[Personalised medicine. Paradigm shift within drug research and therapy]. / Personalisierte Medizin. Paradigmenwechsel in der Arzneimittelforschung und -therapie.

BACKGROUND: In the middle of the 1980s and 1990s, drug research underwent a significant change. With new knowledge gained from molecular medicine, it became possible to understand the development and course of many diseases in much more detail. As a consequence, truly new therapies were developed on the basis of natural sciences. PARADIGM SHIFT TO PERSONALISED MEDICINE: Progress in medicine is not only based on newly available therapeutic options but also implies the identification of the therapy which suits the patient best. And it is exactly here where medicine as well as drug development are currently undergoing a paradigm shift which can be characterised by the catchword "personalised medicine". TANDEMS OF THERAPEUTIC AND DIAGNOSTIC AGENTS: Personalised medicine encompasses defined tandems of therapeutic and diagnostic agents and leads to a therapy which is based on single patient groups rather than solely on disease diagnoses. In this therapy concept--in addition to the regular examination of the patient--a diagnostic test is performed to assess certain patient characteristics as a basis for the choice of therapy and/or therapy control. Primarily, it is the patient who benefits from personalised medicine by a higher probability of therapeutic success or by an increased tolerance. Thereby, personalised medicine may also increase cost efficiency in the health care sector. OUTLOOK: To introduce more personalised therapies and therefore achieve the best possible patient care as well as increased cost efficiency for the health care system in the future, all players in health care should work closely together to meet the challenges of personalised medicine.

[Specific alterations in the retinal microstructure in neovascular age-related macular degeneration under anti-VEGF therapy. A detailed analysis of intraretinal changes and their possible role for follow-up]. / Mikrostrukturelle Veränderungen bei neovaskulärer altersbedingter Makuladegeneration unter Anti-VEGF-Therapie. Eine detaillierte Analyse schichtspezifisch-morphologischer Alterationen und ihre mögliche Eignung im Follow-up.

BACKGROUND: High-definition raster scanning spectral-domain optical coherence tomography (SD-OCT) allows a precise assessment of retinal layers and a more detailed detection of subtle morphological alterations. The aim of this study was to observe such changes in patients with neovascular age-related macular degeneration (nAMD) under anti-VEGF therapy and to evaluate if they show characteristic and reversible properties. METHODS: The study included 20 consecutive patients with untreated nAMD. SD-OCT with an axial resolution of 6 µm and a scan velocity of up to 25,000 A-scans/s was used for high-resolution imaging of the macular region at baseline and at months 1 and 3. Characteristic changes in the retinal microstructure were documented and analyzed. RESULTS: Obvious morphological changes as well as discrete intraretinal alterations showed a clear improvement until the third month following the initial ranibizumab injection. Destructions of the neurosensory retina and the outer retinal layers were partly reversible and significantly reduced after treatment was applied. CONCLUSION: SD-OCT was able to detect additional information on specific morphological alterations within the retina. These changes showed a considerable reduction under consistent treatment indicating their potential value for monitoring treatment success in antiangiogenic strategies.

[Neovascular age-related macular degeneration under anti-angiogenic therapy : Subretinal fluid is a relevant prognostic parameter]. / Neovaskuläre altersbedingte Makuladegeneration unter antiangiogener Therapie : Subretinale Flüssigkeit ist ein für die Funktion wichtiger prognostischer Faktor.

BACKGROUND: Due to its progressive nature neovascular age-related macular degeneration (nAMD) is the most common cause of irreversible vision loss and blindness in people aged 60 or older. Optical coherence tomography (OCT) plays an important role in monitoring this exudative disease. However, prognostic factors for visual rehabilitation under anti-angiogenic therapy are still rare. It was the aim of this study to identify prognostic parameters based on OCT. METHODS: In this study 17 patients with nAMD were included and treated with 3 intravitreal ranibizumab injections. Stratus-OCT and Cirrus-OCT imaging were performed to identify prognostic factors. Different OCT parameters, such as the volume of subretinal fluid and the degree of serous retinal detachment in the fovea, were analyzed and correlated with visual acuity (VA). RESULTS: Baseline VA was an important prognostic factor correlating with final VA at the end of the study. Retinal thickness measured by OCT showed a correlation to VA at the time of examination but not with the final results.. The volume of subretinal fluid (SRFV) however, correlated significantly with VA at weeks 4 and 12. The degree of serous retinal detachment of the fovea did not correlate with retinal function. CONCLUSION: Data show that some retinal thickness values correlated to VA in the spectral domain OCT but not in Stratus OCT. In this study VA at baseline and the SRFV were the most important prognostic factors for VA at 3 months.. This demonstrates the important role of SRFV measurements as a relevant prognostic factor in nAMD and encourages more research into the analysis of OCT parameters in order to have a better understanding of the prognosis of individual patients receiving anti-angiogenic therapy for nAMD.

[Influence of antiangiogenetic therapy on retinal thickness values in age-related macular degeneration]. / Beeinflussung von Netzhautdickenwerten durch antiangiogenetische Therapie bei altersbedingter Makuladegeneration.

BACKGROUND: This study evaluated the impact of antiangiogenetic therapy on differences in central retinal thickness (CRT) as measured with two optical coherence tomography (OCT) systems from the same manufacturer. MATERIAL AND METHODS: Data were obtained from a group of 20 patients with neovascular age-related macular degeneration before and after intravitreal treatment with ranibizumab. Imaging was performed using the Stratus and the high-definition (HD) Cirrus OCT systems. RESULTS: The mean CRT was revealed to be significantly lower as measured by OCT compared with HD-OCT before and after treatment (p<0.002). CRT differences varied more strongly before treatment than after treatment. A higher standard deviation was noted before treatment. The difference in the mean deviation of CRT measurements before and following antiangiogenetic therapy was highly significant. CONCLUSION: This study showed that differences in CRT measurements between different OCT systems were subject not only to technical differences but also to treatment effects of current antiangiogenetic strategies. These effects should be recognized because clinical studies increasingly define OCT parameters as primary or secondary outcome measures.

Molecular orientation studies by pulsed electron-electron double resonance experiments.

Pulsed electron-electron double resonance (PELDOR) has proven to be a valuable tool to measure the distribution of long range distances in noncrystalline macromolecules. These experiments commonly use nitroxide spin labels as paramagnetic markers that are covalently attached to the macromolecule at specific positions. Unless these spin labels are flexible in such a manner that they exhibit an almost random orientation, the PELDOR signals will-apart from the interspin distance-also depend on the orientation of the spin labels. This effect needs to be considered in the analysis of PELDOR signals and can, moreover, be used to obtain additional information on the structure of the molecule under investigation. In this work, we demonstrate that the PELDOR signal can be represented as a convolution of a kernel function containing the distance distribution function and an orientation intensity function. The following strategy is proposed to obtain both functions from the experimental data. In a first step, the distance distribution function is estimated by the Tikhonov regularization, using the average over all PELDOR time traces with different frequency offsets and neglecting angular correlations of the spin labels. Second, the convolution relation is employed to determine the orientation intensity function, using again the Tikhonov regularization. Adopting small nitroxide biradical molecules as simple examples, it is shown that the approach works well and is internally consistent. Furthermore, independent molecular dynamics simulations are performed and used to calculate PELDOR signals, distance distributions, and orientational intensity functions. The calculated and experimental results are found to be in excellent overall agreement.

[Three-dimensional imaging in central serous chorioretinopathy]. / Dreidimensionale Bildgebung bei Chorioretinopathia centralis serosa.

BACKGROUND: Conventional optical coherence tomography (OCT) has brought new insights to retinal diagnostics, but it is restricted due to its low scanning speed and limited resolution. In this study, high-resolution raster scanning OCT (HR-OCT) was used to identify typical changes in central serous chorioretinopathy (CSC). METHODS: Fifteen consecutive patients with acute CSC were imaged using HR-OCT with an axial image resolution of 6 mum. The scanned area measured 6x6 mm2. Three-dimensional (3D) evaluation was performed using various analysing programmes. RESULTS: Topographic changes in CSC could be visualised with 3D reconstructions in all locations. Retinal thickness was measured with the automatic segmentation mode and quantified precisely. Results were presented in 2D and 3D maps. En-face imaging as a modality to present an integrative overview showed specific alterations in CSC. CONCLUSION: HR-OCT was able to provide essential additional information about CSC when combined with appropriate analysing programmes, allowing the identification of typical differences. Aside from precise volumetric measurements, exact localisation of pathological deviations could be achieved.

Automatic segmentation in three-dimensional analysis of fibrovascular pigmentepithelial detachment using high-definition optical coherence tomography.

BACKGROUND/AIMS: A limited number of scans compromise conventional optical coherence tomography (OCT) to track chorioretinal disease in its full extension. Failures in edge-detection algorithms falsify the results of retinal mapping even further. High-definition-OCT (HD-OCT) is based on raster scanning and was used to visualise the localisation and volume of intra- and sub-pigment-epithelial (RPE) changes in fibrovascular pigment epithelial detachments (fPED). Two different scanning patterns were evaluated. METHODS: 22 eyes with fPED were imaged using a frequency-domain, high-speed prototype of the Cirrus HD-OCT. The axial resolution was 6 mum, and the scanning speed was 25 kA scans/s. Two different scanning patterns covering an area of 6 x 6 mm in the macular retina were compared. Three-dimensional topographic reconstructions and volume calculations were performed using MATLAB-based automatic segmentation software. RESULTS: Detailed information about layer-specific distribution of fluid accumulation and volumetric measurements can be obtained for retinal- and sub-RPE volumes. Both raster scans show a high correlation (p<0.01; R2>0.89) of measured values, that is PED volume/area, retinal volume and mean retinal thickness. Quality control of the automatic segmentation revealed reasonable results in over 90% of the examinations. CONCLUSION: Automatic segmentation allows for detailed quantitative and topographic analysis of the RPE and the overlying retina. In fPED, the 128 x 512 scanning-pattern shows mild advantages when compared with the 256 x 256 scan. Together with the ability for automatic segmentation, HD-OCT clearly improves the clinical monitoring of chorioretinal disease by adding relevant new parameters. HD-OCT is likely capable of enhancing the understanding of pathophysiology and benefits of treatment for current anti-CNV strategies in future.

Spinal injuries after falls from hunting tree stands.

BACKGROUND CONTEXT: Spinal injuries are common sequelae of falls from hunting tree stands. Significant neurological injury is not uncommon and can result in significant morbidity as well as enormous expenditure of health care dollars. Recent literature on the subject is limited. PURPOSE: The purpose of this study was to identify precipitating causes, characterize the spectrum of spinal injury, and determine potential interventional safety and prevention recommendations. STUDY DESIGN: A retrospective study. METHODS: Medical record review of 22 patients admitted either directly or via referral to a level I spinal cord injury referral center over a 10-year period (1995-2005) after a fall from a hunting tree stand. RESULTS: All patients were men with a mean age of 46 years (range, 27-80 years). Initial acute care hospitalization averaged 10 days (range, 2-28 days). The average height of fall was 18 feet (range, 10-30 feet). Four of 19 falls (21%) occurred during the morning hours, 2 of 19 falls occurred during the afternoon, and 13 of 19 falls (68%) occurred during the evening hours. Time lapse from injury to presentation to an emergency department ranged from 30 minutes to 14 hours. Alcohol use was a factor in 2 of 20 falls (10%). Hypothermia complicated 3 of 21 cases (14%). Associated injuries were present in 12 of 21 patients (57%) and included fractures to the axial and appendicular skeleton, pneumothoraces, a retroperitoneal bleed, and a brachial plexopathy. Eight of 22 patients (37%) sustained injury to the cervical spine. Five of these 8 patients (63%) had neurological deficits (3 complete and 2 incomplete spinal cord injuries). Thirteen of 22 (59%) patients sustained injury to the thoracic or lumbar spine. Ten of these 13 (77%) had neurologic deficits (3 complete and 7 incomplete). Nine of 22 (41%) patients were treated nonoperatively; the remaining 13 (59%) underwent operative intervention. CONCLUSIONS: Falls from hunting tree stands remain a significant cause of spinal injury and subsequent disability. The best intervention for these injuries is prevention. There is a continued need for hunter safety education to reduce the incidence of these injuries with emphasis on safety harness usage, proper installation and annual inspection of tree stands, hunting in groups with periodic contact, the use of communication devices, and abstinence from alcohol consumption while hunting.

[New perspectives in diagnostic. High-resolution optical coherence tomography for age-related macular degeneration]. / Neue Perspektiven in der Diagnostik. Hochauflösende optische Kohärenztomographie bei altersbedingter Makuladegeneration.

BACKGROUND: Recent advances in optical coherence tomography (OCT) have made it possible to increase resolution and scan velocities so that even greater central areas of the retina can be scanned. The aim of this study is to describe the possibilities offered by this new technology for age-related macular degeneration. MATERIAL AND METHODS: The study included 20 patients with confirmed active choroidal neovascularization (CNV) as well as pigment epithelial detachment (PED). Three-dimensional imaging was performed with a high-definition raster scanning OCT system (HD-OCT) with an axial resolution of 6 microm and a scan velocity of up to 20,000 A-scans/s. The scanned area measured 6 x 6 mm with a depth of 2 mm. Two-dimensional imaging was carried out with a StratusOCT (Carl Zeiss Meditec). RESULTS: Comparison of the individual slices showed improved identification of intra- and subretinal structures with the HD-OCT. Demarcation of pathological changes in individual retinal layers is possible with the HD-OCT. Summation images permit accurate localization of a scan. Topographic and volumetric evaluations enable analysis of individual compartments in the entire scanned area and are suitable for monitoring treatment of CNV with anti-VEGF therapy. The raster method decreases the dependence on exploratory methods that have been necessary until now to generate retinal thickness maps. CONCLUSIONS: This report presents initial experience in using a raster scanning HD-OCT system in patients with neovascular age-related macular degeneration and describes new evaluation functions that aid in obtaining more precise assessment of treatment effect and its impact on the retinal ultrastructure. The results of this study clearly show that development of high-resolution OCT systems in conjunction with development of novel treatment options for exudative diseases offers promising perspectives.

Comparison of speech production in upright and supine position.

Speech is usually produced in an upright sitting or standing posture. Measurements and judgments of speech may be made in conditions requiring a supine position, however. These conditions include MRI recordings, and oral procedures, such as, adjustments to dental appliances, medical and surgical procedures. It is of interest, therefore, to see whether gravity has strong or systematic effects on tongue behavior. In the present study, 13 subjects repeated several words, which contained extreme consonant and vowel tongue positions, during upright and supine condition. Ultrasound imaging provided midsagittal tongue contours, in each condition, for comparison. A neck brace was used to stabilize transducer placement and the palate was used as a physiological reference to register the data sets. Results showed a significant subject effect. In supine position the tongue was more posterior than upright for seven subjects, more anterior for two subjects and varied by phoneme for four subjects. However, there was no significant phoneme effect. The direction of change and the amount of change were not directly related. Most subjects had small upright-supine differences. The largest differences, less than 3 mm on average, were in the posterior tongue.

Caecal impaction and chronic intestinal pseudo-obstruction in a dog.

A 10-year-old female neutered cross-breed dog presented with a 4-month history of chronic intermittent diarrhoea and vomiting. Abdominal ultrasound showed dilated loops of small intestine and a suspected faecolith. Exploratory surgery revealed a caecal impaction and a typhlectomy was performed. Histopathological examination of caecal and full thickness small intestine sections demonstrated atrophy of smooth muscle fibres as well as an influx of plasma cells, lymphocytes and macrophages, and mild lymphoplasmacytic and eosinophilic enteritis. This combination of caecal impaction and chronic intestinal pseudo-obstruction has not been reported previously in the dog.

The AMPPA network as a successful model for public-private or private-private partnership.

In 1997, the Rockefeller Foundation and the Ernst Schering Research Foundation (a subsidiary of Schering AG, Germany, on a non-profit basis) mounted a multi-year global collaborative effort, involving a network of top-level research institutions to intensify research on the regulation of the male reproductive system with special emphasis on post-testicular activity, utilizing new approaches in molecular pharmacology (application of molecular pharmacology for post-testicular activity (AMPPA) network). The new venture proved a success as a public-private sector partnership, as a collaborative scientific program, and as an approach to identify new targets applicable and suitable for drug finding for male fertility regulation.

Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic L-amino acid decarboxylase deficiency.

Aromatic L-amino acid decarboxylase (AADC) is a vitamin B 6 requiring enzyme involved in the biosynthesis of the neurotransmitters dopamine (DA) and serotonin. Lack of AADC leads to a combined deficiency of the catecholamines DA, norepinephrine (NE), epinephrine (E) as well as of serotonin. Here we describe premature twins who presented with severe seizures, myoclonus, rotatory eye movements and sudden clonic contractions. The patients showed an improvement of the clonic contractions under vitamin B 6 supplementation but died in the third week of life. In CSF and urine a biochemical pattern indicative of AADC deficiency was revealed. Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were decreased, in association with increased concentrations of 3-ortho-methyldopa (3-OMD) in CSF and significantly increased vanillactic acid in urine. The AADC enzyme substrates L-dopa and 5-hydroxytryptophan (5-HTP) were elevated in CSF. Elevated concentrations of threonine as well as of an unidentified compound in CSF rounded off the biochemical pattern. AADC activity was found to be increased in plasma and deficient in the liver. Molecular studies effectively ruled out a genetic defect in the AADC gene. The basis for the epileptic encephalopathy in the twins may be located in the metabolism of vitamin B 6 and remains to be defined.

Periodic orbit description of nonadiabatic quantum dynamics.

Classical periodic orbits associated with the nonadiabatic dynamics of a spin-boson-type problem are introduced. To facilitate a classical description of spin states, the formulation employs an exact mapping of the discrete quantum variables onto continuous degrees of freedom. Adopting a one-dimensional spin-boson model, the shortest periodic orbits of the problem are identified and used to analyze the nonadiabatic quantum dynamics. The possibility of directly observing these vibronic periodic orbits in femtosecond time-resolved experiments is discussed.

[A short history of beta-interferon therapy of multiple sclerosis]. / Eine kurze Geschichte der Beta-Interferontherapie der multiplen Sklerose.

Basic sciences including biotechnology and diagnostic imaging as well as dedicated and substantial clinical research have contributed to the progress in the therapy of multiple sclerosis (MS) which is no longer an orphan disease. Pivotal studies using interferon beta-1b for early and later phases of MS are described in their historical context. In addition, possible mechanisms of action of interferon beta-1b and new directions for future research are discussed. Interferon beta-1b already now has become a global standard for the expected further therapeutic progress.

Subpicosecond conformational dynamics of small peptides probed by two-dimensional vibrational spectroscopy.

The observation of subpicosecond fluctuations in the conformation of a small peptide in water is demonstrated. We use an experimental method that is specifically sensitive to conformational dynamics taking place on an ultrafast time scale. Complementary molecular-dynamics simulations confirm that the conformational fluctuations exhibit a subpicosecond component, the time scale and amplitude of which agree well with those derived from the experiment.