Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

Pre-operative Ultrasonographic Evaluation of Axillary Lymph Nodes in Breast Cancer Patients: For Which Group Still of Additional Value and in Which Group Cause for Special Attention?

A non-invasive and widely available method for pre-operative evaluation of the axilla is axillary ultrasonography (US). The purpose of this study was to evaluate the diagnostic accuracy of axillary US and fine-needle aspiration cytology in a large cohort of breast cancer patients. The sensitivity and specificity of US and fine-needle aspiration cytology in our cohort of 1124 patients were 42.2% and 97.1%, respectively. As the number of axillary nodes increased, sensitivity increased. The percentage of false-negative US results was 18.9%; patients in this subgroup were significantly younger, had larger tumors, more often had lymph vascular invasion and were more likely to have estrogen receptor-positive tumors. Ultrasonography in combination with fine-needle aspiration cytology is useful in the pre-operative workup of breast cancer patients, especially patients with three or more nodal metastases. Special attention should be paid to younger women with larger tumors in whom a larger percentage of false-negative results are obtained.

Low frequency electric current noise in glioma cell populations.

Measuring the electrical activity of large and defined populations of cells is currently a major technical challenge to electrophysiology, especially in the picoampere-range. For this purpose, we developed and applied a bidirectional transducer based on a chip with interdigitated gold electrodes to record the electrical response of cultured glioma cells. Recent research determined that also non-neural brain glia cells are electrically active and excitable. Their transformed counterparts, e.g. glioma cells, were suggested to partially retain these electric features. Such electrophysiological studies however are usually performed on individual cells and are limited in their predictive power for the overall electrical activity of the multicellular tumour bulk. Our extremely low-noise measuring system allowed us to detect not only prominent electrical bursts of neuronal cells but also minute, yet constantly occurring and functional, membrane capacitive current oscillations across large populations of C6 glioma cells, which we termed electric current noise. At the same time, tumour cells of non-brain origin (HeLa) proved to be electrically quiescent in comparison. Finally, we determined that the glioma cell activity is primarily caused by the opening of voltage-gated Na+ and K+ ion channels and can be efficiently abolished using specific pharmacological inhibitors. Thus, we offer here a unique approach for studying electrophysiological properties of large cancer cell populations as an in vitro reference for tumour bulks in vivo.

IGFBP7 induces apoptosis of acute myeloid leukemia cells and synergizes with chemotherapy in suppression of leukemia cell survival.

Despite high remission rates after chemotherapy, only 30-40% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. This extremely poor prognosis of AML is mainly caused by treatment failure due to chemotherapy resistance. Chemotherapy resistance can be caused by various features including activation of alternative signaling pathways, evasion of cell death or activation of receptor tyrosine kinases such as the insulin growth factor-1 receptor (IGF-1R). Here we have studied the role of the insulin-like growth factor-binding protein-7 (IGFBP7), a tumor suppressor and part of the IGF-1R axis, in AML. We report that IGFBP7 sensitizes AML cells to chemotherapy-induced cell death. Moreover, overexpression of IGFBP7 as well as addition of recombinant human IGFBP7 is able to reduce the survival of AML cells by the induction of a G2 cell cycle arrest and apoptosis. This effect is mainly independent from IGF-1R activation, activated Akt and activated Erk. Importantly, AML patients with high IGFBP7 expression have a better outcome than patients with low IGFBP7 expression, indicating a positive role for IGFBP7 in treatment and outcome of AML. Together, this suggests that the combination of IGFBP7 and chemotherapy might potentially overcome conventional AML drug resistance and thus might improve AML patient survival.

Diffusion-limited current in organic metal-insulator-metal diodes.

An analytical expression for the diffusion current in organic metal-insulator-metal diodes is derived. The derivation is based on the classical diffusion theory of Schottky, with adaptations to account for the absence of doping, a built-in voltage due to asymmetric contacts, and band bending at the Ohmic contact. The commonly observed deviation of the ideality factor from unity (~1.2) is characteristic of diffusion-limited currents in undoped organic semiconductors. Summing with the classical space-charge limited current provides a full analytic description of the current as a function of voltage, temperature and layer thickness.

Two-dimensional charge transport in disordered organic semiconductors.

We analyze the effect of carrier confinement on the charge-transport properties of organic field-effect transistors. Confinement is achieved experimentally by the use of semiconductors of which the active layer is only one molecule thick. The two-dimensional confinement of charge carriers provides access to a previously unexplored charge-transport regime and is reflected by a reduced temperature dependence of the transfer curves of organic monolayer transistors.

Universal scaling in highly doped conducting polymer films.

Electrical transport of a highly doped disordered conducting polymer, viz. poly-3,4-ethylenedioxythiophene stabilized with poly-4-styrenesulphonic acid, is investigated as a function of bias and temperature. The transport shows universal power-law scaling with both bias and temperature. All measurements constitute a single universal curve, and the complete J(V,T) characteristics are described by a single equation. We relate this scaling to dissipative tunneling processes, such as Coulomb blockade.

DNA adsorption measured with ultra-thin film organic field effect transistors.

Organic ultra-thin film field effect transistors (FET) are operated as label-free sensors of deoxyribonucleic acid (DNA) adsorption. Linearized plasmid DNA molecules (4361 base pairs) are deposited from a solution on two monolayers thick pentacene FET. The amount of adsorbed DNA is measured by AFM and correlated to the concentration of the solution. Electrical characteristics on the dried DNA/pentacene FETs were studied as a function of DNA concentration in the solution. Shift of the pinch-off voltage across a wide range of DNA concentration, from very diluted to highly concentrated, is observed. It can be ascribed to additional positive charges in the semiconductor induced by DNA at a rate of one charge for every 200 base pairs. The sensitivity 74 ng/cm(2), corresponding to 650 ng/ml, is limited by the distribution of FET parameters upon repeated cycles, and is subjected to substantial improvement upon standardization. Our work demonstrates the possibility to develop label-free transducers suitable to operate in regimes of high molecular entanglement.

Photoinduced transient stark spectroscopy in organic semiconductors: a method for charge mobility determination in the picosecond regime.

Subpicosecond photoinduced Stark spectroscopy experiments are carried out for measuring charge carrier mobility in organic semiconductors. The technique is demonstrated in state-of-art devices based on methanofullerene. The transient mobility of photogenerated charge carriers is measured in the picosecond time domain. Electric field dependent mobility is observed from the earliest time scales. In addition, two distinct transport regimes are revealed: a short-lived state, approximately 10 ps, of high mobility and a transient towards the trap limited transport, associated with the mesoscopic structure of the medium.

Unified description of charge-carrier mobilities in disordered semiconducting polymers.

From a numerical solution of the master equation for hopping transport in a disordered energy landscape with a Gaussian density of states, we determine the dependence of the charge-carrier mobility on temperature, carrier density, and electric field. Experimental current-voltage characteristics in devices based on semiconducting polymers are excellently reproduced with this unified description of the mobility. At room temperature it is mainly the dependence on carrier density that plays an important role, whereas at low temperatures and high fields the electric field dependence becomes important. Omission in the past of the carrier-density dependence has led to an underestimation of the hopping distance and the width of the density of states in these polymers.

Unification of the hole transport in polymeric field-effect transistors and light-emitting diodes.

A systematic study of the hole mobility in hole-only diodes and field-effect transistors based on poly(2-methoxy-5-(3('),7(')-dimethyloctyloxy)-p-phenylene vinylene) and on amorphous poly(3-hexyl thiophene) has been performed as a function of temperature and applied bias. The experimental hole mobilities extracted from both types of devices, although based on a single polymeric semiconductor, can differ by 3 orders of magnitude. We demonstrate that this apparent discrepancy originates from the strong dependence of the hole mobility on the charge carrier density in disordered semiconducting polymers.

Solution-processed ambipolar organic field-effect transistors and inverters.

There is ample evidence that organic field-effect transistors have reached a stage where they can be industrialized, analogous to standard metal oxide semiconductor (MOS) transistors. Monocrystalline silicon technology is largely based on complementary MOS (CMOS) structures that use both n-type and p-type transistor channels. This complementary technology has enabled the construction of digital circuits, which operate with a high robustness, low power dissipation and a good noise margin. For the design of efficient organic integrated circuits, there is an urgent need for complementary technology, where both n-type and p-type transistor operation is realized in a single layer, while maintaining the attractiveness of easy solution processing. We demonstrate, by using solution-processed field-effect transistors, that hole transport and electron transport are both generic properties of organic semiconductors. This ambipolar transport is observed in polymers based on interpenetrating networks as well as in narrow bandgap organic semiconductors. We combine the organic ambipolar transistors into functional CMOS-like inverters.

Reproducibility of ultrasound blood flow measurement of the superior mesenteric artery before and after exercise.

This study examines the reproducibility of gastro-intestinal blood flow measurements in the superior mesenteric artery (SMA) both before and immediately after exercise with Doppler ultrasound measurements. Twelve well-trained males (mean +/- SD: age 25.9 +/- 3.8 yr; VO2max 4.8 +/- 0.91 x min(-1)) were measured twice (trial 1 and 2) with a 1 week interval before and immediately after 1 hr cycling at 70% VO2max. Duplex scanning was performed with the athletes in supine position immediately after transition from a chair (before exercise) or bicycle (after exercise). The variability of three measurements before exercise was studied within both trials (short-term reproducibility) and the mean pre-exercise values were compared between the trials (long-term reproducibility). In addition, post-exercise measurements were compared in the same way. Reproducibility was tested using the coefficient of variation and Cronbach's alpha. Mean pre-exercise blood flow was 424 +/- 66 ml/min (n = 12) in trial 1 and 375 +/- 38 ml/min (n = 11) in trial 2. Immediately after exercise blood flow had decreased by 49% to 214 +/- 36 ml/min (p <0.01) in trial 1 and by 38% to 234 +/- 36 ml/min (p < 0.01) in trial 2. Blood flow before and after exercise was not significantly different between trials (paired t-test) and therefore reproducible at the group level. Before exercise a good to fair reproducibility was observed both at the short-term (Cronbach's alpha: 0.88 in trial 1, 0.73 in trial 2, n = 11), and at the long-term (alpha = 0.80, n= 11). In contrast, long-term reproducibility immediately after exercise was poor (alpha = -0.99, n = 8 and alpha = 0.36, n = 7 after the first and second cycling period, respectively). In conclusion, duplex scanning of SMA after a sitting-supine transition in well-trained subjects is not a reproducible method at the individual level for intestinal blood flow measurements immediately after exercise.

From socialist principles to motorcycle maintenance: the origin and development of the salaried physician model in the Israeli Public Health Services, 1918 to 1998.

For more than 70 years, physicians in the Israeli health care system have been employed on a fixed salary rather than on a fee-for-service basis. The present report is a brief review of the origin and development of this unique salaried physician model and its effect on the terms of physicians' employment. Archival documents were reviewed. The salaried physician model was introduced to ensure egalitarian health care for patients rather than equal payment for physicians. It was accepted by physicians because it guaranteed their employment and income. However, over the years, the salaried physician model has evolved into a complex wage scale, with multiple fringe benefits that bypass formal agreements in order to reward individual physicians. In addition, the salaried physician model has encouraged illegal private practice, which is viewed today as one of the major problems of the Israeli Public Health Services.

The influence of septicaemia on spontaneous motility in preterm infants.

The qualitative assessment of general movements (GMs) in preterm infants is a sensitive method to investigate the integrity of the central nervous system. The question arises whether systemic infections affect the quality of GMs in a similar fashion to brain lesions. We were able to provide an answer to this problem in six infants (gestational age 24.4-32.4 weeks, birth weight 600-1660 grams), who had initially normal GMs as analyzed from sequential video-recordings. All infants sustained a proven septicaemia (Candida albicans in two, Staphylococcus aureus in three, a coagulase-negative staphylococcus in one infant). Unintentionally, recordings were also made during the acute phase. The complexity and variability of the GMs remained largely intact in five of the six infants; only one infant had transiently abnormal GMs. Compared with 1 week before the acute phase, the speed and amplitude of the GMs were diminished, giving the GMs a sluggish appearance. One to two weeks after the acute phase of septicaemia, the quality of GMs, i.e. speed and amplitude, had normalized in all infants. This study demonstrates that it is possible to discriminate between abnormal GMs due to cerebral lesions and sluggish GMs due to severe systemic infections, when the complexity of the GMs is considered as the main characteristic for judgement of normality of GM-quality.