Effects of exercise and environmental complexity on deficits in trace and contextual fear conditioning produced by neonatal alcohol exposure in rats.

In rodents, voluntary exercise and environmental complexity increases hippocampal neurogenesis and reverses spatial learning and long-term potentiation deficits in animals prenatally exposed to alcohol. The present experiment extended these findings to neonatal alcohol exposure and to delay, trace, and contextual fear conditioning. Rats were administered either 5.25 g/kg/day alcohol via gastric intubation or received sham-intubations (SI) between Postnatal Day (PD) 4 and 9 followed by either free access to a running wheel on PD 30-41 and housing in a complex environment on PD 42-72 (wheel-running plus environmental complexity; WREC) or conventional social housing (SHSH) from PD 30 to 72. Adult rats (PD 80 ± 5) received 5 trials/day of a 10-s flashing-light conditioned stimulus (CS) paired with .8 mA footshock either immediately (delay conditioning) or after a 10-s trace interval (trace conditioning) for 2 days. Neonatal alcohol exposure impaired context and trace conditioning, but not short-delay conditioning. The WREC intervention did not reverse these deficits, despite increasing context-related freezing in ethanol-exposed and SI animals.

Human Zw10 and ROD are mitotic checkpoint proteins that bind to kinetochores.

Here we show that human Zeste White 10 (Zw10) and Rough deal (Rod) are new components of the mitotic checkpoint, as cells lacking these proteins at kinetochores fail to arrest in mitosis when exposed to microtubule inhibitors. Checkpoint failure and premature mitotic exit may explain why cells defective for hZw10 and hRod divide with lagging chromosomes. As Zw10 and Rod are not conserved in yeast, our data, combined with an accompanying study of Drosophila Zw10 and Rod, indicate that metazoans may require an elaborate spindle checkpoint to monitor complex kinetochore functions.

Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC.

Human cells express two kinases that are related to the yeast mitotic checkpoint kinase BUB1. hBUB1 and hBUBR1 bind to kinetochores where they are postulated to be components of the mitotic checkpoint that monitors kinetochore activities to determine if chromosomes have achieved alignment at the spindle equator (Jablonski, S.A., G.K.T. Chan, C.A. Cooke, W.C. Earnshaw, and T.J. Yen. 1998. Chromosoma. 107:386-396). In support of this, hBUB1 and the homologous mouse BUB1 have been shown to be important for the mitotic checkpoint (Cahill, D.P., C. Lengauer, J. Yu, G.J. Riggins, J.K. Willson, S.D. Markowitz, K.W. Kinzler, and B. Vogelstein. 1998. Nature. 392:300-303; Taylor, S.S., and F. McKeon. 1997. Cell. 89:727-735). We now demonstrate that hBUBR1 is also an essential component of the mitotic checkpoint. hBUBR1 is required by cells that are exposed to microtubule inhibitors to arrest in mitosis. Additionally, hBUBR1 is essential for normal mitotic progression as it prevents cells from prematurely entering anaphase. We establish that one of hBUBR1's checkpoint functions is to monitor kinetochore activities that depend on the kinetochore motor CENP-E. hBUBR1 is expressed throughout the cell cycle, but its kinase activity is detected after cells have entered mitosis. hBUBR1 kinase activity was rapidly stimulated when the spindle was disrupted in mitotic cells. Finally, hBUBR1 was associated with the cyclosome/anaphase-promoting complex (APC) in mitotically arrested cells but not in interphase cells. The combined data indicate that hBUBR1 can potentially provide two checkpoint functions by monitoring CENP-E-dependent activities at the kinetochore and regulating cyclosome/APC activity.

Plasma impurities observed by a pulse height analysis diagnostic during the divertor campaign of the Wendelstein 7-X stellarator.

The paper reports on the optimization process of the soft X-ray pulse height analyzer installed on the Wendelstein 7-X (W7-X) stellarator. It is a 3-channel system that records X-ray spectra in the range from 0.6 to 19.6 keV. X-ray spectra, with a temporal and spatial resolution of 100 ms and 2.5 cm (depending on selected slit sizes), respectively, are line integrated along a line-of-sight that crosses near to the plasma center. In the second W7-X operation phase with a carbon test divertor unit, light impurities, e.g., carbon and oxygen, were observed as well as mid- to high-Z elements, e.g., sulfur, chlorine, chromium, manganese, iron, and nickel. In addition, X-ray lines from several tracer elements have been observed after the laser blow-off injection of different impurities, e.g., silicon, titanium, and iron, and during discharges with prefill or a gas puff of neon or argon. These measurements were achieved by optimizing light absorber-foil selection, which defines the detected energy range, and remotely controlled pinhole size, which defines photon flux. The identification of X-ray lines was confirmed by other spectroscopic diagnostics, e.g., by the High-Efficiency XUV Overview Spectrometer, HEXOS, and high-resolution X-ray imaging spectrometer, HR-XIS.

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK.

The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

Standardized exchange of clinical documents--towards a shared care paradigm in glaucoma treatment.

OBJECTIVES: The exchange of medical data from research and clinical routine across institutional borders is essential to establish an integrated healthcare platform. In this project we want to realize the standardized exchange of medical data between different healthcare institutions to implement an integrated and interoperable information system supporting clinical treatment and research of glaucoma. METHODS: The central point of our concept is a standardized communication model based on the Clinical Document Architecture (CDA). Further, a communication concept between different health care institutions applying the developed document model has been defined. RESULTS: With our project we have been able to prove that standardized communication between an Electronic Medical Record (EMR), an Electronic Health Record (EHR) and the Erlanger Glaucoma Register (EGR) based on the established conceptual models, which rely on CDA rel.1 level 1 and SCIPHOX, could be implemented. The HL7-tool-based deduction of a suitable CDA rel.2 compliant schema showed significant differences when compared with the manually created schema. Finally fundamental requirements, which have to be implemented for an integrated health care platform, have been identified. CONCLUSIONS: An interoperable information system can enhance both clinical treatment and research projects. By automatically transferring screening findings from a glaucoma research project to the electronic medical record of our ophthalmology clinic, clinicians could benefit from the availability of a longitudinal patient record. The CDA as a standard for exchanging clinical documents has demonstrated its potential to enhance interoperability within a future shared care paradigm.

Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation.

Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers.

Overview of diagnostic performance and results for the first operation phase in Wendelstein 7-X (invited).

Wendelstein 7-X, a superconducting optimized stellarator built in Greifswald/Germany, started its first plasmas with the last closed flux surface (LCFS) defined by 5 uncooled graphite limiters in December 2015. At the end of the 10 weeks long experimental campaign (OP1.1) more than 20 independent diagnostic systems were in operation, allowing detailed studies of many interesting plasma phenomena. For example, fast neutral gas manometers supported by video cameras (including one fast-frame camera with frame rates of tens of kHz) as well as visible cameras with different interference filters, with field of views covering all ten half-modules of the stellarator, discovered a MARFE-like radiation zone on the inboard side of machine module 4. This structure is presumably triggered by an inadvertent plasma-wall interaction in module 4 resulting in a high impurity influx that terminates some discharges by radiation cooling. The main plasma parameters achieved in OP1.1 exceeded predicted values in discharges of a length reaching 6 s. Although OP1.1 is characterized by short pulses, many of the diagnostics are already designed for quasi-steady state operation of 30 min discharges heated at 10 MW of ECRH. An overview of diagnostic performance for OP1.1 is given, including some highlights from the physics campaigns.

Targeting the kinetochore for mitosis-specific inhibitors.

Microtubule poisons such as taxol and vinblastine are widely used to treat a variety of cancers. These drugs are believed to kill cells by blocking mitosis. However, there is a critical need to identify new drugs because tumors can often become refractory to treatment with existing drugs. Studies over the past decade on chromosome segregation have uncovered a plethora of novel proteins that function specifically in mitosis. Centrosomes and kinetochores are two organelles that specify formation of the spindle and the attachment of chromosomes to the spindle, respectively. The focus of this review is to highlight the kinetochore as a rich source of targets for the development of mitosis-specific drugs.

Syndrome: le mot de jour.

Syndrome is one of the oldest terms in the medical vocabulary. It has been used as a designation for those disorders that were marked by etiologically nonspecific similar groups of manifestations up to the time of Syndenham. His contention that the terms syndrome and disease were in fact synonymous explains in part infrequent use of syndrome in the literature until the latter part of the 19th century. Redefinition of syndrome early in the 20th century as a disorder characterized by the concurrence of symptoms which are causally related, and further refinement of the definition as a condition marked by a cluster of symptoms occurring together coincidentally, gradually restored the popularity of the term to where syndrome is now one of the most frequently used designations of morbid states in the literature. There are numerous definitions of syndrome currently in use. One which is accepted by most dysmorphologists, geneticists, and some clinicians states that syndrome is an etiologically defined entity of unknown pathogenesis. However, most writers use the term randomly to denote any abnormal condition, whether medical, social, or behavioral, when a more satisfactory designation cannot be found or created, or to emphasize special complexity (syndromic qualities?) of already named diseases, or merely to be amusing. The post-Sydenham custom of naming of syndromes after physicians gave way in the mid-20th century to methods wherein syndrome names incorporate clinical, etiological, genetic, and other significant characteristics. Other methods used in designating syndromes include using the names of the first patient known to be affected, acronyms and abbreviations, personal names of all kinds, and the like.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral artery recanalization in humans using balloon and laser angioplasty.

The treatment of patients with complex peripheral arterial disease and those who have had previous unsuccessful attempted revascularization procedures can be clinically challenging. Initial treatment was begun using therapy by percutaneous balloon and laser angioplasty, then proceeding to bypass surgery if severe ischemia persisted. Both percutaneous and cut-down approaches were used to access totally occluded arteries. An attempt was made to cross the occlusion mechanically with either a guide wire or an activated laser probe. If laser recanalization was not successful, the patient underwent bypass surgery or was managed with medication unless an amputation was necessary. Following initial screening of 381 patients, 115 procedures were performed on 103 patients. In 31 procedures (28 patients), only balloon angioplasty was performed. In 84 procedures (75 patients), laser recanalization was attempted: 55 percutaneously and 29 by cut-down. Overall technical success (crossing the obstruction without perforation) was 86/115 (75%). Technically successful procedures were characterized by shorter arterial occlusions than were technical failures (8.4 +/- 1 cm vs. 14.3 +/- 1.9 cm; p < 0.004). Clinical success (residual stenosis < 50%, symptom relief, improved ankle brachial index > or = 0.15, and no complications) was achieved in 22/31 (71%) of balloon angioplasty procedures alone. The stenoses decreased from 98 +/- 4% to 31 +/- 24%, p < 0.00001. Combined percutaneous laser and balloon angioplasty had a technical success of 36/55 (65%). Stenoses were reduced from 99 +/- 2% to 56 +/- 14% after laser angioplasty, to 30 +/- 15% after balloon angioplasty, p < 0.0001. Laser angioplasty performed via a cut-down had a clinical success of 9/29 (31%). However, major complications were rare. Device staging for treatment of peripheral vascular disease provides additional options for patients who are at high surgical risk and/or in whom standard therapy has failed.

[Clinical effectiveness of acipimox and fenofibrate in patients with hyperlipoproteinemia type II]. / Skutecznosc kliniczna acipimoxu i fenofibratu u osób z hiperlipoproteinemia typu II.

Hypolipaemic effectiveness and unfavourable effects of acipimox and fenofibrate were evaluated in patients with essential hyperlipoproteinaemia type II. The studies were carried out in two groups of 30 patients each. The studied patients were treated for three months with diet, and for another three months one group received acipimox (750 mg/day), and the other group was given fenofibrate (300 mg/day). After three months of pharmacological treatment in both groups a statistically significant decrease was seen of the concentrations of total cholesterol (by 13.8% and 19.3% respectively), LDL cholesterol (by 16.3% and 22.1%). TG (by 22.7% and 28.9%). The increase of HDL cholesterol concentration (twofold increase after fenofibrate) was non-significant. Desired LDL cholesterol values were achieved in eight patients (26.7%) treated with fenofibrate and in two patients (6.6%) receiving acipimox. Both drugs were well tolerated. Unfavourable effects were slight and did not require drug withdrawal.

[Purulent mediastinitis]. / Ropne zapalenie sródpiersia.

The aspects of acute purulent mediastinitis (APM) have been reported on the basis of the analysis of 14 cases treated in the last 5 years. The most frequent causes of APM were the complications after surgery on esophagus ad trachea (10 cases). The other group included patients operated on by sternotomy. Three patients survived. In both of them diagnosis was established within 12 hours from the beginning of APM and early re-thoracotomy was performed. The rest of the patients died because of sepsis and multiply organ failure (MOF). The conclusion is that only early diagnosis as well as aggressive surgical treatment give a chance to save life in such a dangerous severe complication.

[Mediastinal emphysema]. / Odma sródpiersia.

18 patients have been treated in our department for mediastinal emphysema (ME) during last 15 years. Small degree ME was found in 5 cases medium degree ME in 6 cases and in 5 patients tension emphysema was noted. Small degree ME was caused by abdominal and thyroid gland surgery, middle degree ME was recognized after surgical treatment of the mediastinal tumors or after mediastinal traumas. Tension emphysema of the mediastinum was observed in patients artificially ventilated, after blunt chest injuries or in the course of pneumonia. Sometimes it was impossible to establish the cause of ME. Tension emphysema of the mediastinum was usually life-threatening and required decompression.

Neonatal alcohol impairs the context preexposure facilitation effect in juvenile rats: dose-response and post-training consolidation effects.

Alcohol exposure on postnatal days (PND) 4-9 in the rat adversely affects hippocampal anatomy and function and impairs performance on a variety of hippocampus-dependent tasks. Exposure during this developmental window reveals a linear relationship between alcohol dose and spatial learning impairment in the context preexposure facilitation effect (CPFE), a hippocampus-dependent variant of contextual fear conditioning. The purpose of the current report was to examine the effect of a range of alcohol doses administered during a narrower window, PND7-9, than previously reported (Experiment 1) and to begin to determine which memory processes involved in this task are impaired by developmental alcohol exposure (Experiment 2). In Experiment 1, rats pups received a single day binge alcohol dose of either 2.75, 4.00, 5.25 g/kg/day or were sham-intubated (SI) from PND7-9. Conditioned freezing during the test day was evident in all dosing groups, except for Group 5.25 g, indicating no graded dose-related behavioral deficits with alcohol exposure limited to PND7-9. In Experiment 2, rat pups were exposed to the highest effective dose from Experiment 1 (5.25 g/kg/day) or were sham intubated over PND7-9. During training, rats remained in the conditioning context for 5-min following immediate shock delivery. During this test of post-shock freezing, both SI and alcohol-exposed rats given prior exposure to the conditioning context showed comparable freezing levels. Since alcohol-exposed rats showed normal post-shock freezing, deficits by these rats on the test day likely reflect a failure to consolidate or retrieve a context-shock association, rather than a deficit in hippocampal conjunctive processes (consolidation, pattern completion) that occur prior to shock on the training day. These findings illustrate the value of the CPFE for characterizing the separable memory processes that are impaired by neonatal alcohol exposure in this task.

Egr-1 mRNA expression patterns in the prefrontal cortex, hippocampus, and amygdala during variants of contextual fear conditioning in adolescent rats.

We report activation of the immediate-early gene Egr-1 in the lateral amygdala (LA), hippocampus (CA1), and medial prefrontal cortex (mPFC) 30-min following the training phase in the context pre-exposure facilitation effect (CPFE) and standard context fear conditioning (180 s context exposure→shock). On day one of the CPFE paradigm, postnatal day (PD) 31 rats (±1) were pre-exposed to Context A (Pre) or Context B (Alt-Pre) for 5 min followed by five additional 1-min exposures. A day later, Pre and Alt-Pre rats received a 2-s, 1.5 mA footshock immediately upon placement in Context A. Animals included in in situ hybridization were then sacrificed 30 (±3) min later. On day three, the behaviorally-tested Pre rats showed significantly more fear-conditioned freezing in Context A than Alt-Pre rats. Standard context fear conditioning groups showed much greater freezing than the Pre group, as well as no shock and immediate-shock controls. Thirty minutes after immediate shock training, Pre rats showed increased Egr-1 mRNA in the prelimbic mPFC relative to Alt-Pre rats. Standard context conditioning selectively increased Egr-1 in CA1. In the LA and mPFC, Egr-1 increased to a similar extent in no shock, immediate shock, and standard context conditioning relative to homecage controls. The present study demonstrates that Egr-1 mRNA expression has a complex relationship to fear learning in different brain regions and variants of context conditioning.

Exercise and environment as an intervention for neonatal alcohol effects on hippocampal adult neurogenesis and learning.

Neonatal alcohol exposure impairs cognition and learning in adulthood and permanently damages the hippocampus. Wheel running (WR) improves hippocampus-associated learning and memory and increases the genesis and survival of newly generated neurons in the hippocampal dentate gyrus. WR significantly increases proliferation of newly generated dentate granule cells in alcohol-exposed (AE) and control rats on Postnatal Day (PD) 42 but only control rats show an increased number of surviving cells thirty days after WR (Helfer et al., 2009b). The present studies examined whether proliferation-promoting WR followed by survival-enhancing environmental complexity (EC) during adolescence could increase survival of new neurons in AE rats. On PD 4-9, pups were intubated with alcohol in a binge-like manner (5.25g/kg/day, AE), were sham-intubated (SI), or were reared normally (suckle control, SC). On PD 30 animals were assigned to WR (PD 30-42) followed by EC (PD 42-72; WR/EC) or were socially housed (SH/SH) for the duration of the experiment. All animals were injected with 200mg/kg bromodeoxyuridine (BrdU) on PD 41. In Experiment 1, survival of newly generated cells was significantly enhanced in the AE-WR/EC group in comparison with AE-SH/SH group. Experiment 2A examined trace eyeblink conditioning. In the SH/SH condition, AE impaired trace eyeblink conditioning relative to SI and SC controls. In the WR/EC condition, AE rats performed as well as controls. In Experiment 2B, the same intervention was examined using the context preexposure facilitation effect (CPFE); a hippocampus-dependent variant of contextual fear conditioning. Again, the WR/EC intervention reversed the deficit in conditioned fear to the context that was evident in the SH/SH condition. Post-weaning environmental manipulations promote cell survival and reverse learning deficits in rats that were exposed to alcohol during development. These manipulations may provide a basis for developing interventions that ameliorate learning impairments associated with human fetal alcohol spectrum disorders.

Status of the diagnostics development for the first operation phase of the stellarator Wendelstein 7-X.

An overview of the diagnostics which are essential for the first operational phase of Wendelstein 7-X and the set of diagnostics expected to be ready for operation at this time are presented. The ongoing investigations of how to cope with high levels of stray Electron Cyclotron Resonance Heating (ECRH) radiation in the ultraviolet (UV)/visible/infrared (IR) optical diagnostics are described.

Determinants of novel object and location recognition during development.

In the novel object recognition (OR) paradigm, rats are placed in an arena where they encounter two sample objects during a familiarization phase. A few minutes later, they are returned to the same arena and are presented with a familiar object and a novel object. The object location recognition (OL) variant involves the same familiarization procedure but during testing one of the familiar objects is placed in a novel location. Normal adult rats are able to perform both the OR and OL tasks, as indicated by enhanced exploration of the novel vs. the familiar test item. Rats with hippocampal lesions perform the OR but not OL task indicating a role of spatial memory in OL. Recently, these tasks have been used to study the ontogeny of spatial memory but the literature has yielded conflicting results. The current experiments add to this literature by: (1) behaviorally characterizing these paradigms in postnatal day (PD) 21, 26 and 31-day-old rats; (2) examining the role of NMDA systems in OR vs. OL; and (3) investigating the effects of neonatal alcohol exposure on both tasks. Results indicate that normal-developing rats are able to perform OR and OL by PD21, with greater novelty exploration in the OR task at each age. Second, memory acquisition in the OL but not OR task requires NMDA receptor function in juvenile rats [corrected]. Lastly, neonatal alcohol exposure does not disrupt performance in either task. Implications for the ontogeny of incidental spatial learning and its disruption by developmental alcohol exposure are discussed.

Generation of solid-density ultraintense ion beams by a picosecond laser pulse of circular polarization.

This contribution reports particle-in-cell numerical studies of deuteron beam acceleration by a picosecond laser pulse of circular polarization. The effect of laser wavelength λ and the I(L)λ(2) product (I(L) is laser intensity) on the ion beam parameters is investigated. It is shown that at the I(L)λ(2) product fixed, the beam parameters (, I(i), F(i)) as well as the laser-ions energy conversion efficiency quickly increase with a decrease in the laser wavelength and the best results are achieved for a KrF laser (λ = 0.248 µm). In particular, a 2-ps KrF laser pulse of I(L)λ(2) ∼ 2 × 10(20) Wcm(-2) µm(2) interacting with a 10-µm deuteron target produces a quasi-monoenergetic, solid-density deuteron beam of parameters approaching those required for inertial confinement fusion fast ignition.