[The International Classification of Functioning, Disability and Health (ICF) : The implementation of the ICF Core Sets for Hand Conditions in clinical routine as an example of application]. / Die Internationale Klassifikation der Funktionsfähigkeit, Behinderung und Gesundheit (ICF) : Implementierung in der klinischen Routine am Beispiel der ICF Core Sets der Hand.

The International Classification of Functioning, Disability and Health (ICF) provides a standardized language of almost 1500 ICF categories for coding information about functioning and contextual factors. Short lists (ICF Core Sets) are helpful tools to support the implementation of the ICF in clinical routine. In this paper we report on the implementation of ICF Core Sets in clinical routine using the "ICF Core Sets for Hand Conditions" and the "Lighthouse Project Hand" as an example. Based on the ICF categories of the "Brief ICF Core Set for Hand Conditions", the ICF-based assessment tool (ICF HandA) was developed aiming to guide the assessment and treatment of patients with injuries and diseases located at the hand. The ICF HandA facilitates the standardized assessment of functioning - taking into consideration of a holistic view of the patients - along the continuum of care ranging from acute care to rehabilitation and return to work. Reference points for the assessment of the ICF HandA are determined in treatment guidelines for selected injuries and diseases of the hand along with recommendations for acute treatment and care, procedures and interventions of subsequent treatment and rehabilitation. The assessment of the ICF HandA according to the defined reference points can be done using electronic clinical assessment tools and allows for an automatic generation of a timely medical report of a patient's functioning. In the future, the ICF HandA can be used to inform the coding of functioning in ICD-11.

Fingertip and Thumb Tip Wounds: Changing Algorithms for Sensation, Aesthetics, and Function.

Management of fingertip and thumb tip injuries has recently undergone substantial changes. The time-proven traditional armamentarium of local flaps has been expanded and replaced by a wide variety of flaps. Simultaneous with the development of new flaps, the conservative treatment of fingertip and thumb tip injuries with semiocclusive dressings has also become a more acceptable treatment for these injuries. The excellent results with respect to restoring contour, sensibility of the pulp, and aesthetics of the finger justify this more tedious and time-consuming treatment of fingertip and thumb tip injuries. This article gives an update of the most commonly used flaps and the semiocclusive dressing treatments of fingertip and thumb tip injuries.

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414.

Despite recent approvals of anti-obesity drugs there is still a high therapeutic need for alternative options with higher efficacy in humans. As part of our MCH-R1 antagonist program for the treatment of obesity, a series of biphenylacetamide HTS hits was evaluated. Several issues of the initial lead structures had to be resolved, such as potency, selectivity over related GPCRs and P-gp efflux limiting brain exposure in this series. We could demonstrate that all parameters can be significantly improved by structural modifications resulting in BI 414 as a potent and orally available MCH-R1 antagonist tool compound with acceptable in vivo efficacy in an animal model of obesity.

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part III: Discovery of pre-clinical development candidate BI 186908.

Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11 g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic administration of BI 186908 resulted in significant body weight reduction comparable to sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile, BI 186908 was advanced to pre-clinical development.

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part II: Optimization of pyridazines toward reduced phospholipidosis and hERG inhibition.

Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated. During optimization several issues of the initial lead structures had to be resolved, such as selectivity over related GPCRs, inhibition of the hERG channel as well as the potential to induce phospholipidosis. Utilizing property-based design, we could demonstrate that all parameters can significantly be improved by consequently increasing the polarity of the compounds. By this strategy, we succeeded in identifying potent and orally available MCH-R1 antagonists with good selectivity over M1 and 5-HT2A and an improved safety profile with respect to hERG inhibition and phospholipidosis.

Management of thumb tip injuries.

The management of thumb tip injuries has undergone great changes in recent years. The traditional armamentarium of flaps has been expanded and replaced by a wide variety of flaps with more versatility and less donor side morbidity. Parallel to the development of new flaps, the conservative treatment of thumb tip injuries with semi-occlusive dressing has gained ground in the treatment of these injuries. Although tedious and time-consuming, and requiring intensive communication with the patient to explain the look and occasionally fetid smell of the wound, this technique yields excellent results with respect to restoring contour and sensibility in pulp injuries. The article gives an update on the current options for treating thumb tip injuries including the most commonly applied flaps.

Do patient-reported outcome measures capture functioning aspects and environmental factors important to individuals with injuries or disorders of the hand?

STUDY DESIGN: Qualitative study. INTRODUCTION: Clinical outcome evaluation needs to consider the patient perspective for an in-depth understanding of functioning and disability. PURPOSE OF THE STUDY: To explore whether patient-reported outcome measures (PROMs) used in the field of hand injuries or hand disorders, capture functioning aspects and environmental factors important to the patients. METHODS: We performed a qualitative study and a systematic literature review. The focus group sessions were recorded, transcribed verbatim, and the identified concepts were linked to the ICF. We searched in MEDLINE for reviews, related to injuries or disorders of the hand, reporting on PROMs. We linked the items of the identified PROMs to the ICF and compared the qualitative data with the content of the PROMs. RESULTS: Statements from 45 individuals who participated in eight focus groups were linked to 97 categories of the ICF. From 15 reviews included, eight PROMs were selected. The selected PROMs capture 34 of the categories retrieved from the qualitative data. CONCLUSIONS: PROMs used in the context of hand injuries or hand disorders capture only in parts the functioning aspects important to the patients.

Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy.

Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human beta2-adrenoceptor with a high beta1/beta2-selectivity. A complete reversal of acetylcholine-induced bronchoconstriction which lasted over the whole study period of 5h was demonstrated for 4p in a guinea pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching 100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy over 24 h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did not retain efficacy after 24 h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile.

Studies towards topical selective beta2-adrenoceptor agonists with a long duration of action.

Beta2-adrenoceptor agonists with basic and acidic groups attached via an alkyl linker to the phenyl ethanolamine core were prepared and investigated in vitro and in vivo. The compounds exhibited a high potency in a functional cellular assay and a bronchoprotective effect in a guinea pig model which lasted over the complete study period of 5h.

Use of 5-hydroxy-4H-benzo[1,4]oxazin-3-ones as beta2-adrenoceptor agonists.

Novel beta(2)-agonists with a 5-hydroxy-4H-benzo[1,4]oxazin-3-one moiety as head group are described. Systematic chemical variations at the phenethylamine residue of these compounds lead to the discovery of compound 6m as potent, full agonist of the beta(2)-adrenoceptor with a high beta(1)/beta(2)-selectivity. Molecular modeling revealed an interaction between the carboxylic acid group of 6m and a lysine residue (K305) of the beta(2)-receptor as putative explanation for the high observed selectivity. Further, compound 6m displayed in a guinea pig in vivo model a complete reversal of acetylcholine induced bronchoconstriction which lasted over the complete study time of 5h.

CGRP antagonists: unravelling the role of CGRP in migraine.

Migraine is a complex, debilitating neurovascular disorder. Although knowledge on the main molecular players is still incomplete, recent preclinical and clinical findings indicate that there is a clear correlation between migraine-associated headache and the release of the neuropeptide calcitonin gene-related peptide (CGRP). BIBN4096 was the first CGRP antagonist to be tested in clinical trials for the treatment of migraine. The proven efficacy of this agent, and also the CGRP antagonist MK-0974, to alleviate acute migraine headache provided significant support for the hypothesis that CGRP has an important role in migraine pathophysiology. Moreover, the recently published results from Phase II trials are encouraging and suggest that this new type of drug might offer advantages over existing therapies for patients suffering from migraine and related headaches.

Microspectrometer based on holographically recorded diffractive elements using supplementary holograms.

The conception and realization of an imaging microspectrometer, limited to an optical volume of 11 x 6 x 5 mm(3), is presented. The spectrometer is based on a multi-order concept and offers an overall spectral bandwidth of 400-1030 nm with better than 2.5 nm resolution in the visible range. The numerical aperture of NA = 0.2 allows an appropriate energy efficiency. As the most essential element of the microspectrometer, a concave diffraction grating with a diameter of 5 mm and an image distance of f = 8.6 mm was manufactured in a holographic recording process. For the recording process the specifications of the concave grating require two diffraction limited point sources in very close proximity. To provide a point source distance below 1 mm a recording concept based on the introduction of a supplementary hologram was employed.

Accidental sulfur mustard exposure: A case report.

The clinical progression following a sulfur mustard-induced skin exposure is well documented in the literature. Upon skin contact and a characteristic latency period, sulfur mustard (SM) causes erythema, blister formation and ulceration, which is associated with wound healing disorders that may require surgical treatment. Here, we present a case report of accidental exposure to SM in a laboratory setting which required surgical treatment of the skin. The case was illustrated at close intervals over a period of two years and underlines that exposure to SM has to be taken into account when typical clinical symptoms occur. Moreover skin grafts appear to be effective in SM-induced non healing skin ulcerations.

Examination of the Applicability of the Disabilities of the Arm, Shoulder and Hand (DASH) Questionnaire to Patients with Hand Injuries and Diseases Using Rasch Analysis.

BACKGROUND: The Disabilities of the Arm, Shoulder and Hand (DASH) Questionnaire is the most commonly applied patient-reported outcome measure used to assess disability and functioning in clinical research and practice for patients with injuries and diseases of the upper extremities. The objective of this study was to assess whether the DASH is a valid and reliable questionnaire to measure disability and functioning in patients with hand injuries and diseases using Rasch analysis. METHODS: We performed a psychometric study using data derived from two multicentre studies carried out to develop the International Classification of Functioning, Disability and Health (ICF) Core Sets for Hand Conditions. We analysed the data of 417 patients recruited in a clinical setting and suffering from hand injuries (e.g. finger fracture, flexor tendon injury) or diseases (e.g. carpal tunnel syndrome, rhizarthrosis). We examined whether the DASH fulfilled the assumptions for its use as a measure by applying a partial credit model and testing for differential item functioning for sex and age. RESULTS: Bifactor analysis revealed problems with the underlying latent trait of functioning and disability. Rasch analysis raised further issues, including disordered thresholds for eight items and misfit in nine items. One item showed Differential Item Functioning for sex. CONCLUSION: The study reveals that some DASH items do not fit the underlying trait that the DASH aims to measure. Further studies using Rasch analysis are needed to compare our findings with results of studies involving other target groups (e.g. patients with injuries of the upper arm and shoulder).

Medical documentation, bioanalytical evidence of an accidental human exposure to sulfur mustard and general therapy recommendations.

Sulfur mustard (SM) is a chemical warfare agent (CWA) that was first used in World War I and in several military conflicts afterwards. The threat by SM is still present even today due to remaining stockpiles, old and abandoned remainders all over the world as well as to its ease of synthesis. CWA are banned by the Chemical Weapons Convention (CWC) interdicting their development, production, transport, stockpiling and use and are subjected to controlled destruction. The present case report describes an accidental exposure of three workers that occurred during the destruction of SM. All exposed workers presented a characteristic SM-related clinical picture that started about 4h after exposure with erythema and feeling of tension of the skin at the upper part of the body. Later on, superficial blister and a burning phenomenon of the affected skin areas developed. Similar symptoms occurred in all three patients differing severity. One patient presented sustained skin affections at the gluteal region while another patient came up with affections of the axilla and genital region. Fortunately, full recovery was observed on day 56 after exposure except some little pigmentation changes that were evident even on day 154 in two of the patients. SM-exposure was verified for all three patients using bioanalytical GC MS and LC MS/MS based methods applied to urine and plasma. Urinary biotransformation products of the ß-lyase pathway were detected until 5 days after poisoning whereas albumin-SM adducts could be found until day 29 underlining the beneficial role of adduct detection for post-exposure verification. In addition, we provide general recommendations for management and therapy in case of SM poisoning.

Development of human calcitonin gene-related peptide (CGRP) receptor antagonists. 1. Potent and selective small molecule CGRP antagonists. 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-l-lysyl]-4-(4-pyridinyl)piperazine: the first CGRP antagonist for clinical trials in acute migraine.

Although the triptans have greatly improved the acute treatment of migraine headache, there are yet many shortcomings. Therefore, new strategies for the treatment of migraine are needed which offer advantages over current therapy, e.g. triptans. Our novel approach was based on the hypothesis that the release of calcitonin gene-related peptide (CGRP) could play a causative role in migraine headache. Thus we initiated a program aimed at the design and synthesis of small molecule CGRP receptor antagonists. High throughput screening led to the identification of (R)-Tyr-(S)-Lys dipeptide-like compounds that showed weak but unequivocal binding to the human CGRP receptor. Lead optimization afforded highly potent CGRP antagonists, the prototype being compound 19 (BIBN4096). This compound exhibiting a favorable biological profile was selected for initial clinical trials. A proof of concept study indicated that intravenous application of 19 was effective in the treatment of acute migraine headache. This finding strongly supports our initial working hypothesis that CGRP plays an important role in the pathophysiology of migraine.

Development of the International Classification of Functioning, Disability and Health core sets for hand conditions--results of the World Health Organization International Consensus process.

PURPOSE: A formal decision-making and consensus process was applied to develop the first version of the International Classification on Functioning, Disability and Health (ICF) Core Sets for Hand Conditions. METHOD: To convene an international panel to develop the ICF Core Sets for Hand Conditions (HC), preparatory studies were conducted, which included an expert survey, a systematic literature review, a qualitative study and an empirical data collection process involving persons with hand conditions. A consensus conference was convened in Switzerland in May 2009 that was attended by 23 healthcare professionals, who treat hand conditions, representing 22 countries. RESULTS: The preparatory studies identified a set of 743 ICF categories at the second, third or fourth hierarchical level. Altogether, 117 chapter-, second-, or third-level categories were included in the comprehensive ICF Core Set for HC. The brief ICF Core Set for HC included a total of 23 chapter- and second-level categories. CONCLUSIONS: A formal consensus process integrating evidence and expert opinion based on the ICF led to the formal adoption of the ICF Core Sets for Hand Conditions. The next phase of this ICF project is to conduct a formal validation process to establish its applicability in clinical settings.

Operative Treatment and Soft Tissue Management of Open Distal Tibial Fractures - Pitfalls and Results.

Open tibial fractures usually result from high-energy trauma. Severe soft-tissue injuries are often combined with open fractures of the distal tibia. A consecutive series of 42 patients with open extraarticular distal tibial fractures (Gustilo I-IIIc) operated on between July 2006 and February 2009 were included in the study reported here. We performed open reduction and internal fixation for the Gustilo I cases. Soft tissue was closed directly after antibiotic beads had been temporarily applied. For the Gustilo II and III cases, our treatment protocol included soft-tissue debridement of all devitalized soft tissue and bone fragments, pulsatile jet irrigation, and external stabilization. Soft tissue was temporarily closed with Epigard_ after the application of antibiotic beads. A second-look operation was scheduled after 3-5 days. Gustilo II patients needed an average of 1.1 (0-3) revisions until wound closure, compared to the average of 2.1 revisions necessary for the Gustilo III patients. It took 5.6 (0-16) days to obtain definitive wound closure in the Gustilo II patients and 9.9 (3-28) days in the Gustilo III patients. Skin grafting was sufficient for definitive softtissue closure in ten cases, local flaps in eight cases, and free musculocutaneous flaps were needed in six cases. Gustilo II patients with primary wound closure remained hospitalized for 11 days, while patients with secondary wound closure stayed in hospital for an average of 20 days. Our early results concerning infection rate, number of reoperations, and time to bony consolidation can be compared with other studies. Functional results will have to be evaluated at clinical follow-up.