal factors of the ICF]. / Personbezogene Faktoren der ICF.

PURPOSE: The presentation aims at illustrating the draft proposal of personal factors of the ICF for German-speaking regions which has been published in 2010 by the working group ICF of Faculty II "Social Medicine and Rehabilitation" of the German Society for Social Medicine and Prevention, DGSMP. For this reason, each personal factor is illustrated by two examples. Thus, the benefit is intended to be convincing. METHODS: Applying a qualitative approach, the working group ICF consisting of members of various professions and institutions including a patients' representative selected for each item one example the factor serving as a facilitator and a second the factor serving as a barrier. RESULTS: The components of the personal factors, as proposed, are presented, each factor is accompanied by two examples. CONCLUSION: The presentation demonstrates the various possibilities of applying personal factors and intends to prove that the selection of items chosen makes sense. The process of a comprehensive discussion about the possible format of the component of personal factors in the ICF should lead to a further optimization of the proposal and the preparation of a discussion at an international level.

[Personal contextual factors of the ICF draft from the Working Group "ICF" of Specialty Group II of the Geman Society for Social Medicine and Prevention]. / Personbezogene Faktoren der ICF - Entwurf der AG "ICF" des Fachbereichs II der Deutschen Gesellschaft für Sozialmedizin und Prävention (DGSMP).

Personal contextual factors play an essential part in the ICF model in relation to patient-centred care. It is generally assumed that their classification must refer to the country-specific social and cultural setting and its particular linguistic terms. Therefore personal factors are not classified as yet by the WHO for general use. In Germany in 2006 a group of experts working on the medical advisory board of statutory health insurance published a proposal for a systematic classification of relevant personal factors to describe the background of an individual's life and living. This classification was now further analysed and thoroughly revised by a more comprehensive group of German specialists working in different health care insurances and institutions, authorised by the German Society for Social Medicine and Prevention (DGSMP), supported by German-speaking Swiss ICF specialists. This classification is published as work in progress intending to broaden and prepare the process of discussion for a consensus conference to be held in Germany in 2011.

A moderate thermal dose is sufficient for effective free and TSL based thermochemotherapy.

Hyperthermia, i.e. heating the tumor to a temperature of 40-43 °C is considered by many a valuable treatment to sensitize tumor cells to radiotherapy and chemotherapy. In recent randomized trials the great potential of adding hyperthermia to chemotherapy was demonstrated for treatment of high risk soft tissue sarcoma: +11.4% 5 yrs. overall survival (OS) and for ovarian cancer with peritoneal involvement nearly +12 months OS gain. As a result interest in combining chemotherapy with hyperthermia, i.e. thermochemotherapy, is growing. Extensive biological research has revealed that hyperthermia causes multiple effects, from direct cell kill to improved oxygenation, whereby each effect has a specific temperature range. Thermal sensitization of the tumor cell for chemotherapy occurs for many drugs at temperatures ranging from 40 to 42 °C with little additional increase of sensitization at higher temperatures. Increasing perfusion/oxygenation and increased extravasation are two other important hyperthermia induced mechanisms. The combination of free drug and hyperthermia has not been found to increase tumor drug concentration. Hence, enhanced effectiveness of free drug will depend on the thermal sensitization of the tumor cells for the applied drug. In contrast to free drugs, experimental animal studies combining hyperthermia and thermo-sensitive liposomal (TSL) drugs delivery have demonstrated to result in a substantial increase of the drug concentration in the tumor. For TSL based chemotherapy, hyperthermia is critical to both increase perfusion and extravasation as well as to trigger TSL drug release, whereby the temperature controlled induction of a local high drug concentration in a highly permeable vessel is driving the enhanced drug uptake in the tumor. Increased drug concentrations up to 26 times have been reported in rodents. Good control of the tissue temperature is required to keep temperatures below 43 °C to prevent vascular stasis. Further, careful timing of the drug application relative to the start of heating is required to benefit optimal from the combined treatment. From the available experimental data it follows that irrespective whether chemotherapy is applied as free drug or using a thermal sensitive liposomal carrier, the optimal thermal dose for thermochemotherapy should be 40-42 °C for 30-60 min, i.e. equivalent to a CEM43 of 1-15 min. Timing is critical: most free drug should be applied simultaneous with heating, whereas TSL drugs should be applied 20-30 min after the start of hyperthermia.

Hyperthermia and smart drug delivery systems for solid tumor therapy.

Chemotherapy is a cornerstone of cancer therapy. Irrespective of the administered drug, it is crucial that adequate drug amounts reach all cancer cells. To achieve this, drugs first need to be absorbed, then enter the blood circulation, diffuse into the tumor interstitial space and finally reach the tumor cells. Next to chemoresistance, one of the most important factors for effective chemotherapy is adequate tumor drug uptake and penetration. Unfortunately, most chemotherapeutic agents do not have favorable properties. These compounds are cleared rapidly, distribute throughout all tissues in the body, with only low tumor drug uptake that is heterogeneously distributed within the tumor. Moreover, the typical microenvironment of solid cancers provides additional hurdles for drug delivery, such as heterogeneous vascular density and perfusion, high interstitial fluid pressure, and abundant stroma. The hope was that nanotechnology will solve most, if not all, of these drug delivery barriers. However, in spite of advances and decades of nanoparticle development, results are unsatisfactory. One promising recent development are nanoparticles which can be steered, and release content triggered by internal or external signals. Here we discuss these so-called smart drug delivery systems in cancer therapy with emphasis on mild hyperthermia as a trigger signal for drug delivery.

Fasting associated with decrease in hypothalamic beta-endorphin.

In rats that were fasted for 2 to 3 days there was a decline in hypothalamic, but not pituitary, beta-endorphin. There was no change in pituitary or hypothalamic adrenocorticotropin content as a result of fasting. Endogenous opiates may be involved in physiological adaptation to fasting.

Assessing the performance of a bdelloid rotifer Philodina acuticornis odiosa acute toxicity assay.

A bioassay using the bdelloid rotifer, Philodina acuticornis odiosa, was evaluated for use as a standard test method for direct toxicity assessment testing in the Australasian region. Philodina acuticornis odiosa was found to be relatively tolerant to phenol (24 h LC50, 142 mg/L). The mortality endpoint was both reliable and repeatable (the coefficients of variation for mortality at the 24 h LC50 concentration ranged from 11%-24% (n = 8)), sufficiently low to warrant further testing with a range of reference toxicants, so that this organism can be included for use as a regulatory test in Australasia.

Proactive and reactive modes of cognitive control can operate independently and simultaneously.

Cognitive control enables optimal biasing of attention, perception, and actions in the service of mental or behavioral goals. To understand the variability of applied cognitive control, we need to unravel the relation between two underlying mechanisms: proactive and reactive modes. During proactive cognitive control, goal-relevant information is selected before the occurrence of a cognitively demanding event, and is actively maintained for as long as required by the task. During reactive mode, cognitive control is transiently activated only after the cognitively demanding event has occurred. Mechanistically, proactive and reactive control modes may be at least semi-independent and engaged simultaneously, but this has so far not been demonstrated empirically. Situational demands and an individual's cognitive capacity and motivation may bias behavior towards one or the other mode. Reward induces more proactive processing in the AX-CPT task, whereas context load induces reactive processing. We combined these manipulations to investigate the extent to which proactive and reactive control modes can operate independently and simultaneously. The results replicated already published effects of reward incentives and context load. Most importantly, these effects were essentially independent of each other, suggesting that proactive and reactive cognitive control modes depend on separate information-processing and neural mechanisms. The results also show that while proactive processing is influenced by reward, reactive processing seems independent of such factor. These findings have implications for our understanding of the structure of cognitive control and cognitive motivation, and are relevant for the design of interventions to improve cognitive control in various developmental and neuropsychiatric groups.

Lipoic acid significantly restores, in rats, the age-related decline in vasomotion.

BACKGROUND AND PURPOSE: The age-related decline in vasorelaxation is largely due to ceramide-induced induction of phosphatase 2A (PP2A), which limits nitric oxide synthase (eNOS) phosphorylation at stimulatory sites. We hypothesized that ceramide accumulation was from an age-related loss of endothelial glutathione (GSH) and subsequent activation of neutral sphingomyelinase (nSMase), an enzyme whose activity increases when GSH is limited. EXPERIMENTAL APPROACH: Old (30-32 mo) F344xBN rats were given (R)-alpha-lipoic acid (LA), an agent known to induce GSH synthesis. Vasorelaxation was measured in aortic rings; GSH and ceramide levels, activity of nSMase and eNOS phosphorylation (by Western blot) was measured in aortic endothelial cells, isolated from the same aortas. KEY RESULTS: In old animals, endothelium-dependent relaxation in aortic rings was decreased, GSH levels and its redox state in aortic endothelia were over 30% lower and nSMase activity and endothelial ceramide levels were three-fold increased, relative to young (2-4 mo) rats. LA treatment of old animals improved relaxation in aortic rings, reversed the changes in endothelial GSH, in nSMase activities and in ceramide levels. Similar effects on GSH levels and nSMase activity in old rats were also induced by treatment with GSH monoethylester. Activation (by phosphorylation) of eNOS was decreased by about 50% in old rats and this age-related decrease was partially reversed by LA treatment. CONCLUSIONS AND IMPLICATIONS: Decreased endothelial GSH was partly responsible for the age-related loss of vascular endothelial function and LA might be therapeutically evaluated to treat endothelial dysfunction.

Acetyl-L-carnitine and alpha-lipoic acid supplementation of aged beagle dogs improves learning in two landmark discrimination tests.

Beagle dogs between 7.6 and 8.8 years of age administered a twice daily supplement of alpha-lipoic acid (LA) and acetyl-L-carnitine (ALC) over approximately 2 months made significantly fewer errors in reaching the learning criterion on two landmark discrimination tasks compared to controls administered a methylcellulose placebo. Testing started after a 5 day wash-in. The dogs were also tested on a variable delay version of a previously acquired spatial memory task; results were not significant. The improved performance on the landmark task of dogs supplemented with LA + ALC provides evidence of the effectiveness of this supplement in improving discrimination and allocentric spatial learning. We suggest that long-term maintenance on LA and ALC may be effective in attenuating age-associated cognitive decline by slowing the rate of mitochondrial decay and cellular aging.

Application of adjoint Monte Carlo to accelerate simulations of mono-directional beams in treatment planning for boron neutron capture therapy.

This paper deals with the application of the adjoint transport theory in order to optimize Monte Carlo based radiotherapy treatment planning. The technique is applied to Boron Neutron Capture Therapy where most often mixed beams of neutrons and gammas are involved. In normal forward Monte Carlo simulations the particles start at a source and lose energy as they travel towards the region of interest, i.e., the designated point of detection. Conversely, with adjoint Monte Carlo simulations, the so-called adjoint particles start at the region of interest and gain energy as they travel towards the source where they are detected. In this respect, the particles travel backwards and the real source and real detector become the adjoint detector and adjoint source, respectively. At the adjoint detector, an adjoint function is obtained with which numerically the same result, e.g., dose or flux in the tumor, can be derived as with forward Monte Carlo. In many cases, the adjoint method is more efficient and by that is much quicker when, for example, the response in the tumor or organ at risk for many locations and orientations of the treatment beam around the patient is required. However, a problem occurs when the treatment beam is mono-directional as the probability of detecting adjoint Monte Carlo particles traversing the beam exit (detector plane in adjoint mode) in the negative direction of the incident beam is zero. This problem is addressed here and solved first with the use of next event estimators and second with the application of a Legendre expansion technique of the angular adjoint function. In the first approach, adjoint particles are tracked deterministically through a tube to a (adjoint) point detector far away from the geometric model. The adjoint particles will traverse the disk shaped entrance of this tube (the beam exit in the actual geometry) perpendicularly. This method is slow whenever many events are involved that are not contributing to the point detector, e.g., neutrons in a scattering medium. In the second approach, adjoint particles that traverse an adjoint shaped detector plane are used to estimate the Legendre coefficients for expansion of the angular adjoint function. This provides an estimate of the adjoint function for the direction normal to the detector plane. In a realistic head model, as described in this paper, which is surrounded by 1020 mono-directional neutron/gamma beams and from which the best ones are to be selected, the example calculates the neutron and gamma fluxes in ten tumors and ten organs at risk. For small diameter beams (5 cm), and with comparable relative errors, forward Monte Carlo is seen to be 1.5 times faster than the adjoint Monte Carlo techniques. For larger diameter neutron beams (10 and 15 cm), the Legendre technique is found to be 6 and 20 times faster, respectively. In the case of gammas alone, for the 10 and 15 cm diam beams, both adjoint Monte Carlo Legendre and point detector techniques are respectively 2 and 3 times faster than forward Monte Carlo.

Cytokines and vascular permeability: an in vitro study on human endothelial cells in relation to tumor necrosis factor-alpha-primed peripheral blood mononuclear cells.

Tumor response is strongly enhanced by addition of tumor necrosis factor (TNF)-alpha to chemotherapy in local-regional perfusion. TNF primarily targets the endothelial lining of the tumor-associated vasculature, thereby improving permeability of the vascular bed. This augments uptake of the coadministered chemotherapeutic drug in the tumor. In vitro, however the high dose of TNF did not directly affect endothelial cells, indicating that other factors, most likely TNF-induced, are involved in the antivascular activities observed in vivo. This is supported by in vivo studies in our laboratory in which depletion of leukocytes resulted in loss of the antivascular activity of TNF. The present study examined the role of peripheral blood mononuclear cells (PBMCs) on endothelial cells by exposing them to TNF, interferon (IFN)-gamma, and PBMCs. We observed morphological changes of the endothelial cells when exposed to TNF in combination with IFN. Endothelial cells became elongated. and gaps between the cells formed. Addition of PBMCs enhanced these alterations. The endothelial layer became disrupted with highly irregular-shaped cells displaying large gap formations. PBMCs also contributed to an increased permeability of the endothelial layer without augmenting apoptosis. Replacing PBMC by interleukin (IL)-1beta produced similar effect with regard to inhibition of cell growth, morphological changes, and induction of apoptosis. Blocking IL-1beta with a neutralizing antibody diminished the effects inflicted of PBMCs. These observations indicate that endogenously produced IL-1beta by primed PBMCs plays an important role in the antivascular effect of TNF.

Design of a rotating facility for extracorporal treatment of an explanted liver with disseminated metastases by boron neutron capture therapy with an epithermal neutron beam.

In 2001, at the TRIGA reactor of the University of Pavia (Italy), a patient suffering from diffuse liver metastases from an adenocarcinoma of the sigmoid was successfully treated by boron neutron capture therapy (BNCT). The procedure involved boron infusion prior to hepatectomy, irradiation of the explanted liver at the thermal column of the reactor, and subsequent reimplantation. A complete response was observed. This encouraging outcome stimulated the Essen/Petten BNCT group to investigate whether such an extracorporal irradiation could be performed at the BNCT irradiation facility at the HFR Petten (The Netherlands), which has very different irradiation characteristics than the Pavia facility. A computational study has been carried out. A rotating PMMA container with a liver, surrounded by PMMA and graphite, is simulated using the Monte Carlo code MCNP. Due to the rotation and neutron moderation of the PMMA container, the initial epithermal neutron beam provides a nearly homogeneous thermal neutron field in the liver. The main conditions for treatment as reported from the Pavia experiment, i.e. a thermal neutron fluence of 4 x 10(12) +/- 20% cm(-2), can be closely met at the HFR in an acceptable time, which, depending on the defined conditions, is between 140 and 180 min.