[Perthes disease-news in diagnostics and treatment]. / Morbus Perthes ­ Neuigkeiten in der Diagnostik und Behandlung.

DIAGNOSTICS: Perthes disease remains a challenge for paediatric orthopedic surgeons. X­ray imaging is still the method of choice for diagnostics and follow-up examination. A more detailed differentiation of Waldenström's classification, especially in early and late fragmentation stages, might be relevant to optimize timing of containment surgery. So-called "advanced MRI" imaging might help to detect patients at risk earlier than conventional x­ray imaging, which could lead to earlier surgical intervention. TREATMENT: Currently there is no treatment modality available which would improve the bone changes in Perthes disease. Non-operative treatment like improving hip range of motion as well as unloading is still the basic standard of care, with analgesic and/or anti-inflammatory medication, according to symptoms or findings. In the case of loss of containment, especially in children older than 6 years, surgery is indicated. Currently, there is a trend favoring acetabular reorientation techniques-especially the triple osteotomy, since the biomechanical relations would not be additionally impaired as in case of femoral varus osteotomy.

[Fixation techniques for slipped capital femoral epiphysis : Principles, surgical techniques, and complications]. / Fixationstechniken bei der Epiphyseolysis capitis femoris : Prinzipien, operative Techniken und Komplikationen.

The purpose of this review is to present the pros and cons as well as the surgical techniques of conventional implants used for fixation of slipped capital femoral epiphysis (SCFE). Worth mentioning are K­wires, Hansson pins, transfixing screws, and gliding screws. We searched PubMed for "ECF" and "SCFE" in combination with "in situ fixation," "pin," "wire," "screw," and "nail." We considered Johansson nail, Knowles pin, and Nyström nail to be obsolete and of historical interest only. We noticed a trend from absolute stability towards some form of dynamic fixation over time, likely related to considerations of growth disturbance of the proximal femur and also the inherent potential for remodeling with time.

Measurement of lentiviral vector titre and copy number by cross-species duplex quantitative PCR.

Lentiviruses are the vectors of choice for many preclinical studies and clinical applications of gene therapy. Accurate measurement of biological vector titre before treatment is a prerequisite for vector dosing, and the calculation of vector integration sites per cell after treatment is as critical to the characterisation of modified cell products as it is to long-term follow-up and the assessment of risk and therapeutic efficiency in patients. These analyses are typically based on quantitative real-time PCR (qPCR), but as yet compromise accuracy and comparability between laboratories and experimental systems, the former by using separate simplex reactions for the detection of endogene and lentiviral sequences and the latter by designing different PCR assays for analyses in human cells and animal disease models. In this study, we validate in human and murine cells a qPCR system for the single-tube assessment of lentiviral vector copy numbers that is suitable for analyses in at least 33 different mammalian species, including human and other primates, mouse, pig, cat and domestic ruminants. The established assay combines the accuracy of single-tube quantitation by duplex qPCR with the convenience of one-off assay optimisation for cross-species analyses and with the direct comparability of lentiviral transduction efficiencies in different species.

The relationship of age with the clinical phenotype in multiple sclerosis.

BACKGROUND: The multiple sclerosis (MS) clinical course and relapses frequency before progression vary widely. OBJECTIVE: To investigate the influence of age on the MS phenotype. METHODS: Among 751 primary progressive (PP = 217) and secondary progressive (SP = 534) MS patients from the London Ontario database, we assessed the relationship of age on the relapse frequency and on the progressive phase evolution, and the impact of relapses on the age at onset of progression. RESULTS: Age at onset did not influence the early attacks frequency, but patients younger at onset had larger number of total attacks before progression (age = 27.4, 31.0 and 32.8 mean years; ⩾4, 2-3 and 1 relapses, respectively) and longer latency to SP. Although frequent early relapses predicted younger age at SP onset, patients with no attacks (primary progressive multiple sclerosis (PPMS)), or 1, 2-3 and ⩾4 relapses during the relapsing-remitting phase started progressing at similar age (38.6, 41.3, 41.4 and 39.2 mean years, respectively). The age at onset of progressive phase did not affect its evolution. CONCLUSIONS: Age strongly influences the phenotype before progression. Relapsing-remitting patients younger at onset are more likely to display a predominantly inflammatory course, yet relapses number does not affect the age at onset of progression.

Novel method to study neutron capture of 235U and 238U simultaneously at keV energies.

The neutron capture cross sections of the main uranium isotopes, (235)U and (238)U, were measured simultaneously for keV energies, for the first time by combining activation technique and atom counting of the reaction products using accelerator mass spectrometry. New data, with a precision of 3%-5%, were obtained from mg-sized natural uranium samples for neutron energies with an equivalent Maxwell-Boltzmann distribution of kT ∼ 25 keV and for a broad energy distribution peaking at 426 keV. The cross-section ratio of (235)U(n,γ)/(238)U(n,γ) can be deduced in accelerator mass spectrometry directly from the atom ratio of the reaction products (236)U/(239)U, independent of any fluence normalization. Our results confirm the values at the lower band of existing data. They serve as important anchor points to resolve present discrepancies in nuclear data libraries as well as for the normalization of cross-section data used in the nuclear astrophysics community for s-process studies.

Cardiomyocyte-specific RXFP1 overexpression protects against pressure overload-induced cardiac dysfunction independently of relaxin.

Heart failure (HF) prevalence is rising due to reduced early mortality and demographic change. Relaxin (RLN) mediates protective effects in the cardiovascular system through Relaxin-receptor 1 (RXFP1). Cardiac overexpression of RXFP1 with additional RLN supplementation attenuated HF in the pressure-overload transverse aortic constriction (TAC) model. Here, we hypothesized that robust transgenic RXFP1 overexpression in cardiomyocytes (CM) protects from TAC-induced HF even in the absence of RLN. Hence, transgenic mice with a CM-specific overexpression of human RXFP1 (hRXFP1tg) were generated. Receptor functionality was demonstrated by in vivo hemodynamics, where the administration of RLN induced positive inotropy strictly in hRXFP1tg. An increase in phospholamban-phosphorylation at serine 16 was identified as a molecular correlate. hRXFP1tg were protected from TAC without additional RLN administration, presenting not only less decline in systolic left ventricular (LV) function but also abrogated LV dilation and pulmonary congestion compared to WT mice. Molecularly, transgenic hearts exhibited not only a significantly attenuated fetal and fibrotic gene activation but also demonstrated less fibrotic tissue and CM hypertrophy in histological sections. These protective effects were evident in both sexes. Similar cardioprotective effects of hRXFP1tg were detectable in a RLN-knockout model, suggesting an alternative mechanism of receptor activation through intrinsic activity, alternative endogenous ligands or crosstalk with other receptors. In summary, CM-specific RXFP1 overexpression provides protection against TAC even in the absence of endogenous RLN. This suggests RXFP1 overexpression as a potential therapeutic approach for HF, offering baseline protection with optional RLN supplementation for specific activation.

Neutron capture cross section of unstable 63Ni: implications for stellar nucleosynthesis.

The 63Ni(n,γ) cross section has been measured for the first time at the neutron time-of-flight facility n_TOF at CERN from thermal neutron energies up to 200 keV. In total, capture kernels of 12 (new) resonances were determined. Maxwellian averaged cross sections were calculated for thermal energies from kT=5-100 keV with uncertainties around 20%. Stellar model calculations for a 25M⊙ star show that the new data have a significant effect on the s-process production of 63Cu, 64Ni, and 64Zn in massive stars, allowing stronger constraints on the Cu yields from explosive nucleosynthesis in the subsequent supernova.

A web-based tool for personalized prediction of long-term disease course in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: The Evidence-Based Decision Support Tool in Multiple Sclerosis (EBDiMS) is the first web-based prognostic calculator in multiple sclerosis (MS) capable of delivering individualized estimates of disease progression. It has recently been extended to provide long-term predictions based on the data from a large natural history cohort. METHODS: We compared the predictive accuracy and consistency of EBDiMS with that of 17 neurologists highly specialized in MS. RESULTS: We show that whilst the predictive accuracy was similar, neurologists showed a significant intra-rater and inter-rater variability. CONCLUSIONS: Because EBDiMS was consistent, it is of superior utility in a specialist setting. Further field testing of EBDiMS in non-specialist settings, and investigation of its usefulness for counselling patients in treatment decisions, is warranted.

The Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR)--Critical review facing the 20 anniversary.

The SLCMSR was formed as an international Multiple Sclerosis Trials, Research and Resource Center to identify clinical MRI and other predictors of the course of multiple sclerosis (MS) based on a large database of natural history and clinical trial data. Using an elaborate validation concept several key findings were published, challenging established outcome parameters and their assessment in MS such as disability ratings with Expanded Disability Status Scale (EDSS), relapses and MRI endpoints. Sustained increase of EDSS appeared to be an invalid outcome for 2-3 year clinical trials at least in patients with relapsing-remitting MS. The number of gadolinium-enhancing lesions and T2-lesion load on MRI were shown not to have a meaningful additional predictive value for the disease course. These issues risen some 15 years ago had triggered controversial discussions which have also been noticed by regulatory authorities and they all have not been resolved. In addition the SLCMSR contributed to the development of new outcomes such as real-world walking speed as an attractive, ecologically valid tool based on a wearable device. A so-called evidence-based-decision-support tool was constructed to provide individual prognostic estimates based on a matching algorithm to a given database. This paper condensates the findings of 20 years of critical MS research.

Prognosis of the individual course of disease--steps in developing a decision support tool for Multiple Sclerosis.

BACKGROUND: Multiple sclerosis is a chronic disease of uncertain aetiology. Variations in its disease course make it difficult to impossible to accurately determine the prognosis of individual patients. The Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) developed an "online analytical processing (OLAP)" tool that takes advantage of extant clinical trials data and allows one to model the near term future course of this chronic disease for an individual patient. RESULTS: For a given patient the most similar patients of the SLCMSR database are intelligently selected by a model-based matching algorithm integrated into an OLAP-tool to enable real time, web-based statistical analyses. The underlying database (last update April 2005) contains 1,059 patients derived from 30 placebo arms of controlled clinical trials. Demographic information on the entire database and the portion selected for comparison are displayed. The result of the statistical comparison is provided as a display of the course of Expanded Disability Status Scale (EDSS) for individuals in the database with regions of probable progression over time, along with their mean relapse rate. Kaplan-Meier curves for time to sustained progression in the EDSS and time to requirement of constant assistance to walk (EDSS 6) are also displayed. The software-application OLAP anticipates the input MS patient's course on the basis of baseline values and the known course of disease for similar patients who have been followed in clinical trials. CONCLUSION: This simulation could be useful for physicians, researchers and other professionals who counsel patients on therapeutic options. The application can be modified for studying the natural history of other chronic diseases, if and when similar datasets on which the OLAP operates exist.

Ecological validity of walking capacity tests in multiple sclerosis.

BACKGROUND: Ecological validity implicates in how far clinical assessments refer to real life. Short clinical gait tests up to ten meters and 2- or 6-Minutes Walking Tests (2MWT/6MWT) are used as performance-based outcomes in Multiple Sclerosis (MS) studies and considered as moderately associated with real life mobility. OBJECTIVE: To investigate the ecological validity of 10 Meter Walking Test (10mWT), 2MWT and 6MWT. METHODS: Persons with MS performed 10mWT, 6MWT including 2MWT and 7 recorded days by accelerometry. Ecological validity was assumed if walking tests represented a typical walking sequence in real-life and correlations with accelerometry parameters were strong. RESULTS: In this cohort (n=28, medians: age=45, EDSS=3.2, disease duration=9 years), uninterrupted walking of 2 or 6 minutes occurred not frequent in real life (2.61 and 0.35 sequences/day). 10mWT correlated only with slow walking speed quantiles in real life. 2MWT and 6MWT correlated moderately with most real life walking parameters. CONCLUSION: Clinical gait tests over a few meters have a poor ecological validity while validity is moderate for 2MWT and 6MWT. Mobile accelerometry offers the opportunity to control and improve the ecological validity of MS mobility outcomes.

Krypton laser trabeculoplasty. A clinical report.

Krypton red (647.1 nm) or krypton yellow (568.2 nm) laser trabeculoplasty was performed in 15 phakic eyes of 14 patients. After an average follow-up of five months, these patients had an average drop of intraocular pressure of 8.9 mm Hg. In addition, in eight of these patients studied, argon laser trabeculoplasty was performed in the opposite eye. After an average follow-up of more than five months in these eight patients, the average drop of IOP was 7.2 mm Hg in the eyes with krypton laser trabeculoplasty and 6.8 mm Hg in the eyes with argon laser trabeculoplasty. This preliminary study indicates that laser trabeculoplasty may be effectively performed with krypton wavelengths.

Primary angle closure glaucoma in a myopic kinship.

Three related myopic individuals with primary angle closure glaucoma are reported. They had true myopia and not pseudomyopia secondary to increased lenticular index of refraction. We believe one of these individuals (-8.62 spherical equivalent) to have the most myopic case of primary angle closure glaucoma reported in the literature. Although myopia is associated with anatomical factors that offer considerable protection from primary angle closure glaucoma, its presence does not eliminate the possibility of this disease. Laser iridectomy was effective in the treatment of these patients.

Impairment of mitogenic activation of peripheral blood lymphocytes in Alzheimer's disease.

Cell-cycle dysregulation might be critically involved in the process of neurodegeneration in Alzheimer's disease (AD). We now provide evidence for a dysfunction of the cell division cycle as a more general cellular phenomenon of the disease. Peripheral blood lymphocytes, stimulated with mitogenic compounds, were less able to express CD69, an early proliferation marker, in AD patients than in age-matched controls. Expression levels of CD69 of both T-cells and B-cells correlated inversely with the Mini-mental Scale. The results suggest that a systemic failure of cellular proliferation control might be of critical importance for the pathomechanism of AD.

Drop size of commercial glaucoma medications.

We tested 145 samples of 20 different topical medications for the treatment of glaucoma to determine the average drop size of each preparation. The average drop volumes of different preparations varied between a minimum of 25.1 microliter and a maximum of 56.4 microliter, with an average drop volume of 39.0 microliter. Our findings contradict the common assumption that commercial eyedrops contain a volume of 50 to 75 microliters.

See your brands through your customers' eyes.

Subaru markets an L.L. Bean Outback station wagon. Dell stamps Microsoft and Intel logos on its computers. Such inter-weaving of different companies' brands is now commonplace. But one of the central tools of brand management-portfolio mapping--has not kept pace with changes in the marketplace. Most conventional brand maps include only those brands owned by a company, arranged along organizational lines with little regard for how the brands influence customer perceptions. In this article, the authors present a new mapping tool--the brand portfolio molecule--that reveals the way brands appear to customers. The brand portfolio molecule includes all the brands that factor into a consumer's decision to buy, whether or not the company owns them. The first step in creating a brand portfolio molecule is to determine which brands should or should not be included. The second step is to classify each brand by asking five key questions: 1) How important is this brand to customers' purchase decisions about the brand you're mapping? 2) Is its influence positive or negative? 3) What market position does this brand occupy relative to the other brands in the portfolio? 4) How does this brand connect to the other brands in the portfolio? 5) How much control do you have over this brand? The last step is to map the molecule using a 3-D modeling program or by hand with pen and paper. Individual brands take the form of atoms, and they're clustered in ways that reflect how customers see them. The usefulness of the tool lies in its ability to show the many forces that influence a customer's buying decision--and to provide a powerful new way to think about brand strategy.

[Is the patient age a negative predictive factor in the reconstruction of SLAP lesions?]. / Ist das Patientenalter ein negativer Vorhersageparameter bei der Rekonstruktion der SLAP-Läsion?

BACKGROUND: The treatment strategy of SLAP (superior labrum anterior posterior) lesions is generally a matter of controversy, particularly in patients over 40 years of age. Various factors, such as the increasing number of associated injuries in older age, play a role in the decision-making process. There currently is no empirical evidence for the greater efficacy of treatment planning for SLAP repair as compared to tenodesis/tenotomy. The aim of this study was to analyse, as part of a cohort comparison, the results after SLAP repair in patients under and over 40 years of age. METHODS: We followed 45 patients after surgical treatment of a SLAP lesion, with a mean follow-up of 60 months (5 years), clinically using the Constant score (CS), the Rowe score, and the "subjective shoulder value" (SSV). Of these, 18 patients in group 1 (age at surgery<40 years, mean age at surgery 29 years, range: 21-39 years) and 27 patients in group 2 (age≥40 years at surgery, mean age at surgery 50 years, range: 40-60 years). RESULTS: A mean CS of 89% (min 16%-max 105%) resulted. The Rowe score averaged 90 points (min. 35 points-max 100 points), while the SSV averaged 90% (min 20%-max 100%). In comparing the two groups, neither displayed a significant difference in the CS (p=0.198) (group 1: min 58%-max 105%, median 92%, group 2: min 16%-max 105%, median 89%) nor in the Rowe score (p=0.5) (group 1: min 55-max 100 points, median 85 points, group 2: min 35-max 100 points, median 92.5 points). The SSV also showed no significant difference in level (p=0.068) between the two groups (group 1: min 60%-max 100%, median 95%, group 2: min 20%-max 100%, median 90%), although the SSV in group 1 had a better correlation with the CS than in group 2. DISCUSSION: The patient's age seems to have less influence on the outcome after reconstruction of SLAP than previously thought. Even at age≥40 years results show that the reconstruction results of the complex SLAP are comparable with the known literature data, and that it is good clinical practice. Impact on the long-term outcome seems to be particularly dependent on the number and severity of associated injuries, not the patient's age.

Flow dynamics of a novel counterpulsation device characterized by CFD and PIV modeling.

BACKGROUND: Historically, single port valveless pneumatic blood pumps have had a high incidence of thrombus formation due to areas of blood stagnation and hemolysis due to areas of high shear stress. METHODS: To ensure minimal hemolysis and favorable blood washing characteristics, particle image velocimetry (PIV) and computational fluid dynamics (CFD) were used to evaluate the design of a new single port, valveless counterpulsation device (Symphony). The Symphony design was tested in 6-h acute (n=8), 5-day (n=8) and 30-day (n=2) chronic experiments in a calf model (Jersey, 76 kg). Venous blood samples were collected during acute (hourly) and chronic (weekly) time courses to analyze for temporal changes in biochemical markers and quantify plasma free hemoglobin. At the end of the study, animals were euthanized and the Symphony and end-organs (brain, liver, kidney, lungs, heart, and spleen) were examined for thrombus formations. RESULTS: Both the PIV and the CFD showed the development of a strong moving vortex during filling phase and that blood exited the Symphony uniformly from all areas during ejection phase. The laminar shear stresses estimated by CFD remained well below the hemolysis threshold of 400 Pa inside the Symphony throughout filling and ejection phases. No areas of persistent blood stagnation or flow separation were observed. The maximum plasma free hemoglobin (<10mg/dl), average platelet count (pre-implant = 473 ± 56 K/µl and post-implant = 331 ± 62 K/µl), and average hematocrit (pre-implant = 31 ± 2% and post-implant = 29 ± 2%) were normal at all measured time-points for each test animal in acute and chronic experiments. There were no changes in measures of hepatic function (ALP, ALT) or renal function (creatinine) from pre-Symphony implantation values. The necropsy examination showed no signs of thrombus formation in the Symphony or end organs. CONCLUSIONS: These data suggest that the designed Symphony has good washing characteristics without persistent areas of blood stagnation sites during the entire pump cycle, and has a low risk of hemolysis and thrombus formations.

Disability as an outcome in MS clinical trials.

BACKGROUND: Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Preventing progressive disability is the key therapeutic goal but there remains no validated definition for its measurement in a trial context. Meanwhile, MS trials continue to shorten and to depend on unvalidated surrogates. Since there have been no treatment claims for improving unremitting disability, worsening of disability in the placebo/control arm must occur for effectiveness on this outcome to be shown. METHODS: We examined widely-used clinical surrogates of long-term disability progression in individual patients with MS within a unique database from the placebo arms of 31 randomized clinical trials. RESULTS: Detection of treatment effects in secondary progressive MS trials is undermined by noise in disability measurement. Whereas existing measures can be partially validated in secondary progressive MS, this is not the case in relapsing-remitting MS. Here, examination of widely used definitions of treatment failure demonstrated that disability progression was no more likely than similarly defined improvement. Existing definitions of disease progression in short-term intervention trials in relapsing-remitting patients reflect random variation, measurement error, and remitting relapses. CONCLUSION: Clinical surrogates of unremitting disability used in trials of relapsing-remitting multiple sclerosis cannot be validated. Trials have been too short or degrees of disability change too small to measure the key outcomes. These analyses highlight the difficulty in determining effectiveness of therapy in chronic diseases.