Detection of spatial change points in the mean and covariances of multivariate simultaneous autoregressive models.

In this paper, we propose a test procedure to detect change points of multidimensional autoregressive processes. The considered process differs from typical applied spatial autoregressive processes in that it is assumed to evolve from a predefined center into every dimension. Additionally, structural breaks in the process can occur at a certain distance from the predefined center. The main aim of this paper is to detect such spatial changes. In particular, we focus on shifts in the mean and the autoregressive parameter. The proposed test procedure is based on the likelihood-ratio approach. Eventually, the goodness-of-fit values of the estimators are compared for different shifts. Moreover, the empirical distribution of the test statistic of the likelihood-ratio test is obtained via Monte Carlo simulations. We show that the generalized Gumbel distribution seems to be a suitable limiting distribution of the proposed test statistic. Finally, we discuss the detection of lung cancer in computed tomography scans and illustrate the proposed test procedure.

Mode shaping in semiconductor broad area lasers by monolithically integrated phase structures.

By broadening the stripe width of the active waveguide region, it is possible to extract high optical powers from semiconductor broad area lasers. However, a weak output beam quality, optical filamentation, and high peak power densities will result, which are invoked by the amplification of higher order modes. We show an approach to influence the optical field inside the resonator by integrating optical phase structures directly into the waveguide. Those elements offer the possibility to enlarge the active gain area for the desired fundamental laser mode, while additional diffraction losses for higher order modes are generated, thus achieving an improved beam quality. We report on considerations in designing those elements and demonstrate a first experimental realization.

Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages.

Sepsis is controlled by endogenous glucocorticoids (GCs). Previous studies provided evidence that crosstalk of the monomeric GC receptor (GR) with proinflammatory transcription factors is the crucial mechanism underlying the suppressive GC effect. Here we demonstrate that mice with a dimerization-deficient GR (GR(dim)) are highly susceptible to sepsis in 2 different models, namely cecal ligation and puncture and lipopolysaccharide (LPS)-induced septic shock. TNF-α is normally regulated in these mice, but down-regulation of IL-6 and IL-1ß is diminished. LPS-treated macrophages derived from GR(dim) mice are largely resistant to GC actions in vitro in terms of morphology, surface marker expression, and gene expression. Treatment with recombinant IL-1 receptor antagonist improved survival of GR(dim) mice and mice lacking the GR in macrophages (GR(LysMCre)) mice. This suggests that regulation of IL-1ß in macrophages by GCs is pivotal to control sepsis.

Disruption of CREB function in brain leads to neurodegeneration.

Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem(-/-) background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.

Exploring the potential for groundwater-related ground deformation in Southern New South Wales, Australia.

Unsustainable groundwater extraction can lead to aquifer compaction, damages to infrastructure, changes of water accumulation in rivers and lakes and to a decrease of the aquifer's ability to store water for future generations. While this phenomenon is well identified across the globe, the potential for groundwater-related ground deformation is still largely unknown for most of the heavily exploited aquifers of Australia. This study fills that science gap by exploring signs of this phenomenon across a large region comprising seven of Australia's most intensively exploited aquifers, in the New South Wales Riverina region. To detect ground deformation, we processed 396 Sentinel-1 swaths acquired during 2015-2020 using a multitemporal spaceborne radar interferometry (InSAR), leading to the production of a near-continuous ground deformation maps covering ~280,000 km2. To explore potential groundwater-induced deformation hotspots, four criteria are used in a multiple-line of evidence approach: (1) the amplitude, shape, and extent of the InSAR ground displacement anomaly, (2) the spatial correspondence with groundwater extraction hotspots. (3) The correlations between InSAR deformation time series and change in head levels in 975 wells. Four areas are identified as potentially prone to inelastic, groundwater-related deformations, with average deformation rates ranging from -10 to -30 mm/yr, high rates of groundwater extraction, and ample critical head drops. Comparison of ground deformation and groundwater level time series also suggests potential for elastic deformation in some of these aquifers. This study will help water managers mitigating the groundwater-related ground deformation risk.

Community-dwelling persons with dementia: what do they need? What do they demand? What do they do? A systematic review on the subjective experiences of persons with dementia.

OBJECTIVES: Including the perspectives of persons with dementia (PwD) is essential in order to organize care structures for them. With this systematic review, we set out to screen the existing scientific evidence on self-expressions of community-dwelling individuals with dementia in order to provide a research base for developing an intervention for persons in early stages of the disease. The leading research questions for this review are: What needs do PwD living at home express? What are their subjective demands? What do they do to cope with their situation? METHODS: We performed a systematic literature review of review publications on subjective experiences of PwD. The publications were analysed using MAXQDA 10 to perform a thematic analysis. RESULTS: We identified 41 relevant reviews, of which 6 met our inclusion criteria. PwD experience the whole range of human emotions. Their needs and demands do not differ significantly from those of other groups of patients with chronic conditions. Coming to terms with the disease and maintaining normality appeared to be major themes. With regard to expectations from the side of professional health care, the need for accompanying, continuous support and counselling appeared to be central. Furthermore, disclosure of diagnosis represents a critical stage for PwD, but our findings indicated that they prefer to be included in this process. CONCLUSIONS: PwD are well able to express their needs. They should be included in research since they can provide valuable findings. Furthermore, those findings should be implemented in applied dementia care.

Control charts for measurement error models.

We consider a linear measurement error model (MEM) with AR(1) process in the state equation which is widely used in applied research. This MEM could be equivalently re-written as ARMA(1,1) process, where the MA(1) parameter is related to the variance of measurement errors. As the MA(1) parameter is of essential importance for these linear MEMs, it is of much relevance to provide instruments for online monitoring in order to detect its possible changes. In this paper we develop control charts for online detection of such changes, i.e., from AR(1) to ARMA(1,1) and vice versa, as soon as they occur. For this purpose, we elaborate on both cumulative sum (CUSUM) and exponentially weighted moving average (EWMA) control charts and investigate their performance in a Monte Carlo simulation study. The empirical illustration of our approach is conducted based on time series of daily realized volatilities.

New Approaches for Monitoring Image Data.

In this paper, we develop new techniques for monitoring image processes under a fairly general setting with spatially correlated pixels in the image. Monitoring and handling the pixels directly is infeasible due to an extremely high image resolution. To overcome this problem, we suggest control charts that are based on regions of interest. The regions of interest cover the original image which leads to a dimension reduction. Nevertheless, the data are still high-dimensional. We consider residual charts based on the generalized likelihood ratio approach. Existing control statistics typically depend on the inverse of the covariance matrix of the process, involving high computing times and frequently generating instable results in a high-dimensional setting. As a solution of this issue, we suggest two further control charts that can be regarded as modifications of the generalized likelihood ratio statistic. Within an extensive simulation study, we compare the newly proposed control charts using the median run length as a performance criterion.

Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy.

Glucocorticoids (GCs) are widely used in the treatment of allergic skin conditions despite having numerous side effects. Here we use Cre/loxP-engineered tissue- and cell-specific and function-selective GC receptor (GR) mutant mice to identify responsive cell types and molecular mechanisms underlying the antiinflammatory activity of GCs in contact hypersensitivity (CHS). CHS was repressed by GCs only at the challenge phase, i.e., during reexposure to the hapten. Inactivation of the GR gene in keratinocytes or T cells of mutant mice did not attenuate the effects of GCs, but its ablation in macrophages and neutrophils abolished downregulation of the inflammatory response. Moreover, mice expressing a DNA binding-defective GR were also resistant to GC treatment. The persistent infiltration of macrophages and neutrophils in these mice is explained by an impaired repression of inflammatory cytokines and chemokines such as IL-1beta, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and IFN-gamma-inducible protein 10. In contrast TNF-alpha repression remained intact. Consequently, injection of recombinant proteins of these cytokines and chemokines partially reversed suppression of CHS by GCs. These studies provide evidence that in contact allergy, therapeutic action of corticosteroids is in macrophages and neutrophils and that dimerization GR is required.

Home-based music therapy--a systematic overview of settings and conditions for an innovative service in healthcare.

BACKGROUND: Almost every Western healthcare system is changing to make their services more centered around out-patient care. In particular, long-term or geriatric patients who have been discharged from the hospital often require home-based care and therapy. Therefore, several programs have been developed to continue the therapeutic process and manage the special needs of patients after discharge from hospital. Music therapy has also moved into this field of healthcare service by providing home-based music therapy (HBMT) programs. This article reviews and summarizes the settings and conditions of HBMT for the first time. METHODS: The following databases were used to find articles on home-based music therapy: AMED, CAIRSS, EMBASE, MEDLINE, PsychINFO, and PSYNDEX. The search terms were "home-based music therapy" and "mobile music therapy". Included articles were analyzed with respect to participants as well as conditions and settings of HBMT. Furthermore, the date of publication, main outcomes, and the design and quality of the studies were investigated. RESULTS: A total of 20 international publications, 11 clinical studies and nine reports from practice, mainly from the United States (n = 8), were finally included in the qualitative synthesis. Six studies had a randomized controlled design and included a total of 507 patients. The vast majority of clients of HBMT are elderly patients living at home and people who need hospice and palliative care. Although settings were heterogeneous, music listening programs played a predominant role with the aim to reduce symptoms like depression and pain, or to improve quality of life and the relationship between patients and caregivers as primary endpoints. CONCLUSIONS: We were able to show that HBMT is an innovative service for future healthcare delivery. It fits with the changing healthcare system and its conditions but also meets the therapeutic needs of the increasing number of elderly and severely impaired people. Apart from music therapists, patients and their families HBMT is also interesting as a blueprint for home based care for other groups of caregivers.

Attunement in Music Therapy for Young Children with Autism: Revisiting Qualities of Relationship as Mechanisms of Change.

This study examined whether musical and emotional attunement predicts changes in improvisational music therapy with children with autism (4-7 years, N = 101, majority: no/limited speech, low IQ), assessed over 12 months. Attunement, as observed from session videos, and changes in generalized social skills, judged by blinded assessors and parents, were evaluated using standardized tools (Assessment of the Quality of Relationship, Improvisational Music Therapy Principles, ADOS, SRS). In contrast to the smaller pilot, we did not find significant effects between attunement and changes in outcomes, only tendencies in the same direction are observed. Findings suggest that symptom severity is associated with the therapist's ability to attune to the child. They further raise questions concerning outcome selection and user involvement.

The Therapeutic Relationship as Predictor of Change in Music Therapy with Young Children with Autism Spectrum Disorder.

This study examined whether the therapeutic relationship in music therapy with children with Autism Spectrum Disorder predicts generalized changes in social skills. Participants (4-7 years, N = 48) were assessed at baseline, 5 and 12 months. The therapeutic relationship, as observed from session videos, and the generalized change in social skills, as judged by independent blinded assessors and parents, were evaluated using standardized tools (Assessment of the Quality of Relationship; ADOS; SRS). Linear mixed effect models showed significant interaction effects between the therapeutic relationship and several outcomes at 5 and 12 months. We found the music therapeutic relationship to be an important predictor of the development of social skills, as well as communication and language specifically.

Phosphorylation of CREB Ser142 regulates light-induced phase shifts of the circadian clock.

Biological rhythms are driven in mammals by a central circadian clock located in the suprachiasmatic nucleus (SCN). Light-induced phase shifting of this clock is correlated with phosphorylation of CREB at Ser133 in the SCN. Here, we characterize phosphorylation of CREB at Ser142 and describe its contribution to the entrainment of the clock. In the SCN, light and glutamate strongly induce CREB Ser142 phosphorylation. To determine the physiological relevance of phosphorylation at Ser142, we generated a mouse mutant, CREB(S142A), lacking this phosphorylation site. Light-induced phase shifts of locomotion and expression of c-Fos and mPer1 in the SCN are significantly attenuated in CREB(S142A) mutants. Our findings provide genetic evidence that CREB Ser142 phosphorylation is involved in the entrainment of the mammalian clock and reveal a novel phosphorylation-dependent regulation of CREB activity.

Material and tablet properties of pregelatinized (thermally modified) Dioscorea starches.

The material and tablet formation properties of pregelatinized (thermally modified) forms of four Dioscorea starches have been investigated. Dioscorea starches were pregelatinized followed by either oven drying (PS) or freeze drying (FD) and used as excipient in direct compression. The physicochemical, morphological and material properties of the pregelatinized starches have been investigated. The tablet formation properties were assessed using the 3-D modeling parameters, the Heckel equation and the force-displacement profiles. The tablet properties were evaluated using the elastic recovery, compactibility plots and the disintegration test. The results indicate that pregelatinization improved the compressibility and flowability of the Dioscorea starches. The high bulk and tap densities of PS coupled with their good flowability offer a unique possibility of the starches being used as filler in capsule formulations. The modified starches generally showed differences in their time and pressure dependent deformation behaviour. PS exhibited higher elasticity during tableting. FD Chinese and FD Bitter showed higher plasticity and low fast elastic deformation than the PS forms of the starches indicating that the FD starches undergo the highest plastic deformation. However, FD starches generally showed higher compactibility compared to the PS forms of the Dioscorea starches. While FD White and FD Water showed fast disintegration time and high compactibility, FD Chinese and FD Bitter were non-disintegrating and showed high compactibility. The high compactibility observed with the FD starches appears to be as a result of material change occurring during tableting probably due to the effect of temperature or pressure or a combination of both factors. Thus, FD White and FD Water starches could be useful when high crushing force and fast disintegration are of concern while FD Chinese and FD Bitter, which were non-disintegrating, could find application as excipients for controlled drug delivery.

Metal-based paullones as putative CDK inhibitors for antitumor chemotherapy.

Paullones constitute a class of potent cyclin-dependent kinase inhibitors. To overcome the insufficient solubility and bioavailability, which hamper their potential medical application, we aim at the development of metal-based derivatives. Two types of paullone ligands, L (1) - L (3) and L (4) , with different locations of metal-binding sites, were prepared. They were found to form organometallic complexes of the general formula [M (II)Cl(eta (6)- p-cymene)L]Cl ( 1- 4, L = L (1) - L (4) ; a, M = Ru; b, M = Os). The complexes were characterized by X-ray crystallography, one- and two-dimensional NMR spectroscopy and other physical methods. Complexes 1- 3, with a coordinated amidine unit, were found to undergo E/ Z isomerization in solution. The reaction was studied by NMR spectroscopy, and activation parameters Delta H (double dagger) and Delta S (double dagger) were determined. Antiproliferative activity in the low micromolar range was observed in vitro in three human cancer cell lines by means of MTT assays. (3)H-Thymidine incorporation assays revealed the compounds to lower the rate of DNA synthesis, and flow cytometric analyses showed cell cycle arrest mainly in G 0/ G 1 phase.

Activating transcription factor 1 and CREB are important for cell survival during early mouse development.

Activating transcription factor 1 (ATF1), CREB, and the cyclic AMP (cAMP) response element modulatory protein (CREM), which constitute a subfamily of the basic leucine zipper transcription factors, activate gene expression by binding as homo- or heterodimers to the cAMP response element in regulatory regions of target genes. To investigate the function of ATF1 in vivo, we inactivated the corresponding gene by homologous recombination. In contrast to CREB-deficient mice, which suffer from perinatal lethality, mice lacking ATF1 do not exhibit any discernible phenotypic abnormalities. Since ATF1 and CREB but not CREM are strongly coexpressed during early mouse development, we generated mice deficient for both CREB and ATF1. ATF1(-/-) CREB(-/-) embryos die before implantation due to developmental arrest. ATF1(+/-) CREB(-/-) embryos display a phenotype of embryonic lethality around embryonic day 9.5 due to massive apoptosis. These results indicate that CREB and ATF1 act in concert to mediate signals essential for maintaining cell viability during early embryonic development.

Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions.

Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR+/-) with a 50% GR gene dose reduction, and (2) mice overexpressing GR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR+/- mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR+/- mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression.

Preparative isolation of isoflavones from soy and red clover.

Numerous studies have demonstrated the potential of isoflavones occurring in soy (Glycine max L.) and red clover (Trifolium pratense L.) to alleviate climacteric complaints. They have also shown beneficial effects on the cardiovascular system and in the prevention of osteoporosis. As a result, several companies offer nutraceuticals based on soy or red clover extracts. The aim of the present study was the isolation of pure isoflavones on a preparative scale, in order to obtain standards for biological tests and for the quantification of isoflavones in nutraceuticals and foods. High-speed countercurrent chromatography, a special type of liquid-liquid partition chromatography, was applied to the preparative isolation of isoflavones. By using this technique the major monoglucosylated and acetylated isoflavones from soy extracts were obtained after a cleaning-up step on Amberlite XAD-7 material. Furthermore, it was possible to isolate isoflavone aglycones as well as glycosides from a red clover extract. Purity and identity of the isolated isoflavones were confirmed by HPLC with DAD, HPLC-ESI multiple-MS, and NMR spectroscopy.

Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting hypoglycemia and ameliorates hyperglycemia in streptozotocin-induced diabetes mellitus.

Hepatic glucose production by gluconeogenesis is the main source of glucose during fasting and contributes significantly to hyperglycemia in diabetes mellitus. Accordingly, glucose metabolism is tightly controlled by a variety of hormones including insulin, epinephrine, glucagon, and glucocorticoids (GCs) acting on various cell types. GC effects are mediated by the GC receptor (GR), a ligand-dependent transcription factor, which in the liver and kidney controls gluconeogenesis by induction of gluconeogenic enzymes. To specifically study the contribution of GC on liver carbohydrate metabolism, we generated mice with an inactivation of the GR gene exclusively in hepatocytes using the Cre/loxP technology. Half of the mutant mice die within the first 2 d after birth most likely due to hypoglycemia. Adult mice have normal blood sugar under basal conditions but show hypoglycemia after prolonged starvation due to reduced expression of genes involved in gluconeogenesis. We further demonstrate that absence of GR in hepatocytes limits the development of hyperglycemia in streptozotocin-induced diabetes mellitus probably due to impaired induction of gluconeogenesis. These findings show the essential role of GR function in liver glucose metabolism during fasting and in diabetic mice and indicate that liver-specific GC antagonists could be beneficial in control of diabetic hyperglycemia.

Analysis of CREM-dependent gene expression during mouse spermatogenesis.

The transcription factors CREM, CREB, and ATF-1 constitute a subfamily of beta-Zip transcription factors. Several different kinase cascades regulate the activity of these proteins. The activator splice-isoform CREMtau is specifically and highly expressed in post-meiotic germ cells during mouse spermatogenesis. Male mice lacking CREMtau expression are sterile because of stage-specific arrest of sperm maturation as the spermatids undergo apoptosis. In order to characterize the genes that are controlled by CREM during post-meiotic differentiation of round spermatids, we compared the expression levels of mRNA prepared from testes of wild-type and CREM-deficient mice by suppression subtractive hybridization (SSH) and affymetrix oligonucleotide arrays. A set of 956 unique sequences found in the CREM SSH library was further characterized by generating stage-specific expression profiles during spermatogenesis by hybridization with cDNA from pre-pubertal mice at defined stages of spermatogenesis using nylon DNA arrays. The resulting expression profiles were arranged in a linear order according to similarity in their profile shapes to find co-regulation of functionally related genes. Our data shows that a large number of genes are transcriptionally activated in round spermatids when CREM activity is maximal, including functional groups like transcription factors, proteins involved in signal transduction, and metabolic enzymes, therefore providing novel information of post-meiotic expression of many known as well as novel genes that are either directly or indirectly influenced by CREM expression.