Co-morbidities and bleeding in elderly patients with haemophilia-A survey of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH).

BACKGROUND: Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co-morbidities and co-medication in elderly patients. OBJECTIVES: To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co-morbidities, co-medication, bleeding sites and patient mortality. METHODS: A retrospective multi-centre data collection study was initiated on behalf of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). Parameters of interest were investigated over the 5 years prior to study entry. RESULTS: A total of 185 haemophilia patients (mean age, 69.0±7.0 years, 29% with severe haemophilia) were included in the study. Regular prophylaxis was performed in 30% of the patients with severe haemophilia. In total, the annual bleeding rate was 2.49 and in patients with severe haemophilia 5.61, mostly caused by joint bleeds. Hypertension was the most common co-morbidity, but it occurred significantly less frequently than in an age-matched general population older than 70 years; 12% of the patients suffered from ischaemic heart disease, and 13% of the patients received anticoagulant or antiplatelet therapy. Within the observation period, 17% of the patients with severe haemophilia developed a higher frequency of bleeding symptoms, which was significantly associated with the use of antiplatelet or anticoagulant drugs. CONCLUSIONS: The most common co-morbidity of the patient population was hypertension, a considerable part had ischemic heart disease and antiplatelet or anticoagulant drugs.

European retrospective study of real-life haemophilia treatment.

INTRODUCTION: Haemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available. AIM: To provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe. METHODS: Non-interventional, 12-month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL-1 , without inhibitors, were included. Data were summarized descriptively. RESULTS: In total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL-1 ) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on-demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg-1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on-demand-treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0. CONCLUSION: Treatment practice varied greatly between centres and countries and patients treated on-demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care.

Kmasker--a tool for in silico prediction of single-copy FISH probes for the large-genome species Hordeum vulgare.

Specific localization of large genomic fragments by fluorescence in situ hybridization (FISH) is challenging in large- genome plant species due to the high content of repetitive sequences. We report the automated work flow (Kmasker) for in silico extraction of unique genomic sequences of large genomic fragments suitable for FISH in barley. This method can be widely used for the integration of genetic and cytogenetic maps in plants and other species with large and complex genomes if the probe sequence (e.g. BACs, sequence contigs) and a low coverage (8-fold) of unassembled sequences of the species of interest are available. Kmasker has been made publicly available as a web tool at http://webblast.ipk-gatersleben.de/kmasker.

[BEO'S - physical activity and healthy eating at schools in Oberfranken, Bavaria concept and first results of a resource-oriented, systemic approach in school-based health promotion]. / BEO'S - Bewegung und Ernährung an Oberfrankens Schulen Konzept und Erfahrungen bei der Umsetzung eines ressourcenorientierten, systemischen Ansatzes zur schulischen Gesundheitsförderung.

BACKGROUND: The high prevalence of overweight among children and adolescents has led to an increase in school-based prevention programmes. The aim of the present paper is to present the concept of an initiative called "BEO'S" as well as the experience made with the implementation und acceptance of this programme in the participating schools. METHODS: Different from the majority of school-based projects for healthy eating and physical activity, BEO'S pursues a systemic approach that includes the whole school and is tailored to the school's respective resources. Characteristics are (1) the participation of teachers, students, parents, and caretakers, (2) the motivation and empowerment of schools to plan and implement activities by themselves, (3) the focus on environmental approaches, and (4) addressing and considering the individual school's needs and resources. The university project team supports the schools by individual counselling as well as providing information materials, trainings and workshops for teachers, an internet page, newsletters, and financial support. In the school years 2007/08 and 2008/09, BEO'S was conducted at 14 primary and secondary schools in the district of Oberfranken, Bavaria. It was extended to other schools in 2009/10. The short- and mid-term goals are the improvement of the school's environments as well as the eating behaviour and physical activity of the students. In the long run, it is intended to prevent obesity and improve the students' health and school performance. RESULTS: The implementation processes showed that the teachers for physical education and domestic science as well as the headmasters were especially committed. The participation of the teaching staff, the students and the parents proved to be difficult, however. The schools implemented many activities for healthy eating and physical activity, but the planning process was not very systematic: needs assessment, status quo analysis, identification of successful strategies and definition of aims was difficult for the schools. The provided financial support, training programmes and workshops, and the exchange with other schools were widely used, in contrast to the offered internet-based tools. The acceptance of BEO'S was (very) good by teachers (n=97), students (n=674) and their parents (n=522). The teachers preferred the workshops and trainings to the internet page. The students appreciated the possibilities for physical activity and the emphasis on healthy eating; primary school students and girls more than secondary school students and boys. One third of the parents would like to be involved to a higher degree. CONCLUSION: BEO'S was well received by all the people involved. Yet, there are still deficits concerning the implementation process, especially in the participation of students and parents.

[Von Willebrand disease type 1 and pregnancy]. / Von-Willebrand-Syndrom Typ 1 und Schwangerschaft.

The von Willebrand-Jürgens syndrome (VWJS) type 1 is a common hereditary bleeding disorder with a bleeding tendency located especially in the mucous membranes. Women suffering from VWJS type 1 show menorrhagia and prolonged postoperative bleedings. During pregnancy the clinical presentation varies by the increase of the von Willebrand factors. In this article the laboratory findings and the clinical presentation of patients with VWJS during pregnancy was examined. The necessity of interventions during pregnancy and at the time of delivery was under consideration.

[Caregiver burden with dementia patients. A validation study of the German language version of the Zarit Burden Interview]. / Die subjektive Belastung pflegender Ehepartner von Demenzkranken. Hinweise zur Validität der deutschen Version des Zarit Burden Interviews.

Despite the large number of studies dealing with dementia caregivers in Europe, a valid German version of the most widely used measurement of caregiver burden, the Zarit Burden Interview, has not been published. The purpose of this study was to evaluate the psychometric properties of the German Zarit Burden Interview (G-ZBI). A sample of community-dwelling older couples (n=37) with the husband suffering from dementia and the wife being the primary caregiver participated in this study. The G-ZBI and related constructs were assessed in order to test for reliability and construct validity. The G-ZBI revealed psychometric properties comparable with those of the original instrument and empirically validated translations. Results indicate high internal consistency (Cronbach's alpha=0.91) and good validity due to strong correlations with caregiver life satisfaction and depression, as well as patients' dependency, neuropsychiatric symptoms, and dementia severity. The psychometric qualities of the G-ZBI indicate that it is both a reliable and valid instrument to assess caregiver burden and to detect highly stressed individuals.

[The total ankle replacement for severe arthropathy in haemophilia]. / Die endoprothetische Versorgung des oberen Sprunggelenkes bei hämophiler Arthropathie.

The endoprosthetic surgery of the upper ankle joint in profound arthrosis has significantly increased over the last years. Along with the established arthodesis the alloarthroplastic became a good alternative. The main indication for the implantation of an ankle joint endoprosthesis is a secondary arthrosis in patients with rheumatic diseases or post-traumatic status. In accordance with our experience case reports on the total ankle arthroplasty in haemophilic arthropathy show that the artificial substitute of the upper ankle joint can be a successful treatment of these patients under certain conditions. The outstanding benefit is to be seen in the preservation of a sufficient mobility for everyday movements and a more physiological process of walking. In case of endoprosthetic failure a relatively save opportunity for revision in the mostly younger patients can be found in the new osteosynthesis techniques. Also in haemophilic arthropathy with painful advanced arthrosis and functional limitation of the upper ankle joint the endoprosthetic care can be taken into consideration.

CR-EST: a resource for crop ESTs.

The crop expressed sequence tag database, CR-EST (http://pgrc.ipk-gatersleben.de/cr-est/), is a publicly available online resource providing access to sequence, classification, clustering and annotation data of crop EST projects. CR-EST currently holds more than 200,000 sequences derived from 41 cDNA libraries of four species: barley, wheat, pea and potato. The barley section comprises approximately one-third of all publicly available ESTs. CR-EST deploys an automatic EST preparation pipeline that includes the identification of chimeric clones in order to transparently display the data quality. Sequences are clustered in species-specific projects to currently generate a non-redundant set of approximately 22,600 consensus sequences and approximately 17,200 singletons, which form the basis of the provided set of unigenes. A web application allows the user to compute BLAST alignments of query sequences against the CR-EST database, query data from Gene Ontology and metabolic pathway annotations and query sequence similarities from stored BLAST results. CR-EST also features interactive JAVA-based tools, allowing the visualization of open reading frames and the explorative analysis of Gene Ontology mappings applied to ESTs.

Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study.

UNLABELLED: Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. SUMMARY: Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration (< 300 arbitrary units, 1.0; 300-1050, 0.65; > 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference standard for demonstrating neutralizing antibodies, the detection of FVIII-binding antibodies by ELISA is similarly sensitive and specific for diagnosing acquired hemophilia. In addition, anti-FVIII IgG may provide prognostic information.

Application of the local effect model to predict DNA double-strand break rejoining after photon and high-LET irradiation.

In the recent version of the local effect model (LEM), the biological effects of ionising radiation can be well described trough the consideration of DNA double-strand breaks (DSB) clustering at the micrometre scale. Assuming a giant-loop organisation for the chromatin higher-order structure, two classes of DSB are defined, namely isolated (iDSB) and clustered DSB (cDSB), according to whether exactly one or more than one DSB are induced in a loop, respectively. Here, a DSB kinetic rejoining model based on the LEM is applied to the description of two specific aspects of DSB rejoining, namely the dose dependence of the rejoining capacity after photon radiation and the residual damage observed at late times after ion irradiation. Based on the hypothesis that iDSB and cDSB can be associated to the fast and slow components of rejoining, the model is able to reproduce the experimental data, therefore supporting the relevance of micrometre scale clustering of damage for photon radiation as well as for high-LET radiation.

Integration of a model-independent interface for RBE predictions in a treatment planning system for active particle beam scanning.

Especially for heavier ions such as carbon ions, treatment planning systems (TPSs) for ion radiotherapy depend on models predicting the relative biological effectiveness (RBE) of the particles involved. Such models are subject to intensive research and the choice of the optimal RBE model is a matter of debate. On the other hand TPSs are often strongly coupled to particular RBE models and transition even to extended models of the same family can be difficult. We present here a model-independent interface which allows the unbiased use of any RBE model capable of providing dose-effect curves (even sampled curves) for a TPS. The full decoupling between the RBE model and TPS is based on the beam-mixing model proposed by Lam which is, in contrast to the often-used Zaider-Rossi model, independent of the explicit form of the underlying dose-effect curves. This approach not only supports the refinement of RBE models without adaptations of the TPS--which we demonstrate by means of the local effect model (LEM)--but also allows the comparison of very different model approaches on a common basis. We exemplify this by a comparison between the LEM and a model from the literature for proton RBE prediction.

Three-year clinical outcome after penetrating keratoplasty for keratoconus with the guided trephine system.

PURPOSE: To determine the long-term clinical outcome after keratoplasty with the guided trephine system in keratoconus eyes. METHODS: In a prospective study, all consecutive cases of penetrating keratoplasty had trephination performed with the guided trephine system, with which both donor and recipient cornea are trephined from the epithelial side with a same-sized blade. For wound closure, a double running antitorque suture technique with 10-0 nylon was used. Uncorrected and best-corrected Snellen visual acuity, subjective refraction, and astigmatism by keratometry were evaluated after final suture removal, 2 and 3 years postoperatively. RESULTS: In the 31 patients (31 eyes) enrolled, mean best-corrected visual acuity improved from 0.72 +/- 0.16 (20/30) after final suture removal to 0.88 +/- 0.15 (20/25) 3 years postoperatively (P < .001). The mean spherical equivalent increased from -0.86 +/- 2.10 diopters after final suture removal to -2.35 +/- 2.65 diopters 3 years postoperatively (P < .001). Mean keratometric astigmatism decreased from 4.68 +/- 1.76 diopters after final suture removal to 3.57 +/- 1.37 diopters 3 years postoperatively (P = .001). Furthermore, an increase in mean keratometric levels with time (P = .01) was observed and associated with myopic shift (r(s) = -.46, P = .008). CONCLUSION: With the guided trephine system, we attained favorable visual results, with prolonged improvement of visual acuity during the entire follow-up period. Our data show low and decreasing degrees of corneal astigmatism over time. During the follow-up period, a myopic shift was found after final suture removal. Nevertheless, this technique of performing same-sized grafts reduces postoperative residual myopia.

Postoperative astigmatism after no-stitch, small incision cataract surgery with 3.5 mm and 4.5 mm incisions.

We studied postoperative astigmatism in 107 patients who were followed for 12 months after phacoemulsification and posterior chamber lens implantation. A scleral incision of 3.5 mm was used in Group A patients and one of 4.5 mm in Group B patients. In both groups a no-stitch wound closure technique was used. A high correlation between preoperative and 12-month postoperative height and time shift of keratometric values was found. In both groups the mean difference was less than 0.60 diopters (D). The mean postoperative cylinder increase was less than 0.50 D; it was less than 0.25 D after six months. The induced astigmatism was confirmed by three different methods. Immediately after surgery, a negative induced astigmatism was found in both groups. After 12 months, induced astigmatism in Group A was -0.37 D and in Group B, -0.67 D. Immediately after surgery there was an axis change; a decrease of with-the-rule astigmatism occurred concurrently with an increase toward oblique and against-the-rule astigmatism. This axis change was somewhat evident after 12 months.

Corneal flap incision technique for sutureless cataract surgery.

A self-sealing incision technique for cataract surgery has been developed. It is appropriate for implantation of rigid-optic intraocular lenses (IOLs) up to 7.0 mm. The incision is designed to meet the principle criteria of sutureless cataract surgery, such as optimal instrument handling, easy IOL implantation, and minimal postoperative patient care.

Astigmatism correction with a foldable toric intraocular lens in cataract patients.

PURPOSE: To determine the efficacy and rotational stability of a toric posterior chamber silicone intraocular lens (IOL) to correct preoperative astigmatism in cataract patients. SETTING: Department of Ophthalmology, University Hospital of Vienna, Vienna Austria. METHODS: Between 1993 and 1998, foldable toric single-piece plate-haptic silicone IOLs were implanted in 37 eyes (30 patients). The cylindrical IOL power was 2.00 diopters (D) (n = 29), 3.50 D (n = 7), or 4.00 D (n = 1). Phacoemulsification was performed through a scleral or a corneal sutureless self-sealing incision. Outcomes of Snellen visual acuity (without, with spherical, and with best correction), refractive and keratometric astigmatism, and IOL rotation after early postoperative (mean 15.9 days +/- 10.1 [SD]) and long-term (mean 20.3 +/- 16.6 months) follow-ups were evaluated. RESULTS: At last follow-up, 31 eyes (83.8%) had a spherically corrected and 34 (91.9%) a best corrected visual acuity of 0.5 (20/40) or better. Mean preoperative refractive and keratometric astigmatism was 2.68 and 2.70 D, respectively. At the last postoperative follow-up, mean refractive astigmatism was reduced to 0.84 D; keratometric astigmatism was 2.30 D. In 7 eyes (18.9%), the IOL axis was rotated a maximum of 25 degrees. In all 37 eyes, the axis of the toric IOL remained within 30 degrees of rotation. CONCLUSIONS: Early postoperative and long-term follow-ups showed effective and stable correction of astigmatism after implantation of a foldable toric posterior chamber silicone IOL.

Long-term course of induced astigmatism after clear corneal incision cataract surgery.

PURPOSE: To determine whether a small clear corneal temporal incision produces less surgically induced astigmatism than a larger incision. METHODS: One hundred three consecutive cases of postoperative astigmatism after clear corneal incision cataract surgery were studied for a minimum of 1 year. Only self-sealing incisions from the temporal side were made as follows: 3.2 mm (Group A); 4.0 mm (Group B); 5.2 mm (Group C). We considered the amount and axes of the keratometric readings at different times as well as their course over time. Induced astigmatism was calculated using three methods. Axial changes were also analyzed. RESULTS: Immediately after the surgery, there was a small, surgically induced, with-the-rule astigmatic shift in all groups, which in most cases decreased to near preoperative levels with time. One year postoperatively. mean induced astigmatism was 0.09 diopter (D) in Group A, 0.26 D in Group B, and 0.54 D in Group C. Most cases had minimal axial changes. In Group A, 86% had an axial change of fewer than 30 degrees; in Group B, 76%; and Group C, 73%. CONCLUSIONS: The smallest incision group had the least surgically induced astigmatism and axial change. All incision groups remained stable and had satisfactory clinical results.

Topical versus peribulbar anesthesia in clear corneal cataract surgery.

PURPOSE: To evaluate the efficacy of topical anesthesia as an alternative to peribulbar anesthesia in clear corneal cataract surgery. SETTING: Department of Ophthalmology, University of Vienna, Austria. METHODS: In this prospective, double-blind clinical trial, 36 patients had bilateral cataract surgeries performed from 1 to 3 months apart. Half of the patients had topical anesthesia for the first surgery and peribulbar anesthesia for the second surgery. The other half had peribulbar first and then topical. All surgery was done using a temporal clear corneal approach and bimanual phacoemulsification followed by in-the-bag intraocular lens implantation. Subjective pain was assessed using a visual analog scale of no pain (0%) to worst pain imaginable (100%) and intraoperative motility using a rank scale of adverse motility (-5) to ideal patient cooperation (+5). RESULTS: Subjective pain was comparable whether topical or peribulbar anesthesia was used (mean 10.75 versus 10.97%; P > .6). Patient cooperation (motility) was significantly better when topical anesthesia was used (+2.16 versus +1.11; P = .03). There were no significant differences in complications. A peribulbar block was given in addition to the topical anesthesia in two cases. CONCLUSIONS: Topical anesthesia is a safe, effective alternative to peribulbar anesthesia in clear corneal cataract surgery.

Vegetative background of sleep: spectral analysis of the heart rate variability.

Phasic events during sleep, either arousal or REM-burst related, and the associated transient cardiovascular responses have been the subject of intensive research in previous studies. However, nontransient (stationary) fluctuations in heart rate have been studied less extensively in the past. They allow a differentiation of the sympathetic and parasympathetic activation, which are related to a low-frequency (LF) and a high-frequency (HF) component of the heart rate variability (HRV) signal, respectively. The resulting LF/HF ratio is a quantitative index of the sympatho-vagal balance. Sleep polygrams from 20 healthy volunteers were recorded in a sleep laboratory. Standard vegetative tests (orthostatic and Valsalva tests) were evaluated. A segmentation procedure, performed on the HRV signal, separated 70-130 transients during the night from the records of stationary heart rate fluctuations. From these periods the sympatho-vagal balance, quantified by the LF/HF, was computed by means of spectral analysis. The more synchronized the sleep was, the more the LF/HF decreased, whereas the LF/HF was significantly increased during REM sleep, indicating a sympathetic predominance during this period. Such an increase was also evident during the last 15 min before REM sleep onset. Results suggest that spectral analysis of the HRV provides additional information of the ultradian rhythmic behavior of the autonomic nervous system function beyond the traditional cardiovascular measurements (mean heart rate, blood pressure, etc.). In contrast to these measurements, which generally show a continuously decreasing cardiovascular activity, as the night proceeds, the results of this study reveal a high sympathetic peak activity during the later REM sleep periods, which is comparable in magnitude to that found in the upright position in wakefulness. This activity may be associated to the well-known incidence peak of ischemic events in the early morning hours.

A phase I study. UFT/leucovorin combined with paclitaxel for anthracycline-pretreated advanced breast cancer.

Taxanes are the most active drugs in the treatment of metastatic breast and ovarian cancer. Weekly therapy with paclitaxel produces notable activity, with remarkably low toxicity. Moreover, combination therapy with paclitaxel and fluorouracil (5-FU) exhibits high activity in anthracycline-pretreated breast cancer patients: recent studies report response rates of 54% to 69%. UFT plus oral leucovorin constitutes an orally administered compound that provides activity comparable to that of intravenously administered 5-FU plus leucovorin. An open-label phase I study was initiated to determine the maximum tolerated dose and dose-limiting toxicities of the combination of weekly paclitaxel and UFT plus leucovorin administered to patients with anthracycline-resistant metastatic breast cancer.

UFT/oral calcium folinate plus weekly paclitaxel for metastatic breast cancer.

Paclitaxel (Taxol) is one of the most active drugs in the treatment of ovarian and breast cancers. Combination therapy with paclitaxel and 5-fluorouracil (5-FU) exhibits high activity in anthracycline-pretreated breast cancer, yielding response rates of 54% to 69% in recent studies. Weekly dosing of paclitaxel produces notable activity, while maintaining relatively low toxicity in heavily pretreated metastatic breast cancer patients. Uracil and tegafur (UFT) plus oral calcium folinate constitute an orally administered compound known as Orzel. This agent provides activity comparable to that of intravenously administered 5-FU plus calcium folinate, with the additional attributes of ease of administration and a more favorable side-effect profile. We initiated a phase I dose-finding trial to determine the maximum tolerated dose and dose-limiting toxicities of the combination of weekly paclitaxel by 1-hour infusion plus UFT/oral calcium folinate administered to patients with anthracycline-resistant metastatic breast cancer.