[Return to Work After Shoulder Arthroscopy as an Index of Cost Effectiveness]. / Nutzenbewertung der minimal-invasiven Schulterchirurgie aus Sicht der Kostenträger.

Cost-effectiveness of shoulder arthroscopy was analyzed and assessed by the days off work as part of the indirect costs. We retrospectively evaluated a group of 266 inpatients on sick leave after arthroscopic shoulder surgery. Mean duration till return to full duty was 9.5 days, the mean sick leave benefit was € 485. There was a statistically significant difference in the mean time to return to work between the older (age >50) and the younger group (age under 50). Secondary data analysis of sick leave and sickness benefits as indirect costs of medical treatment seems to be well suited to provide essentiell information to health care policy makers and those charged with distributing disability funds.

[Achilles tendon rupture : Current diagnostic and therapeutic standards]. / Achillessehnenruptur : Aktuelle Standards in Diagnostik und Therapie.

A superior life expectancy and an increased activity in the population result in an increase in degenerative diseases, such as Achilles tendon ruptures. The medical history and physical examinations are the methods of choice to diagnose Achilles tendon ruptures. Ultrasound and radiography represent reasonable extended diagnostic procedures. In order to decide on the medical indications for the therapy concept, the advantages and disadvantages of conservative and surgical treatment options have to be weighed up on an indivdual basis. There are explicit contraindications for both treatment options. For the surgical treatment concept open suture techniques, minimally invasive methods and reconstructive procedures are available. The postoperative management of the patient is as important as the choice of surgical technique. With the correct medical indications and supervision of the patient it is possible to achieve extremely satisfying results for the patient with both conservative and surgical treatment options.

CYT003, a TLR9 agonist, in persistent allergic asthma - a randomized placebo-controlled Phase 2b study.

BACKGROUND: New treatment options are required for patients with asthma not sufficiently controlled with inhaled therapies. In a Phase 2a trial, CYT003, a Toll-like receptor-9 agonist immunomodulator, improved asthma control during inhaled glucocorticosteroid reduction in patients with allergic asthma. This double-blind Phase 2b study assessed the efficacy and safety of CYT003 in patients with persistent moderate-to-severe allergic asthma not sufficiently controlled on standard inhaled glucocorticosteroid therapy with/without long-acting beta-agonists (LABAs). METHODS: Overall, 365 patients received seven doses of subcutaneous CYT003 (0.3, 1, or 2 mg) or placebo as add-on therapy to conventional controller medication. Change from baseline in Asthma Control Questionnaire (ACQ) score was the primary outcome; secondary outcomes included change in forced expiratory volume, Mini Asthma Quality of Life Questionnaire, and safety. RESULTS: All groups, including placebo, showed a clinically important improvement in ACQ score; however, there was no significant difference between the CYT003 and placebo groups at week 12 (least-squares mean difference 0.3 mg: -0.027 [95% confidence interval -0.259 to 0.204]; 1 mg: 0.097 [-0.131 to 0.325]; 2 mg: 0.081 [-0.148 to 0.315]). No significant differences were seen in secondary outcomes. CYT003 was well tolerated; the most common treatment-emergent adverse events were injection site reactions. Due to lack of efficacy, the study was prematurely terminated at the end of the treatment phase with no further follow-up. CONCLUSIONS: Toll-like receptor-9 agonism with CYT003 showed no additional benefit in patients with insufficiently controlled moderate-to-severe allergic asthma receiving standard inhaled glucocorticosteroid therapy with or without LABAs.

[Health-related Quality of Life After Oropharyngeal Cancer Treatment]. / Gesundheitsbezogene Lebensqualität nach Behandlung von Plattenepithelkarzinomen des Oropharynx.

BACKGROUND: Oropharyngeal cancer is a diagnosis which means a change in life and even after successful treatment a tremendous reduction in the quality of life. Aim of this study is to analyse the health-related quality of life in patients with oropharyngeal cancer dependent on different treatment options. METHODS AND PATIENTS: Charts of 256 patients treated for oropharyngeal cancer between 1997 and 2007 were analysed in a retrospective study. Inclusion criteria for this study has been fulfilled by 98 patients, 82 of these completed the study. Therefore, standardised questionnaires (EORTC QLQ-C30 und EORTC QLQ-H&N35) have been used and 2 groups were compared: patients with primary radiochemotherapy (pRCT) vs. patients treated by an operation and adjuvant radiation. RESULTS: Most of the health-related quality of life domains in our patients were significantly reduced compared to the general population. There have been just very few significant differences in the quality of life domains in between the 2 groups. CONCLUSIONS: Health-related quality of life after treatment of oropharyngeal cancer is significantly compromised for these patients compared to the general population, but there have been no obvious differences depending on the compared treatment options. Only regarding the items "physical and cognitive functioning" patients after primary radiochemotherapy showed significantly better results and thus a better quality of life, despite the fact, that this group has a significantly advanced cancer stadium.

[Immunotherapy of allergic rhinitis without allergens? : new options for immunomodulation by vaccination with virus-like particles and CpG motifs]. / Immuntherapie der allergischen Rhinitis ohne Allergene? : Neue Möglichkeiten einer Immunmodulation durch Vakzinierung mittels "virus-like particles" und CpG-Motiven.

BACKGROUND: Allergen-specific immunotherapy is generally accepted as the only causal therapy for allergic rhinitis. Up to now there has been a dogma in immunotherapy for inhalation allergies that at least allergen components are necessary for effective therapy. This dogma could, however, be swayed by current results of effective immunotherapy without allergens. Virus-like particles (VLP) represent a novel and interesting aspect for immunotherapy for inhalation allergies. AIM: Initial experiences with successful immunotherapy without allergens are available. This article describes the currently available clinical experiences with bacteriophage VLPs filled with oligonucleotides which contain CpG motifs with tumor antigens on the surface for the treatment of allergic rhinitis. RESULTS: Vaccination with VLPs was found to be well tolerated, immunogenic and effective for prophylactic treatment of various infections. Bacteriophage VLPs filled with CpG motifs with tumor antigens on the surface led clinically to an induction of specific T-cells in tumor patients and were successfully implemented as adjuvants during prophylactic vaccinations. CONCLUSION: The VLP technique in combination with the use of CpG motifs could contribute to the causal treatment of complex diseases, such as malignancies, autoimmune diseases and allergies.

In vitro suppression of drug-induced methaemoglobin formation by Intralipid(®) in whole human blood: observations relevant to the 'lipid sink theory'.

To provide further evidence for the lipid sink theory, we have developed an in vitro model to assess the effect of Intralipid® 20% on methaemoglobin formation by drugs of varying lipid solubility. Progressively increasing Intralipid concentrations from 4 to 24 mg.ml⁻¹ suppressed methaemoglobin formation by the lipid soluble drug glyceryl trinitrate in a dose-dependent manner (p < 0.001). Both dose and timing of administration of Intralipid to blood previously incubated with glyceryl trinitrate for 10 and 40 min resulted in significant suppression of methaemoglobin formation (p < 0.0001 and p < 0.05, respectively). Mathematical modelling demonstrated that the entire process of methaemoglobin formation by glyceryl trinitrate was slowed down in the presence of Intralipid. Intralipid did not significantly suppress methaemoglobin formation induced by 2-amino-5-hydroxytoluene (partially lipid soluble) or sodium nitrite (lipid insoluble; both p > 0.5). This work may assist determination of the suitability of drugs taken in overdose for which Intralipid might be deployed.

Injury incidence and specific injury patterns in app-based bodyweight training (Freeletics): results of an international survey with 3668 participants.

BACKGROUND: The aim of this study was to analyze incidences and sport-specific injury patterns among users of a bodyweight-based training method instructed by a smartphone app (Freeletics Bodyweight App). METHODS: An online questionnaire based on current validated epidemiological observation methods was designed using the statistic website Surveymonkey. Subscribers of the Freeletics Bodyweight App were contacted via an online link. Injury incidence, defined as an event leading to a training pause of at least 1 day, was recorded. The type of injury was reported and classified. Furthermore, all participants were asked whether they recognized any positive or negative effects on their subjective health status. The collected data were analyzed using Surveymonkey statistic services. RESULTS: A total of 4365 Freeletics users responded to the questionnaire, 3668 completed forms were subject of further investigation. The injury period prevalence reported by users of the Freeletics App was 24% in men and 21% in women. The most frequently reported site of injury was the shoulder (29%) and the knee joint (28%), with strains (28.5%) and other muscle injuries (14.4%) being the most frequently reported types of injuries. An injury incidence rate of 4.57 per 1000 h was calculated, with injuries occurring less frequently in experienced users. Most participants reported a distinct positive effect of the app-based training on their health status. CONCLUSION: In comparison to other sports activities app-based bodyweight training is associated with a comparably low injury period prevalence. The vast majority of injuries were reported to have resolved within one week.

Assessment of clinical efficacy of CYT003-QbG10 in patients with allergic rhinoconjunctivitis: a phase IIb study.

BACKGROUND: Allergic symptoms are generally caused by exposure to substances to which people have become sensitized. Associated with this is an 'unbalanced' Th1/Th2 immune response with T cell responses skewed towards the production of Th2 cytokines, IL-4, 5, and 13 and high levels of IgE antibodies. Current immune modulating therapies require the use of allergens, carrying the risk to induce potentially severe allergic reactions. OBJECTIVE: Goal of the present study was to assess the safety and efficacy of an allergen-free immune modulator in patients suffering from perennial allergy. METHODS: In order to be protected from immediate degradation upon injection, a toll-like receptor 9 (TLR9) agonist was packaged into virus-like particles. These nanoparticles loaded with TLR9 ligands (CYT003-QbG10) were injected six times, at weekly intervals, into patients with house dust mite allergy in an attempt to ameliorate allergic symptoms by modifying the immune response towards allergens. Two different doses were compared against placebo in this double-blind, randomized phase IIb study (n=299). Public trial registry: http://clinicaltrials.gov (NCT00800332). RESULTS: The treatment was safe and generally well tolerated. Rhinoconjunctivitis symptoms were significantly lower in patients treated with high dose of CYT003-QbG10 as compared with placebo (scores 0.31 vs. 0.52, P=0.04) based on a standardized average combined symptom and medication score. Furthermore, patients in the high dose group reported a significantly better quality of life score post-treatment than patients on placebo (scores 0.71 vs. 1.21, P=0.02). The conjunctival provocation test revealed a median 10-fold increase in allergen tolerance in the high dose group while in the placebo group it remained unchanged. CONCLUSION AND CLINICAL RELEVANCE: Treatment with high-dose CYT003-QbG10 improved disease symptoms and reduced medication use in allergic individuals thus providing first evidence for a new potential immunotherapeutic.

Early treatment of a quetiapine and sertraline overdose with Intralipid.

We describe the initial management and subsequent recovery of a 61 year-old male patient following attempted suicide by oral ingestion of a potentially fatal overdose of quetiapine and sertraline. Intravenous Intralipid was given soon after initiation of basic resuscitation. There was a rapid improvement in the patient's level of consciousness. No other clinical signs of drug toxicity were observed. Intralipid may have reversed the deep coma associated with ingestion and prevented other manifestations of drug toxicity occurring, thus expediting this patient's recovery.

Higher Fertilizer Inputs Increase Fitness Traits of Brown Planthopper in Rice.

Rice (Oryza sativa L.) is the primary staple food source for more than half of the world's population. In many developing countries, increased use of fertilizers is a response to increase demand for rice. In this study, we investigated the effects of three principal fertilizer components (nitrogen, phosphorus and potassium) on the development of potted rice plants and their effects on fitness traits of the brown planthopper (BPH) [Nilaparvata lugens (Stål) (Homoptera: Delphacidae)], which is a major pest of rice in Bangladesh and elsewhere. Compared to low fertilizer inputs, high fertilizer treatments induced plant growth but also favored BPH development. The BPH had higher survival, developed faster, and the intrinsic rate of natural increase (r m ) was higher on well-fertilized than under-fertilized plants. Among the fertilizer inputs, nitrogen had the strongest effect on the fitness traits of BPH. Furthermore, both the "Plant vigor hypothesis" and the "Plant stress hypothesis" were supported by the results, the former hypothesis more so than the latter. These hypotheses suggest that the most suitable/attractive hosts for insect herbivores are the most vigorous plants. Our findings emphasized that an exclusive focus on yield increases through only enhanced crop fertilization may have unforeseen, indirect, effects on crop susceptibility to pests, such as BPH.

Genetic Variants of the FADS Gene Cluster Are Associated with Erythrocyte Membrane LC PUFA Levels in Patients with Mild Cognitive Impairment.

BACKGROUND: Long-chain (> 20 C-atoms) polyunsaturated fatty acids (LC PUFAs) of both the omega-6 (n-6) and omega-3 (n-3) series are important for the functional integrity of brain and thereby cognition, memory and mood. Clinical studies observed associations between altered LC PUFA levels and neurodegenerative diseases such as Alzheimer´s disease and its prodromal stage, mild cognitive impairment (MCI). METHODS: The present study examined the LC PUFA status of MCI patients with specific view on the relative LC n-3 PUFA levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocyte membranes (omega-3 index). 12 single nucleotide polymorphisms (SNPs) of the FADS1, FADS2, and FADS3 gene clusters were genotyped in 111 MCI patients and evaluated associations with PUFA levels in erythrocyte membranes (primary outcome). In addition, the associations between FADS SNPs and LC PUFA levels with serum lipid levels as well as depressive symptoms were examined (secondary outcomes). RESULTS: Minor allele carrier of rs174546, rs174548 (FADS1), rs3834458, rs1535, rs174574, rs174575, rs174576, and rs174578 (FADS2) showed significant higher n-6 and n-3 precursor PUFA levels (linoleic acid, and alpha-linolenic acid, respectively) and lower arachidonic acid (AA) levels in erythrocyte membranes compared to the major allele carriers. Differences in EPA and DHA levels were not significant. Minor allele carriers of rs174574, rs174576 and rs174578 (FADS2) and rs174455 (FADS3) exhibited significant higher triglyceride levels, whereas minor allele carriers for rs174449 and rs174455 (FADS3) exhibited significant higher total- and LDL-cholesterol levels compared to the more common variant. The mean omega-3 index of the study cohort was 6.19 ± 1.55 %. In more than 85 % of the patients, the omega-3 index was below 8 % and in 23 % below 5 %. Moreover, it was shown that a low DHA status and omega-3 index was associated with depressive symptoms (Beck's depression-inventory). DISCUSSION AND CONCLUSION: These findings indicate an association between several FADS genotypes for higher n-6 and n-3 precursor PUFA and lower AA levels in erythrocyte membranes in minor compared to major allele carriers. To what extent FADS genotypes and a lower conversion of LA and ALA to biologically important LC PUFAs such as AA, EPA and DHA contributes to cognitive decline should be investigated in further trials. Nevertheless, the omega-3 index in this cohort of MCI patients can be classified as insufficient.

The interferon inhibiting cytokine IK is overexpressed in cutaneous T cell lymphoma derived tumor cells that fail to upregulate major histocompatibility complex class II upon interferon-gamma stimulation.

Cutaneous T cell lymphomas are characterized by an accumulation of malignant clonal lymphocytes in the skin and occasionally in the blood. We compared gene transcription profiles from cultured clonal lymphocytes with autologous healthy blood lymphocytes by microarray hybridization. Cutaneous T cell lymphoma derived cells transcribed high amounts of an interferon inhibiting cytokine factor. The presence of an interferon inhibiting cytokine factor was confirmed in 12 skin biopsies of mycosis fungoides and Sézary syndrome derived blood lymphocytes by reverse transcriptase-polymerase chain reaction. The presence of interferon inhibiting cytokine factor mRNA in Sézary syndrome derived lymphocytes was associated with a lack of HLA class II upregulation after stimulation with interferon-alpha and interferon-gamma. This was not due to a loss of the interferon signaling cascade as the presence of interferon-signaling components was confirmed by reverse transcriptase--polymerase chain reaction on the transcriptional level. The elevated constitutive interferon inhibiting cytokine factor expression observed in cutaneous T cell lymphoma derived cells was insensitive to interferon-gamma stimulation, but was enhanced in normal peripheral blood mononuclear cells. We suggest that interferon inhibiting cytokine factor contributes to the lack of HLA class II upregulation in lymphoma cells. Interferon inhibiting cytokine factor may participate in providing a microenvironment at the tumor site insensitive to interferon-gamma stimulation and thus prevents an efficient local immune response.

Decreased intraindividual HLA class I expression is due to reduced transcription in advanced melanoma and does not correlate with HLA-G expression.

The presentation of endogenously synthesized peptides in association with HLA class I molecules allows the activation of CD8(+) lymphocytes. Tumor cells often fail to present antigenic peptides resulting in the immune escape of metastasizing cells. The aim of this study was to elucidate possible molecular mechanisms leading to reduced antigen presentation in melanoma. Melanoma cell short-time cultures were genotypically and phenotypically HLA-typed by sequence-specific primer polymerase chain reaction and complement-mediated microlymphocytotoxicity assays, respectively. Flow cytometric analysis of HLA-A2 and HLA-A3 allospecificities were performed to confirm typing results. Transcriptional levels of classical HLA-A, HLA-B genes and nonclassical HLA-G genes were detected using quantitative real-time reverse transcriptase polymerase chain reaction (LightCycler). We found loss or downregulation of HLA proteins in 18% (for HLA-A) and 53% (for HLA-B) of all tested metastases. Genomic analysis, however, revealed the presence of the corresponding HLA class I gene in six out of seven cases. On the level of gene transcription we observed a differential regulation of HLA-A, HLA-B, and HLA-G mRNA expression. There was no correlation between classical and nonclassical HLA gene transcription, but the transcriptional levels of classical HLA corresponded to the protein expression levels. Furthermore, an overall reduced amount of HLA class I gene transcription was observed in melanoma metastases during disease progression in three individuals. We postulate that there is a transcriptional regulation of HLA class I gene expression in melanoma cells. These data suggest that treatment approaches aimed at activating specific cytotoxic T lymphocytes are most successful in early disease.

Estimation of classical pathway of mouse complement activity by use of sensitized rabbit erythrocytes.

A simple photometric assay was devised for determining classical complement pathway activity in mouse serum using sensitized rabbit erythrocytes as target cells. These cells appeared more sensitive to lysis by mouse complement than sensitized mouse and sheep erythrocytes, most probably by their ability to escape the C3b inactivator system. Advantages of the assay over other techniques are the high sensitivity and the avoidance of the use of radioisotopes. With this test it is possible to get more insight in the complement system of an animal species that has been most widely in use in immunological research.

Determination of alternative pathway of complement activity in mouse serum using rabbit erythrocytes.

Rabbit, mouse and sheep erythrocytes expressing different concentrations of membrane sialic acid were used to study possible modes of activation of the alternative complement (C) pathway in mouse, human and guinea pig serum. Mouse erythrocytes activated only human serum, whereas rabbit erythrocytes activated the sera of all three species. Based on the observation that rabbit erythrocytes activate the murine alternative C pathway a method for estimation of alternative C pathway activity (AP50 value) in mouse serum was devised analogous to that used for human AP50 determination. The method is not very sensitive to ageing or to batch variation of the indicator cells. The AP50 value of mouse serum measured by this method is of the same order as for human and guinea pig serum. Mouse serum AP50 activity is partly determined by natural anti-rabbit erythrocyte antibodies and is sensitive to heating (15' at 48 degrees C and 4' at 56 degrees C), and to the actions of cobra venom factor, zymosan and cysteine. Strain and sex differences with respect to AP50 activities of mouse sera were observed.

A one-step isolation procedure for phospholipase A2-free cobra venom factor by fast protein liquid chromatography.

A very rapid and efficient procedure for isolation of cobra venom factor (CoF) from Naja naja venom is presented. The method is based on Mono Q anion exchange chromatography on a system for fast protein liquid chromatography (FPLC). CoF was eluted by a buffer of pH 7.4 at 280 mM salt. A purification of 33.7 X was reached with a yield of at least 27%. Contamination with phospholipase was under the detection limit of a sensitive radiometric assay (less than 25 ppm), while the starting material contained 5%. The preparation displays high C-depleting activity in vivo.