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Introduction: Cutaneous squamous cell carcinoma (cSCC) is a common tumor of elderly Caucasian patients., Methods: Competing multivariable risk models to analyze different types of cSCC associated death (local infiltration [LI], locoregional [LR], and distant metastases [DM]) in terms of prognostic factors., Results and Discussion: 1400 patients were analyzed. In the adjusted multivariable subdistribution hazard approach for tumor volume, the best model for death of cSCC overall revealed the presence of desmoplasia (HR 4.52; p < 0.001), bone invasion (HR 10.06; p < 0.01), and immunosuppression (HR 3.19; p = 0.003) as significant factors. Death due to LI indicated desmoplasia (HR 15.39; p < 0.01) and bone invasion (HR 16.9; p < 0.001) as significant factors. For death by LM, immunosuppression with a HR of 3.27; p = 0.004 was the only significant prognostic factors as well as in death by DM with a HR of 4.54; p = 0.02., Conclusions: The three types of death caused by cSCC can be distinguished based on risk factors with different weights. Patients with these factors should be monitored closely., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: We examined measles mortality in the European past in an outbreak in an isolated German village, Hagelloch, in 1861., Methods: Pfeilsticker's contemporary thesis was used to describe the measles case fatality ratio (CFR) and complications. Data on onset of prodromes and rash was used to determine index cases and secondary cases of measles within the household. The church register provided information on survival in 1862., Results: The epidemic affected nearly all children under 14 years of age. The overall CFR was 6.4%(12/187), and 10%(7/70) for children under five years of age; 44% of children were secondary cases (82/187). Secondary cases had higher CFR than index cases (RR = 3.03 (95% CI: 0.91-10.07). Boys had higher CFR than girls (RR = 4.46 (1.03-19.22)). Boys infected by a girl had higher CFR than boys infected by other boys (RR = 6.30 (1.18-85.64)). Children who survived measles virus infection in 1861, did not have higher mortality in the following year compared with those who had not had measles in 1861 (RR = 0.24 (0.07-0.82))., Conclusions: Severe measles in the European past had determinants similar to those observed more recently in low-income countries., Brief Summary: The measles case fatality was 6% in rural Germany in 1861. Mortality was highest for boys infected in the household by a girl. There was no excess mortality after the acute phase of measles infection., Competing Interests: Declaration of Competing Interest Nothing to declare, (Copyright © 2022. Published by Elsevier Ltd.)

Background: Inserting a chest drain for a left-sided neonatal pneumothorax carries a risk of penetrating the pericardium. We identified reference ranges for the chest wall thickness (CWT) and distance between the pericardium and parietal pleura to improve safety of chest tube insertion., Method: We prospectively measured the CWT using ultrasound in 20 neonates (body weight [BW] 640-2,700 g, age <10 days) at the usual site of puncture in the 4th and 5th intercostal space (ICS). Furthermore, we measured the minimal distance between the parietal pleura and the cardiac silhouette in 131 neonatal chest X-rays (birth weight, 420-4,930 g [divided into 11 weight groups]; age <10 days). Both data sets were transformed into weight-dependent percentiles (Ps). We considered the difference between the sum of P 2.5 for the CWT plus P 2.5 for pleura-heart distance minus P 97.5 for the CWT as a safe corridor for placing the tip of the needle., Results: At both ICSs, curves for the above metrics did not cross, indicating a narrow but safe corridor for each BW with at least 97.5% probability. This safety corridor was 4.6-5.2 mm wide for the 4th and 2.8-3.4 mm for the 5th ICS., Conclusion: These data offer a reference for left-sided chest drain insertion for BW <2,700 g, which may help to improve safety of the procedure., (© 2021 S. Karger AG, Basel.)

Aim: Oximetry values are influenced by the averaging time (AT) used. We aimed to evaluate the effect of different ATs on number, duration, mean single event and total integral of desaturations in preterm infants and children to convert between parameters obtained with different ATs., Methods: In a prospective observational study, 49 children underwent sleep laboratory-based polysomnography and 15 preterm infants were studied in the intensive care unit. Their raw red-to-infrared-saturation-data were reprocessed using seven different ATs (3-16 seconds). Desaturation thresholds were <80% (infants) and <90% (children), conversion formulas and their median percentage errors were calculated., Results: We found a linear relationship between the logarithms of the ATs and those of the desaturation parameters, leading to a conversion formula with different exponents. Based on this relationship, the number of desaturations decreased from AT = 3s to AT = 16s by factor 0.28 (children) and 0.18 (infants); total oxygen saturation integral decreased by factor 0.72 (children) and 0.48 (infants). The desaturation duration increased by factor 1.89 (children) and 3.34 (infants)., Conclusion: The number and total integral decreased, but the duration and mean single event integral increased with increasing AT. These changes were stronger in infants. Conversion formulas may facilitate comparisons between studies using different averaging times., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Postnatally acquired cytomegalovirus (pCMV) infection through breast milk (BM) may cause severe illness and even death, yet BM is advantageous for preterm infants. Therefore, effective methods to prevent CMV transmission are needed., Methods: To assess the effectiveness of short-term pasteurization (62°C for 5 seconds) in preventing CMV transmission via BM in preterm infants. Design: Prospective interventional bicentric cohort study with infant enrollment between 6/2010 and 1/2012. A cohort from the Tuebingen neonatal intensive care unit (NICU) from 1995-1998 served as historical controls. Differences in CMV transmission were compared with reference to the cumulative time at risk for CMV transmission. Setting: Two German level-3 NICUs. Eighty-seven preterm infants of 69 CMV immunoglobulin G-positive mothers with birth weight <1500 g or gestational age <32 weeks and 83 historical controls were included. Intervention: BM samples were short-term pasteurized from postnatal day 4 to discharge. Primary endpoint: CMV status at discharge, evaluated by polymerase chain reaction and short-term microculture from urine., Results: Two of 87 (2.3%) study infants had a pCMV transmission. This compared to 17 of 83 (20.5%) controls. Total time under risk for infection was 9.6 years vs 10.0 years in controls, yielding an incidence of 0.21/year (95% confidence interval [CI], 0.03 to 0.75/year) vs 1.70/year (95% CI, 0.99 to 2.72/year), respectively. The risk ratio controls vs study infants was 8.3 (95% CI, 2.4 to 52.4) according to Cox proportional hazard model (P = .0003)., Conclusions: Short-term pasteurization significantly reduces the incidence of pCMV infection through BM in the NICU., Clinical Trials Registration: NCT01178905., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Karl-Peter Hadeler is a first-generation pioneer in mathematical biology. His work inspired the contributions to this special issue. In this preface we give a brief biographical sketch of K.P. Hadelers scientific life and highlight his impact to the field.

The most frequently cited articles out of KP Hadeler's 45 papers with epidemiological applications are summarized. Parasitic diseases which increase the death rate of the hosts proportional to the integer number of parasites present were described by integral equations for the generating function of the age- and time-dependent number of parasites. A model was derived for a population structured by the continuous level of parasitic infection. Stimulated by the spread of AIDS a new class of epidemic models was developed which take into account explicitly the formation and separation of pairs. For predator-prey populations with parasitic infections threshold conditions for the persistence of the predator were derived. The interaction of epidemics and demography was analysed. Several epidemiological conditions led to backward bifurcations associated with multiple infective stationary states.

Introduction: Complete lymph node dissection (CLND) after a positive sentinel node (SN) biopsy provides important prognostic information in melanoma patients but has been questioned for therapeutic use recently. We explored whether quantification of the tumour spread to SNs may replace histopathology of non-sentinel nodes (NSNs) for staging purposes., Patients and Methods: We quantified melanoma spread in SNs and NSNs in 128 patients undergoing CLND for a positive SN. In addition to routine histopathology, one-half of each of all 1496 SNs and NSNs was disaggregated into a single cell suspension and stained immunocytochemically to determine the number of melanoma cells per 10 6 lymph node cells, i.e. the disseminated cancer cell density (DCCD)., Results: We uncovered melanoma spread to NSNs in the majority of patients; however, the tumour load and the proportion of positive nodes were significantly lower in NSNs than in SNs. The relation between SN and NSN spread could be described by a mathematical function with DCCD NSN  = DCCD SN c /10 1 - c (c = 0.69; 95% confidence interval [CI]: 0.62-0.76). At a median follow-up of 67 months, multivariable Cox regression analyses revealed that DCCD SN (p = 0.02; HR 1.34, 95% CI: 1.05-1.71) and the total number of pathologically positive nodes (p = 0.02; HR 1.53, 95% CI: 1.07-2.22) were significant risk factors after controlling for age, gender, thickness of melanoma and ulceration status. A prognostic model based on DCCD SN and melanoma thickness predicted outcome as accurately as a model including pathological information of both SNs and NSNs., Conclusion: The assessment of DCCD SN renders CLND for staging purposes unnecessary., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mouse models indicate that metastatic dissemination occurs extremely early; however, the timing in human cancers is unknown. We therefore determined the time point of metastatic seeding relative to tumour thickness and genomic alterations in melanoma. Here, we find that lymphatic dissemination occurs shortly after dermal invasion of the primary lesion at a median thickness of ~0.5 mm and that typical driver changes, including BRAF mutation and gained or lost regions comprising genes like MET or CDKNA2, are acquired within the lymph node at the time of colony formation. These changes define a colonisation signature that was linked to xenograft formation in immunodeficient mice and death from melanoma. Thus, melanoma cells leave primary tumours early and evolve at different sites in parallel. We propose a model of metastatic melanoma dormancy, evolution and colonisation that will inform direct monitoring of adjuvant therapy targets.

The asymptotically homogeneous SIR model of Thieme (1992) for growing populations, with incidence depending in a general way on total population size, is reconsidered with respect to other parameterizations that give clear insight into epidemiological relevant relations and thresholds. One important feature of the present approach is case fatality as opposed to differential mortality. Although case fatality models and differential mortality models are equivalent via a transformation in parameter space, the underlying ideas and the dynamic behaviors are different, e.g. the basic reproduction number depends on differential mortality but not on case fatality. The persistent distributions and exponents of growth of infected solutions are computed and discussed in terms of the parameters. The notion of asymptotically exponentially growing state (as opposed to stationary state or exponential solution) coined by Thieme is interpreted in terms of stability theory. Of some interest are limiting cases of models without recovery where two infected solutions exist., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: With the advent of computer-assisted three-dimensional surface imaging and rapid data processing, oral and maxillofacial surgeons and orthodontists are enabled to analyze facial growth three dimensionally. Normative data, however, are still rare and inconsistent. The aim of the present study was to establish a valid reference system and to give normative data for facial growth., Methods: Three-dimensional facial surface images were obtained from 344 healthy Caucasian children (aged 0 to 7 years). The images were put in correspondence by means of six landmarks close to the skull base (exocanthion, endocanthion, otobasion inferius). Growth curves for 21 landmarks were estimated in the three dimensions., Results: Facial regions close to the skull base (orbit and ear) showed a biphasic growth pattern, with accelerated growth during the first year of life that subsided to a decreased and linear velocity thereafter. Landmarks on the nose, lips, and chin demonstrated either a curvilinear or a linear growth pattern., Conclusions: The rapid increase of the orbit and ear region in infancy is a secondary phenomenon to the rapid growth of the neurocranium during the first year of life. Thereafter, maxillary and mandibular growth prevails. The present study gives three-dimensional normative data for an expanded growth span between birth and childhood.

Background: Sentinel lymph node spread is a crucial factor in melanoma outcome. We aimed to define the impact of minimal cancer spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival., Methods and Findings: We analyzed 1,834 sentinel nodes from 1,027 patients with ultrasound node-negative melanoma who underwent sentinel node biopsy between February 8, 2000, and June 19, 2008, by histopathology including immunohistochemistry and quantitative immunocytology. For immunocytology we recorded the number of disseminated cancer cells (DCCs) per million lymph node cells (DCC density [DCCD]) after disaggregation and immunostaining for the melanocytic marker gp100. None of the control lymph nodes from non-melanoma patients (n = 52) harbored gp100-positive cells. We analyzed gp100-positive cells from melanoma patients by comparative genomic hybridization and found, in 45 of 46 patients tested, gp100-positive cells displaying genomic alterations. At a median follow-up of 49 mo (range 3-123 mo), 138 patients (13.4%) had died from melanoma. Increased DCCD was associated with increased risk for death due to melanoma (univariable analysis; p<0.001; hazard ratio 1.81, 95% CI 1.61-2.01, for a 10-fold increase in DCCD + 1). Even patients with a positive DCCD ≤3 had an increased risk of dying from melanoma compared to patients with DCCD = 0 (p = 0.04; hazard ratio 1.63, 95% CI 1.02-2.58). Upon multivariable testing DCCD was a stronger predictor of death than histopathology. The final model included thickness, DCCD, and ulceration (all p<0.001) as the most relevant prognostic factors, was internally validated by bootstrapping, and provided superior survival prediction compared to the current American Joint Committee on Cancer staging categories., Conclusions: Cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death. A model based on the combined quantitative effects of DCCD, tumor thickness, and ulceration predicted outcome best, particularly at longer follow-up. If these results are validated in an independent study, establishing quantitative immunocytology in histopathological laboratories may be useful clinically.

Objective: The number of desaturations determined in recordings of pulse oximeter saturation (SpO2) primarily depends on the time over which values are averaged. As the averaging time in pulse oximeters is not standardized, it varies considerably between centers. To make SpO2 data comparable, it is thus desirable to have a formula that allows conversion between desaturation rates obtained using different averaging times for various desaturation levels and minimal durations., Methods: Oxygen saturation was measured for 170 hours in 12 preterm infants with a mean number of 65 desaturations <90% per hour of arbitrary duration by using a pulse oximeter in a 2-4 s averaging mode. Using 7 different averaging times between 3 and 16 seconds, the raw red-to-infrared data were reprocessed to determine the number of desaturations (D). The whole procedure was carried out for 7 different minimal desaturation durations (≥ 1, ≥ 5, ≥ 10, ≥ 15, ≥ 20, ≥ 25, ≥ 30 s) below SpO2 threshold values of 80%, 85% or 90% to finally reach a conversion formula. The formula was validated by splitting the infants into two groups of six children each and using one group each as a training set and the other one as a test set., Results: Based on the linear relationship found between the logarithm of the desaturation rate and the logarithm of the averaging time, the conversion formula is: D2 = D1 (T2/T1)(c), where D2 is the desaturation rate for the desired averaging time T2, and D1 is the desaturation rate for the original averaging time T1, with the exponent c depending on the desaturation threshold and the minimal desaturation duration. The median error when applying this formula was 2.6%., Conclusion: This formula enables the conversion of desaturation rates between different averaging times for various desaturation thresholds and minimal desaturation durations.

Background: The optimal treatment of complex, displaced proximal humeral fractures is controversial. A systematic literature review of the time period from 1970 to 2009 was conducted. The purpose was to evaluate the clinical success and complications of the available treatment modalities to determine specific treatment recommendations for the different fracture patterns., Methods: The databases (PubMed/EMBASE) were searched for the time period (01/1970-09/2009). Study quality, treatment modalities, classification, outcome scores and complications of 200 publications including 9377 patients were analyzed. Interventions were compared by analysis of variance with subsequent Tukey's-test. Complication rates among methods were compared by using Pearson's-chi-square-test and pairwise comparisons using Fisher's-two-tailed-exact-test., Results: Hemiarthroplasty, angle-stable plate and non-operative treatment were used for 63% of the follow-up-patients. For 3- and 4-part fractures, patients with hemiarthroplasty [3-Part: 56.4 (lower/upper 95% confidence interval (CI): 43.3-68.7); 4-Part: 49.4 (CI: 42.2-56.7)] received a lower score than different surgical head-preserving methods such as ORIF [3-Part: 82.4 (CI: 76.6-86.9); 4-Part: 83.0 (CI:78.7-86.6)], intramedullary nailing [3-Part: 79.1 (CI:74.0-83.4)] or angle-stable plates [4-Part: 66.4 (CI: 59.7-72.4)].The overall complication rate was 56%. The most common complications were fracture-displacement, malunion, humeral head necrosis and malreduction. The highest complication rates were documented for conventional plate and hemiarthroplasty and for AO-C, AO-A, for 3- and 4-part fractures. Only 25% of the data were reported with detailed classification results and the corresponding outcome scores., Discussion: Despite the large amount of patients included, it is difficult to determine adequate recommendations for the treatment of proximal humeral fractures because a relevant lack of follow-up data impaired subsequent analysis. For displaced 3- and 4-part fractures head-preserving therapy received better outcome scores than hemiarthroplasty. However, a higher number of complications occurred in more complex fractures and when hemiarthroplasty or conventional plate osteosynthesis was performed. Thus, when informing the patient for consent, both the clinical results and the possibly expected complications with a chosen treatment modality should be addressed.

Background: Pulse oximeter saturation values are usually obtained by averaging over preceding measurements. This study investigates the dynamics between the averaging time and desaturation level, duration and extent., Methods and Results: Prospective observational study of 15 preterm infants. Oxygen saturation was recorded for 168 h using a pulse oximeter. The raw red-to-infrared data were reprocessed using seven different averaging times to determine the number of desaturations below four thresholds and for seven different minimal desaturation durations. The total number of desaturations <80% was 339 with an averaging time of 16 s and 1958 with an averaging time of 3 s (minimal event duration >0 s). There was a significantly lower pulse oximeter saturation nadir with the shorter averaging time, while the maximum duration was significantly longer when using a 16 s averaging time., Conclusions: When using pulse oximeters, more attention should be given to averaging time and duration of desaturations.

Rubella in early pregnancy bears a high risk for congenital defects (e.g., cataracts, hearing loss, and heart disease) and for long-term sequelae in the newborn. Despite implementation of vaccination programs in many regions, the threat of devastating consequences from congenital rubella virus infection remains and careful screening of maternal immune status before and during pregnancy helps to reduce the risk. This study compared the performance of the Elecsys Rubella IgG assay with that of other assays routinely used for screening. Samples from 1,090 women undergoing routine antenatal care were tested using the Elecsys and Enzygnost Rubella IgG assays and the hemagglutination inhibition test. Samples with hemagglutination inhibition titers of <32 (n = 148) were additionally tested using the Vidas, AxSYM, Liaison, and Architect Rubella IgG assays. Agreement of qualitative results from the Elecsys, Enzygnost, and hemagglutination inhibition assays was good in all samples. All assays showed 100.0% specificity. In samples with hemagglutination inhibition titers of <32, the Elecsys, AxSYM, and Enzygnost assays showed higher sensitivity (>90.0%) than the other immunoassays (78.6 to 82.4%). The Elecsys assay reported significantly higher rubella virus IgG levels than the other immunoassays across the whole set of 1,090 samples, with the largest bias and deviation from limits of agreement in Bland-Altman analysis. In conclusion, the Elecsys assay is highly sensitive and specific with regard to qualitative results and suitable for routine automated screening. However, given the considerable variation between quantitative results from different immunoassays, testing methods should be documented and the same assay used throughout an individual's antenatal follow-up wherever possible.

Children with cleft lip or cleft lip and alveolus represent a minor group in the cleft population. The aim of this study was to analyze the faces of these children. In a prospective, cross-sectional study, 344 healthy children and 30 children with cleft lip or cleft lip and alveolus were scanned three-dimensionally at the age of 0 to 6 years. Twenty-one standard anthropometric landmarks were identified, and the images were superimposed. Growth curves for normal facial development were calculated. The facial morphology of cleft children was compared with that of unaffected children.Facial morphology and growth in the transverse direction of the examined patients appeared broadened in all levels. Especially the nasal landmarks indicated a widening of the nose. The landmarks ac l, sbal l, sbal r, c l, sn l, and ls l differed significantly from unaffected children. In the sagittal and vertical dimensions, there was no significant difference compared with unaffected children.Our study demonstrates that surgical and orthodontic treatment can restore the vertical and sagittal dimensions of the face in children with cleft lip with and without alveolar clefts; however, the transverse dimension-especially the nose-remains too broad.

Purpose: There is a need for standardized texts to assess reading performance, for multiple equivalent texts for repeated measurements, and for texts equated across languages for multi-language studies. Paragraphs are preferable to single sentences for accurate speed measurement. We developed such texts previously in 6 languages. The aim of our current study was to develop texts in more languages for a wide range of countries and users, and to assess the reading speeds of normally-sighted readers., Methods: Ten texts were designed for 17 languages each by a linguist who matched content, length, difficulty, and linguistic complexity. The texts then were used to assess reading speeds of 436 normally-sighted native speakers (age 18-35 years, 25 per language, 36 in Japanese), presented at a distance of 40 cm and size 1 M, that is 10-point Times New Roman font. Reading time (aloud) was measured by stopwatch., Results: For all 17 languages, average mean reading speed was 1.42 ± 0.13 texts/min (±SD), 184 ± 29 words/min, 370 ± 80 syllables/min, and 863 ± 234 characters/min. For 14 languages, mean reading time was 68 ms/character (95% confidence interval [CI] 65-71 ms). Our analysis focussed on words per minute. The variability of reading speed within subjects accounts only for an average of 11.5%, between subjects for 88.5%., Conclusions: The low within-subject variability shows the equivalence of the texts. The IReST (second edition) can now be provided in 17 languages allowing standardized assessment of reading speed, as well as comparability of results before and after interventions, and is a useful tool for multi-language studies (for further information see www.amd-read.net).

Purpose: The aim of this study was to assess the brain regions associated with impaired performance in a virtual, dynamic collision avoidance task, in a group of patients with homonymous visual field defects (HVFDs) because of unilateral vascular brain lesions., Methods: Overall task performance was quantitatively assessed as the number of collisions while crossing an intersection at two levels of traffic density. Twenty-six patients were divided into two subgroups using the median split method: patients with 'performance above average' (HVFD(A), i.e. lower number of collisions) and patients with 'performance below average' (HVFD(B), i.e. higher number of collisions). In order to identify the anatomical structures that might be specifically affected in HVFD(B) patients but spared in HVFD(A) patients, overlap, subtraction and voxel-based lesion-symptom mapping analyses were performed using the MRIcron software., Results: No significant difference in collision avoidance between patients with left- and right-hemispheric lesions was revealed. Separate lesion analysis in 12 patients with right- and 14 patients with left-hemispheric lesions showed that the cortical structures associated with impaired collision avoidance were the parieto-occipital region and posterior cingulate gyrus in the right hemisphere and the inferior occipital cortex and parts of the fusiform (occipito-temporal) gyrus in the left hemisphere., Conclusion: In the present collision avoidance paradigm, impaired performance of patients with right-hemispheric lesions is associated with damage in the dorsal processing stream and potential impact on the visual spatial working memory (WM), while impaired performance of patients with left-hemispheric lesions is associated with damage in the ventral stream and potential impact on the visual object WM., (© 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To identify the variable with the strongest association between the magnitude of the relative afferent pupillary defect (RAPD) and visual field indices in patients with glaucomatous optic neuropathy., Methods: Seventy-nine consecutive subjects with manifest glaucomatous optic neuropathy at least in one eye were enrolled in this retrospective study. RAPD was assessed with the swinging flashlight test and quantified with a neutral density filter. Perimetry was performed using the fast thresholding strategy German Adaptive Threshold Estimation. The values of the central differential luminance sensitivity (DLS), of the MD (mean defect) and of the 'loss volume' (LVOL) based on the individually modelled 3D hill of vision-the latter two within the eccentricities of 10°, 20° and 30°, respectively-were entered into a linear regression model without intercept as a function of RAPD., Results: An absolute value of RAPD of 0.3 log(10) units or more was present in 20 out of 79 glaucoma subjects (25%). The magnitude of RAPD was most closely associated with LVOL-30° (R(2)=0.77), followed by MD-30° (R(2)=0.73), MD-20° (R(2)=0.71), LVOL-20° (R(2)=0.67), MD-10° (R(2)=0.58), LVOL-10° (R(2)=0.54) and central DLS (R(2)=0.04)., Conclusions: The prevalence of RAPD in glaucoma patients is comparatively small (25%). The magnitude of RAPD in glaucoma subjects is associated most closely with the LVOL within 30° eccentricity (which is the maximum visual field region tested in this study) and most loosely with central DLS, underscoring the impact of the entire (30°) visual field area on the afferent pupillary system.

Objective: To provide data on type 1 diabetes (T1D) epidemiology in childhood over a period of 20 years and to predict prevalence and cohort-age-specific incidence rates (IRs) for the next two decades in Germany., Methods: The Baden-Wuerttemberg Diabetes Incidence Registry (DIARY) includes children and adolescents below 15 years of age with new onset of T1D (period 1987-2006, n = 5108 cases)., Results: The mean age- and sex-standardized IR was 15.3/100 000/year (95% CI 14.8-15.7) and the average increase in the IR was 4.4% per year (95% CI 3.9-4.9). Within the next 20 years (2007-2026), the risk for developing diabetes will increase like the square of a linear function with calendar year for all age ranges. There is a strong correlation between the predicted IRs of the cohorts and the observed IRs (n = 300; root mean square error = 0.56; r(2) = 0.71) and a negative correlation between mean age at onset and T1D IR (p = 0.02). On 31 December 2006, the prevalence of T1D was 0.126% (95% CI 0.121-0.132). The predicted prevalence (end of 2026) is estimated to be 0.265% (95% CI 0.25-0.28; predicted cases: n = 2950; 95% CI 2900-3000)., Conclusions: In comparison to observations made in the past, the risk of disease rises even faster than expected: The younger the child, the quicker the increase of the cohort-age-specific IR and the higher the risk for T1D during lifetime., (© 2011 John Wiley & Sons A/S.)

Background: Hypericin (HYP) is a naturally occurring photosensitizer. Cellular uptake and photodynamic inactivation after incubation with this photosensitizer have neither been examined in medulloblastoma cells in vitro, nor compared with 5-aminolevulinic acid-derived protoporphyrin IX (5-ALA-derived PpIX)., Methods: In 3 medulloblastoma cell lines (D283 Med, Daoy, and D341 Med) the time- and concentration-dependent intracellular accumulation of HYP and 5-ALA-derived PpIX was analyzed by fluorescence microscopy (FM) and FACS. Photocytotoxicity was measured after illumination at 595 nm (HYP) and 635 nm (5-ALA-derived PpIX) in D283 Med cells and compared to U373 MG glioma cells., Results: All medulloblastoma cell lines exhibited concentration- and time-dependent uptake of HYP. Incubation with HYP up to 10 µM resulted in a rapid increase in fluorescence intensity, which peaked between 2 and 4 hours. 5-ALA-derived PpIX accumulation increased in D283 Med cells by 22% over baseline after 5-ALA incubation up to 1.2 mM. Photocytotoxicity of 5-ALA-derived PpIX was higher in D283 Med medulloblastoma compared to U373MG glioma. The LD50 [lethal dose (light dose that is required to reduce cell survival to 50% of control)] of 5-ALA-derived PpIX was 3.8 J/cm(2) in D283 Med cells versus 5.7 J/cm2 in U373MG glioma cells. Photocytotoxicity of HYP in D283 Med cells was determined at 2.5 µM after an incubation time of 2 h and an illumination wavelength of 595 nm. The [Formula: see text] value was 0.47 J/cm(2)., Conclusion: By its 5-fold increase in fluorescence over autofluorescence levels HYP has excellent properties for tumor visualization in medulloblastomas. The high photocytotoxicity of HYP, compared to 5-ALA-derived PpIX, is convincingly demonstrated by its 8- to 13-fold lower LD50. Therefore HYP might be a promising molecule for intraoperative visualization and photodynamic treatment of medulloblastomas.

The aim of the present study was to examine the effect of homonymous visual field defects (HVFDs) on collision avoidance of dynamic obstacles at an intersection under virtual reality (VR) conditions. Overall performance was quantitatively assessed as the number of collisions at a virtual intersection at two difficulty levels. HVFDs were assessed by binocular semi-automated kinetic perimetry within the 90° visual field, stimulus III4e and the area of sparing within the affected hemifield (A-SPAR in deg(2)) was calculated. The effect of A-SPAR, age, gender, side of brain lesion, time since brain lesion and presence of macular sparing on the number of collisions, as well as performance over time were investigated. Thirty patients (10 female, 20 male, age range: 19-71 years) with HVFDs due to unilateral vascular brain lesions and 30 group-age-matched subjects with normal visual fields were examined. The mean number of collisions was higher for patients and in the more difficult level they experienced more collisions with vehicles approaching from the blind side than the seeing side. Lower A-SPAR and increasing age were associated with decreasing performance. However, in agreement with previous studies, wide variability in performance among patients with identical visual field defects was observed and performance of some patients was similar to that of normal subjects. Both patients and healthy subjects displayed equal improvement of performance over time in the more difficult level. In conclusion, our results suggest that visual-field related parameters per se are inadequate in predicting successful collision avoidance. Individualized approaches which also consider compensatory strategies by means of eye and head movements should be introduced., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A plaque reduction neutralisation test (PRNT) is still regarded as the gold standard for the investigation of anti-measles immunity. In this study, an alternative simplified automatable focus reduction neutralisation test (AFRNT) based on the classical PRNT was developed. The AFRNT uses the conventional Edmonston strain of measles, immunoperoxidase staining with monoclonal antibodies, and automated plaque counts performed with AID ViruSpot software. The assay is performed in 96-well plates, requires 2 days, and is fully automatable. The AFRNT was evaluated in comparison with PRNT and Enzygnost anti-measles enzyme immunoassay (EIA). A total of 130 samples, which included two available WHO international anti-measles standards, sera from 90 patients, and 38 different lots of immunoglobulin products, were tested. Overall, good agreement was observed between EIA and both neutralisation tests; however, the EIA values for the immunoglobulin products and international standards were slightly but significantly higher than those of the neutralisation tests. The Bland-Altman analysis showed excellent agreement between AFRNT and PRNT. AFRNT is a fully automatable high-throughput neutralisation assay, which can be performed with measles and other types of viruses, including wild-type strains. It is perfectly suited for epidemiological and vaccine studies., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Chloroquine resistance (CR) decreased after the removal of chloroquine from national treatment guidelines in Malawi, Kenia and Tanzania. In this investigation the prevalence of the chloroquine resistance (CQR) conferring mutant pfcrt allele and its associated chromosomal haplotype were determined before and after the change in Gabonese national treatment guidelines from chloroquine (CQ) to artesunate plus amodiaquine (AQ) in 2003., Methods: The prevalence of the wild type pfcrt allele was assessed in 144 isolates from the years 2005 - 07 by PCR fragment restriction digest and direct sequencing. For haplotype analysis of the chromosomal regions flanking the pfcrt locus, microsatellite analysis was done on a total of 145 isolates obtained in 1995/96 (43 isolates), 2002 (47 isolates) and 2005 - 07 (55 isolates)., Results: The prevalence of the mutant pfcrt allele decreased from 100% in the years 1995/96 and 2002 to 97% in 2005 - 07. Haplotype analysis showed that in 1995/96 79% of the isolates carried the same microsatellite alleles in a chromosomal fragment spanning 39 kb surrounding the pfcrt locus. In 2002 and 2005 - 07 the prevalence of this haplotype was 62% and 58%, respectively. Pfcrt haplotype analysis showed that all wild type alleles were CVMNK., Conclusion: Four years after the withdrawal of CQ from national treatment guidelines the prevalence of the mutant pfcrt allele remains at 97%. The data suggest that the combination of artesunate plus AQ may result in continued selection for the mutant pfcrt haplotype even after discontinuance of CQ usage.

Aim: (i) To map the spatial distribution of absolute visual field loss (AL) in patients exposed to vigabatrin and to compare the findings with AL in normal individuals, and (ii) to describe the relationship between the major risk factors for absolute loss (gender, age, cumulative dose), and the severity of field loss, expressed as the number of locations with AL per eye., Methods: Visual field plots were retrospectively reviewed from 428 individuals. Perimetry was done with the Tübingen Automated Perimeter (using a threshold-oriented, marginally supraliminal strategy, 80° eccentricity, 99 test locations). Three hundred and sixty-one individuals were ophthalmologically normal, and 67 were patients exposed to vigabatrin who had performed reliably during perimetry prior to neurosurgery for epilepsy. Two hundred and sixty-six of the 361 normals were included on the empirical basis that they manifested AL at no more than 19 stimulus locations per eye (the 74th percentile). The frequency per eye of AL at each of 99 stimulus locations was determined for the normals and patients. The effects of age, gender and cumulative dose of vigabatrin on the number of ALs per individual was assessed by an analysis of covariance. A stochastic model was developed to determine the 50% probability of AL at each location., Results: Thirty-nine of the 67 vigabatrin patients exhibited at least 20 locations with AL. The number of ALs was independent of age (p  =  0.7603). The frequency of AL was 14.8% in the peripheral field and 1.0% in the central field (odds ratio 16.7; 95% CI 15.0-18.6%; p  <  0.0001). Those exposed to vigabatrin exhibited a frequency of 17.1% ALs, compared to 5.2% for the normal individuals (odds ratio 3.77, 95% CI 3.6-4.0%; p  <  0.0001). According to the modelled data, males exhibited 20.9% (95% CI 1.3-44%; p  =  0.0360) more absolute losses than did females. The number of absolute losses per person doubled with an increase in cumulative dose of vigabatrin of 936 g (95% CI 775-1181 g)., Conclusions: According to this retrospective study, the spatial configuration of absolute defects attributable to vigabatrin indicates sparing of the temporal field up to approximately 60° eccentricity. Such a finding is likely to explain, at least in part, the initially asymptomatic nature of the defect. This study reconfirms a (cumulative) dose effect of vigabatrin on the extent of absolute field loss, with a greater risk for male gender.

Despite the blood-brain barrier (BBB) the human CNS is continuously screened by blood-derived immunological cells. In certain brain areas the local BBB configuration grants passage of large molecules, whereas others are better shielded. We investigated whether these regional BBB compositions are paralleled by differences in the degree of cellular immunosurveillance by investigating tissue from 23 normal human brains for several CD markers, FoxP3, granzyme B, and perforin. Our results provide evidence that immunosurveillance is associated with locoregional BBB configuration and is mainly performed by CD3(+)/CD8(+)/granzyme B(-)/perforin(-) lymphocytes., (© 2010 Japanese Society of Neuropathology.)

We investigate the efficacy of a multisectoral road safety campaign initiated at Luang Namtha Provincial Hospital (LNPH), North-Laos. Road safety days (RSD) with helmet promotion were organised prior to the Lao and International New Year 2007. Motorbike helmet protectiveness was demonstrated by dropping peeled versus unpeeled coconuts from 6-m high sticks simulating city speed-limit (40 km/h). The primary outcome was the number of road traffic injuries (RTI) needing admission (severe RTI) before and after the first RSD. Secondary outcomes were helmet usage, total RTI, hospital staff's behavioural changes and law enforcement. Neighbouring Bokeo Provincial Hospital (BPH) had no intervention. Severe RTI dropped by 34.7% within 12 months (from 449 to 293, p ≤ 0.0001, BPH +123% [from 88 to 196]). Total RTI increased by 10.8% (from 772 to 855, p = 0.0396, BPH +260.8% [from 186 to 671]). Police started the law enforcement right after the RSD. Helmet use increased from 11.2 to 42.5% (p < 0.0001). Coconut test was the main reason for safer behaviour among RSD participants seven months later (16/32). The intervention effectively prevented severe RTI. The speed-adapted coconut drop test was a simple, convincing and efficient educational tool, easily adaptable to other settings.

Co-infections of helminths and malaria parasites are common in human populations in most endemic areas. It has been suggested that concomitant helminth infections inhibit the control of malaria parasitemia but down-modulate severe malarial disease. We tested this hypothesis using a murine co-infection model of schistosomiasis and cerebral malaria. C57BL/6 mice were infected with Schistosoma mansoni and 8-9 weeks later, when Schistosoma infection was patent, mice were co-infected with Plasmodium berghei ANKA strain. We found that a concomitant Schistosoma infection increased parasitemia at the beginning of the P. berghei infection. It did not protect against P. berghei-induced weight loss and hypothermia, and P. berghei-mono-infected as well as S. mansoni-P. berghei-co-infected animals showed a high case fatality between days 6 and 8 of malarial infection. However, co-infection significantly reduced P. berghei-induced brain pathology. Over 40% of the S. mansoni-P. berghei-co-infected animals that died during this period were completely protected against haemorrhaging, plugging of blood vessels and infiltration, indicating that mortality in these animals was not related to cerebral disease. Schistosoma mansoni-P. berghei-co-infected mice had elevated plasma concentrations of IL-5 and IL-13 and on day 6 lower levels of IFN-γ, IL-10, monocyte chemoattractant protein-1 (MCP-1) and monokine induced by IFN-γ (MIG) than P. berghei-mono-infected mice. We conclude that in P. berghei infections, disease and early death are caused by distinct pathogenic mechanisms, which develop in parallel and are differentially influenced by the immune response to S. mansoni. This might explain why, in co-infected mice, death could be induced in the absence of brain pathology., (Copyright © 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.)

Background: This study examined the effect of proximal humeral fractures on the age- and shoulder-specific prevalence of rotator cuff tears (RCTs) as well as the association with fracture severity, patient age, and clinical outcome., Methods: Sixty-three fractures were treated conservatively; in 114 cases, minimally invasive osteosynthesis, and in 125 cases, open reduction and plate fixation were performed without rotator cuff reconstruction. After 4.4 years, all 302 patients were clinically and sonographically examined., Results: We examined 139 two-part, 95 three-part, and 68 four-part fractures according to Neer and 134 A, 86 B, and 82 C fractures according to the AO classification. There were 52 patients (17%) with a complete rotator tear (RCT) only at the injured shoulder and 11 patients (4%) with a complete RCT only at the contralateral shoulder (p < 0.0001). Independent of the patient's age at follow-up, the prevalence of an RCT in the fractured shoulder was 13% higher than the prevalence in the opposite shoulder. Four-part fractures showed a significant association with a complete RCT (p = 0.047).Of 74 patients with a satisfactory or poor Constant Score, 33 (44.6%) had RCTs. In the remaining 228 patients with a good to excellent result, only 26 (11.4%) had RCTs. We showed that 66% of the RCTs observed at the fractured shoulder were caused by trauma. There was no association between treatment modality and a complete RCT., Conclusion: RCTs may need special attention in initial diagnostics, management, and follow-up especially in severe proximal humeral fractures.

Object: The objective of this study was to evaluate and analyze morphometric and volumetric changes of the skull due to acromegaly in areas relevant for neurosurgical practice, focusing on the surgical implications., Methods: On preoperatively acquired CT scans, cephalometric and volumetric measurements were performed on 45 patients with acromegaly (Group A) and 45 control patients (Group B). The authors determined thickness of the cranial vault, inner and outer diameters of the skull, and the diameter of sphenoidal and maxillary sinus, as well as frontal and maxillary sinus volumetry. The morphometric and volumetric CT data of the patients with acromegaly were compared with the data of a control group and correlated with clinical parameters., Results: Cranial vault thickness differed significantly (p < 0.0001) between the 2 groups. A correlation of the vault thickness with preoperative human growth hormone, insulin-like growth factor-I levels, and duration of clinical history in acromegaly could not be established. The outer anterior-posterior skull diameter of Group A (18.47 ± 0.94 cm) differed significantly (p = 0.0146) from Group B (17.98 ± 0.93 cm) and correlated significantly with preoperative human growth hormone (r = 0.3277; p = 0.0299) and insulin-like growth factor-–I serum levels (r = 0.3756; p = 0.0120). Measurements of the anterior-posterior diameter of the sphenoidal sinus differed significantly (p = 0.0074) between patients with acromegaly and controls. Volumetric analysis of the frontal sinus resulted in a statistically significant difference (p = 0.0382) between patients with acromegaly (14.89 ± 10.85 cm3) and controls (10.06 ± 6.93 cm3)., Conclusions: Significant craniometric changes and volumetric remodelling of the paranasal sinus occur in acromegaly. The bone alterations are of surgical importance for using the transsphenoidal approach. Detailed preoperative diagnostic examination and planning as well as selection of appropriate instruments are mandatory for safe and successful pituitary adenoma removal in patients with acromegaly.

Rationale and Objectives: The objective of this investigation was to evaluate 6 magnetic resonance contrast media (CM) with regard to their different effects on human embryonic lung fibroblasts (HEL-299)., Methods: Human embryonic fibroblasts (HEL-299) were incubated with 1x, 5x, 10x, and 20x of the normal molar blood concentration (1x, 5x, 10x, 20x conc.) reached through routine contrast media applications for MRI examinations. Four gadolinium-based CM, ie, Gadovist, Magnevist, Multihance, Omniscan, Teslascan (Manganese-based), and Resovist (Iron-based), with incubation periods over 4 hours and 24 hours were investigated. Proliferation kinetics, colony formation, and viability assays were performed after 4 and 24 hours of treatment. Apoptotic cells were quantified after tetramethylrhodamine ethyl ester staining following 24 hours of CM media incubation (20x conc.) by fluorescence activated cell sorting cytometry. Furthermore, immunofluorescence images with vimentin staining were obtained (20x conc., 24 hours treatment). Cell cycle analysis was performed after 24 hours of incubation and 20x conc. directly after incubation and 24 hours later (fluorescence activated cell sorting cytometry)., Results: The proliferation kinetics performed with 20x conc. revealed a persistent increase in cell numbers until day 11 for all CM without significant differences after 4 hours of incubation. A significant reduction in initial cell numbers was recorded in the 24-hours-group after 4 days of CM incubation with Magnevist, Multihance, Omniscan, and Teslascan. Solely cells incubated with Resovist and Gadovist failed to show decreased cell numbers when compared with the control group. However, a considerable cell regain occurred afterward reaching control-group levels on day 21. Colony numbers were significantly reduced (about 20%, respectively) with Magnevist at 10x and 20x conc., as well as Omniscan and Multihance at 20x conc. when compared with all other groups, P < 0.05. Cell-cycle distribution showed a reduction of S-phase cells for Magnevist, Omniscan, and Multihance (2.9%-10.5%) when compared with Gadovist, Resovist and Teslascan (16.7%-21.0%). Twenty-four hours after incubation, the percentiles of cells in S-phase were significantly increased for Magnevist, Omniscan, and Multihance (31.4%-38.5%) when compared with Gadovist, Resovist, and Teslascan (18.6%-26.8%), P < 0.05. Viability was not impaired by administration of any CM and no apoptosis was seen after tetramethylrhodamine ethyl ester staining at 24 hours of incubation. Cell morphology remained unchanged in vimentin-staining for all CM and conditioning regimens., Conclusions: No toxic effects on embryonic fetal lung fibroblasts were detectable after 4 and 24 hours of incubation in 6 MRI CM and 10x to 20x conc. in our setting. Antiproliferative effects, initially detected with Magnevist, Omniscan and Multihance, were rapidly compensated for.

Background: Infection with human cytomegalovirus (HCMV) is the most common congenital virus infection, affecting about 0.5-2% of newborns. Using DBS on Guthrie cards, it is possible to discriminate congenital from postnatal HCMV-infection. However, a recent European trial revealed serious problems in detection of low HCMV-DNA levels from DBS-filter-cards (Barbi et al., 2008).(7), Objectives: Evaluation of the most sensitive combination of sample size, DNA extraction method and PCR system for the detection of low copy numbers of HCMV-DNA from DBS-filter-cards., Study Design: We compared three different manual extraction methods for the detection of HCMV-DNA out of DBS: the QIAmp-blood-Mini-Kit, a heat-extraction-method and traditional phenol-chloroform extraction. Additionally, we tested an automated nucleic acid extraction system (NucliSense EasyMag/Biomerieux). Different punch-sizes of DBS spiked with defined HCMV AD169-DNA copy numbers were analyzed. For detection, we used a quantitative in-house-LightCycler-PCR targeting the gB-region using the hybridisation-probe-format. We compared the sensitivity of the real-time-PCR with IE1Ex4-targeted nested-PCR., Results: The highest sensitivity with 200 copies HCMV DNA/ml was achieved using the phenol-chloroform method in combination with the nested-PCR and 6mm, 3x3mm punches or the whole DBS. The QIAmp-blood-Mini-Kit also showed a very high sensitivity by using the whole DBS and the nested-PCR., Conclusion: These results may have strong implications for retrospective diagnosis of congenital HCMV (cHCMV) infection, since a defined combination of the area of punch, the extraction method, and PCR method determine the probability of detection of viral DNA from DBS according to a logistic model., (Copyright 2010 Elsevier B.V. All rights reserved.)

A retrospective study was conducted to evaluate displaced proximal humeral fractures treated with a non-plate head-preserving fixation and to detect factors predicting functional outcome. After a median follow-up period of 79.7 months, 105 patients with nine A-fractures, 36 B-fractures and 60 C-fractures (nine two-part-fractures, 41 three-part fractures and 55 four-part fractures) were assessed. Functional outcome was measured based on the Constant and UCLA scores. Of all patients, 70-75% had excellent or good Constant and UCLA scores. In 74% a good or satisfactory quality of initial reduction fracture was achieved. About one-fifth (21%) of the fractures showed a secondary displacement. Twenty-seven percent of the patients had signs of humeral head necrosis and 22% had implant related problems. There were significant correlations between a high final score and young age, low AO fracture severity, good quality of fracture reduction and residual osseous deformity, absence of secondary fracture displacement, implant-related complications, shoulder arthrosis and humeral head necrosis at the time of follow-up. In conclusion, the non-plate head-preserving fixation of proximal humeral fractures is an alternative treatment for displaced proximal humeral fractures. Especially in severely displaced C-fractures in older patients, non-anatomical reduction leads to a high rate of secondary displacement, residual osseous deformity and only a fair shoulder function. For these cases alternative methods such as prosthetic replacement should be chosen.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by an increased skin cancer risk due to defective repair of ultraviolet (UV)-radiation induced DNA damage. Therefore patients with XP are required to apply stringent sun-protection. Since the skin needs UV-B irradiation for de novo vitamin D synthesis, it has been postulated that sun-protection may lead to a clinically relevant reduction of vitamin D levels. To investigate whether reduced vitamin D levels in XP-patients are caused by the stringent sun-protection measures employed, in this study we examined 15 patients with XP. The 25-hydroxyvitamin (25-OHD) and 1,25-dihydroxyvitamin D (1,25-(OH)2D) serum levels were measured. Additionally, patients received a questionnaire about their sun-protection-behaviour. Serum levels for 25-OHD were decreased in 10 of 15 (67%) patients, however there was no statistically significant association between decreased 25-OHD serum levels and duration of sun-protection (p = 0.84). Results for 1,25-(OH)2D levels showed a probability of < 0.16 and between 0.16 and 0.77 for sun-protection duration of < 20 and 20 to 40 years, respectively (p = 0.0058). There was no statistically significant association between the duration of sun-protection with drometrizole trisiloxane and the probability of reduced 25-OHD and 1,25-(OH)2D levels. In conclusion, this investigation indicates that vitamin D serum levels in patients with XP may be normal, increased or decreased but this is not causally linked to the stringent photoprotective measures carried out in our group of investigated XP-patients.

Background: Polymorphisms of the mannose-binding lectin gene (MBL2) affect the concentration and functional efficiency of the protein. We recently used haplotype-specific sequencing to identify 23 MBL2 haplotypes, associated with enhanced susceptibility to several diseases., Results: In this work, we applied the same method in 288 and 470 chromosomes from Gabonese and European adults, respectively, and found three new haplotypes in the last group. We propose a phylogenetic nomenclature to standardize MBL2 studies and found two major phylogenetic branches due to six strongly linked polymorphisms associated with high MBL production. They presented high Fst values and were imbedded in regions with high nucleotide diversity and significant Tajima's D values. Compared to others using small sample sizes and unphased genotypic data, we found differences in haplotyping, frequency estimation, Fu and Li's D* and Fst results., Conclusion: Using extensive testing for selective neutrality, we confirmed that stochastic evolutionary factors have had a major role in shaping this polymorphic gene worldwide.

Introduction: The purpose of this prospective study was to assess the Constant score and radiographic outcome in 66 patients (mean age 58.7 years/mean follow-up 51 months) with a minimally displaced and/or impacted fracture of the proximal humerus treated with early mobilization., Method: Special attention was paid to analyze the specific intrinsic parameters (age, gender, ASA grade and length of physiotherapy), injury-related parameters (classification, osteoporosis) and therapy-related parameters (initial fracture displacement, residual bony-deformity after healing, secondary fracture displacement during healing period, non-union, humeral head necrosis and omarthrosis) that may influence the final score., Patients: There were 31 A (47%), 22 B (33%) and 13 C-fractures (19%). The median Constant score for the fractured shoulder was 89 points., Results: All fractures healed without non-union. The radiological assessment showed in 80% a fracture-displacement with <15 degrees angulation and/or <5-mm displacement of the greater tuberosity. At time of follow-up, the residual bony-deformity was perfect and good in 88% of cases. There was a significant association between the final Constant score and the age, ASA classification, AO (ABC) classification and initial fracture displacement., Conclusion: Early physiotherapy, with a short period of immobilization is a sufficient therapy for management of minimally displaced and/or impacted fractures of the proximal humerus.

Introduction: The goals of this study were to investigate differences between the most popular female and male faces, past and present, and to determine whether they had changed over time and, if so, to what extent., Methods: Internet film databases were searched for photographs of men and women who were considered attractive between 1940 and 2008. Images meeting defined inclusion criteria were compared. Measurements were taken on a minimum of 20 images per sex per decade. Intersex facial differences were grouped by decades, and we examined whether these differences remained stable or whether and how they changed over time., Results: The women had fuller and more protrusive lip profiles than did the men, particularly during the first decade of the 21st century. Significant sex-specific developments were noted over time with respect to chin lengths, frontonasal angles, and total face angles. The men had decreases in chin size and length, but a small opposite trend was observed in the women's faces. During the observation period, female and male faces considered highly attractive became slightly more similar in terms of chin position and size., Conclusions: Notions of facial attractiveness might be influenced by developments in society., (Copyright (c) 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

One class of oligonucleotides with a high potential for use in medical applications is short nucleic acids, widely known as aptamers. Although several aptamers are already being used clinically, there are very few studies dealing with the impact aptamers have on the hemostatic system. In this study, we have performed a comprehensive evaluation of the hemostatic system including coagulation, platelets, complement, and inflammatory activation by using different aptamer concentrations and fresh human whole blood in a well-established flow model. We found that single-stranded aptamers did not have a negative influence on platelets, complement, or inflammation but were able to activate factor XII, kallikrein, and prothrombin in a concentration-dependent manner. Consequently, the influence of aptamers on the coagulation system should be taken into consideration before the use of any aptamer-based drugs in patients.

Background: Alkylphosphocholines (APCs) are synthetic phospholipid derivatives, and have been demonstrated to inhibit ocular cell proliferation in vitro and in vivo. Currently, they are applied clinically for their antitumoral and antiparasitic properties, but have not yet been implemented for clinical use in proliferative ophthalmic disorders. The purpose of this study was to assess the safety of APC in the ex vivo model of the isolated perfused vertebrate retina., Methods: Bovine retina preparations were perfused with an oxygen pre-equilibrated standard solution. The electroretinogram (ERG) was recorded using Ag/AgCl-electrodes. After recording stable b-wave amplitudes, an APC was applied at the following concentrations to the nutrient solution: 0.25 microM, 2.5 microM and 25 microM. To investigate the effects of APC on photoreceptor function, a test series at the same concentrations was performed to evaluate the effects of APC on the a-wave amplitude. Aspartate at a concentration of 1 mM was added to the nutrient solution to obtain stable a-wave amplitudes. Thereafter, APC was applied at the same concentrations to the nutrient solution. The recovery of the ERG amplitudes was followed up for 75 minutes., Results: No reduction of the a- and b-wave amplitude was found at the end of the exposure time with APC added in each test series. No differences were found between the ERG amplitudes before and after application of APC at the end of the washout., Conclusions: In the ex vivo model of the isolated perfused vertebrate retina, APC has proved to be a safe compound in the concentrations applied. Thus, APCs should further be considered as promising candidates for future clinical applications in ophthalmology.

Objective: To predict the frequency of type 1 diabetes in childhood and adolescence (<15 years of age) in Germany for the next 20 years., Research Design and Methods: Data on diabetes onset has been collected by means of a registry in the federal German state of Baden-Württemberg (documentation period, 1987-2006; n = 5,108; completeness of data 98.1%)., Results: The current incidence rate (2000-2006) is 19.4 per 100,000 per year (95% CI 18.6-20.2). The annual incidence rate can be expressed as a square of a linear function of the calendar year X [y = (3.05 + 0.0778 x {X-1986})(2); r(2) = 0.90]. The highest increase per year was observed in the age-groups comprising 2- and 3-year-olds (12 and 13% per year, respectively). The incidence rate for the year 2026 is estimated to be 37.9 per 100,000 per year (95% CI 33.3-42.9)., Conclusions: The increase that we found in younger children is characteristic of a left shift toward an earlier age.

Common sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control-or cis modulation-rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alternative transcripts, combined with eQTL maps and selective gene resequencing, revealed that between 17 and 25% of apparent cis modulation is caused by SNPs that overlap probes rather than by genuine quantitative differences in mRNA levels. This estimate climbs to 40-50% when qualitative differences between isoform variants are included. We have developed an analytical approach to filter differences in expression and improve the yield of genuine cis-modulated transcripts to approximately 80%. This improvement is important because the resulting variation can be successfully used to study downstream consequences of altered expression on higher-order phenotypes. Using a systems genetics approach we show that two validated cis-modulated genes, Stk25 and Rasd2, are likely to control expression of downstream targets and affect disease susceptibility.

During 1997-2008 two long-term (I and II) and two life-long (III and IV) experiments were performed analyzing the effect of chronic exposure to a low-intensity GSM-like signal (900 MHz pulsed with 217 Hz, 100 µW/cm² average power flux density, 38-80 mW/kg mean specific absorption rate for whole body) on health and survival of unrestrained female Sprague-Dawley rats kept under identical conditions. Radiofrequency (RF)-exposure was started at 52-70 days of age and continued for 24 (I), 17 (II) and up to 36 and 37 months, respectively (III/IV). In the first two experiments (1997-2000) 12 exposed and 12 sham-exposed animals each were observed until they were maximally 770 or 580 days old. In experiment I no adverse health effects of chronic RF-exposure were detectable, neither by macroscopic nor detailed microscopic pathological examinations. Also in experiment II no apparent macroscopic pathological changes due to treatment were apparent. Median survival time could not be estimated since in none of the groups more than 50% of the animals had died. In the course of two complete survival experiments (2002-2005; 2005-2008) 30 RF- and 30 sham-exposed animals each were followed up until their natural end or when they became moribund and had to be euthanized. A synoptical data analysis was performed. Survival data of all four groups could be fitted well by the Weibull distribution. According to this analysis median survival was significantly shortened under RF-exposure in both experiments by 9.06% (95% CI 2.7 to 15.0%) (p=0.0064); i.e by 72 days in experiment III and 77 days in experiment IV as compared to the corresponding sham-treated animals (III: 799 days; IV: 852 days). Both groups of animals of experiment III showed reduced median survival times by 6.25% (95% CI -0.3 to 12.4%) (p=0.0604) compared to the corresponding groups of experiment IV (53 days: sham-exposed animals, 48 days: RF-exposed animals) which may be due to the fact that animals of experiment III were born in October and animals of experiment IV in May indicating that the month of birth affects life span. From the results of the last two experiments it has to be concluded that chronic exposure to a low-intensity GSM-like signal may exert negative health effects and shorten survival if treatment is applied sufficiently long and the observational period covers the full life span of the animals concerned. The current data show that survival of rats kept under controlled laboratory conditions varies within certain limits depending on the month of birth. In view of our previous observations regarding an inhibitory or no effect of RF-exposure on DMBA-induced mammary cancer during the 1997-2000 period, an additional modulatory influence on a year-to-year basis should be considered which might be related to changing solar activity during the the 11-years' sunspot cycle. These potentially complex influences of the natural environment modulating the effects of anthropogenic RF-signals on health and survival require a systematic continuation of such experiments throughout solar cycle 24 which started in 2009.

Background: Plasmodium falciparum malaria accounts for >1 million deaths annually, mostly among young children in sub-Saharan Africa. Identifying those individuals who are likely to die is crucial. Several factors have been independently associated with death. Because malaria is a systemic disease, a quantitative score combining such risk factors may be superior., Methods: We used both forward and backward stepwise logistic regression to select the best predictors of death, as evaluated for 23,890 African children with severe P. falciparum malaria. The study was conducted from December 2000 through May 2005 in 6 hospital-based research units (in Banjul in the Gambia, Blantyre in Malawi, Kilifi in Kenya, Kumasi in Ghana, and Lambaréné and Libreville in Gabon) in a network established to study severe malaria in African children (ie, the SMAC Network)., Results: The Lambaréné Organ Dysfunction Score (LODS) combines 3 variables: coma, prostration, and deep breathing. A LODS >0 (odd ratio, 9.6; 95% confidence interval, 8.0-11.4) has 85% sensitivity to predict death, and a LODS <3 is highly (98%) specific for survival., Conclusions: The LODS is a simple clinical predictor of fatal malaria in African children. This score provides accurate and rapid identification of children needing either referral or increased attention.

Background: The objective of this study is to evaluate the significance of reduced intercarotid artery distance in the C5 segment in acromegalic patients and the implications for transsphenoidal surgery., Methods: The skull base with the carotid canal was examined with a helical CT scan in 45 patients with acromegaly and 45 age group-matched controls. The distances between the inner walls (IWs) of the carotid sulcus (CS), the outer walls (OWs) of the CS, and the diameter of the ICA at the C5 segment were assessed. Preoperative IGF-1 and growth hormone levels and concomitant diseases were evaluated and correlated with the biometric findings. Statistical analysis was performed with JMP (JMP version 7.0.2, SAS, Cary, USA)., Results: The mean distance between the IW was 1.64 +/- 0.40 cm in the acromegalic patients and 1.90 +/- 0.26 cm in the control group (P = .0005). The distance between the OW measured 3.01 +/- 0.39 and 2.97 +/- 0.33 cm in the acromegalics and in the control group, respectively (P = .6230). The difference in the diameter of the ICA was statistically significant (P < .0001) between patients and control group. Within the patient group, the distance between the IW of both ICA was significantly smaller in the subgroup with arterial hypertension (P = .0256)., Conclusion: Narrowing of the inner borders of the CS between the right and left side is a statistically significant parameter in acromegaly. Attention should be given to an altered vascular course of the ICAs when planning and performing transsphenoidal microsurgery in acromegalic patients. A preoperative skull base CT may furnish important anatomical information and further reduce the risk of vascular injury.

Newborns with Pierre Robin sequence (PRS) have mandibular hypoplasia, glossoptosis, and possibly cleft palate. Their facial appearance is characteristic. The further facial development is controversial. The aim of this study was to analyze the facial development of children with PRS.In a prospective, cross-sectional study, 344 healthy children and 37 children with PRS and cleft palate younger than 8 years were scanned three-dimensionally. Twenty-one standard anthropometric landmarks were identified, and the images were superimposed. Growth curves for normal facial development were calculated. The facial morphology of children with PRS was compared with that of healthy children.The facial growth of children with PRS in the transversal and vertical direction was normal. In the sagittal direction, the mandibular deficit was confirmed. Except for the orbital landmarks and nasion, all landmarks of the midface demonstrated a significant sagittal deficit. This difference to healthy children remained constant for all ages.Our study cannot support the theory of mandibular catch-up growth. The sagittal deficit of the midface could be observed in all ages. This indicates that children with PRS have a very early, severe, and persistent underdevelopment of this part of the face. We conclude that this disturbance must be addressed in early childhood with orthodontic and speech therapy.

Objective: The aim of the study was to assess variations in the diameter of the common bile duct in patients with gastrointestinal graft-versus-host disease (GVHD) undergoing abdominal CT after allogeneic hematopoietic stem cell transplantation and to correlate the findings with laboratory results on cholestasis., Materials and Methods: We performed a retrospective analysis of the caliber of the common bile duct in 27 adult patients with histologically validated gastrointestinal GVHD who underwent two or more follow-up abdominal CT examinations. Another 25 patients who underwent allogeneic hematopoietic stem cell transplantation during the same period at our institution but who did not have GVHD constituted the control group. The diameters of the common bile duct were correlated with cholestasis values., Results: A pathologic diameter of the common bile duct was defined as greater than 7 mm (48 patients) in patients who had not undergone cholecystectomy and greater than 8 mm in those who had (four patients). The median diameter of the common bile duct was 7 mm (range, 4-14.8 mm) in the GVHD group and 5.8 mm (range, 3.9-10.2 mm) in the control group. Pathologic diameters of the common bile duct were found in 67% of the patients in the GVHD group and in 12% of the control group (p < 0.0001). The variation coefficient of the diameter of the common bile duct was 12.4% in the GVHD group (83 examinations) and 6.4% in the control group (92 examinations) (p < 0.0001). Ninety-six percent of the patients in the GVHD group had elevated cholestasis values with a significant positive correlation between bilirubin concentration and diameter of the common bile duct (r = 0.421; p = 0.032). Enhancement of the common bile duct and gallbladder wall was seen in the majority of GVHD patients but no controls (p < 0.0001)., Conclusion: Temporary dilatation of the common bile duct seems to be a common finding in gastrointestinal GVHD after hematopoietic stem cell transplantation and correlates with bilirubin concentration. This knowledge of fluctuation in bile duct diameter can help to avoid unnecessary tests to evaluate for pathologic causes of biliary dilatation.

The aim of the study was to assess the influence of carbogen (95% O(2), 5% CO(2)) or pure oxygen breathing on renal oxygenation measured by blood oxygenation level dependent (BOLD) magnetic resonance imaging at 3.0 T. Seven healthy young volunteers (median age 25, range 23-35 years) participated in the study. A T2*-weighted fat-saturated spoiled gradient-echo sequence was implemented on a 3.0 T whole-body imager (TE/TR = 27.9 ms/49 ms, excitation angle 20 degrees ) with an acquisition time of approximately 5.3 s. A total of 100 images were acquired during 22 min. A block design was applied for gas administration: 4 min room air, 4 min carbogen/oxygen, 4 min room air, 4 min carbogen/oxygen and 6 min room air. A compartment model was fitted to the data sets accounting for time-dependent increase/decrease of renal oxygenation as well as baseline changes of the scanner. T2*-weighted images showed good image quality without notable artefacts or distortions. Mean relative signal increase due to carbogen breathing was 2.73% (95% confidence interval: 1.34-5.54) in the right kidney and 3.76% (1.53-9.20) in the left kidney, while oxygen breathing led to a signal enhancement of 3.20% (2.57-3.98) in the right kidney and 3.16% (1.83-5.45) in the left kidney. No statistical difference was found between carbogen and oxygen breathing or between the oxygenation of the right and the left kidney. A significant difference was found in the characteristic time constant for the signal increase with a faster saturation taking place for oxygen breathing. Renal tissue oxygenation is clearly influenced by carbogen or oxygen breathing. The changes can be assessed by T2*-weighted MRI at high field strengths. The effects are in the expected range for the BOLD effect of 3-4% at 3.0 T. The proposed technique might be interesting for the assessment of renal tissue oxygenation and its regulation in patients with kidney diseases., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

Background: A phase I/II trial was conducted to assess feasibility and tolerability of tumor associated antigen peptide vaccination in hormone sensitive prostate carcinoma (PC) patients with biochemical recurrence after primary surgical treatment., Methods: Nineteen HLA-A2 positive patients with rising PSA without detectable metastatic disease or local recurrence received 11 HLA-A*0201-restricted and two HLA class II synthetic peptides derived from PC tumor antigens subcutaneously for 18 months or until PSA progression. The vaccine was emulgated in montanide ISA51 and combined with imiquimod, GM-CSF, mucin-1-mRNA/protamine complex, local hyperthermia or no adjuvant. PSA was assessed, geometric mean doubling times (DT) calculated and clinical performance monitored., Results: PSA DT of 4 out of 19 patients (21%) increased from 4.9 to 25.8 months during vaccination. Out of these, two patients (11%) exhibited PSA stability for 28 and 31 months which were still continuing at data cut-off. One patient showed no change of PSA DT during vaccination but decline after the therapy. Three patients had an interim PSA decline or DT increase followed by DT decrease compared to baseline PSA DT. Three of the responding patients received imiquimod and one the mucin-1-mRNA/protamine complex as adjuvant; both are Toll-like receptor-7 agonists. Eleven (58%) patients had progressive PSA values. The vaccine was well tolerated, and no grade III or IV toxicity occurred., Conclusion: Multi-peptide vaccination stabilized or slowed down PSA progress in four of 19 cases. The vaccination approach is promising with moderate adverse events. Long-term stability delayed androgen deprivation up to 31 months. TLR-7 co-activation seems to be beneficial.

The effect of polyparasite infections on cytokine and chemokine responses as well as the effect of antiparasite treatment was studied in children without parasite infection (the G0 group), in children singly infected with Schistosoma haematobium (the G1 group), and in children multiply infected with S. haematobium/Schistosoma mansoni, Entamoeba histolytica/Entamoeba dispar, and Necator americanus (the G3+ group). Linear regression analysis disclosed a significant risk for coinfection with hookworm and Schistosoma species. Polyparasite infections detected in 23% of children before treatment were present in 5% at 15 months after treatment. Chemokine responses to S. mansoni adult worm antigen (SmAg) diminished after treatment for macrophage inflammatory chemokine (MIP)-1alpha/chemokine (C-C motif) ligand (CCL)-3 (among G3+ children, by a factor of 200 [95% confidence interval {CI}, 33-1111]) and for MIP-1beta/CCL-4 (among G3+ children, by a factor of 26 [95% CI, 6-117]) but were enhanced for thymus- and activation-regulated chemokine/CCL-17 (among G3+ children, by a factor of 10 [95% CI, 3-32]) (P < .001 for all). In response to E. histolytica antigen, interleukin (IL)-13 levels increased after treatment among G1 children by a factor of 138 (95% CI, 12-1569) and among G3+ children by a factor of 21 (95% CI, 7-64) (P < .001 for both). Cellular production of interferon (IFN)-gamma in response to SmAg decreased 4 weeks after treatment among G3+ children, whereas T helper cell type 2 (Th2) IL-13 production was enhanced among G1 and G3+ children. In summary, polyparasite infections with S. haematobium/S. mansoni, E. histolytica/E. dispar, and N. americanus generated prominent proinflammatory cytokine and chemokine responses, and, after antihelminth treatment, the inflammatory chemokine response lessened as the Th2 responsiveness in coinfected children increased.