The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) has an incidence of 1-10 cases per 100,000 births. About 60% of patients with IHH present with associated anosmia, also known as Kallmann syndrome, characterized by total or partial loss of olfaction. Many of the gene mutations associated with Kallmann syndrome have been mapped to KAL1 or FGFR1.

Towards an understanding of the atomic scale magnetic contrast formation in NC-AFM: a tip material dependent MExFM study on NiO(001).

Recently, magnetic exchange force microscopy (MExFM) was established as a new force microscopy based technique capable of imaging arrangements of magnetic moments with atomic resolution on NiO(001). However, before this final achievement many unsuccessful experiments were performed on this particular sample system, and it is still not entirely clear which factors are important to attain an atomic scale magnetic contrast. Varying the tip's magnetic properties, we investigate the contrast formation on NiO(001).

Structural imaging of beta-Si3N4 by spherical aberration-corrected high-resolution transmission electron microscopy.

Modern transmission electron microscopes (TEM) allow utilizing the spherical aberration coefficient as an additional free parameter for optimizing resolution and contrast. By tuning the spherical aberration coefficient of the objective lens, isolated nitrogen atom columns as well as the Si-N dumbbells within the six-membered ring were imaged in beta-Si3N4 along [0001] and [0001 ] projections with a dumbbell spacing of 0.94 A in white atom contrast.

The biology of gonadotroph regulation.

Purpose Of Review: To discuss recent progress in our understanding of pituitary gonadotroph development and gonadotropin gene regulation, with an emphasis on differential luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion and subunit synthesis, and the implications this may have on female reproductive health.

Recent Findings: In the mature gonadotroph, there is an emerging concept that differential synthesis of gonadotropin beta-subunit genes, essential for cyclic reproductive function, is associated with modification of activation and/or stability of important regulatory proteins and transcription factors. Recent studies suggest that cellular events, which affect histone modification, play an essential role in both gonadotroph development and the ontogeny of gonadotropin subunit gene expression.

Selective sputtering and atomic resolution imaging of atomically thin boron nitride membranes.

We report on the preparation, atomic resolution imaging, and element selective damage mechanism in atomically thin boron nitride membranes. Flakes of less than 10 layers are prepared by mechanical cleavage and are thinned down to single layers in a high-energy electron beam. At our beam energies, we observe a highly selective sputtering of only one of the elements and predominantly at the exit surface of the specimen, and then subsequent removal of atoms next to a defect.

Exterior surface damage of calcium fluoride outcoupling mirrors for DUV lasers.

Damage of optical components due to laser irradiation reduces reliability and limits durability. Calcium fluoride (CaF(2)) is commonly used for deep UV laser optics because it shows a very low tendency of color center formation as, compared to other UV-X optical materials. Here, we report on the exterior damage of CaF(2) UV-X optics due to radiation with high pulse-energy densities (80 mJ/cm(2)) from an ArF laser.

Expression of a gonadotropin-releasing hormone receptor-simian virus 40 T-antigen transgene has sex-specific effects on the reproductive axis.

The GnRH receptor (GnRHR) responds to pulsatile GnRH signals to coordinate pituitary gonadotropin synthesis and secretion. Previously, a 1.2-kb fragment of the 5'-flanking region isolated from the mouse GnRHR gene was shown to target expression to pituitary gonadotropes in vivo.

3D imaging of nanomaterials by discrete tomography.

The field of discrete tomography focuses on the reconstruction of samples that consist of only a few different materials. Ideally, a three-dimensional (3D) reconstruction of such a sample should contain only one grey level for each of the compositions in the sample. By exploiting this property in the reconstruction algorithm, either the quality of the reconstruction can be improved significantly, or the number of required projection images can be reduced.

Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with adeno- or undifferentiated carcinoma of unknown primary: a randomised prospective phase II trial.

Platinum/taxane combinations are widely used in patients with carcinoma of unknown primary (CUP), yielding response rates of 30% and median overall survival of 9-11 months in selected patients. Yet these combinations have not been subject to a randomised trial to overcome selection bias, a major problem in CUP. We randomised 92 patients to either paclitaxel/carboplatin (arm A) or the non-platinum non-taxane regimen gemcitabine/vinorelbine (arm B).

A composite element that binds basic helix loop helix and basic leucine zipper transcription factors is important for gonadotropin-releasing hormone regulation of the follicle-stimulating hormone beta gene.

Although FSH plays an essential role in controlling gametogenesis, the biology of FSHbeta transcription remains poorly understood, but is known to involve the complex interplay of multiple endocrine factors including GnRH. We have identified a GnRH-responsive element within the rat FSHbeta promoter containing an E-box and partial cAMP response element site that are bound by the basic helix loop helix transcription factor family members, upstream stimulating factor (USF)-1/USF-2, and the basic leucine zipper member, cAMP response element-binding protein (CREB), respectively. Expression studies with CREB, USF-1/USF-2, and activating protein-1 demonstrated that the USF transcription factors increased basal transcription, an effect not observed if the cognate binding site was mutated.

Heat- and electron-beam-induced transport of gold particles into silicon oxide and silicon studied by in situ high-resolution transmission electron microscopy.

In this study, we describe the transport of gold (Au) nanoparticles from the surface into crystalline silicon (Si) covered by silicon oxide (SiO(2)) as revealed by in situ high-resolution transmission electron microscopy. Complete crystalline Au nanoparticles sink through the SiO(2) layer into the Si substrate when high-dose electron irradiation is applied and temperature is raised above 150 degrees C. Above temperatures of 250 degrees C, the Au nanoparticles finally dissolve into fragments accompanied by crystallization of the amorphized Si substrate around these fragments.

The gonadotropin-releasing hormone (GnRH) neuronal population is normal in size and distribution in GnRH-deficient and GnRH receptor-mutant hypogonadal mice.

Hypothalamic GnRH neurons are essential for initiation and regulation of reproductive function. In addition to pituitary gonadotrope stimulation, activity of GnRH through its receptor (GnRHR) has been suggested to include autocrine regulation of the GnRH neuron. Two hypogonadal mouse strains, the Gnrh1 mutant (hpg) mice and Gnrhr mutant mice were used to investigate the potential role of GnRH signaling in the proper development and maintenance of GnRH neurons.

Atomic layer deposition process with TiF4 as a precursor for depositing metal fluoride thin films.

A novel atomic layer deposition process for the preparation of fluoride thin films in a temperature range of 225 degrees C-400 degrees C is introduced. The crystallinity, morphology, composition, thicknesses, refractive indices, and transmittance of the films are analyzed. Low impurity levels are obtained at 350 degrees C-400 degrees C with good stoichiometry.

Optical and structural properties of LaF3 thin films.

LaF(3) thin films of different thicknesses were deposited on CaF(2) (111) and silicon substrates at a relatively low substrate temperature of 150 degrees C. Optical (transmittance, reflectance, refractive index, and extinction coefficient) and mechanical (morphology and crystalline structure) properties have been investigated and are discussed. It is shown that LaF(3) thin films deposited on CaF(2) (111) substrates are monocrystalline and have a bulklike dense structure.

A GPR54-activating mutation in a patient with central precocious puberty.

Gonadotropin-dependent, or central, precocious puberty is caused by early maturation of the hypothalamic-pituitary-gonadal axis. In girls, this condition is most often idiopathic. Recently, a G protein-coupled receptor, GPR54, and its ligand, kisspeptin, were described as an excitatory neuroregulator system for the secretion of gonadotropin-releasing hormone (GnRH).

Pubertal impairment in Nhlh2 null mice is associated with hypothalamic and pituitary deficiencies.

Pubertal development is impaired in mice lacking the basic helix-loop-helix transcription factor Nhlh2. The mechanisms underlying changes in reproduction in Nhlh2-deficient mice (Nhlh2(-/-)) are unclear. Here we show that hypothalamic GnRH-1 content is reduced in adult Nhlh2(-/-) mice as is the number of GnRH-1 neurons localized to mid- and caudal hypothalamic regions.

Mutations in the human gonadotropin-releasing hormone receptor: insights into receptor biology and function.

Pulsatile hypothalamic release of GnRH tightly controls reproduction by activating a specific cell membrane receptor (GnRHR) on the surface of pituitary gonadotrophs to stimulate luteinizing hormone and follicle-stimulating hormone secretion. During the last 10 years, 21 loss-of-function GNRHR mutations have been identified in patients with idiopathic hypogonadotropic hypogonadism. Although most patients with hypogonadotropic hypogonadism can be treated by delivery of exogenous pulsatile GnRH, in several cases, patients with GNRHR mutations fail to respond efficiently to GnRH treatment.

Improvement in reproductive parameters in hypogonadal female mice by regulated gene replacement therapy in the central nervous system.

One of the challenges of gene targeting is to achieve regulated transgene expression in specific target cells. The hypogonadal (hpg) mice are genetically deficient in hypothalamic gonadotropin-releasing hormone (GnRH) production due to a deletion in the GnRH gene, resulting in hypogonadotropic hypogonadism. Here we show an improvement in reproductive parameters of adult female homozygous hpg mice by direct infusion into the hypothalamic preoptic area (POA) of a herpes simplex virus (HSV)-based amplicon vector containing a 13.

Expression of chemokine receptors in insulin-resistant human skeletal muscle cells.

Adipokines including chemokines are able to induce insulin resistance in human skeletal muscle cells, which may also be relevant for the observed link between obesity and diabetes. This study is aimed to analyze the expression of chemokine CC motif receptors (CCRs) in the insulin-resistant state in human skeletal muscle cells. Differentiated skeletal muscle cells were incubated for 24-72 hours with high concentrations of glucose and insulin (GI) or TNFalpha.

High-dose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma - results of a comprehensive meta-analysis.

Background: Randomized controlled trials (RCTs) reported conflicting results on the impact of high-dose chemotherapy (HDCT) and autologous stem cell transplantation in the first-line treatment of patients with aggressive non-Hodgkin lymphoma (NHL).

Methods: We performed a systematic meta-analysis to assess the efficacy HDCT compared to conventional chemotherapy in aggressive NHL patients with regard to complete response (CR), overall survival (OS), event-free survival (EFS), toxicity, and impact of the age-adjusted International Prognostic Index (aaIPI) risk factors. We searched the Cochrane Library, MEDLINE and other databases (1/1990 to 1/2005).

Magnetic exchange force microscopy with atomic resolution.

The ordering of neighbouring atomic magnetic moments (spins) leads to important collective phenomena such as ferromagnetism and antiferromagnetism. A full understanding of magnetism on the nanometre scale therefore calls for information on the arrangement of spins in real space and with atomic resolution. Spin-polarized scanning tunnelling microscopy accomplishes this but can probe only conducting materials.

GPR54 and KiSS-1: role in the regulation of puberty and reproduction.

The finding of inactivating mutations in GPR54 in IHH patients and the lack of reproductive maturation of the GPR54 null mouse have uncovered a previously unrecognized role for GPR54 and KiSS-1 in the physiologic regulation of puberty and reproduction. This newly identified function for GPR54 and its cognate ligand, kisspeptin, has led to additional studies that have localized GPR54 and KiSS-1 mRNA in the hypothalamus, colocalized GPR54 in GnRH neurons, demonstrated GnRH-dependent activation of LH and FSH release by kisspeptin, and shown increased hypothalamic KiSS-1 and GPR54 mRNA levels at the time of puberty. Taken together, these findings establish the role of the kisspeptin-GPR54 system in the stimulation of GnRH neurons during puberty.

Incidence and risk factors of central nervous system recurrence in aggressive lymphoma--a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL).

Background: Central nervous system (CNS) relapse is a devastating and usually fatal complication of aggressive lymphoma. The extent of the disease, the proliferation rate and the sites of extranodal involvement have been discussed as risk factors. We analyzed the patients treated on protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL) between 1990 and 2000, evaluated the rate and prognostic factors for CNS recurrence and developed a risk model trying to identify subsets of patients suitable for future prophylactic strategies.

Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: potential impact on reduced GnRH neuron population in CaR-null mice.

The factors controlling the migration of mammalian gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus are not well understood. We studied whether the extracellular calcium-sensing receptor (CaR) promotes migration/chemotaxis of GnRH neurons. We demonstrated expression of CaR in GnRH neurons in the murine basal forebrain and in two GnRH neuronal cell lines: GT1-7 (hypothalamus derived) and GN11 (olfactory bulb derived).