Disrupted relationship between blood glucose and brain dopamine D2/3 receptor binding in patients with first-episode schizophrenia.

An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behavior, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signaling in drug-naïve patients with first-episode psychosis. We quantified blood glucose levels and binding of the dopamine D2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naïve patients and 27 healthy volunteers employing positron emission tomography. Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[11C]-PHNO binding-potential values. We observed positive relationships between blood glucose levels and binding-potential values in healthy volunteers but negative ones in patients with first episode psychosis in a cluster surviving rigorous multiple testing correction located in the in the right ventral tegmental area. Another cluster of homologous behavior, however at a lower level of statistical significance, comprised the ventral striatum and pallidum. Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signaling occurs when goal-directed behavior is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are high when blood glucose levels are low and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting an underlying pathogenic alteration that links two seemingly unrelated aspects of the illness: altered dopamine signaling and dysfunctional glucose homeostasis.

An electrochemical cell for 2-dimensional surface optical reflectance during anodization and cyclic voltammetry.

We have developed an electrochemical cell for in situ 2-Dimensional Surface Optical Reflectance (2D-SOR) studies during anodization and cyclic voltammetry. The 2D-SOR signal was recorded from electrodes made of polycrystalline Al, Au(111), and Pt(100) single crystals. The changes can be followed at a video rate acquisition frequency of 200 Hz and demonstrate a strong contrast between oxidizing and reducing conditions. Good correlation between the 2D-SOR signal and the anodization conditions or the cyclic voltammetry current is also observed. The power of this approach is discussed, with a focus on applications in various fields of electrochemistry. The combination of 2D-SOR with other techniques, as well as its spatial resolution and sensitivity, has also been discussed.

Combining high-energy X-ray diffraction with Surface Optical Reflectance and Planar Laser Induced Fluorescence for operando catalyst surface characterization.

We have combined three techniques, High Energy Surface X-Ray Diffraction (HESXRD), Surface Optical Reflectance, and Planar Laser Induced Fluorescence in an operando study of CO oxidation over a Pd(100) catalyst. We show that these techniques provide useful new insights such as the ability to verify that the finite region being probed by techniques such as HESXRD is representative of the sample surface as a whole. The combination is also suitable to determine when changes in gas composition or surface structure and/or morphology occur and to subsequently correlate them with high temporal resolution. In the study, we confirm previous results which show that the Pd(100) surface reaches high activity before an oxide can be detected. Furthermore, we show that the single crystal catalyst surface does not behave homogeneously, which we attribute to the surface being exposed to inhomogeneous gas conditions in mass transfer limited scenarios.

68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making.

OBJECTIVE: To evaluate the diagnostic performance of [68Ga]Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA-PET) in the early detection of metastases in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) for clinically non-metastatic prostate cancer, to compare it to CT/MRI alone and to assess its impact on further therapeutic decisions. MATERIAL AND METHODS: We retrospectively assessed 117 consecutive hormone-naïve BCR patients who had 68Ga-PSMA 11 PET/CT (n = 46) or PET/MRI (n = 71) between May 2014 and January 2017. BCR was defined as two PSA rises above 0.2 ng/ml. Two dedicated uro-oncological imaging experts (radiology/nuclear medicine) reviewed separately all images. All results were presented in a blinded sequential fashion to a multidisciplinary tumorboard in order to assess the influence of PSMA-PET imaging on decision-making. RESULTS: The median time from RP to BCR was 36 months (IQR 16-72). Overall, 69 (59%) patients received postoperative radiotherapy. Median PSA level at the time of imaging was 1.04 ng/ml (IQR 0.58-1.87). PSMA-positive lesions were detected in 100 (85.5%) patients. Detection rates were 65% for a PSA value of 0.2 to <0.5 ng/ml, 85.7% for 0.5 to <1, 85.7% for 1 to <2 and 100% for ≥2. PSMA-positive lesions could be confirmed by either histology (16%), PSA decrease in metastasis-directed radiotherapy (45%) or additional information in diffusion-weighted imaging when PET/MRI was performed (18%) in 79% of patients. PSMA-PET detected lesions in 67 patients (57.3%) who had no suspicious correlates according to the RECIST 1.1 criteria on MRI or CT. PSMA-PET changed therapeutic decisions in 74.6% of these 67 patients (p < 0.001), with 86% of them being considered for metastases-directed therapies. CONCLUSIONS: We confirm the high performance of PSMA-PET imaging for the detection of disease recurrence sites in patients with BCR after RP, even at relatively low PSA levels. Moreover, it adds significant information to standard CT/MRI, changing treatment strategies in a significant number of patients.

[Polypoid basal cell carcinoma]. / Polypoides basalzellkarzinom.

The basal cell carcinoma is a malignant tumor which originates from the epidermal stem cells. The polypoid basal cell carcinoma is an uncommon variant. We report on a 70-year-old man with a red nodule on his left breast. Clinical and histopathologic criteria led to the diagnosis of polypoid basal cell carcinoma. This variant is characterized by exophytic, polypoid growth. Histologically, the aggregates of tumor cells are usually limited to the polypoid zone.

[Mycosis fungoides palmaris et plantaris]. / Mycosis fungoides palmaris et plantaris.

Mycosis fungoides (MF) is a low-grade cutaneous T-cell lymphoma characterized by skin-homing CD4- positive helper T cells. Mycosis fungoides palmaris et plantaris is an uncommon variant primarily involving the palms and soles. An 80-year old man presented with hyperkeratotic erythematous palmoplantar changes. Clinical and histopathologic criteria led to the diagnosis mycosis fungoides palmaris et plantaris. Tumor staging using sonography of the abdomen and lymph nodes, chest x-ray and blood examination is recommended, because extracutaneous manifestations may be present.

[Cylindromatosis]. / Zylindromatose.

Cylindromatosis describes a rare autosomal dominantly inherited disease characterized by multiple cylindromas, which are located on the scalp and the neck. We report on an 80-year-old patient with a long history of multiple asymptomatic, skin-colored tumors on head, neck and upper part of the body. Clinical and histopathologic criteria lead to the diagnosis of cylindromatosis. Development of cylindrocarcinoma has been reported, so one must choose on an individual basis between close follow-up and prophylactic excision.

Transcriptional networks regulating neuronal identity in the developing spinal cord.

The spinal cord is composed of anatomically distinct classes of neurons that perform sensory and motor functions. Because of its relative simplicity, the spinal cord has served as an important system for defining molecular mechanisms that contribute to the assembly of circuits in the central nervous system. At early embryonic stages, the neural tube contains multipotential cells whose identity becomes specified by cell-to-cell signaling. This review will focus on the progress made in understanding the transcriptional networks that become activated by these cell-cell interactions, with particular emphasis on the neurons that contribute to locomotor control. Remarkably, many of the transcription factors implicated in neuronal specification in the spinal cord are found to inhibit transcription, which has led to a 'derepression' model for cell fate specification in the developing spinal cord.

Cracking the transcriptional code for cell specification in the neural tube.

The bHLH repressor Olig2 participates in the transcriptional code governing cell fate specification in the ventral spinal cord. By temporally selective interactions with other transcription factors, Olig2 first directs motor neuron fate and later switches to promoting oligodendrocyte production.

Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse.

The development of chemical synapses is regulated by interactions between pre- and postsynaptic cells. At the vertebrate skeletal neuromuscular junction, the organization of an acetylcholine receptor (AChR)-rich postsynaptic apparatus has been well studied. Much evidence suggests that the nerve-derived protein agrin activates muscle-specific kinase (MuSK) to cluster AChRs through the synapse-specific cytoplasmic protein rapsyn. But how postsynaptic differentiation is initiated, or why most synapses are restricted to an 'end-plate band' in the middle of the muscle remains unknown. Here we have used genetic methods to address these issues. We report that the initial steps in postsynaptic differentiation and formation of an end-plate band require MuSK and rapsyn, but are not dependent on agrin or the presence of motor axons. In contrast, the subsequent stages of synaptic growth and maintenance require nerve-derived agrin, and a second nerve-derived signal that disperses ectopic postsynaptic apparatus.

Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling.

Topographic maps are a fundamental feature of sensory representations in nervous systems. The formation of one such map, defined by the connection of ganglion cells in the retina to their targets in the superior colliculus of the midbrain, is thought to depend upon an interaction between complementary gradients of retinal EphA receptors and collicular ephrin-A ligands. We have tested this hypothesis by using gene targeting to elevate EphA receptor expression in a subset of mouse ganglion cells, thereby producing two intermingled ganglion cell populations that express distinct EphA receptor gradients. We find that these two populations form separate maps in the colliculus, which can be predicted as a function of the net EphA receptor level that a given ganglion cell expresses relative to its neighbors.

Genetic and epigenetic mechanisms contribute to motor neuron pathfinding.

Many lines of evidence indicate that genetically distinct subtypes of motor neurons are specified during development, with each type having characteristic properties of axon guidance and cell-body migration. Motor neuron subtypes express unique combinations of LIM-type homeodomain factors that may act as intrinsic genetic regulators of the cytoskeletal events that mediate cell migration, axon navigation or both. Although experimentally displaced motor neurons can pioneer new routes to their targets, in many cases the axons of motor neurons in complete isolation from their normal territories passively follow stereotypical pathways dictated by the environment. To investigate the nonspecific versus genetically controlled regulation of motor connectivity we forced all motor neurons to express ectopically a LIM gene combination appropriate for the subgroup that innervates axial muscles. Here we show that this genetic alteration is sufficient to convert the cell body settling pattern, gene-expression profile and axonal projections of all motor neurons to that of the axial subclass. Nevertheless, elevated occupancy of the axial pathway can override their genetic program, causing some axons to project to alternative targets.

Evidence for multistability in the visual perception of pigeons.

Perceptual multistability refers to cases where perception alternates between two or more interpretations of an unchanging sensory stimulus. In a first experiment we trained eight pigeons to discriminate horizontal and vertical apparent motion stimuli and then presented a multistable display. In five cases their behavior showed alternations similar to human experiments. In a second experiment we varied the aspect ratio of the display in order to support the hypothesis of a percept-driven nature of the switching behavior. The pecking rates and mean phase durations varied as predicted. This is the first evidence of visual multistability in animals confronted with classical ambiguous figures. The data suggest a stochastic mechanism.

Transcriptional mechanisms in the development of motor control.

Considerable progress has been made in understanding how combinatorially expressed transcription factors control the development of neuronal subtypes in the fly and vertebrate central nervous systems. The mode of action of many of these factors has been conserved from invertebrates to vertebrates throughout evolution, such as the formation and regulation of specific transcriptional complexes, the utilization of repressors for maintaining specificity, and the use of phosphorylation as an important means for transiently altering transcriptional activity.

Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice.

In most mammals the pancreas develops from the foregut endoderm as ventral and dorsal buds. These buds fuse and develop into a complex organ composed of endocrine, exocrine and ductal components. This developmental process depends upon an integrated network of transcription factors. Gene targeting experiments have revealed critical roles for Pdx1, Isl1, Pax4, Pax6 and Nkx2-2 (refs 3,4,5,6,7, 8,9,10). The homeobox gene HLXB9 (encoding HB9) is prominently expressed in adult human pancreas, although its role in pancreas development and function is unknown. To facilitate its study, we isolated the mouse HLXB9 orthologue, Hlxb9. During mouse development, the dorsal and ventral pancreatic buds and mature beta-cells in the islets of Langerhans express Hlxb9. In mice homologous for a null mutation of Hlxb9, the dorsal lobe of the pancreas fails to develop. The remnant Hlxb9-/- pancreas has small islets of Langerhans with reduced numbers of insulin-producing beta-cells. Hlxb9-/- beta-cells express low levels of the glucose transporter Glut2 and homeodomain factor Nkx 6-1. Thus, Hlxb9 is key to normal pancreas development and function.

Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9.

Sonic hedgehog (Shh) specifies the identity of both motor neurons (MNs) and interneurons with morphogen-like activity. Here, we present evidence that the homeodomain factor HB9 is critical for distinguishing MN and interneuron identity in the mouse. Presumptive MN progenitors and postmitotic MNs express HB9, whereas interneurons never express this factor. This pattern resembles a composite of the avian homologs MNR2 and HB9. In mice lacking Hb9, the genetic profile of MNs is significantly altered, particularly by upregulation of Chx10, a gene normally restricted to a class of ventral interneurons. This aberrant gene expression is accompanied by topological disorganization of motor columns, loss of the phrenic and abducens nerves, and intercostal nerve pathfinding defects. Thus, MNs actively suppress interneuron genetic programs to establish their identity.

LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons.

The circuits that control movement are comprised of discrete subtypes of motor neurons. How motor neuron subclasses develop and extend axons to their correct targets is still poorly understood. We show that LIM homeodomain factors Lhx3 and Lhx4 are expressed transiently in motor neurons whose axons emerge ventrally from the neural tube (v-MN). Motor neurons develop in embryos deficient in both Lhx3 and Lhx4, but v-MN cells switch their subclass identity to become motor neurons that extend axons dorsally from the neural tube (d-MN). Conversely, the misexpression of Lhx3 in dorsal-exiting motor neurons is sufficient to reorient their axonal projections ventrally. Thus, Lhx3 and Lhx4 act in a binary fashion during a brief period in development to specify the trajectory of motor axons from the neural tube.

Formation of Rathke's pouch requires dual induction from the diencephalon.

Targeted disruption of the homeobox gene T/ebp (Nkx2.1, Ttf1, Titf1) in mice results in ablation of the pituitary. Paradoxically, while T/ebp is expressed in the ventral diencephalon during forebrain formation, it is not expressed in Rathke's pouch or in the pituitary gland at any time of embryogenesis. Examination of pituitary development in the T/ebp homozygous null mutant embryos revealed that a pouch rudiment is initially formed but is eliminated by programmed cell death before formation of a definitive pouch. In the diencephalon of the mutant, Bmp4 expression is maintained, whereas Fgf8 expression is not detectable. These data and additional genetic and molecular observations suggest that Rathke's pouch develops in a two-step process that requires at least two sequential inductive signals from the diencephalon. First, BMP4 is required for induction and formation of the pouch rudiment, a role confirmed by analysis of Bmp4 homozygous null mutant embryos. Second, FGF8 is necessary for activation of the key regulatory gene Lhx3 and subsequent development of the pouch rudiment into a definitive pouch. This study provides firm molecular genetic evidence that morphogenesis of the pituitary primordium is induced in vivo by signals from the adjacent diencephalon.

Xenopus TFIIIA gene transcription is dependent on cis-element positioning and chromatin structure.

The Xenopus TFIIIA gene is transcribed very efficiently in oocytes. In addition to a TATA element at -30, we show that from -425 to +7 the TFIIIA gene contains only two positive cis elements centered at -267 (element 1) and -230 (element 2). This arrangement of the cis elements in the TFIIIA gene is striking because these two elements are positioned very close to each other yet separated from the TATA element by approximately 190 nucleotides. We show that the 190-nucleotide spacing between the TATA element and the upstream cis elements (elements 1 and 2) is critical for efficient transcription of the gene in oocytes and that a nucleosome is positioned in this intervening region. This nucleosome may act positively on TFIIIA transcription in oocytes by placing transcription factors bound at elements 1 and 2 in a favorable position relative to the transcription complex at the TATA element.

Neuronal diversification: development of motor neuron subtypes.

Recent progress has been made in defining the developmental mechanisms that contribute to the diversification of motor neuron subtypes, which differ in transcription factor gene expression and synaptic connections. These studies suggest that progenitor cells acquire specific motor neuron identities through the coordinate actions of multiple factors. Current evidence suggests that Sonic hedgehog initiates a common pathway for motor neuron differentiation, while positionally distributed factors act to assign subtype identities.