Search Dynamics on Multimodal Multiobjective Problems.

We continue recent work on the definition of multimodality in multiobjective optimization (MO) and the introduction of a test bed for multimodal MO problems. This goes beyond well-known diversity maintenance approaches but instead focuses on the landscape topology induced by the objective functions. More general multimodal MO problems are considered by allowing ellipsoid contours for single-objective subproblems. An experimental analysis compares two MO algorithms, one that explicitly relies on hypervolume gradient approximation, and one that is based on local search, both on a selection of generated example problems. We do not focus on performance but on the interaction induced by the problems and algorithms, which can be described by means of specific characteristics explicitly designed for the multimodal MO setting. Furthermore, we widen the scope of our analysis by additionally applying visualization techniques in the decision space. This strengthens and extends the foundations for Exploratory Landscape Analysis (ELA) in MO.

Expression of the cAMP binding protein EPAC1 in thyroid tumors and growth regulation of thyroid cells and thyroid carcinoma cells by EPAC proteins.

The thyrotropin receptor-cAMP pathway is central in growth regulation of thyroid cells and thyroid tumorigenesis, and it regulates expression of thyroid specific genes. Recently, 2 new protein kinase A-independent cAMP effectors named EPAC1 and 2 were described that activate additional intracellular pathways. The aim of our study was to investigate the role of EPAC proteins in growth regulation of thyroid cells and thyroid carcinomas. EPAC1 expression was investigated immunohistochemically in tissues of various thyroid tumors. Utilizing MTT assay, the effect of EPAC stimulation on proliferation in thyroid carcinoma cells and in non-transformed rat FRTL5 cells was investigated. The activation of intracellular signaling pathways was examined by RAP pull-down assay and Western blots. EPAC1 expression was strong in non-oxyphilic follicular thyroid adenomas and carcinomas and in follicular papillary thyroid carcinomas. It was moderate in oxyphilic follicular tumors and classical and tall cell papillary carcinomas. In contrast, EPAC1 expression was low in poorly differentiated carcinomas and very low in anaplastic carcinomas. Thyroid carcinoma cell lines showed no or very weak EPAC1 expression and exhibited no growth-promoting effect after EPAC stimulation. Non-transformed rat FRTL5 cells were growth-stimulated by an EPAC-specific cAMP-analogue and showed EPAC-dependent activation of RAP, ERK, and p70S6 kinase. EPAC1 expression and cellular response to EPAC activation in rat FRTL5 cells reflect cellular responses to cAMP and TSH stimulation in non-transformed thyroid cells. In undifferentiated thyroid carcinomas, loss of EPAC1 expression may be in accordance with the loss of thyroid-specific functions and the loss of responsiveness of the TSHR-cAMP pathway.

Adult long-term outcome of patients after congenital hydrocephalus shunt therapy.

INTRODUCTION: Even though shunt surgery has been an established and widely accepted treatment for congenital hydrocephalus for five decades, long-term follow-up and functional outcome data is rare. PATIENTS AND METHODS: Sixty-nine patients were examined after congenital hydrocephalus had been treated between 1971 and 1987 at the Department of Pediatric Surgery (University of Leipzig) within the first 12 months of life. Median age of patients was 32 years (range 25-42 years). Patients agreed to undergo a contemporary hydrocephalus assessment. RESULTS: Seven patients (10.1%) became shunt-independent before adulthood. By the age of 20, 82% of the patients had needed at least one shunt revision, 100% by the age of 30. 21.7% of the primary valves (Spitz-Holter) remained intact without revision until today up to 35 years (mean functional intactness 23 years). Shunt infections occurred in 4.3% of primary implantations. 48% of the patients had a good functional outcome (mRS = 0-1). 40.9% of the patients attended regular school. In summary, 75% patients work on a daily basis. 44.6% live an independent life, 35.4% rely on parental supervision, and 20% depend on professional care institutions. CONCLUSION: Compared to the pre-shunt era, surgery within the first year of life is advantageous regarding visual function, educational progress, and social results. The outcome achieved throughout childhood remains stable during adult life as long as catastrophic events of shunt malfunction can be prevented. Epilepsy, motor deficits, acute shunt dysfunction, and problems of social integration as well as aging parental caregivers seem to be prominent factors of morbidity in adulthood.

[Reconciling activities of working women providing care and the influence of structural and cultural factors]. / Vermittlungshandlungen erwerbstätiger pflegender Frauen und der Einfluss struktureller und kultureller Rahmenbedingungen.

BACKGROUND: Today, an increasing proportion of society has to reconcile eldercare and work. This task poses challenges for them, which they meet through an adjustment of their everyday living arrangements. These coping strategies have been so far scarcely noted within research on the reconciliation of elder care and employment. Knowledge about the active dealing with this parallel involvement in both spheres of life is of vital importance when wanting to derive precisely tailored support measures for employed care givers. MATERIALS AND METHODS: A goal of this article is to deliver insight on reconciling activities of employed women who provide care, while it tries to specify respective factors which determine those actions. Moreover, an ideal typology is presented, which systematizes these associations. RESULTS: With this ideal typology, conceptual instruments have been developed which illustrate the complex reality of the reconciliation actions and the dependence on various coping resources. In gerontological practice, these findings may provide support to design an intervention strategy tailored to the individual situation that addresses the everyday level of action and strengthens the performance of those affected.

Analyzing the BBOB results by means of benchmarking concepts.

We present methods to answer two basic questions that arise when benchmarking optimization algorithms. The first one is: which algorithm is the "best" one? and the second one is: which algorithm should I use for my real-world problem? Both are connected and neither is easy to answer. We present a theoretical framework for designing and analyzing the raw data of such benchmark experiments. This represents a first step in answering the aforementioned questions. The 2009 and 2010 BBOB benchmark results are analyzed by means of this framework and we derive insight regarding the answers to the two questions. Furthermore, we discuss how to properly aggregate rankings from algorithm evaluations on individual problems into a consensus, its theoretical background and which common pitfalls should be avoided. Finally, we address the grouping of test problems into sets with similar optimizer rankings and investigate whether these are reflected by already proposed test problem characteristics, finding that this is not always the case.

B-type natriuretic peptide predicts stroke of presumable cardioembolic origin in addition to coronary artery calcification.

BACKGROUND AND PURPOSE: B-type natriuretric peptide (BNP) is a marker of cardiac dysfunction that is released from myocytes in response to ventricular wall stress. Previous studies suggested that BNP predicts stroke events in addition to classical risk factors. It was suggested that the BNP-associated risk results from coronary atherosclerosis or atrial fibrillation. METHODS: Three thousand six hundred and seventy five subjects from the population-based Heinz Nixdorf Recall study (45-75 years; 47.6% men) without previous stroke, coronary heart disease, myocardial infarcts, open cardiac valve surgery, pacemakers and defibrillators were followed up over 110.1 ± 23.1 months. Cox proportional hazards regressions were used to examine BNP as a stroke predictor in addition to vascular risk factors (age, gender, systolic blood pressure, low-density lipoprotein, high-density lipoprotein, diabetes, smoking), renal insufficiency, atrial fibrillation/known heart failure and coronary artery calcification. RESULTS: Eighty-nine incident strokes occurred (80 ischaemic, 9 hemorrhagic). Subjects suffering stroke had significantly higher BNP values at baseline than the remaining subjects [26.3 (Q1; Q3 = 12.9; 51.0) vs. 17.4 (9.4; 31.4); P < 0.001]. In a multivariable regression, log10 BNP was an independent stroke predictor [hazard ratio 1.96, 95% confidence interval (CI) 1.13-3.41; P = 0.017] in addition to age (1.24 per 5 years, CI 1.04-1.49; P = 0.016), systolic blood pressure (1.25 per 10 mmHg, CI 1.14-1.38; P < 0.001), smoking (2.05, CI 1.24-3.39; P = 0.005), atrial fibrillation/heart failure (2.25, CI 1.05-4.83; P = 0.037) and computed-tomography-based log10 (coronary artery calcification + 1) (1.47, CI 1.15-1.88; P = 0.002). Log10 BNP predicted stroke in men but not women, both in subjects ≤65 and >65 years. In subsequent analyses, BNP discriminated the incidence of cardioembolic stroke (P for trend = 0.001), but not stroke of macroangiopathic (P = 0.555), microangiopathic (P = 0.809) or unknown (P = 0.367) origin. CONCLUSIONS: BNP predicts presumable cardioembolic stroke independent of coronary calcification.

Updated physiology and pathophysiology of CSF circulation--the pulsatile vector theory.

INTRODUCTION: Hydrocephalus is still a not well-understood diagnostic and a therapeutic dilemma because of the lack of sufficient and comprehensive model of cerebrospinal fluid circulation and pathological alterations. CONCLUSIONS: Based on current studies, reviews, and knowledge of cerebrospinal fluid dynamics, brain water dynamics, intracranial pressure, and cerebral perfusion physiology, a new concept is deducted that can describe normal and pathological changes of cerebrospinal fluid circulation and pathophysiology of idiopathic intracranial hypertension.

The use of 5-aminolevulinic acid fluorescence guidance in resection of pediatric brain tumors.

INTRODUCTION: Whereas in the adult population 5-Aminolevulinic acid (5-ALA) fluorescence guidance has been widely accepted for improving the extent of tumor resection, the application in children remains an off-label use. Even though most pediatric study protocols require a complete resection for improving outcome parameters, only few pediatric patients have been operated with fluorescence guidance, and it remains questionable, whether and which pediatric tumors show useful fluorescence. We present casuistic reports of application of 5-ALA in children collected from three different neurosurgical departments. PATIENTS AND METHODS: In children with suspected malignant intracerebral tumor or recurrence, individual informed consent was obtained in each case from the parents. 5-ALA was administered according to the adult protocol, with 20 mg/kg, 2 h before induction of anesthesia. We retrospectively analyzed 18 patients (13 male, 5 female; age 3-18 years), using the intraoperative neurosurgical protocol, the postoperative MRI results, and the follow-up clinical examinations. RESULTS: The use of 5-ALA fluorescence guidance proved to be safe in our group of pediatric patients. Fluorescence guidance was most useful for recurrent glioblastoma resection. Medulloblastoma tissue displayed fluorescence only inconsistently, and most pilocytic astrocytoma remained without staining. Ganglioglioma showed partial staining in the central tumor areas, without allowing the use for circumferent resection. CONCLUSION: The off-label use of 5-ALA fluorescence guidance in pediatric patients appears to be most useful in recurrent high-grade gliomas. Fluorescence accumulation in other pediatric brain tumor entities is not predictable and should be evaluated in future clinical studies before being integrated into the current treatment protocols.

Acute two-compartment low pressure hydrocephalus--a case report.

A case of an 8-year-old-boy with shunt-dependent occlusive hydrocephalus after resection of a cerebellar medulloblastoma is presented, who experienced repeated episodes of severe neurologic deterioration with signs and symptoms of raised intracranial pressure after spinal tapping. However, intracranial pressure was recorded within low ranges, only up to the opening pressure of the implanted adjustable shunt valve. Multiple shunt revisions were performed, until the condition was recognized as acute normal pressure hydrocephalus. Either enforced recumbency and downadjustment of the valve system to 0 cm H(2)O alone or external ventricular drainage seems to be successful to resolve the critical condition, depending on severity of the symptoms. The case illustrates that acute pathologic enlargement of the ventricular system is not always associated with increased intracranial pressure, even when typical signs and symptoms are present. The very rare entity of acute normal pressure hydrocephalus by two separated compartments is postulated based on the pulsatile vector force theory of brain water circulation.

Effectiveness of bevacizumab for radiation-induced cerebral necrosis in children.

INTRODUCTION: Bevacizumab has been reported to effectively reduce cerebral edema caused by radiation therapy. However, only limited data with a short follow-up in tumor patients are available so far. PATIENTS AND METHODS: Two children suffering from hemorrhage from arteriovenous malformation (AVM) have been treated with stereotactic radiotherapy and developed radiation-induced cerebral edema with deteriorating neurological status despite maximized steroid therapy. Bevacizumab administration at 5 mg/kg body weight was initiated every 2 weeks. RESULTS: Bevacizumab treatment rapidly ameliorated the neurological deficits, malignant edema and prevented catastrophic complications. Corticoid therapy could be reduced and discontinued. However, after 18 months, both patients showed identical or worse neurological status than before bevacizumab therapy. AVM radiation therapy had been successful to completely obliterate AVMs. DISCUSSION: In our limited experience, bevacizumab may be an effective and safe option for rescue therapy for malignant cerebral edema on the basis of radiation-induced necrosis especially in patients who experience rapid deterioration despite corticoid therapy and/or intolerable steroid side effects. Despite the fact that functional improvement could not be achieved in long-term outcome patients significantly stabilized and improved during periods of acute deterioration. In order to determine the long-term effectiveness of bevacizumab further investigation in placebo-controlled studies with a higher number of patients are required.

[Vascular surgery in old people]. / Gefäßchirurgie bei alten Menschen.

The age pyramid in Germany is upside down. According to the Federal Statistical Office this development will continue in the coming years, which presents a challenge for surgeons to surgically treat increasingly more and increasingly older people. Particularly in vascular surgery, which is a surgery of old people, this fact represents a special challenge. The frailty of old people is, among other things, due to a series of comorbidities, which must be taken into consideration within the framework of surgical treatment. They can have an important influence on the perioperative planning, the operation, the postoperative treatment and the outcome of the patient. This treatment planning becomes more and more challenging, because due to the progress in endovascular surgery there will soon be no limits to what is feasible; however, the question arises whether the feasible is also reasonable? Within the scope of this article the authors try to give answers to the treatment of old patients in vascular surgery and to find strategies for planning and to establish an individualized optimal treatment.

Experimental studies of Debye-like process and structural relaxation in mixtures of 2-ethyl-1-hexanol and 2-ethyl-1-hexyl bromide.

Binary solutions of 2-ethyl-1-hexanol (2E1H) with 2-ethyl-1-hexyl bromide (2E1Br) are investigated by means of dielectric, shear mechanical, near-infrared, and solvation spectroscopy as well as dielectrically monitored physical aging. For moderately diluted 2E1H the slow Debye-like process, which dominates the dielectric spectra of the neat monohydroxy alcohol, separates significantly from the α-relaxation. For example, the separation in equimolar mixtures amounts to four decades in frequency. This situation of highly resolved processes allows one to demonstrate unambiguously that physical aging is governed by the α-process, but even under these ideal conditions the Debye process remains undetectable in shear mechanical experiments. Furthermore, the solvation experiments show that under constant charge conditions the microscopic polarization fluctuations take place on the time scale of the structural process. The hydrogen-bond populations monitored via near-infrared spectroscopy indicate the presence of a critical alcohol concentration, x(c) ≈ 0.5-0.6, thereby confirming the dielectric data. In the pure bromide a slow dielectric process of reduced intensity is present in addition to the main relaxation. This is taken as a sign of intermolecular cooperativity probably mediated via halogen bonds.

Measurement of urinary free cortisol by current immunoassays: need for sex-dependent reference ranges to define hypercortisolism.

Urinary free cortisol (UFC) is used to assess disease activity in hypercortisolemic patients. However, reference ranges are often lacking, especially with respect to potential confounding variables. This study analyzed upper limits of normal (ULN, mean + 2 SD) for 2 newer immunoassays, using gas chromatography-mass spectrometry (GC-MS) as reference method. Each 10 healthy subjects were grouped by age (18-29; 30-49; ≥ 50 years), BMI (< 25; ≥ 25 kg/m2), and sex, resulting in a total of 120 controls (60 males; age: 39.3±1.3 years; BMI: 25.9±0.4 kg/m2). ULN were calculated for a radioimmunoassay (RIA, Immunotech) and an electrochemiluminescence immunoassay (ECLIA, Roche) and applied to 12 hypercortisolemic patients (4 males; age: 53.1±3.1 years; BMI: 29.1±1.8 kg/m2). To determine degradation, samples were stored at 4°C (without light) or 22°C (with and without light) for 0, 24, and 72 h. Cortisol concentrations were significantly correlated: r=0.88 for RIA vs. ECLIA, r=0.75 for RIA vs. GC-MS, and r=0.77 for ECLIA vs. GC-MS (always p<0.0001). For each procedure, multiple stepwise regression analysis identified sex as the only significant predictor, resulting in sex-dependent ULN (males vs. females): 294 vs. 208 nmol/24 h (RIA), and 379 vs. 277 nmol/24 h (ECLIA). These ULN classified samples from patients as hypercortisolemic in 100% (RIA) and 95% (ECLIA). Different storage conditions over 72 h did not alter UFC levels significantly. Results of the 3 procedures were well correlated, and the use of assay- and sex-specific ULN allowed excellent identification of hypercortisolic states. UFC is stable over 72 h irrespective of the storage conditions applied.

Differential miRNA expression profiles in variants of papillary thyroid carcinoma and encapsulated follicular thyroid tumours.

BACKGROUND: Recent studies showed a significant upregulation of distinct microRNAs (miRNAs) in papillary thyroid carcinoma (PTC). The objective of this study was to explore whether this upregulation could also be assigned to distinct histomorphological variants of PTC, especially the follicular variant and other encapsulated follicular thyroid tumours. METHODS: We used total RNA of 113 formalin-fixed paraffin-embedded tissues of 50 PTCs ((10 conventional type (PTC-CT), 10 tall cell variants (PTC-TCVs), 30 follicular variants (PTC-FVs)), 10 follicular adenomas (FAs), 10 multinodular goitres (MNGs), 21 follicular thyroid carcinomas and 22 well-differentiated tumours of unknown malignant potential (WDT-UMP) to analyse the miRNA expression pattern of five selected miRNAs (146b, 181b, 21, 221 and 222) using RT-PCR TaqMan miRNA assay to explore the diagnostic utility of this method. RESULTS: The mean values of the expression pattern of all miRNAS in PTCs show a statistically significant difference from those in MNG and FA with fold changes up to 90 for miRNA 146b, P<0.001. No differences in expression pattern could be showed between MNG and FA. The PTC-FVs differ significantly from FA in all five miRNAS, from MNG in three and from WDT-UMP in one miRNA with fold changes between 1.7 and 21.2, but failed to be of diagnostic value regarding individual cases with substantial overlaps. CONCLUSION: We conclude that analysis of a set of five selected miRNAS distinguish common variants of PTC from FA/MNG but failed to be a useful diagnostic method in individual and doubtful cases, especially in the differential diagnosis of encapsulated follicular thyroid tumours.

Accuracy of three-dimensional photogrammetric images in non-synostotic cranial deformities.

OBJECTIVE: Given the increasing incidence of deformational plagiocephaly due to infants' supine sleeping position to prevent sudden infant death syndrome, reliable anthropometric diagnostics are needed. Besides the traditional method of measuring landmarks with callipers, three-dimensional (3D) photography has great potential. In this investigation the accuracy of 3D photogrammetry is studied. METHODS: The study included 100 randomly chosen children between the ages of 4 and 20 months with a non-synostotic cranial deformity in a retrospective analysis. Measurements of diagonals A and B on the infant's head were obtained once using callipers. 3D photographs of these children were measured 5 times by 5 clinicians separately. RESULTS: The inter- and intra-rater agreements of the 3D measurements had low variability in the variance component analysis. The standard deviations for reproducibility and repeatability were 0.117-0.283 cm for diagonals A and B. The intra-class correlation coefficients for the inter-rater reliability resulted in excellent agreement (0.97 for plagiocephaly, 0.98 for brachycephaly, 0.96 for combined deformity). The comparison of the 3D photographic and callipers measurements showed that 3D photography resulted in a slight over-estimation. CONCLUSION: 3D photogrammetry is potentially a reliable tool for treatment planning and follow-up of abnormal head shapes in infancy.

Two cases of Walker-Warburg syndrome complicated by hydrocephalus.

Walker-Warburg syndrome is a very rare autosomal recessive disorder with congenital muscular dystrophy, brain malformations on the basis of a neuronal migration defect and ocular abnormalities. We report our experience in treating two cases of Walker-Warburg syndrome complicated by hydrocephalus with shunting and endoscopic techniques.

Progressive biological behavior of a dysembryoplastic neuroepithelial tumor.

We present the case of a 13-month-old girl with a right occipital cortical alteration on MRI that proved to be a growing lesion. Tumor growth had been observed over a period of 15 months before total resection was performed, revealing a dysembryoplastic neuroepithelial tumor WHO grade I. This case shows that dysembryoplastic neuroepithelial tumors can present as growing neoplasias. It underlines the importance of obtaining histologic diagnosis and close follow-up examinations using MRI, even in so-called stable lesions that are only unveiling through epileptic seizures.

Association of impaired fasting glucose and coronary artery calcification as a marker of subclinical atherosclerosis in a population-based cohort--results of the Heinz Nixdorf Recall Study.

AIMS/HYPOTHESIS: Atherosclerosis and cardiovascular diseases are often present at the time of diagnosis of type 2 diabetes mellitus. Whether subclinical atherosclerosis can be detected in the pre-diabetic (borderline fasting hyperglycemia) state is not clear. This study investigated the association of impaired fasting glucose (IFG) and coronary artery calcification (CAC), a marker of subclinical atherosclerosis, among participants without a history of coronary heart disease or manifest diabetes mellitus. METHODS: Study participants (aged 45-75 years) of the population-based Heinz Nixdorf Recall Study were categorised into those with normal fasting glucose (glucose <6.1 mmol/l) and those with IFG (glucose >or=6.1 to <7.0 mmol/l), excluding participants with a history of CHD or diabetes mellitus. CAC was assessed by electron-beam computed tomography, and risk factors were assessed by extended interviews, anthropometric measurements and laboratory tests. Various CAC cut-off points were used in multiple logistic and ordinal logistic regression models to estimate ORs and 95% CIs. RESULTS: Of the 2,184 participants, more men had IFG than did women (37% vs 22%). Participants with IFG showed a higher prevalence of CAC > 0 (men OR 1.90, 95% CI 1.33-2.70; women 1.63, 1.23-2.15). Risk factor adjustment weakened this association in both sexes (men 1.63, 1.12-1.36; women 1.26, 0.93-1.70). When the age- and sex-specific 75th percentile was used as the cut-off point for CAC, the association further decreased in men (1.10, 0.81-1.50), but became stronger in women (1.41, 1.02-1.94). CONCLUSIONS/INTERPRETATION: These data support the hypothesis that CAC is already present in the pre-diabetic state and that IFG has a modest and independent impact on the atherosclerotic process. Biological sex appears to modify the association between IFG and CAC.

Mba1, a novel component of the mitochondrial protein export machinery of the yeast Saccharomyces cerevisiae.

The biogenesis of mitochondria requires the integration of many proteins into the inner membrane from the matrix side. The inner membrane protein Oxa1 plays an important role in this process. We identified Mba1 as a second mitochondrial component that is required for efficient protein insertion. Like Oxa1, Mba1 specifically interacts both with mitochondrial translation products and with conservatively sorted, nuclear-encoded proteins during their integration into the inner membrane. Oxa1 and Mba1 overlap in function and substrate specificity, but both can act independently of each other. We conclude that Mba1 is part of the mitochondrial protein export machinery and represents the first component of a novel Oxa1-independent insertion pathway into the mitochondrial inner membrane.

Statistical methods for convergence detection of multi-objective evolutionary algorithms.

In this paper, two approaches for estimating the generation in which a multi-objective evolutionary algorithm (MOEA) shows statistically significant signs of convergence are introduced. A set-based perspective is taken where convergence is measured by performance indicators. The proposed techniques fulfill the requirements of proper statistical assessment on the one hand and efficient optimisation for real-world problems on the other hand. The first approach accounts for the stochastic nature of the MOEA by repeating the optimisation runs for increasing generation numbers and analysing the performance indicators using statistical tools. This technique results in a very robust offline procedure. Moreover, an online convergence detection method is introduced as well. This method automatically stops the MOEA when either the variance of the performance indicators falls below a specified threshold or a stagnation of their overall trend is detected. Both methods are analysed and compared for two MOEA and on different classes of benchmark functions. It is shown that the methods successfully operate on all stated problems needing less function evaluations while preserving good approximation quality at the same time.