Electron holography on HfO2/HfO2-x bilayer structures with multilevel resistive switching properties.

Unveiling the physical nature of the oxygen-deficient conductive filaments (CFs) that are responsible for the resistive switching of the HfO2-based resistive random access memory (RRAM) devices represents a challenging task due to the oxygen vacancy related defect nature and nanometer size of the CFs. As a first important step to this goal, we demonstrate in this work direct visualization and a study of physico-chemical properties of oxygen-deficient amorphous HfO2-x by carrying out transmission electron microscopy electron holography as well as energy dispersive x-ray spectroscopy on HfO2/HfO2-x bilayer heterostructures, which are realized by reactive molecular beam epitaxy. Furthermore, compared to single layer devices, Pt/HfO2/HfO2-x /TiN bilayer devices show enhanced resistive switching characteristics with multilevel behavior, indicating their potential as electronic synapses in future neuromorphic computing applications.

Kinetic Monte Carlo simulation analysis of the conductance drift in Multilevel HfO2-based RRAM devices.

The drift characteristics of valence change memory (VCM) devices have been analyzed through both experimental analysis and 3D kinetic Monte Carlo (kMC) simulations. By simulating six distinct low-resistance states (LRS) over a 24-hour period at room temperature, we aim to assess the device temporal stability and retention. Our results demonstrate the feasibility of multi-level operation and reveal insights into the conductive filament (CF) dynamics. The cumulative distribution functions (CDFs) of read-out currents measured at different time intervals provide a comprehensive view of the device performance for the different conductance levels. These findings not only enhance the understanding of VCM device switching behaviour but also allow the development of strategies for improving retention, thereby advancing the development of reliable nonvolatile resistive switching memory technologies.

Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors.

Substantial evidence links alcohol drinking and serotonin (5-HT) functioning in animals. Lowered central 5-HT neurotransmission has been found in a subgroup of alcoholics, possibly those with more aggressive, assaultive tendencies. Several rodent studies have also suggested that intact 5-HT systems are important determinants of sensitivity and/or tolerance to ethanol-induced ataxia and hypothermia. Null mutant mice lacking the 5-HT1B receptor gene (5-HT1B-/-) have been developed that display enhanced aggression and altered 5-HT release in slice preparations from some, but not all, brain areas. We characterized these mice for sensitivity to several effects of ethanol. Mutant mice drank twice as much ethanol as wild-type mice, and voluntarily ingested solutions containing up to 20% ethanol in water. Their intake of food and water, and of sucrose, saccharin and quinine solutions, was normal. Mutants were less sensitive than wild-types on a test of ethanol-induced ataxia and, with repeated drug administration, tended to develop tolerance more slowly. In tests of ethanol withdrawal and metabolism, mutants and wild-type mice showed equivalent responses. Our results suggest that the 5-HT1B receptor participates in the regulation of ethanol drinking, and demonstrate that serotonergic manipulations lead to reduced responsiveness to certain ataxic effects of ethanol without affecting dependence.

Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors.

Although dopaminergic transmission has been strongly implicated in alcohol self-administration, the involvement of specific dopamine receptor subtypes has not been well established. We studied the ethanol preference and sensitivity of D2-receptor-deficient mice to directly evaluate whether dopamine D2 receptors contribute to alcohol (ethanol) consumption. We report a marked aversion to ethanol in these mice, relative to the high preference and consumption exhibited by wild-type littermates. Sensitivity to ethanol-induced locomotor impairment was also reduced in these mutant mice, although they showed a normal locomotor depressant response to the dopamine D1 antagonist SCH-23390. These data demonstrate that dopamine signaling via D2 receptors is an essential component of the molecular pathway determining ethanol self-administration and sensitivity.

Risk factors for invasive aspergillosis in neutropenic patients with hematologic malignancies.

Risk factors for invasive aspergillosis (IA) are incompletely identified and may undergo changes due to differences in medical practice. A cohort of 189 consecutive, adult patients with neutropenia hospitalized in the hemato-oncology ward of the University hospital Berne between 1995 and 1999 were included in a retrospective study to assess risk factors for IA. In total, 45 IA cases (nine proven, three probable, 33 possible), 11 patients with refractory fever and 133 controls were analyzed. IA cases had more often acute leukemia or myelodysplastic syndrome (MDS) (88 vs 38%, P < 0.001) and a longer duration of neutropenia (mean 20.6 vs 9.9 days, P < 0.001). They also had fewer neutropenic episodes during the preceding 6 months (mean 0.42 vs 1.03, P < 0.001), that is, confirmed (82%) and probable (73%) IA occurred most often during the induction cycle. A short time interval ( < or = 14 days) between neutropenic episodes increased the risk of IA four-fold (P = 0.06). Bacteremia, however, was not related to the number of preceding neutropenic episodes. Therefore, neutropenic patients with leukemia or MDS have the highest risk of IA. The risk is highest during the first induction cycle of treatment and increases with short-time intervals between treatment cycles.

Risk factors for recruit exertional heat illness by gender and training period.

INTRODUCTION: Exertional heat illness (EHI) is a recurrent problem for both male and female recruits during basic military training. A matched case control study investigated the effects of fitness and conditioning on EHI risk among Marine Corps recruits during 12 wk of basic training at Marine Corps Recruit Depot, Parris Island, SC. METHODS: Physical fitness and anthropometric measurements at entrance were acquired for 627 EHI cases that occurred during the period 1988-1996 and for 1802 controls drawn from the same training platoons. Conditional logistic regression was used to estimate EHI risk. RESULTS: Slower physical fitness test run times during processing week strongly predicted risk for subsequent EHI in both male and female recruits. A 9% increase in risk for EHI associated with body mass index (BMI = kg x m(-2); weight/height2) was found in male recruits, while BMI was not associated with risk among female recruits. BMI and initial run time were important predictors for EHI in early training, while in late training the initial BMI was no longer as important a risk factor and improvements in fitness reduced risk. CONCLUSION: Tables of estimated absolute risks categorized by BMI and VO2max are provided as a guide for identifying recruits who are at high risk for developing EHI during training.

Technology modules from micro- and nano-electronics for the life sciences.

The capabilities of modern semiconductor manufacturing offer remarkable possibilities to be applied in life science research as well as for its commercialization. In this review, the technology modules available in micro- and nano-electronics are exemplarily presented for the case of 250 and 130 nm technology nodes. Preparation procedures and the different transistor types as available in complementary metal-oxide-silicon devices (CMOS) and BipolarCMOS (BiCMOS) technologies are introduced as key elements of comprehensive chip architectures. Techniques for circuit design and the elements of completely integrated bioelectronics systems are outlined. The possibility for life scientists to make use of these technology modules for their research and development projects via so-called multi-project wafer services is emphasized. Various examples from diverse fields such as (1) immobilization of biomolecules and cells on semiconductor surfaces, (2) biosensors operating by different principles such as affinity viscosimetry, impedance spectroscopy, and dielectrophoresis, (3) complete systems for human body implants and monitors for bioreactors, and (4) the combination of microelectronics with microfluidics either by chip-in-polymer integration as well as Si-based microfluidics are demonstrated from joint developments with partners from biotechnology and medicine. WIREs Nanomed Nanobiotechnol 2016, 8:355-377. doi: 10.1002/wnan.1367 For further resources related to this article, please visit the WIREs website.

Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells.

CTGF is an immediate early growth responsive gene that has been shown to be a downstream mediator of TGFbeta actions in fibroblasts and vascular endothelial cells. In the present study hCTGF was isolated as immediate early target gene of EGF/TGFalpha in human pancreatic cancer cells by suppression hybridization. CTGF transcripts were found in 13/15 pancreatic cancer cell lines incubated with 10% serum. In 3/7 pancreatic cancer cell lines EGF/TGFalpha induced a significant rise of CTGF transcript levels peaking 1-2 h after the start of treatment. TGFbeta increased CTGF transcript levels in 2/7 pancreatic cancer cell lines after 4 h of treatment and this elevation was sustained after 24 h. Only treatment with TGFbeta was accompanied by a parallel induction of collagen type I transcription. 15/19 human pancreatic cancer tissues were shown to overexpress high levels of CTGF transcripts. CTGF transcript levels in pancreatic cancer tissues and nude mouse xenograft tumors showed a good correlation to the degree of fibrosis. In situ hybridization and the nude mouse experiments revealed that in pancreatic cancer tissues, fibroblasts are the predominant site of CTGF transcription, whereas the tumor cells appear to contribute to a lesser extent. We conclude that CTGF may be of paramount importance for the development of the characteristic desmoplastic reaction in pancreatic cancer tissues.

Rituximab plus gemcitabine: a therapeutic option for elderly or frail patients with aggressive non Hodgkin's lymphoma?

The standard treatment for patients with aggressive B-cell lymphoma--particularly diffuse large-B-cell lymphoma [DLBCL)--is cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP) plus rituximab, a chimeric monoclonal antibody against the CD20 antigen. However, some patients are not fit enough to tolerate CHOP or they relapse after previous therapy with CHOP. Gemcitabine as a monotherapy is active and relatively non-toxic in the treatment of NHL. We investigated the toxicity and efficacy of a combination of gemcitabine with rituximab in a small series of elderly patients with high-grade B-cell lymphoma who had either a relapse after CHOP, or were medically unfit to tolerate CHOP as a first-line therapy. Gemcitabine was given at 1000 mg/m2/week x 3, q28 days; rituximab at 325 mg/m2/week x 4 in the first cycle, and on day 1 of all subsequent cycles. Seven patients have been treated. The median number of cycles given was 4. The major toxicity was haematologic: grade 3/4 leukocytopenia occurred in 4 patients, grade 3/4 thrombocytopenia in 3 patients. There were no episodes of clinically significant bleeding. One patient developed febrile neutropenia and died in the course of treatment; another patient developed non-Q-wave myocardial infarction possibly related to hydration pre-treatment to rituximab and erythrocyte transfusion. He recovered well after symptomatic therapy. In 7 patients, 2 complete and 3 partial remissions were achieved, with an estimated median time to progression of 12 months. This series of patients shows that the combination of gemcitabine and rituximab is feasible in this population not able to undergo standard poly-chemotherapy, shows promising activity, and merits further evaluation.

The effects of continuous hot weather training on risk of exertional heat illness.

PURPOSE: To determine whether cumulative daily average wet-bulb globe temperature (WBGT) index, over one or two preceding days, is a better measure for predicting cases of exertional heat illness (EHI) than current daily average WBGT, which is the standard heat index used by the Marine Corps; and to identify the most accurate index of heat stress to prevent and predict future cases of EHI. METHODS: A case-crossover study was conducted in male and female Marine Corps recruits in basic training at Marine Corps Recruit Depot, Parris Island, SC. Weather measurements were obtained for 2069 cases of EHI during 1979-1997 and for randomly selected control periods before and after each EHI episode. RESULTS: The risk of EHI increased with WBGT (OR = 1.11 degrees F(-1); 95% CI, 1.10-1.13). EHI risk was associated not only with the WBGT at the time of the event (OR = 1.10 degrees F(-1); 95% CI, 1.08-1.11) but with the previous day's average WBGT as well (OR = 1.03 degrees F(-1); 95% CI, 1.02-1.05). Alternative combinations of WBGT components were identified that better predicted EHI risk. CONCLUSION: Our results provide evidence for a cumulative effect of previous day's heat exposure on EHI risk in these Marine Corps recruits. A simple index for use in predicting EHI risk is proposed that includes the dry-bulb temperature and the relative humidity.

Modelling Tumor Treating Fields for the treatment of lung-based tumors.

Tumor Treating Fields (TTFields), low-intensity electric fields in the frequency range of 100-500 kHz, exhibit antimitotic activity in cancer cells. TTFields were approved by the U. S. Food and Drug Administration for the treatment of recurrent glioblastoma in 2011. Preclinical evidence and pilot studies suggest that TTFields could be effective for treating certain types of lung cancer, and that treatment efficacy depends on the electric field intensity. To optimize TTFields delivery to the lungs, it is important to understand how TTFields distribute within the chest. Here we present simulations showing how TTFields are distributed in the thorax and torso, and demonstrate how the electric field distribution within the body can be controlled by personalizing the layout of the arrays used to deliver the field.

Strategies for the detection of disease genes in pancreatic cancer.

The present review summarizes our strategies aimed at identifying and characterizing genetic alterations occurring at the transcriptional and chromosomal level in pancreatic cancer. To study transcriptional alterations we have used a number of techniques including modified versions of differential hybridizations and cDNA RDA (representational difference analysis). These approaches have led to the identification of more than 500 genes with differential expression in pancreatic cancer. To study chromosomal aberrations occurring in pancreatic cancer tissues we used comparative genomic hybridization (CGH). This allowed the identification of a number of chromosomal regions containing putative tumor suppressor genes or oncogenes. Genes isolated in both approaches represent potential new disease genes for pancreatic cancer and are at present being characterized by individual or serial analysis.

Effect of nerve block on response of forearm blood flow to local temperature.

To determine the role of neurotransmitter in the response of forearm blood flow (ABF) to local (forearm) skin temperature (Tsk) we measured ABF of six subjects at Tsk from 25 to 40 degrees C before (control) and after brachial plexus block (BPB). Control experiments were conducted in an ambient temperature of 27-29 degrees C, adjusted to minimize the subject's overall thermal sensation. Tsk was regulated by blowing a controlled-temperature airstream through a plastic bag enclosing the arm. We first lowered Tsk to 25 degrees C and after 20 min began to measure ABF with Whitney strain gauges. We then raised Tsk by 2.5 degrees C steps to 40 degrees C and measured ABF every 30 s for at least 10 min at each level of Tsk. Mean ABF rose from 1.1 ml X 100 ml-1 X min-1 at Tsk of 25 degrees C to 2.1 ml X 100 ml-1 X min-1 at 32.5 degrees C to 13.7 ml X 100 ml-1 X min-1 at 40 degrees C in control experiments and from 2.8 to 4.4 to 14.8 ml X 100 ml-1 X min-1 after BPB. The effect of Tsk on ABF was highly significant (P less than 0.0001) but the effect of BPB was not (P approximately equal to 0.2). At thermoneutrality, the effect of Tsk on ABF is largely independent of neural activity, since this effect is unaffected by nerve block.

Interaction of local and reflex thermal effects in control of forearm blood flow.

We measured forearm blood flow (ABF) bilaterally on six subjects during 15-min periods of leg exercise and the first 10 min of recovery. One forearm (control) was kept at about 33 degrees C skin temperature in all experiments. In experiments at ambient temperature (Ta) of 15 degrees C, the other arm (experimental) was kept at about 26, 33, and 40 degrees C, respectively, during three successive cycles of exercise and recovery. ABF in the 26 degrees C forearm was linearly related to and averaged 42% of control. The relation of ABF in the 40 degrees C forearm to control ABF showed a bend at control ABF of 4-5 ml X 100 ml-1 X min-1. Below the bend, experimental ABF average 213% of control. Above the bend, experimental ABF averaged 5.09 ml X 100 ml-1 X min-1 above control. In four subjects, after heating the experimental forearm to 40 degrees C, we measured ABF for 25-30 min at rest in Ta of both 15 and 25 degrees C. At 25 degrees C Ta, ABF in the heated forearms rose gradually, but control ABF showed little change. At 15 degrees C Ta, the effect on ABF of local heating to 40 degrees C was much reduced, apparently due to reflex vasoconstrictor signals.

Exertional heat injury and gene expression changes: a DNA microarray analysis study.

This study examined gene expression changes associated with exertional heat injury (EHI) in vivo and compared these changes to in vitro heat shock responses previously reported by our laboratory. Peripheral blood mononuclear cell (PBMC) RNA was obtained from four male Marine recruits (ages 17-19 yr) who presented with symptoms consistent with EHI, core temperatures ranging from 39.3 to 42.5 degrees C, and elevations in serum enzymes such as creatine kinase. Controls were age- and gender-matched Marines from whom samples were obtained before and several days after an intense field-training exercise in the heat ("The Crucible"). Expression analysis was performed on Affymetrix arrays (containing approximately 12,600 sequences) from pooled samples obtained at three times for EHI group (at presentation, 2-3 h after cooling, and 1-2 days later) and compared with control values (average signals from two chips representing pre- and post-Crucible samples). After post hoc filtering, the analysis identified 361 transcripts that had twofold or greater increases in expression at one or more of the time points assayed and 331 transcripts that had twofold or greater decreases in expression. The affected transcripts included sequences previously shown to be heat-shock responsive in PBMCs in vitro (including both heat shock proteins and non-heat shock proteins), a number of sequences whose changes in expression had not previously been noted as a result of in vitro heat shock in PBMCs (including several interferon-induced sequences), and several nonspecific stress response genes (including ubiquitin C and dual-specificity phosphatase-1). We conclude that EHI produces a broad stress response that is detectable in PBMCs and that heat stress per se can only account for some of the observed changes in transcript expression. The molecular evidence from these patients is thus consistent with the hypothesis that EHI can result from cumulative effects of multiple adverse interacting stimuli.

Distribution and mitogen response of peripheral blood lymphocytes after exertional heat injury.

To determine whether immune disturbances during exertional heat injury (EHI) could be distinguished from those due to exercise (E), peripheral lymphocyte subset distributions and phytohemagglutinin-stimulated CD69 mitogen responses as discriminated by flow cytometry were studied in military recruits [18.7 +/- 0.3 (SE) yr old] training in warm weather. An E group (3 men and 3 women) ran 1.75-2 miles. During similar E, 11 recruits (10 men and 1 woman) presented with suspected EHI. EHI (40.4 +/- 0.3 degrees C) vs. E (38.6 +/- 0.2 degrees C) body temperature was significantly elevated (P < 0.05). Heat illness was largely classified as EHI, not heatstroke, because central nervous system manifestations were generally mild. Blood was collected at E completion or EHI onset (0 h) and 2 and 24 h later. At 0 h (EHI vs. E), suppressor, natural killer, and total lymphocyte counts were significantly elevated, helper and B lymphocyte counts remained similar, and the helper-to-suppressor ratio was significantly depressed. By 2 h, immune cell dynamics between groups were similar. From 0 to 24 h, T lymphocyte subsets revealed significantly reduced phytohemagglutinin responses (percent CD69 and mean CD69 fluorescent intensity) in EHI vs. E. Thus immune cell dynamics with EHI were distinguishable from E. Because heat stress as reported in exercise or heatstroke is associated with similar immune cell disturbances, these findings in EHI contributed to the suggestion that heat stress of varying severity shares a common pathophysiological process influencing the immune system.

Influence of polycythemia on blood volume and thermoregulation during exercise-heat stress.

We studied the effects of autologous erythrocyte infusion on blood volume and thermoregulation during exercise in the heat. By use of a double-blind design, nine unacclimated male subjects were infused with either 600 ml of a NaCl-glucose-phosphate solution containing a approximately 50% hematocrit (n = 6, reinfusion) or 600 ml of this solution only (n = 3, saline). A heat stress test (HST) was attempted approximately 2-wk pre- and 48-h postinfusion during the late spring months. After 30 min of rest in a 20 degrees C antechamber, the HST consisted of a 120-min exposure (2 repeats of 15 min rest and 45 min treadmill walking) in a hot (35 degrees C, 45% rh) environment while euhydrated. Erythrocyte volume (RCV, 51Cr) and plasma volume (PV, 125I) were measured 24 h before each HST, and maximal O2 uptake (VO2max) was measured 24 h after each HST. Generally, no significant effects were found for the saline group. For the reinfusion group, RCV (11%, P less than 0.01) and VO2max (11%, P less than 0.05) increased after infusion, and the following observations were made: 1) the increased RCV was associated with a reduction in PV to maintain the same blood volume as during the preinfusion measurements; 2) polycythemia reduced total circulating protein but did not alter F-cell ratio, plasma osmolality, plasma protein content, or plasma lactate at rest or during exercise-heat stress; 3) polycythemia did not change the volume of fluid entering the intravascular space from rest to exercise-heat stress; and 4) polycythemia tended to reduce the rate of heat storage during exercise-heat stress.

GRP-receptor-mediated signal transduction, gene expression and DNA synthesis in the human pancreatic adenocarcinoma cell line HPAF.

Bombesin-like peptides have been implicated as growth factors in various human cancers. Human adenocarcinoma cell lines (Capan-1, Capan-2, MiaPaCa-2 and HPAF) were tested to determine whether they express the gastrin-releasing peptide-preferring bombesin receptor (GRPR) and neuromedin B-preferring bombesin receptor (NMBR). Using RT-PCR the highest level of GRP receptor mRNA was found in HPAF cells. NMB receptor mRNA expression moderate in all cell lines investigated. We therefore selected the HPAF cell line to investigate whether bombesin treatment affects intracellular Ca(2+) ([Ca(2+)](i)), cAMP level, DNA synthesis as a measure of cell proliferation, and expression of three transcription factors: c-fos, c-myc and high mobility group protein IY (HMG-I(Y)).Bombesin administration led to an immediate increase in free intracellular Ca(2+) concentration ([Ca(2+)](i)) but did not change cAMP levels. The peptide also enhanced [(3)H]thymidine incorporation in HPAF cells (but not in the other cell lines), an effect that was concentration dependent, reaching 36 +/- 5% stimulation over control values at 24 h with an EC(50) of 2.27 x 10(-12) M. Furthermore, bombesin stimulated c-fos, c-myc and HMG-I(Y) expression in a time-dependent manner: the c-fos mRNA level increased dramatically in the first 30 min of exposure, then returned to basal level within 2 h, while the c-myc and HMG-I(Y) mRNA levels peaked at 2 h and 4h, respectively. All actions of bombesin were blocked by BME (D-Phe(6)-bombesin-(6-13)-methylester), a selective GRP receptor antagonist, but not by the NMB receptor antagonist BIM-23127 (D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH(2)). We conclude that HPAF cells express mRNA for GRP receptors and that functional receptors are present in the cell membrane. The occupation of these receptors leads to a sequence of intracellular events involving rapid mobilization of intracellular Ca(2+), expression of c-fos, c-myc and HMG-I(Y) mRNA, and stimulation of cell proliferation. Conversely, although NMB receptor mRNA can be detected, its actual translation to functional receptors does not reach a detectable level.

Individual differences in phenomenological experience: states of consciousness as a function of absorption.

State manifestations of the trait of absorption--a trait associated with differential responsivity to hypnosis, meditation, marijuana intoxification, and electromyograph (EMG) biofeedback--were assessed to determine (a) if absorption correlates with various (sub)dimensions of phenomenological experience, and (b) if individuals of differing absorption ability experience different states of consciousness. In two experiments 249 and 304 participants completed Tellegen's absorption scale and experienced several stimulus conditions. Each condition's phenomenological state was assessed by means of a retrospective self-report questionnaire and quantified in terms of intensity and pattern parameters. The results indicated that absorption correlated with increased and more vivid imagery, inward and absorbed attention, and positive affect; decreased self-awareness; and increased alterations in state of consciousness and various aspects of subjective experience. In addition, individuals of high absorption ability, relative to lows, experienced a different state of consciousness during ordinary, waking consciousness that became an altered state with eye closure and an hypnoticlike induction. The usefulness of the results for understanding altered-state induced procedures such as hypnosis is discussed.

Long-term follow-up after exertional heat illness during recruit training.

PURPOSE: To evaluate long-term susceptibility to subsequent serious exertional heat illness (EHI) in military recruits who suffered exertional heat illness during basic training. METHODS: We identified Marine Corps members who completed at least 6 months of military service and suffered EHI treated as outpatients (N = 872) or inpatients (N = 50) during basic training in 1979-1991 at the Parris Island Marine Corps Recruit Depot, SC (EHI cases). We compared them to 1391 similar members (noncases) who did not experience EHI during basic training. These subjects were followed from 6 months after accession into the military through the subsequent 4 yr. Follow-up was through military personnel records to determine retention and military hospital databases to determine subsequent hospitalizations during military service. RESULTS: Military retention rates were slightly lower for those who suffered EHI during basic training, compared with those who did not (24% vs 30% at 4 yr, respectively). Outpatient EHI cases also had about 40% higher subsequent hospitalization rates in military hospitals than noncases during their continued military service, although these differences declined over time and diagnoses showed little relationship to EHI. EHI cases had higher rates of subsequent hospitalization for EHI, but the number was too small (five hospitalizations) to provide stable comparisons. CONCLUSION: Hospitalization for EHI is uncommon during subsequent military service after an initial episode during basic training, and occurrence of EHI during basic training has only a small impact on subsequent military retention and hospitalization.