Suppression of the vacuum space-charge effect in fs-photoemission by a retarding electrostatic front lens.

The performance of time-resolved photoemission experiments at fs-pulsed photon sources is ultimately limited by the e-e Coulomb interaction, downgrading energy and momentum resolution. Here, we present an approach to effectively suppress space-charge artifacts in momentum microscopes and photoemission microscopes. A retarding electrostatic field generated by a special objective lens repels slow electrons, retaining the k-image of the fast photoelectrons. The suppression of space-charge effects scales with the ratio of the photoelectron velocities of fast and slow electrons. Fields in the range from -20 to -1100 V/mm for Ekin = 100 eV to 4 keV direct secondaries and pump-induced slow electrons back to the sample surface. Ray tracing simulations reveal that this happens within the first 40 to 3 µm above the sample surface for Ekin = 100 eV to 4 keV. An optimized front-lens design allows switching between the conventional accelerating and the new retarding mode. Time-resolved experiments at Ekin = 107 eV using fs extreme ultraviolet probe pulses from the free-electron laser FLASH reveal that the width of the Fermi edge increases by just 30 meV at an incident pump fluence of 22 mJ/cm2 (retarding field -21 V/mm). For an accelerating field of +2 kV/mm and a pump fluence of only 5 mJ/cm2, it increases by 0.5 eV (pump wavelength 1030 nm). At the given conditions, the suppression mode permits increasing the slow-electron yield by three to four orders of magnitude. The feasibility of the method at high energies is demonstrated without a pump beam at Ekin = 3830 eV using hard x rays from the storage ring PETRA III. The approach opens up a previously inaccessible regime of pump fluences for photoemission experiments.

Long-term evaluation of combined prolonged-release oxycodone and naloxone in patients with moderate-to-severe chronic pain: pooled analysis of extension phases of two Phase III trials.

BACKGROUND: While opioids provide effective analgesia, opioid-induced constipation (OIC) can severely impact quality of life and treatment compliance. This pooled analysis evaluated the maintenance of efficacy and safety during long-term treatment with combined oxycodone/naloxone prolonged-release tablets (OXN PR) in adults with moderate-to-severe chronic pain. METHODS: Patients (N = 474) received open-label OXN PR during 52-week extension phases of two studies, having completed 12-week, double-blind, randomized treatment with oxycodone prolonged-release tablets (Oxy PR) or OXN PR. Analgesia and bowel function were assessed at each study visit using 'Average pain over last 24 h scale and Bowel Function Index (BFI), respectively. Treatment Satisfaction Questionnaire for Medication was assessed at study end only. KEY RESULTS: Improvement in bowel function was particularly marked in patients who switched from Oxy PR in the double-blind phase to OXN PR during the extension phase, resulting in a clinically meaningful reduction (≥12 points) in BFI score: at the start of the extension phases, mean (SD) BFI score was 44.3 (28.13), and was 29.8 (26.36) for patients who had received OXN PR in the double-blind phase. One week later, BFI scores were similar for the two groups (26.5 [24.40] and 27.5 [25.60], respectively), as was observed throughout the following months. Fewer than 10% of patients received laxatives regularly. Mean 24-h pain scores were low and stable throughout the extension phases. No unexpected adverse events were observed. CONCLUSIONS & INFERENCES: Pooled data demonstrate OXN PR is an effective long-term therapy for patients with chronic non-cancer pain, and can address symptoms of OIC. No new safety issues were observed which were attributable to the long-term administration of OXN PR.

Pigmented villo-nodular synovitis and giant-cell tumor of tendon sheaths: a binational retrospective study.

AIM: Pigmented villonodular synovitis is rare. Thus, we initiated a retrospective multi-center study regarding symptoms, location, type of disease, type of surgery, number of recurrences, use of adjuvant therapies and functional outcome. RESULTS: Ten centers contributed. Data from 173 patients were sampled. The disease was seen predominantly in joints, less frequently in tendon sheaths and bursae. Patients with articular lesions suffered mainly from the diffuse type. In tendon sheaths, the relation "diffuse versus nodular" was nearly 50 % each, in bursae most often the nodular type was found. Anatomically, mostly the knee was affected. Institutions with more than 20 patients had a lower rate of recurrence than those with less than 20 cases. Regarding the knee, there were less recurrences in joints treated with open synovectomy than in those treated arthroscopically. CONCLUSIONS: Since the rate of recurrence has been rather high, the use of adjuvant treatments (radiosynoviorthesis or radiotherapy) is recommended. In our study, the rate of their application was quite low. Patients who received an adjuvant therapy after primary surgery did not show any recurrence. In 14 % of patients in whom an adjuvant therapy had been used, after at least one recurrence, further recurrences were observed. Functional results were excellent in 84 % of patients. LEVEL OF EVIDENCE: Prognostic multi-center study, Level III.

Relations between haemoglobin mass, cardiac dimensions and aerobic capacity in endurance trained cyclists.

AIM: Chronic endurance exercise triggers increased cardiac dimensions, blood volumes and haemoglobin mass (Hb mass). Cardiac output and Hb mass are considered as independent contributors to aerobic performance. Therefore, increased Hb mass could counterbalance for a relative deficiency in cardiac adaptation. The purpose of the present study is to investigate relations between Hb mass and cardiac dimensions in a group of endurance athletes with respect to aerobic capacity. METHODS: Two groups of highly trained cyclists featuring high (HHB group, N.=13) and low (LHB group, N.=13) Hb mass (measured by a CO-rebreathing method) were compared for measures of aerobic performance, cardiac wall thickness, cavity size and left ventricular mass (determined by 2-D-echocardiography). Lean body mass (LBM) was chosen as anthropometrical reference for Hb mass. RESULTS: HHB featured higher cardiac wall thickness than LHB, but no difference appeared in cardiac cavity size, left ventricular mass and the performance parameters. Normalising Hb mass for body weight instead of LBM improved correlations between Hb mass and performance parameters. CONCLUSIONS: Our data provides new evidence for a connection between cardiac wall thickness and Hb mass in endurance athletes but no further evidence for a counterbalance between Hb mass and cardiac adaptation was found. Moreover, we postulate that Hb mass loses predictive value for aerobic performance when normalised for LBM.

Diagnostic value of nodule palpation in onchocerciasis.

Nodule palpation is the major diagnostic tool for determining the prevalence of infection in areas of the African Programme for Onchocerciasis Control (APOC) and is recommended for identifying communities at risk and selecting them for mass drug administration. The diagnostic value of palpation, however, has not been quantified in terms of sensitivity and predictive values. We derive these measures from the probability that a nodule is palpable, which has been estimated by stochastic simulations from an extensive pre-control database. We show that nodule palpation is only reliable in highly endemic areas and that false-positive diagnoses can lead to considerable misclassifications of regions where endemicity is actually low. Its diagnostic precision is poor because of large intra- and inter-individual variability. The findings underline the need for further development of available diagnostics that allow long-term monitoring when endemicity declines.

The impact of contact structure on infectious disease control: influenza and antiviral agents.

Planning adequate public health responses against emerging infectious diseases requires predictive tools to evaluate the impact of candidate intervention strategies. With current interest in pandemic influenza very high, modelling approaches have suggested antiviral treatment combined with targeted prophylaxis as an effective first-line intervention against an emerging influenza pandemic. To investigate how the effectiveness of such interventions depends on contact structure, we simulate the effects in networks with variable degree distributions. The infection attack rate can increase if the number of contacts per person is heterogeneous, implying the existence of high-degree individuals who are potential super-spreaders. The effectiveness of a socially targeted intervention suffers from heterogeneous contact patterns and depends on whether infection is predominantly transmitted to close or casual contacts. Our findings imply that the various contact networks' degree distributions as well as the allocation of contagiousness between close and casual contacts should be examined to identify appropriate strategies of disease control measures.

High infection rates at low transmission potentials in West African onchocerciasis.

Onchocerciasis has been successfully controlled for many years in endemic countries but more than 120 million people are still at risk. Factors which stabilise the persistence of the parasite in the population must be studied to minimise the future risk of re-infection. Among these factors, the relationship between the annual transmission potential and the parasite establishment rate is a main determinant which has to date not been quantified. Using entomological information and palpation data collected by the Onchocerciasis Control Programme in West Africa prior to the initiation of control activities, we derive annual transmission potential-dependent estimates of the parasite establishment rate from statistical analyses and computer simulations. Even at very low transmission intensities, the filarial parasite Onchocerca volvulus can efficiently establish in the human population, originating from an infection process which is strongly limited with respect to the annual transmission potential. Implementing the estimates into a simplified transmission model predicts that the critical annual biting rate, below which transmission is not possible, is much lower than previously assumed. We conclude that under the current strategy of mass distribution of microfilaricides without additional measures of vector control, the risk of re-infection is higher than previously assumed.

The relationships between the burden of adult parasites, host age and the microfilarial density in human onchocerciasis.

We investigate the relationship between the microfilarial density in the skin and the burden of adult female Onchocerca volvulus by analysing pre-control nodulectomy data which allow for a direct approach, independent of exposure. The data of 169 patients in Burkina Faso and 182 patients in Liberia represent savannah and forest onchocerciasis in West Africa, respectively. Whereas in Burkina Faso, a saturating relationship between microfilarial density and worm burden suggests the operation of density-dependent processes within human hosts, the Liberian data show a linear relationship implying no density dependence. The differences may derive from differences between both parasite strains, i.e. the savannah or the forest strain of O. volvulus. Consistently for both parasite strains and independent of the worm burden, the microfilarial density increases with host age emphasising the concept of the acquisition of immunological tolerance. In male hosts in Liberia, the microfilarial density increases stronger with the worm burden than in female hosts, whereas such sex-specific differences cannot be found in Burkina Faso. In the methodological part of this investigation, we suggest the beta-distribution to be most appropriate for describing variability in microfilarial densities and we present an approach to consider the uncertainty in the adult parasite burden which cannot be determined precisely in helminth infections. Implications of density dependence are discussed with respect to immunological processes in the human host and with respect to the success of control programs. The relationships described show that regulatory processes between the parasite and the human host are multi-dimensional, operating within a high degree of biological variability.

Impact of parental onchocerciasis and intensity of transmission on development and persistence of Onchocerca volvulus infection in offspring: an 18 year follow-up study.

This study analysed the impact and the extent by which parental Onchocerca volvulus infection, intensity of transmission of O. volvulus infective 3rd-stage larvae (L3) and anthropometric factors may influence the acquisition, development and persistence of O. volvulus infection in offspring. A total of 15290 individuals in 3939 families with 9640 children were surveyed for microfilariae of O. volvulus, and prevalence and level of O. volvulus infection in children aged 0 to 20 years from infected and non-infected parents were followed longitudinally for 18 years. Children from O. volvulus-infected mothers had not only a substantially higher risk to become infected; they also acquired infection earlier in life and developed higher infection levels. Multiple logistic regression analysis showed that maternal O. volvulus infection and children's age are the predominant predictors for patent O. volvulus infection, while the intensity of transmission, measured by the annual transmission potential (ATP) of O. volvulus L3, was less decisive. Longitudinal follow up of children showed that during vector control activities by the Onchocerciasis Control Programme (OCP) and in low-level transmission areas, infection persisted at higher levels in children from O. volvulus-positive mothers. In summary, the dominant risk factor for children to become infected is maternal onchocerciasis, and also age-associated factors will strongly impact on the development of patent O. volvulus infection in offspring.

Density-dependent parasite establishment suggests infection-associated immunosuppression as an important mechanism for parasite density regulation in onchocerciasis.

The modulation of human immune response by filarial parasites has yielded contradictory experimental findings and attracted much controversy. We address the unresolved question of acquisition, establishment and accumulation of Onchocerca volvulus by using a modelling approach that relates computer simulations to cross-sectional data concerning parasite burdens in 913 West African onchocerciasis patients. It is shown that the acquisition of O. volvulus is not constant with host age; instead, the analysis of age profiles of parasite burdens strongly indicate the operation of immunosuppressive processes within the human host, associated with the presence of adult parasites or microfilariae. It is suggested that these processes suppress immunity against incoming infective larvae (L3), which themselves act as an immune modulating component once they have successfully overcome the barrier of concomitant immunity. Suppression of parasite-specific immunity leads to parasite establishment rates which increase along with the parasite burden, but which hardly depend on hyperendemic annual transmission potentials. Children, still immunocompetent due to low parasite burdens, acquire 0.1-0.5 adult female parasites per year, whereas older people, immunosuppressed due to high burdens, acquire 2-4 adult female parasites per year. Differences in parasite establishment between the forest and the savannah strains of O. volvulus are quantified and dynamic aspects of density-dependent parasite establishment discussed.

On the interpretation of age-intensity profiles and dispersion patterns in parasitological surveys.

The present paper describes how age-intensity profiles of macroparasite burdens are affected by processes underlying the distribution of the parasite numbers in host populations. In a comparative way, we consider the following 6 processes: (i) age-dependent exposure, (ii) parasite-induced host mortality, (iii) heterogeneity within, the host population, (iv) clumped infection, (v) density-dependent parasite mortality and (vi) density-dependent parasite establishment. For each of these processes, we show typical patterns in the age-intensity profile and provide, if possible, explicit and simple solutions for the age-dependent mean parasite burden and the corresponding dispersion patterns. Emphasis is given to density-dependent parasite establishment and to age-intensity profiles resulting from the superposition of different processes. By means of 2 examples we show that the interpretation of observed patterns can be ambiguous if more than 1 process takes place. These findings underline that age-intensity profiles should be interpreted on the basis of available a priori knowledge about the processes assumed to be involved. For purposes of testing different hypotheses, a simulation program is provided with which discrepancies between model prediction and data can be explored.

A stochastic model for the aggregation of Onchocerca volvulus in nodules.

A model is presented which describes the aggregation of female Onchocerca volvulus in nodules and their distribution in the human population. The basic model is based on a single parameter, the formation probability q, which represents the probability with which incoming larvae form a new nodule. This parameter describes parasite behaviour which cannot easily be recognized in available data without modelling. The estimate for the average formation probability of muq = 0.39 suggests an attraction of the invading infective larvae to already existing nodules or resident worms with probability 0.61. No significant difference in muq was found between the forest and savanna parasite strains. The model can be used inversely to estimate the worm burden of persons from palpation data. The observed variance in the number of nodules per person requires the assumption of a variance-increasing mechanism which was implemented by heterogeneity within the host population (extended model with 2 parameters). Possible reasons for this heterogeneity are presented and its implications concerning the reproductive biology of the parasite are discussed.

Stochastic models for aggregation processes.

Three models are presented, which describe the aggregation of objects into groups and the distributions of groups sizes and group numbers within habitats. The processes regarded are pure accumulation processes which involve only formation and invasion of groups. Invasion represents the special case of fusion when only single objects - and not groups - join a group of certain size. The basic model is derived by a single parameter, the formation probability q, which represents the probability of an object to form a new group. A novel, discrete and finite distribution that results for the group sizes is deduced from this aggregation process and it is shown that it converges to a geometric distribution if the number of objects tends to infinity. Two extensions of this model, which both converge to the Waring distribution, are added: the model can be extended either with a beta distributed formation probability or with the assumption that the invasion probability depends on the group size. Relationships between the limiting distributions involved are discussed.

Castor oil decreases pain during extracorporeal shock wave application.

In a prospective single-blind study the contact media ultrasound gel, vaseline and castor oil were examined for their effect on surface pain caused by extracorporeal shock waves used for tendinosis calcarea (n = 25), radiohumeral epicondylitis (n = 23) and plantar heel spur (n = 12). A total of 60 patients was divided into six groups. Using a Compact S shockwave source (Dornier MedTech), an energy flux density up to 0.12 mJ/mm2 was applied three times within 3 weeks. Independent of the diagnosis, there was a statistically significant influence of the contact medium on the intensity of application pain. In this comparison castor oil was best. For the diagnosis of tendinosis calcarea and plantar heel spur, castor oil was significantly better than the other two contact media, while for epicondylitis there was no significant difference. Castor oil was found to have an advantage over ultrasound jelly and vaseline in all indications used with regard to application pain. The positive effect of castor oil can be explained by its cavitation-free quality.

Single-dose interaction study of diprafenone HCl and propranolol HCl in healthy volunteers.

Using a 3 x 3 Latin Square design, a possible interaction between diprafenone HCl a class IC antiarrhythmic drug with nonspecific beta-antagonist activity and propranolol HCl was investigated in nine young, healthy, caucasian, male volunteers. The volunteers randomly received 3 single-dose treatments: (A) 200 mg DHCl, (B) 80 mg PHCl, and (C) 200 mg DHCl and 80 mg PHCl. Scheduled blood samples were taken and plasma concentrations of both diprafenone and propranolol were measured by sensitive and specific assay methods. Lead II electrocardiogram intervals at rest, heart rate during erect bicycle ergometry, and echocardiographic variables at rest and shortly after exercise were recorded. The data analysis used compartment model independent methods. There was no evidence for a pharmacokinetic interaction between the two drugs. With DHCl, two of the nine subjects showed greatly increased areas under the plasma concentration-time curves and apparent disposition half-lives in the presence and absence of PHCl, indicating that metabolism of diprafenone may be subject to pharmacogenetic polymorphism. There was evidence for a pharmacodynamic interaction between DHCl and PHCl regarding the negative chronotropic effect at rest and during exercise. There was no difference in the pharmacodynamics and tolerability of the three treatments in suspected "poor" and "extensive metabolizers" of DHCl.