Structural connections between the noradrenergic and cholinergic system shape the dynamics of functional brain networks.

Complex cognitive abilities are thought to arise from the ability of the brain to adaptively reconfigure its internal network structure as a function of task demands. Recent work has suggested that this inherent flexibility may in part be conferred by the widespread projections of the ascending arousal systems. While the different components of the ascending arousal system are often studied in isolation, there are anatomical connections between neuromodulatory hubs that we hypothesise are crucial for mediating key features of adaptive network dynamics, such as the balance between integration and segregation. To test this hypothesis, we estimated the strength of structural connectivity between key hubs of the noradrenergic and cholinergic arousal systems (the locus coeruleus [LC] and nucleus basalis of Meynert [nbM], respectively). We then asked whether the strength of structural LC and nbM inter-connectivity was related to individual differences in the emergent, dynamical signatures of functional integration measured from resting state fMRI data, such as network and attractor topography. We observed a significant positive relationship between the strength of white-matter connections between the LC and nbM and the extent of network-level integration following BOLD signal peaks in LC relative to nbM activity. In addition, individuals with denser white-matter streamlines interconnecting neuromodulatory hubs also demonstrated a heightened ability to shift to novel brain states. These results suggest that individuals with stronger structural connectivity between the noradrenergic and cholinergic systems have a greater capacity to mediate the flexible network dynamics required to support complex, adaptive behaviour. Furthermore, our results highlight the underlying static features of the neuromodulatory hubs can impose some constraints on the dynamic features of the brain.

Generation of an equine biobank to be used for Functional Annotation of Animal Genomes project.

The Functional Annotation of Animal Genomes (FAANG) project aims to identify genomic regulatory elements in both sexes across multiple stages of development in domesticated animals. This study represents the first stage of the FAANG project for the horse, Equus caballus. A biobank of 80 tissue samples, two cell lines and six body fluids was created from two adult Thoroughbred mares. Ante-mortem assessments included full physical examinations, lameness, ophthalmologic and neurologic evaluations. Complete blood counts and serum biochemistries were also performed. At necropsy, in addition to tissue samples, aliquots of serum, ethylenediaminetetraacetic acid (EDTA) plasma, heparinized plasma, cerebrospinal fluid, synovial fluid, urine and microbiome samples from all regions of the gastrointestinal and urogenital tracts were collected. Epidermal keratinocytes and dermal fibroblasts were cultured from skin samples. All tissues were grossly and histologically evaluated by a board-certified veterinary pathologist. The results of the clinical and pathological evaluations identified subclinical eosinophilic and lymphocytic infiltration throughout the length of the gastrointestinal tract as well as a mild clinical lameness in both animals. Each sample was cryo-preserved in multiple ways, and nuclei were extracted from selected tissues. These samples represent the first published systemically healthy equine-specific biobank with extensive clinical phenotyping ante- and post-mortem. The tissues in the biobank are intended for community-wide use in the functional annotation of the equine genome. The use of the biobank will improve the quality of the reference annotation and allow all equine researchers to elucidate unknown genomic and epigenomic causes of disease.

Unified neural field theory of brain dynamics underlying oscillations in Parkinson's disease and generalized epilepsies.

The mechanisms underlying pathologically synchronized neural oscillations in Parkinson's disease (PD) and generalized epilepsies are explored in parallel via a physiologically-based neural field model of the corticothalamic-basal ganglia (CTBG) system. The basal ganglia (BG) are approximated as a single effective population and their roles in the modulation of oscillatory dynamics of the corticothalamic (CT) system and vice versa are analyzed. In addition to normal EEG rhythms, enhanced activity around 4 Hz and 20 Hz exists in the model, consistent with the characteristic frequencies observed in PD. These rhythms result from resonances in loops formed between the BG and CT populations, analogous to those that underlie epileptic oscillations in a previous CT model, and which are still present in the combined CTBG system. Dopamine depletion is argued to weaken the dampening of these loop resonances in PD, and network connections then explain the significant coherence observed between BG, thalamic, and cortical population activity around 4-8 Hz and 20 Hz. Parallels between the afferent and efferent connection sites of the thalamic reticular nucleus (TRN) and BG predict low dopamine to correspond to a reduced likelihood of tonic-clonic (grand mal) seizures, which agrees with experimental findings. Furthermore, the model predicts an increased likelihood of absence (petit mal) seizure resulting from pathologically low dopamine levels in accordance with experimental observations. Suppression of absence seizure activity is demonstrated when afferent and efferent BG connections to the CT system are strengthened, which is consistent with other CTBG modeling studies. The BG are demonstrated to have a suppressive effect on activity of the CTBG system near tonic-clonic seizure states, which provides insight into the reported efficacy of current treatments in BG circuits. Sleep states of the TRN are also found to suppress pathological PD activity in accordance with observations. Overall, the findings demonstrate strong parallels between coherent oscillations in generalized epilepsies and PD, and provide insights into possible comorbidities.

[Defect coverage with myofasciocutaneous free flaps. Consequence of corticosteroid infiltration of the wrist in a patient on immunosuppressive therapy]. / Defektdeckung mit myofasziokutanem Lappen. Folge einer Kortikoidinfiltration des Handgelenks bei einer immunsuppressiv behandelten Patientin.

Intra-articular corticosteroid injection and radiation of the wrist was performed in a patient on immunosuppressive therapy. She sustained empyema and impending compartment syndrome. After fasciotomy, debridement and antibiotic therapy had been performed, we provided soft tissue coverage by a combined ALTP and muscular free flap on the vascular trunk of the descending branch of the lateral circumflex femoral artery. There were no complications and the patient is very satisfied with the outcome.

[Reconstruction of the elbow with the deep circumflex iliac artery. Multicomponent free flap plasty after a gunshot wound]. / Rekonstruktion des Ellenbogens durch eine A. circumflexa iliaca profunda. Mehrkomponentenlappenplastik nach einer Schussverletzung.

A 20-year-old woman sustained massive elbow trauma from a gunshot wound. After initial surgery soft tissue coverage, reconstruction of the proximal third of the ulna, of the ulnar collateral ligament and of the triceps tendon was performed by one multicomponent microvascular free flap. There were no complications, the elbow is stable and reached full weight bearing 11 months after trauma. Active range of motion for extension and flexion is 0-20°-80°.

A comprehensive test system to identify suitable antibodies against p53 for immunohistochemical analysis of canine tissues.

The tumour suppressor p53 is commonly detected in tissues of companion animals by means of antibodies raised against the human protein. The following three-step procedure was devised to test the suitability of such antibodies for immunohistochemistry on canine tissues. (1) Western blot and immunohistochemical analyses on bacterially expressed recombinant canine protein to assess human-to-canine cross-reactivity. (2) Immunohistochemistry of cultured, UVB-irradiated canine keratinocytes to evaluate suitability for detection of endogenous p53. (3) Immunohistochemistry on tissue arrays to further substantiate suitability of the antibodies on a panel of normal and neoplastic human and canine tissues. Five of six antibodies cross-reacted with recombinant canine p53. Three of these (PAb122, PAb240, CM-1) also immunolabelled stabilized wild type p53 in cell cultures and elicited a consistent, characteristic labelling pattern in a subset of tumours. However, two alternative batches of polyclonal antibody CM-1 failed to detect p53 in cell cultures, while showing a characteristic labelling pattern of a completely different subset of tumours and unspecific labelling of normal tissues. The test system described is well suited to the selection of antibodies for immunohistochemical p53 detection. The results emphasize the need to include appropriate controls, especially for polyclonal antibodies.

[Avascular necrosis of the capitate in athletes]. / Die avaskuläre Kapitatumnekrose bei Sportlern.

The possibility of osteonecrosis of the carpal bones should always be considered when athletes present with pain of unknown origin in the hand and wrist, in particular, if they are participating in sports such as gymnastics or weight-lifting that involve extreme loading of the wrist with axial compression and microtrauma. This sort of extreme loading of the wrist combined with a constitutionally "weak" blood supply to the individual carpal bones may lead to the formation of osteo-necrotic zones. A treatment method that can produce excellent results, depending on the pathomorphology, is available in the form of vascularized bone grafting.

Expression of neural cell adhesion molecule-related sialoglycoprotein in small cell lung cancer and neuroblastoma cell lines H69 and CHP-212.

Monoclonal antibodies (MAbs) 123C3 and 123A8 generated against a membrane preparation of a small cell lung carcinoma (SCLC) specimen recognize not only SCLC and bronchial carcinoids but also a significant portion of non-small cell lung carcinomas (non-SCLC) of various histological types. Together with 13 other monoclonal antibodies, which show preference for SCLC, they have been ranked as SCLC cluster 1 (SC-1) Mabs. In this study we show that SC-1 MAbs are directed against a restricted number of epitopes, and that SC-1 MAbs and a polyclonal antiserum directed against the neural cell adhesion molecule (NCAM) recognize identical glycoproteins, indicating that SC-1 antigens are closely related to or identical with NCAM. Long polysialic acid units composed of alpha-(2,8)-linked N-acetylneuraminic acid units, which in mammals are found exclusively on NCAM, were present on SC-1 antigens in SCLC. This provides further evidence that SC-1 MAbs recognize NCAM. The SC-1 antigens in the SCLC cell line H69 were present in two forms, NCAM-containing alpha-(2,8)-polysialic acid units identified by antiserum 735, the NCAM-H form, and the less sialylated NCAM-L form. The NCAM-H form consisted of diffusely migrating sialoglycoproteins with a molecular weight of 200,000-250,000, which resolved after neuraminidase treatment into two proteins with molecular weights of 140,000 and 180,000. Since the NCAM-H form is expressed in the lung tumor type with a poor prognosis, our results suggest that NCAM might be implicated in the invasive behavior of these NCAM-positive lung tumors.

Activation of the fibrinolytic system during intracoronary streptokinase administration.

Serial biochemical studies were performed in 12 patients treated with intracoronary streptokinase infusion for acute myocardial infarction, in order to study the method of activation of the fibrinolytic system during local administration of a relatively low dose of this drug and to determine correlations between systemic effects and reperfusion. Plasma samples were obtained before and every 15 minutes during the infusion of streptokinase and after completion of the therapy. Streptokinase dosage in this study was 211,000 +/- 88,000 IU (+/- SD). The average time from the onset of symptoms to the start of infusion was 2 hours 50 minutes (range 1 hour 10 minutes to 3 hours 30 minutes). Reperfusion occurred in six patients and temporary recanalization in three; in three patients no recanalization was achieved. Fibrinolytic assays of pretreatment plasma samples revealed elevated levels of plasminogen activators, presumably caused by the release of tissue-type plasminogen activator after a condition of stress. Plasminogen concentrations decreased from 94 +/- 17% to 44 +/- 30%. Alpha 2-antiplasmin fell from 84 +/- 27% to 12 +/- 19%; in seven patients no plasmin inhibitor activity was measurable at the completion of the infusion. Free plasmin occurred in samples only when this inhibitor had disappeared. This resulted in a lytic state leading to degradation of fibrinogen, the levels of which fell from 2.9 +/- 0.7% to 1.5 +/- 1.1%. Fibrinogen degradation products, measured in plasma with monoclonal antibodies, increased exponentially during streptokinase infusion in at least four patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatocyte growth factor/scatter factor (HGF/SF) is produced by human bone marrow stromal cells and promotes proliferation, adhesion and survival of human hematopoietic progenitor cells (CD34+).

The fate of hematopoietic progenitor cells (HPCs) in the bone marrow (BM) microenvironment is determined by two different interactions: 1) they adhere (via integrins) to both extracellular matrix molecules and BM stromal cells; and 2) stromal cells produce cytokines that influence their survival, proliferation, differentiation, and mobilization. The ligands for the protein tyrosine kinase receptors c-KIT and FLT3/FLK2, stem cell factor (SCF), and FL are produced by BM stromal cells and are known to affect several facets of hematopoiesis. We studied another protein tyrosine kinase receptor, c-MET, and its ligand hepatocyte growth factor (HGF), also known as scatter factor (SF), which play a similar role in hematopoiesis. c-MET mRNA is expressed in immature human BM HPCs (CD34+CD33- or CD34+CD38-), but not in more mature HPCs (CD34+CD33+ or CD34+CD38+). The ligand HGF/SF is predominantly produced by BM stromal cells at both the mRNA and protein levels. We confirmed functionally that HGF/SF alone has no effect on proliferation of HPCs, but that when combined with granulocyte/macrophage colony-stimulating factor (GM-CSF) or interleukin-3 it acts as a synergistic proliferative factor, although not as potently as kit-ligand or FLT-3/FLK-2 ligand. Furthermore, HGF/SF promotes adhesion of HPCs to immobilized fibronectin. HGF/SF-induced adhesion to fibronectin is probably caused by activation of the integrins alpha4beta1 and alpha5beta1, insofar as we were able to block this interaction by using monoclonal blocking antibodies directed against these integrin subunits. Addition of the tyrosine-phosphorylation inhibitor genistein inhibited HGF/SF-induced adhesion, supporting the idea that HGF/SF-induced effects are the result of signaling via the receptor c-MET after ligand binding. The enhanced adhesion of HGF/SF to fibronectin proved to be beneficial for the maintenance of the colony-forming potential of HPCs. HGF/SF alone and especially in combination with fibronectin prolongs survival of GM colony-forming cells in liquid culture. Our data indicate that HGF/SF is a polyfunctional cytokine in the BM microenvironment. It is produced by human BM stromal cells and directly or indirectly promotes proliferation, adhesion, and survival of human HPCs.