Damped Perturbations in the No-Boundary State.

We evaluate the no-boundary path integral exactly in a Bianchi type IX minisuperspace with two scale factors. In this model the no-boundary proposal can be implemented by requiring one scale factor to be zero initially together with a judiciously chosen regularity condition on the momentum conjugate to the second scale factor. Taking into account the nonlinear backreaction of the perturbations we recover the predictions of the original semiclassical no-boundary proposal. In particular we find that large perturbations are strongly damped, consistent with vacuum state wave functions.

On the possibility of using X-ray Compton scattering to study magnetoelectrical properties of crystals.

This paper discusses the possibility of using Compton scattering--an inelastic X-ray scattering process that yields a projection of the electron momentum density--to probe magnetoelectrical properties. It is shown that an antisymmetric component of the momentum density is a unique fingerprint of such time- and parity-odd physics. It is argued that polar ferromagnets are ideal candidates to demonstrate this phenomenon and the first experimental results are shown, on a single-domain crystal of GaFeO3. The measured antisymmetric Compton profile is very small (≃ 10(-5) of the symmetric part) and of the same order of magnitude as the statistical errors. Relativistic first-principles simulations of the antisymmetric Compton profile are presented and it is shown that, while the effect is indeed predicted by theory, and scales with the size of the valence spin-orbit interaction, its magnitude is significantly overestimated. The paper outlines some important constraints on the properties of the antisymmetric Compton profile arising from the underlying crystallographic symmetry of the sample.

Lysosome-Related Effector Vesicles in T Lymphocytes and NK Cells.

Lysosome-related secretory organelles combine metabolic functions of conventional lysosomes with an inducible secretory potential. Specialized variants of such bi-functional organelles are present in several haematopoietic cell types that store, mobilize and/or secrete effector proteins, for example in mast cells, macrophages or cytotoxic effector cells. In the case of T lymphocytes and NK cells, it was believed that secretory lysosomes serve as a common storage and transport compartment for the most relevant cytotoxic effector proteins including FasL, perforin, granzymes and granulysin. However, recent observations suggest that cytotoxic effector cells might be able to mobilize two distinct lysosomal entities in order to react to differential stimulation with either FasL surface appearance or degranulation-associated release of perforin and granzymes. This assumption is supported by the proteomic characterization of enriched organelles from T and NK cells. FasL-associated light lysosomes biochemically segregate from morphologically distinct heavy lysosomes that preferentially contain granzymes, perforin and mature granulysin. Here, we briefly summarize the current knowledge about cargo proteins that are stored and transported in secretory vesicles and how these vesicles might be generated and mobilized. In addition, we describe common features and major differences of the two distinct effector organelles and discuss how these observations might expand existing models of cytotoxic effector function.

Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications.

The activating natural killer group 2 member D (NKG2D) receptor is expressed on NK cells, cytotoxic T cells and additional T cell subsets. Ligands for human NKG2D comprise two groups of MHC class I-related molecules, the MHC class I chain-related proteins A and B (MICA/B) and 6 UL16-binding proteins (ULBP1-6). While NKG2D ligands are absent from most normal cells, expression is induced upon stress and malignant transformation. In fact, most solid tumours and leukaemia/lymphomas constitutively express at least one NKG2D ligand and thereby are susceptible to NKG2D-dependent immunosurveillance. However, soluble NKG2D ligands are released from tumour cells and can down-modulate NKG2D activation as a means of tumour immune escape. In some tumour entities, levels of soluble NKG2D ligands in the serum correlate with tumour progression. NKG2D ligands can be proteolytically shed from the cell surface or liberated from the membrane by phospholipase C in the case of glycosylphosphatidylinositol (GPI)-anchored molecules. Moreover, NKG2D ligands can be secreted in exosomal microvesicles together with other tumour-derived molecules. Depending on the specific tumour/immune cell setting, these various forms of soluble and/or exosome-bound NKG2D ligands can exert multiple effects on NKG2D/NKG2D ligand interactions. In this review, we focus on the role of various proteases in the shedding of human NKG2D ligands from tumour cells and discuss the not completely unanimous reported functional implications of soluble and exosome-secreted NKG2D ligands for immunosurveillance.

[Acne tarda. Acne in adults]. / Acne tarda. Akne im Erwachsenenalter.

Acne is one of the most common skin diseases in the general population, especially among adolescents. Acne tarda (adult acne) is defined as acne that develops (late-onset acne) or continues (persistent acne) after 25 years of age. The disease is more common in women. The clinical features are quite specific: inflammatory acne in the lower facial region or macrocomedones (microcysts) spread over the face. Involvement of the trunk is much more common in men. The etiology of acne tarda is still controversial, as cosmetics, drugs, smoking, stress, diet, and endocrine abnormalities have been implicated. Women with acne tarda and other symptoms of hyperandrogenism have a high probability of endocrine abnormalities such as polycystic ovary syndrome. Treatment is similar to that of acne in adolescence. Long-term treatment over years or decades may be required.

Near-field resonance at far-field-induced transparency in diffractive arrays of plasmonic nanorods.

We numerically demonstrate that a periodic array of metallic nanorods sustains a maximum near-field enhancement and a far field (FF)-induced transparency at the same energy and in-plane momentum. The coupling of bright and dark plasmonic lattice resonances, and electromagnetic retardation along the nanorod length, are responsible for this effect. A standing wave with a quadrupolar field distribution is formed, giving rise to a collective suppression of FF scattering and simultaneously enhanced local fields.

[Atypical presentation of subacute thyroiditis]. / Atypische Präsentation einer Thyreoiditis de Quervain.

HISTORY AND ADMISSION FINDINGS: A 41-year-old woman had been treated with an antibiotic for a sore throat and a tender neck. Later, moderate hyperthyroidism developed and was treated with antithyroid drugs. She presented herself for further work-up when neck pain and malaise persisted. On palpation, the thyroid was tender and firm, but not enlarged. Signs and symptoms indicated moderate hyperthyroidism. INVESTIGATIONS: Laboratory findings included suppressed TSH, elevated thyroid hormones, and both elevated erythrocyte sedimentation rate and CRP. On ultrasound, the thyroid was found to be of normal size but severely hypoechoic. A thyroid scan showed low uptake of technetium. TREATMENT AND COURSE: The findings supported the diagnosis of subacute thyroiditis. Prednisolone treatment provided relief of pain within 2 days. The patient later developed hypothyroidism suggestive of Hashimoto's thyroiditis and required thyroxin supplementation.

Functional expression of NOD2 in freshly isolated human peripheral blood γδ T cells.

γδ T cells play an important role in anti-infective immunity. The major subset of human γδ T cells selectively recognizes phosphorylated bacterial metabolites of the isoprenoid biosynthesis pathway, so-called phosphoantigens. The activation of γδ T cells is modulated by functionally expressed innate immune receptors, notably Toll-like receptor 2 and 3. It was also reported that in vitro expanded γδ T cells respond to muramyl dipeptide (MDP), the minimal peptidoglycan motif activating the nucleotide-binding oligomerization domain containing 2 (NOD2) receptor, although it is unknown whether ex vivo isolated human γδ T cells express functional NOD2. Here, we report that freshly isolated, highly purified peripheral blood γδ T cells express NOD2 mRNA and detectable amounts of NOD2 protein. The biologically active MDP L-D isomer but not the inactive D-D isomer augmented the interferon-γ (IFN-γ) secretion in phosphoantigen-stimulated peripheral blood mononuclear cells. Moreover, a moderate but reproducible and statistically significant increase in IFN-γ secretion was also observed when highly purified peripheral blood γδ T cells were activated by T cell receptor cross-linking in the presence of MDP. Taken together, our results indicate that in addition to the T cell receptor and Toll-like receptors, circulating human γδ T cells express NOD2 as a third class of pattern recognition receptor for sensing bacterial products.

Modulation of CD4+ T-cell activation by CD95 co-stimulation.

CD95 is a dual-function receptor that exerts pro- or antiapoptotic effects depending on the cellular context, the state of activation, the signal threshold and the mode of ligation. In this study, we report that CD95 engagement modulates TCR/CD3-driven signaling pathways in resting T lymphocytes in a dose-dependent manner. While high doses of immobilized CD95 agonists silence T cells, lower concentrations augment activation and proliferation. We analyzed the co-stimulatory capacity of CD95 in detail in resting human CD4(+) T cells, and demonstrate that low-dose ligand-induced co-internalization of CD95 and TCR/CD3 complexes enables non-apoptotic caspase activation, the prolonged activation of MAP kinases, the upregulation of antiapoptotic proteins associated with apoptosis resistance, and the activation of transcription factors and cell-cycle regulators for the induction of proliferation and cytokine production. We propose that the levels of CD95L on antigen-presenting cells (APCs), neighboring T cells or epithelial cells regulate inhibitory or co-stimulatory CD95 signaling, which in turn is crucial for fine-tuning of primary T-cell activation.

Stanniocalcin 1 induction by thyroid hormone depends on thyroid hormone receptor ß and phosphatidylinositol 3-kinase activation.

CONTEXT: Thyroid hormone (TH) mediated changes in gene expression were thought to be primarily initiated by the nuclear TH receptor (TR) binding to a thyroid hormone response element in the promoter of target genes. A recently described extranuclear mechanism of TH action consists of the association of TH-liganded TRß with phosphatidylinositol 3-kinase (PI3K) in the cytosol and subsequent activation of the PI3K pathway. OBJECTIVE: The aim of this study was to examine the effect of TH, TRß and PI3K on stanniocalcin 1 (STC1) expression in human cells. DESIGN: We treated human skin fibroblasts with triiodothyronine (T3) in the absence or presence of the PI3K inhibitor LY294002, a dominant negative PI3K subunit, Δp85α, and the protein synthesis inhibitor cycloheximide (CHX). The role of the TRß was studied in cells from patients with resistance to thyroid hormone (RTH). STC-1 mRNA expression was measured by real-time PCR. RESULTS: We found an induction of STC1 by T3 in normal cells, but less in cells from subjects with RTH (2.7 ± 0.2 vs. 1.6 ± 0.04, P < 0.01). The effect of T3 was completely abrogated by blocking PI3K with LY294002 (3.9 ± 0.5 vs. 0.85 ± 0.5; P < 0.05) and greatly reduced after transfection of a dominant negative PI3K subunit, demonstrating dependency on the PI3K pathway. CONCLUSION: These results establish STC1 as a TH target gene in humans. Furthermore, we show that STC1 induction by TH depends on both TRß and PI3K activation.

Efficient optimization method for the light extraction from periodically modulated LEDs using reciprocity.

The incoherent emission of periodically structured Light Emitting Diodes (LEDs) can be computed at relatively low computational cost by applying the reciprocity method. We show that by another application of the reciprocity principle, the structure of the LED can be optimized to obtain a high emission. We demonstrate the method by optimizing one-dimensional grating structures. The optimized structures have twice the extraction efficiency of an optimized flat structure.

[Combined analyses of paraoxonase-1 and IGF-2 polymorphism in polycystic ovary syndrome]. / Kombinierte Analyse von Paraoxonase-1- und IGF-2-Polymorphismen bei polyzystischem Ovarsyndrom.

BACKGROUND: Apart from impaired reproductive function patients with polycystic ovary syndrome (PCOS) also have signs and symptoms belonging to the metabolic syndrome. A genetic basis for PCOS is likely as the syndrome clusters in families. Putative candidate genes are paraoxonase (PON)-1 gene and the IGF-2 INS1/VTR IGF cluster, which have been shown to be genetically linked to lipid metabolism o insulin sensitivity, two major aspects of the PCOS phenotype. PATIENTS AND METHODS: The ApaI polymorphism (rs:680) in the IGF-2 cluster and the -108 polymorphism (rs:705 379) in PON-1 were evaluated in a collective of 153 PCOS patients and 178 age and BMI matched controls for an association to PCOS. RESULTS: The polymorphism in the IGF-2 cluster was identified in both groups in comparable frequencies (PCOS/control: A: 0.351/0.325; G: 0.648/0.674; OR: 0.8886, 95 %CI 0,648-1.2236) and equal genotype distribution (PCOS/control: GG: 0.399/0.461; AG: 0.4962/0.4277; AA: 0.1042/0.111). Frequencies of the PON-1 polymorphism were also comparable (PCOS/control: T: 0.493/0.483; C: 0.5633/0.5168; OR: 0.9569 95 % CI: 0.707-1.43024), but the distribution (PCOS/control: CC: 0.2679/0.2032; CT: 0.4768/0.628; TT: 0.258/0.169) was significantly different. The combined analyses of both polymorphism revealed that the genotypes IGF-2 (GG)/ PON-1 (TT) with OR 1.64741 (95 % CI 0.7388 - 3.6735) and IGF-2 (AA)/ PON-1 (TT) with OR 2.6733 (95 % CI 0.7579 - 9.4291) were more frequent in the PCOS group, whereas the genotype IGF-2 (AA)/ PON-1 (CC) did not occur in the PCOS group at all. According to the molecular analyses significant differences in serum parameters were identified. CONCLUSION: This investigation indicates, that only the combined analyses of putative candidate genes allowed a genotype-phenotype correlation in PCOS.

Vectorial aerial-image computations of three-dimensional objects based on the extended Nijboer-Zernike theory.

We present details of a novel imaging algorithm based on the extended Nijboer-Zernike (ENZ) theory of diffraction. We derive integral expressions relating the electric field distribution in the entrance pupil of an optical system to the electric field in its focal region. The evaluation of these integrals is made possible by means of a highly accurate and efficient series expansion similar to those occurring in standard ENZ theory. Based on these results an ENZ imaging scheme is constructed and evaluated in detail with attention to the convergence properties and computational complexity of the new method.

Prevalence and implications of anxiety in polycystic ovary syndrome: results of an internet-based survey in Germany.

BACKGROUND: Comparatively little attention has been paid to the symptoms of anxiety in polycystic ovary syndrome (PCOS), although anxiety disorders constitute the most common psychiatric diagnoses among endocrine patients and in the general population. Therefore, our goal was to address the prevalence, determinants and implications of anxiety alone or anxiety in combination with depression in German women with PCOS. METHODS: In this nation-wide, internet-based survey, anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and quality of life (SF-12) were assessed together with sociodemographic information and clinical PCOS symptoms in 448 PCOS women. RESULTS: Of the patients, 34% showed clinically relevant HADS anxiety scores and 21% had clinically relevant HADS depression scores. Quality of life was significantly impaired in PCOS women with anxiety (P < 0.001), in particular, in women with comorbid anxiety and depression (P < 0.001). The risk for clinically relevant HADS anxiety scores was significantly enhanced in PCOS women with acne (odds ratio (OR) = 1.52; 95% confidence interval (CI) = 1.03-2.52) and an unfulfilled wish to conceive (OR = 1.50; 95% CI = 1.01-2.23). CONCLUSIONS: PCOS women may be at an increased risk for clinically relevant anxiety, and comorbid anxiety and depression is also very common. Anxiety contributes to impaired quality of life in PCOS. Given the high prevalence and the serious implications, and the availability of effective treatment options given proper diagnosis, clinicians should be more aware of anxiety disorders in women with PCOS.

FasL expression and reverse signalling.

FasL plays a central role in the induction of apoptosis within the immune system. It mediates activation-induced cell death (AICD) of T lymphocytes and contributes to the cytotoxic effector function of T and NK cells. Moreover, FasL is discussed as direct effector molecule for the establishment of immune privilege and tumour survival. Besides its death-promoting activity, FasL has been implicated in reverse signalling and might thus also play a role in T cell development and selection and the modulation of T cell activation. Considering these diverse functions, the overall FasL expression has to be tightly controlled to avoid unwanted damage. Based on an activation-associated transcriptional control, several post-transcriptional processes ensure a safe storage, a rapid mobilisation, a target-directed activity and a subsequent inactivation. Over the past years, the identification and characterisation of FasL-interacting proteins provided novel insight into the mechanisms of FasL transport, processing and reverse signalling, which might be exemplary also for the other members of the TNF family.

Disturbed stress responses in women with polycystic ovary syndrome.

BACKGROUND: We analyzed the neuroendocrine and immune cell responses to psychosocial stress in PCOS patients compared to BMI-matched healthy controls. METHODS: Responses to public speaking stress were analyzed in 32 PCOS patients and 32 BMI-matched healthy controls. At baseline, during, and 10- and 45-min after stress, state anxiety, cardiovascular responses, cortisol, ACTH, as well as circulating leukocyte subpopulations were analyzed, together with hsCRP and serum IL-6 concentrations. RESULTS: In response to public speaking stress, both groups showed significant but comparable increases in state anxiety, and blood pressure (all p<0.001; time effects). The ACTH and cortisol stress responses were significantly enhanced in PCOS (both p<0.05; interaction effect). In addition, heart rate was significantly higher in PCOS (p<0.05; group effect). PCOS patients displayed a reduced upregulation of IL-6 levels in response to stress (p<0.05; interaction effect). Baseline levels of circulating leukocyte subpopulations, IL-6 and hsCRP concentrations did not differ between BMI-matched controls and PCOS patients. PCOS patients were characterized by markedly increased psychological distress. CONCLUSIONS: PCOS patients showed enhanced HPA-axis and heart rate reactivity as well as a reduced upregulation of IL-6 in response to stress. The altered stress reactivity in PCOS patients may constitute a link between depression, overweight, and the cardiovascular and diabetes risks associated with the diagnosis.

Effects of obesity on neuroendocrine, cardiovascular, and immune cell responses to acute psychosocial stress in premenopausal women.

OBJECTIVE: To analyze the neuroendocrine and immune cell responses to acute psychosocial stress in obese compared to non-obese premenopausal women. METHODS: N=15 obese (BMI> or =30) and N=24 (BMI<30) non-obese premenopausal women underwent public speaking stress. State anxiety, ACTH, cortisol, and the redistribution of immune cells were measured before, during, and 10 and 45min after public speaking. Serum hsCRP and serum IL-6 levels were analyzed before, and IL-6 additionally 45min after stress. RESULTS: In response to public speaking stress, both groups showed significant but comparable increases in state anxiety, plasma ACTH, and blood pressure (all p<0.01; time effects). The cortisol stress response was significantly enhanced in obese women (p<0.05; interaction effect). In addition, heart rate and diastolic blood pressure were significantly higher in obese women 10min following stress (p<0.05, t-tests). Public speaking stress led to a significant increase in IL-6 concentrations (p<0.001; time effect), and obese women displayed higher IL-6 levels both pre- and post-stress (p<0.05; group effect; between-group t-tests: pre-stress p<0.05; post-stress p<0.01). Baseline numbers of circulating leukocytes, granulocytes, CD3+ cells and hsCRP concentration were significantly higher in obese women (between-group t-tests: all p<0.05, but the groups did not differ in the stress-induced redistribution of circulating leukocyte subpopulations. CONCLUSIONS: Our data reveal a strong association of obesity with chronic low-grade inflammation in premenopausal women. This pro-inflammatory state, together with altered neuroendocrine and cardiovascular stress responsiveness, may conceivably constitute one of the mechanisms linking psychological stress and the long-term health risks associated with obesity.

Increased low grade inflammatory serum markers in patients with Polycystic ovary syndrome (PCOS) and their relationship to PPARgamma gene variants.

The Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in premenopausal women and is associated with features of the insulin resistance syndrome, altered glucose homeostasis, and central obesity. Inflammation appears to be a link between obesity and insulin resistance, because adipose tissue is one major source of proinflammatory cytokines. Since peroxisome proliferator-activated receptor (PPAR)gamma affects adipocyte differentiation as well as insulin sensitivity, we investigated whether the levels of proinflammatory factors in PCOS patients are related to sequence variations of the PPAR gamma gene. Proinflammatory cytokine levels, i.e. IL-1 beta, IL-6, IL-7, IL-8, IL-17 and TNFalpha, were evaluated in PCOS patients (n=21) in comparison to obese controls (n=120). Next to this the complete coding sequence of the PPAR gamma gene was investigated by resequencing all probands. We show that the levels of IL-8 and IL-17 were unchanged, IL-1 beta, IL-6 and TNFalpha were elevated and the level of IL-7 was decreased in PCOS patients compared to obese controls. Sequence analyses of the PPAR gamma gene indicated that neither the common polymorphisms P12A or H478 H, nor novel polymorphisms (E79Q, V32G, -39 T>C, c.480 +33 t > g,) or unique sequence variations (S22S, A23A, T41A, S226C, K272 T, I484I, c.819 +24 a>c) detected in this investigation revealed evidence for a direct association of PPAR gamma with altered IL-7, IL-1beta, IL-6 and TNFalpha levels in PCOS patients. So, alterations in inflammatory serum markers appear to be a feature of PCOS per se, and are independent of PPAR gamma variants.