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.

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.

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.

Más allá del tensor de difusión: experiencia preliminar en tractografía HARDI-CSD y super-resolución en 1. 5T / Beyond the diffusion tensor model: preliminary experience inHARDI tractography-CSD and super-resolution 1. 5T

Introduction: For more than a decade the diffusion tensor imaging model has been widely used in order to resolve and represent the intracranial white-matter microanatomy. Howeverthere are numerous studies that have successfully demonstrated the limitations associated with DTI in trying to define crossing-fibre regions. Various models have been developed with the intention of overcoming these limitations. This is why our study focuses on the description and preliminary experience in the use of tractography based on high-angular-resolution-diffusion imaging (HARDI) using the constrained spherical deconvolution (CSD) technique. Methods: The data was acquired on a Philips Achieva 1.5T resonator using a diffusion weighted single-shot echoplanar sequence along 32 directions with a b-value of 1000s/mm2. The images were processed using FSL v5.0 and MRtrix v0.2.10 software. Results: We achieved tensor free high-angular-resolution-diffusion tractographic images that better represented the white-matter micro-architecture than those obtained from the tensor model. Additionally, it was possible to generate track-density images (TDI) with a final resolution more than 500 times that of the acquired data.

Introducción: Desde hace más de una década que el modelo de tensor de difusión ha sido ampliamente utilizado con el fin de resolver y representar la microanatomía de la sustancia blanca intra-cerebral. Sin embargo, no son pocos los estudios que han logrado demostrar las grandes desventajas que el modelo presenta al tratar de definir regiones de entrecruzamiento de fibras. Diversos modelos han sido desarrollados para ofrecer una solución consistente, capaz de representar dichas regiones con mayor grado de correlación anatómica. Es por ello que nuestro estudio se enfoca en la descripción y experiencia preliminar en el uso de tractografía basada en imágenes de difusión de alta resolución angular (HARDI) usando el modelo de deconvolución esférica restringida (CSD). Métodos: La adquisición se realizó en un resonador Philips Achieva 1.5T mediante secuencia de difusión single-shot echo-planar de 32 direcciones con un b-value de 1.000s/mm² procesamiento de las imágenes se realizó mediante software FSL v5.0 y MRtrix v0.2.10. Resultados: Se lograron tractografías libres de tensor de difusión de alta resolución angular que representan la micro-arquitectura de la sustancia blanca de mejor manera que con las generadas a partir del modelo de tensor. Adicionalmente, se logró generar imágenes de densidad tractográfica (TDI) con una resolución final de más de 500 veces a la de adquisición.

Morphometric classification and spatial organization of spiral ganglion neurons in the human cochlea: consequences for single fiber response to electrical stimulation.

The unique, unmyelinated perikarya of spiral ganglion cells (SGCs) in the human cochlea are often arranged in functional units covered by common satellite glial cells. This micro anatomical peculiarity presents a crucial barrier for an action potential (AP) travelling from the sensory receptors to the brain. Confocal microscopy was used to acquire systematically volumetric data on perikarya and corresponding nuclei in their full dimension along the cochlea of two individuals. Four populations of SGCs within the human inner ear of two different specimens were identified using agglomerative hierarchical clustering, contrary to the present distinction of two groups of SGCs. Furthermore, we found evidence of a spatial arrangement of perikarya and their accordant nuclei along the cochlea spiral. In this arrangement, the most uniform sizes of cell bodies are located in the middle turn, which represents the majority of phonational frequencies. Since single-cell recordings from other mammalians may not be representative to humans and human SGCs are not accessible for physiological measurements, computer simulation has been used to quantify the effect of varying soma size on single neuron response to electrical micro stimulation. Results show that temporal parameters of the spiking pattern are affected by the size of the cell body. Cathodic stimulation was found to induce stronger variations of spikes while also leading to the lowest thresholds and longest latencies. Therefore, anodic stimulation leads to a more uniform excitation profile among SGCs with different cell body size.

Which elements of the mammalian central nervous system are excited by low current stimulation with microelectrodes?

Low current cortex stimulation produces a sparse and distributed set of activated cells often with distances of several hundred micrometers between cell bodies and the microelectrode. A modeling study based on recently measured densities of high threshold sodium channels Nav1.2 in dendrites and soma and low threshold sodium channels Nav1.6 in the axon shall identify spike initiation sites including a discussion on dendritic spikes. Varying excitability along the neural axis has been observed while studying different electrode positions and configurations. Although the axon initial segment (AIS) and nodes of Ranvier are most excitable, many thin axons and dendrites which are likely to be close to the electrode in the densely packed cortical regions are also proper candidates for spike initiation sites. Cathodic threshold ratio for thin axons and dendrites is about 1:3, whereas 0.2 mum diameter axons passing the electrode tip in 10 mum distance can be activated by 100 mus pulses with 2.6 muA. Direct cathodic excitation of dendrites requires a minimum electrode-fiber distance, which increases with dendrite diameter. Therefore thin dendrites can profit from the stronger electrical field close to the electrode but low current stimulation cannot activate large diameter dendrites, contrary to the inverse recruitment order known from peripheral nerve stimulation. When local depolarization fails to generate a dendritic spike, stimulation is possible via intracellular current flow that initiates an action potential, for example 200 mum distant in the low threshold AIS or in certain cases at the distal dendrite ending. Beside these exceptions, spike initiation site for cathodic low current stimulation appears rather close to the electrode.

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.

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.

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.

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.

Predictors of hospitalization in male Marine Corps recruits with exertional heat illness.

Exertional heat illness can have serious consequences and is a common cause of hospitalization during basic military training. The objective of this case-control study was to determine risk factors for hospitalization in male Marine Corps recruits who received medical care for heat illness during their basic military training course at Parris Island, South Carolina. Of 565 heat casualties, 61 (11%) were hospitalized (case subjects) and 504 were treated as outpatients (control subjects). Using univariate and multivariate analyses, demographic, clinical, and laboratory factors were assessed to determine predictors of hospitalization. Nineteen of the 24 analyzed variables were significantly associated with hospitalization. Three clinical variables (disorientation, rectal temperature, systolic blood pressure) and three laboratory variables (serum lactate dehydrogenase, potassium, and creatinine values) were highly predictive for hospitalization in recruits with exertional heat illness. A simple scoring system using these six variables predicted hospitalization with 87% sensitivity, 91% specificity, and a likelihood ratio of 9.7.

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.

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.

Hyponatremia associated with exercise: risk factors and pathogenesis.

Exercise-related hyponatremia is an infrequent but potentially life-threatening accompaniment of prolonged exercise. This condition results from sodium losses in sweat, excessive water intake, or both. We review the risk factors for development of this condition and discuss evidence that there is a population at increased risk of hyponatremia during prolonged exercise.

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.

[Multiple morbidity in a patient (87 years old)]. / Die polymorbide Patientin (87 Jahre).

The group of aged people--in particular of highly aged persons--increases and with it also the risk of polymorbidity. Atherosclerosis often occurs in the elderly population; it is not astonishing that atherosclerosis also increasingly affects the renal arteries. Another problem in this age group is chronic back- and leg pain. Considering a medicine that respects the patient's attitude and is reasonable and cost-effective, the care and therapy of a polymorbid patient offers a special challenge in the modern evidence-based medicine.

Use of DNA arrays/microarrays in pancreatic research.

In recent years, enormous technical advances in experimental protocols as well as robotic and bioinformatic techniques have allowed DNA array/microarray technology to emerge as the leading technology in the field of functional, disease-related genome analysis. Multiple applications exist for DNA arrays/microarrays including comparative genomic analysis to identify chromosomal imbalances (Matrix-CGH), the study of mutations and genetic polymorphisms, and the study of gene expression (expression profiling). Expression profiling is the most widely used application of DNA array/microarray technology and allows to measure gene expression of thousands of genes simultaneously. The present review describes the basic principles of expression profiling analyses and outlines some applications in pancreatic cancer research.

Novel technology for detection of genomic and transcriptional alterations in pancreatic cancer.

AIM: The present review summarizes our strategies aimed at identifying and characterizing genetic alterations occurring at the transcriptional and chromosomal level in pancreatic cancer. METHODS: To study transcriptional alterations we have used a number of techniques including modified versions of differential hybridizations and cDNA-RDA (representational difference analysis). Comparative genomic hybridization (CGH) was used to study chromosomal aberrations occurring in pancreatic cancer tissues. RESULTS: The study of transcriptional alterations led to the identification of more than 500 genes with differential expression in pancreatic cancer. The sum of these alterations represented the first expression profile characteristic for pancreatic tumors. The CGH analysis allowed the identification of a number of chromosomal regions containing putative tumor suppressor genes or oncogenes. These regions are presently being characterized at the molecular level. In a first approach the myb-oncogene was identified as the relevant oncogene of an amplification on 6q occurring in up to 10% of pancreatic cancer patients. CONCLUSIONS: Genes isolated in both approaches represent potential new disease genes for pancreatic cancer and are at present being characterized by individual or serial analysis.