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About 20 Å of hafnium were deposited on silicon substrates using the electron beam evaporation technique. Two types of samples were investigated. In one type, the substrate was kept at the ambient temperature. After the deposition, the substrate temperature was increased to 100, 200, and 300°?C. In the other type, the substrate temperature was held fixed at some value during the deposition. For this type, the substrate temperatures used were 100, 200, 300, 400, 500, 550, and 600°?C. The samples were characterized in situ by the technique of X-ray photoelectron spectroscopy. No trace of elemental hafnium is observed in the deposited overlayer. Also, there is no evidence of any chemical reactivity between the overlayer and the silicon substrate over the temperature range used. The hafnium overlayer shows a mixture of the dioxide and the suboxide. The ratio of the suboxide to dioxide is observed to be more in the first type of samples. The spectral data indicate that hafnium has a strong affinity for oxygen. The overlayer gets completely oxidized to form HfO2 at substrate temperature around 300°?C for the first type of samples and at substrate temperature greater than 550°?C for the second type. [ABSTRACT FROM AUTHOR]

Advanced airway management in the prehospital arena remains controversial. This paper aims to explore some of the evidence and options available and propose a way forward. Options for provision of, and training in, pre-hospital emergency anaesthesia are explored and alternative strategies are discussed. Where classical rapid sequence induction of anaesthesia proves impractical for operational reasons or due to lack of facilities, training opportunities or skills maintenance, a potential 'silver standard' is suggested as an alternative. [ABSTRACT FROM AUTHOR]

Presents a scale for measuring teacher efficacy in classroom management and discipline, along with results from a factor analysis of intercorrelations of items from the scale and items from two other teacher efficacy scales. Data sources included 119 preservice teacher education students and 42 student teachers. Methods; Results; Discussion.

We derive analytical solutions for the autocorrelation and cross-correlation functions of the kinetic, potential, and total energy of a Langevin oscillator. These functions are presented in both the time and frequency domains and validated by independent numerical simulations. The results are applied to address the long-standing issue of temperature fluctuations in canonical systems. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations of a quasiharmonic solid are conducted to elucidate the meaning of temperature fluctuations in canonical systems and validate a well-known but frequently contested equation predicting the mean square of such fluctuations. The simulations implement two virtual and one physical (natural) thermostat and examine the kinetic, potential, and total energy correlation functions in the time and frequency domains. The results clearly demonstrate the existence of quasiequilibrium states in which the system can be characterized by a well-defined temperature that follows the mentioned fluctuation equation. The emergence of such states is due to the wide separation of time scales between thermal relaxation by phonon scattering and slow energy exchanges with the thermostat. The quasiequilibrium states exist between these two time scales when the system behaves as virtually isolated and equilibrium. [ABSTRACT FROM AUTHOR]

Many grain boundaries (GBs) in crystalline materials develop highly disordered, liquidlike structures at high temperatures. In alloys, this premelting effect can be fueled by solute segregation and can occur at lower temperatures than in single-component systems. A premelted GB can be modeled by a thin liquid layer located between two solid-liquid interfaces interacting by a disjoining potential. We propose a single analytical form of the disjoining potential describing repulsive, attractive, and intermediate interactions. The potential predicts a variety of premelting scenarios, including thin-to-thick phase transitions. The potential is verified by atomistic computer simulations of premelting in three different GBs in Cu-Ag alloys employing a Monte Carlo technique with an embedded atom potential. The disjoining potential has been extracted from the simulations by analyzing GB width fluctuations. The simulations confirm all shapes of the disjoining potential predicted by the analytical model. One of the GBs was found to switch back and forth between two (thin and thick) states, confirming the existence of thin-to-thick phase transformations in this system. The proposed disjoining potential also predicts the possibility of a cascade of thin-to-thick transitions caused by compositional oscillations (patterning) near solid-liquid interfaces. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Should medical journals try to influence political debates?" by J. P. Kassirer, seen in the February 11, 1999 issue.

5 Megat, et al., Integrative genetic analysis illuminates ALS heritability and identifies novel risk genes, in review. Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo. Sod1 deficiency reduces incubation time in mouse models of prion disease. [Extracted from the article]

Dispersal within agricultural fields and the effects of different barriers on between-field movement of the New Zealand hover fly Melanostoma fasciatum were studied using ingested pollen as markers. Hover flies did not generally disperse more than 20 m from the pollen source. Gravid females had no significant wind-directed movement pattern whereas males significantly flew downwind. Flies tended to avoid flying over barren land: a dirt track, an asphalt road or a ploughed field all seemed to hamper hover fly dispersal equally. The implications for spatial arrangement of the flowering strips to enhance the biocontrol potential of hover flies are discussed. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and strongly correlates with the growing incidence of obesity and type II diabetes. We have developed a human-on-a-chip model composed of human hepatocytes and adipose tissue chambers capable of modeling the metabolic factors that contribute to liver disease development and progression, and evaluation of the therapeutic metformin. This model uses a serum-free, recirculating medium tailored to represent different human metabolic conditions over a 14-day period. The system validated the indirect influence of adipocyte physiology on hepatocytes that modeled important aspects of NAFLD progression, including insulin resistant biomarkers, differential adipokine signaling in different media and increased TNF-α-induced steatosis observed only in the two-tissue model. This model provides a simple but unique platform to evaluate aspects of an individual factor's contribution to NAFLD development and mechanisms as well as evaluate preclinical drug efficacy and reassess human dosing regimens. [ABSTRACT FROM AUTHOR]

This report details the development of a non-invasive in vitro assay system for investigating the functional maturation and performance of human skeletal myotubes. Data is presented demonstrating the survival and differentiation of human myotubes on microscale silicon cantilevers in a defined, serum-free system. These cultures can be stimulated electrically and the resulting contraction quantified using modified atomic force microscopy technology. This system provides a higher degree of sensitivity for investigating contractile waveforms than video-based analysis, and represents the first system capable of measuring the contractile activity of individual human muscle myotubes in a reliable, high-throughput and non-invasive manner. The development of such a technique is critical for the advancement of body-on-a-chip platforms toward application in pre-clinical drug development screens. [ABSTRACT FROM AUTHOR]

Oncogenic mutations in components of the JAK/STAT pathway, including those in cytokine receptors and JAKs, lead to increased activity of downstream signaling and are frequently found in leukemia and other hematological disorders. Thus, small-molecule inhibitors of this pathway have been the focus of targeted therapy in these hematological diseases. We previously showed that t(8;21) fusion protein acute myeloid leukemia (AML)1-ETO and its alternatively spliced variant AML1-ETO9a (AE9a) enhance the JAK/STAT pathway via downregulation of CD45, a negative regulator of this pathway. To investigate the therapeutic potential of targeting JAK/STAT in t(8;21) leukemia, we examined the effects of a JAK2-selective inhibitor TG101209 and a JAK1/2-selective inhibitor INCB18424 on t(8;21) leukemia cells. TG101209 and INCB18424 inhibited proliferation and promoted apoptosis of these cells. Furthermore, TG101209 treatment in AE9a leukemia mice reduced tumor burden and significantly prolonged survival. TG101209 also significantly impaired the leukemia-initiating potential of AE9a leukemia cells in secondary recipient mice. These results demonstrate the potential therapeutic efficacy of JAK inhibitors in treating t(8;21) AML. [ABSTRACT FROM AUTHOR]

Rigorous analysis of muscle function in in vitro systems is needed for both acute and chronic biomedical applications. Forces generated by skeletal myotubes on bio-microelectromechanical cantilevers were calculated using a modified version of Stoney's thin-film equation and finite element analysis (FEA), then analyzed for regression to physical parameters. The Stoney's equation results closely matched the more intensive FEA and the force correlated to cross-sectional area (CSA). Normalizing force to measured CSA significantly improved the statistical sensitivity and now allows for close comparison of in vitro data to in vivo measurements for applications in exercise physiology, robotics, and modeling neuromuscular diseases. [ABSTRACT FROM AUTHOR]

As a component of the apoptosome, a caspase-activating complex, Apaf-1 plays a central role in the mitochondrial caspase activation pathway of apoptosis. We report here the identification of a novel Apaf-1 interacting protein, hepatocellular carcinoma antigen 66 (HCA66) that is able to modulate selectively Apaf-1-dependent apoptosis through its direct association with the CED4 domain of Apaf-1. Expression of HCA66 was able to potentiate Apaf-1, but not receptor-mediated apoptosis, by increasing downstream caspase activity following cytochrome c release from the mitochondria. Conversely, cells depleted of HCA66 were severely impaired for apoptosome-dependent apoptosis. Interestingly, expression of the Apaf-1-interacting domain of HCA66 had the opposite effect of the full-length protein, interfering with the Apaf-1 apoptotic pathway. Using a cell-free system, we showed that reduction of HCA66 expression was associated with a diminished amount of caspase-9 in the apoptosome, resulting in a lower ability of the apoptosome to activate caspase-3. HCA66 maps to chromosome 17q11.2 and is among the genes heterozygously deleted in neurofibromatosis type 1 (NF1) microdeletion syndrome patients. These patients often have a distinct phenotype compared to other NF1 patients, including a more severe tumour burden. Our results suggest that reduced expression of HCA66, owing to haploinsufficiency of HCA66 gene, could render NF1 microdeleted patients-derived cells less susceptible to apoptosis.Cell Death and Differentiation (2007) 14, 1222–1233. doi:10.1038/sj.cdd.4402122; published online 23 March 2007 [ABSTRACT FROM AUTHOR]

We have studied the role of cyclins and cyclin-dependent kinase (CDK) activity in apoptosis induced by camptothecin (CPT). In this model, 22% of the cells stain for annexin-V at 24 h and then proceed to be 93% positive by 72 h. This time window permits the analysis of cyclins in cells that are committed to apoptosis but not yet dead. We provide evidence that cyclin protein levels and then associated kinase levels increase after CPT treatment. Strikingly, cyclin B1 and cyclin E1 proteins are present at the same time in CPT treated HT29 cells. Although cyclin B1 and E1 CDK complexes are activated in CPT treated cells, only the cyclin B1 complex is required for apoptosis since reduction of cyclin B1 by RNAi or roscovitine treatment reduces the number of annexin-V-stained cells. We have detected poorly organized chromosomes and phosphorylated histone H3 epitopes at the time of maximum cyclin B1/CDK kinase activity in CPT-treated cells, which suggests that these cells enter a mitotic catastrophe. Understanding which CDKs are required for apoptosis may allow us to better adapt CDK inhibitors for use as anti-cancer compounds.Oncogene (2006) 25, 7361–7372. doi:10.1038/sj.onc.1209718; published online 19 June 2006 [ABSTRACT FROM AUTHOR]

Objective: To determine predictors of in-hospital and long-term mortality and length of stay in patients admitted to the neurosciences critical care unit.Design: Retrospective analysis of a prospectively collected database.Setting: Neurosciences critical care unit of a large academic tertiary care hospital.Patients: Adult patients (n = 2381) admitted to our neurosciences critical care unit from January 1997 to April 2000.Interventions: Introduction of a specialized neurocritical care team.Measurements and Main Results: Data obtained from the database included demographics, admission source, length of stay, neurosciences critical care unit and hospital disposition, admission Acute Physiology and Chronic Health Evaluation (APACHE) III score, and principal and secondary diagnoses. The introduction of a neurocritical care team in September 1998 was also collected, as was death at 1 yr after admission. Univariate analysis was carried out using Student's t-test, Mann-Whitney U test, or chi-square test (significance, p < .05). A logistic regression model was used to create a prediction model for in-hospital and long-term mortality. A general linear model was used to determine predictors of length of stay (after log transformation). Independent predictors of in-hospital mortality included APACHE III (odds ratio, 1.07 [1.06-1.08]) and admission from another intensive care unit (odds ratio, 2.9 [1.4-6.2]). The presence of a neurocritical care team was an independent predictor of decreased mortality (odds ratio, 0.7 [0.5-1.0], p = .044). Admission after the neurocritical care team was implemented was associated with reduced length of stay in both the neurosciences critical care unit (4.2 +/- 4.0 vs. 3.7 +/- 3.4, p < .001) and the hospital (9.9 +/- 8.0 vs. 8.4 +/- 6.9, p < .0001). There was no difference in readmission rates to the intensive care unit or discharge disposition to home before and after the neurocritical care team was established. The availability of the neurocritical care team was not associated with significant changes in long-term mortality. Factors independently associated with long-term mortality included female gender, admission from another intensive care unit, APACHE III score, and being moderately disabled before admission.Conclusion: Introduction of a neurocritical care team, including a full-time neurointensivist who coordinated care, was associated with significantly reduced in-hospital mortality and length of stay without changes in readmission rates or long-term mortality. [ABSTRACT FROM AUTHOR]

Protein adsorption on surfaces is a complex phenomenon that is described by the balance of convective/diffusive transport of the protein species to the surface and its adsorption/desorption at the surface. The extent of binding depends on a variety of factors such as protein/surface interactions, availability of binding sites, localized concentrations of protein near biomaterial surfaces and flow characteristics of the protein in that region. Factors such as time-varying flows, complex device geometries, presence of multiple competitive species, or possible denaturing of proteins when they attach to the surface make it extremely difficult to quantitatively analyze protein interactions with surfaces. Adsorption/desorption rate constants are often inferred using simplistic models which neglect mass transport and have limited use across different microfluidic systems and flow protocols. In this work, we have developed and demonstrated a fluidics-resolved model that evaluates protein adsorption, accounting for both the fluidic transport and the biochemical kinetics in complex biomicrofluidic devices. The model is valid for both flow and static conditions. An automated procedure was also developed to extract the “intrinsic” mass-transport-independent adsorption kinetic rate constants from experimental data using a least squares optimization method. The automated data extraction methodology is applied to two proteins (alkaline phosphatase and glucose oxidase) that have been brought into contact with poly(etheretherketone) and Teflon capillaries. The applicability of the procedure in analyzing flow and adsorption in complex microfluidic structures is also demonstrated. [Copyright &y& Elsevier]

Context: Inner-city high-risk infants often receive limited and fragmented care, a problem that may increase serious illness.Objective: To assess whether access to comprehensive care in a follow-up clinic is cost-effective in reducing life-threatening illnesses among high-risk, inner-city infants.Design: Randomized controlled trial.Setting and Participants: A total of 887 very-low-birth-weight infants born in a Texas county hospital between January 1988 and March 1996 and followed up in a children's hospital clinic. One hundred four infants who became ineligible or died after randomization but before nursery discharge were excluded from the analysis.Interventions: Infants were randomly assigned to receive routine follow-up care (well-baby care and care for chronic illnesses; n = 441) or comprehensive care (which included the components of routine care plus care for acute illnesses, with 24-hour access to a primary caregiver; n = 446).Main Outcome Measures: Life-threatening illnesses (ie, causing death or hospital admission for pediatric intensive care) occurring between nursery discharge and age 1 year, assessed by blinded evaluators from inpatient charts and state Medicaid and vital statistics records; and hospital costs (estimated from department-specific cost-to-charge ratios).Results: Comprehensive care resulted in a mean of 3.1 more clinic visits and 6.7 more telephone conversations with clinic staff (P<.001 for both). One-year outcomes were unknown for fewer comprehensive-care infants than routine-care infants (9 vs 28; P =.001). Identified deaths were similar (11 in comprehensive care vs 13 in routine care; P =.68). The comprehensive-care group had 48% fewer life-threatening illnesses (33 vs 63; P<.001), 57% fewer intensive care admissions (23 vs 53; P =.003), and 42% fewer intensive care days (254 vs 440; P =.003). Comprehensive care did not increase the mean estimated cost per infant for all care ($6265 with comprehensive care and $9913 with routine care).Conclusion: Comprehensive follow-up care by experienced caregivers can be highly effective in reducing life-threatening illness without increasing costs among high-risk inner-city infants. JAMA. 2000;284:2070-2076. [ABSTRACT FROM AUTHOR]

The potential role of the bcl-2 relative bcl-w as a physiological regulator of apoptosis in intestinal epithelia has been investigated. Immunoblots for bcl-w with new monoclonal antibodies revealed that it was expressed in the small intestine and colon, among other murine tissues, as well as in six human tumour cell lines of epithelial origin, including two colon carcinoma lines. To assess whether bcl-w regulates either spontaneous or damage-induced apoptosis in the small intestine or colon, apoptosis in intestinal crypts of bcl-w -/- and wild-type mice was quantified microscopically on a cell positional basis. Spontaneous apoptosis within crypt epithelia was not significantly increased by loss ofbcl-w, in either the small intestine or midcolon. However, after treatment with the cytotoxic drug 5-fluorouracil or with γ-radiation, the bcl-w-null animals exhibited substantially more apoptosis than their wild-type counterparts in both tissues. The greatest enhancement of apoptosis attributable to the absence of bcl-w (up to sixfold) occurred in the small intestine. Hence, bcl-w is an important determinant of damage-induced apoptosis in intestinal epithelia, and unlike bcl-2, which regulates only colonic apoptosis, plays a major role in small intestinal epithelium. Oncogene (2000) 19, 3955–3959 [ABSTRACT FROM AUTHOR]

Background: Epigenetic factors (i.e., alterations of gene activity not involving mutations), as well as genetic changes in surviving cancer cells, may play an important role in drug resistance following cancer chemotherapy-a common cause of tumor relapse. Bcl-2 family proteins are central to the regulation of apoptotic cell death and modulate drug sensitivity. We investigated how survival signals in the cellular microenvironment affect the expression, protein conformation, and protein-protein interactions of the Bcl-2 family proteins Bax and Bcl-x(L) and how changes in response to microenvironmental signals alter the response of cancer cells to the drug etoposide.Methods: JLP119 human B-lymphoma cells were treated with etoposide (40 microM) and then cultured in the presence of an activating anti-CD40 antibody, vascular cellular adhesion molecule-1 (VCAM-1)-to activate VLA-4 (alpha4beta1) integrin, and interleukin 4. Cell fate was monitored after etoposide treatment with or without these microenvironmental signals. Bcl-x(L) gene transcription and protein levels of Bcl-x(L) and Bax were measured by northern and western blotting, respectively. Nuclear translocation of transcription factor NF-kappaB was monitored by immunofluorescence and inhibited by (E)-capsaicin. Bax conformation and Bax-Bcl-x(L) interactions were monitored by immunofluorescence and immunoprecipitation, respectively.Results: Microenvironmental survival signals produced statistically significant reductions in etoposide-induced apoptotic cell death, from 84.6% (95% confidence interval [CI] = 76.7%-92.4%) to 21.3% (95% CI = 19.5%-23.0%); P<.001. Activation of surface protein CD40 increased Bcl-x(L) protein levels via an (E)-capsaicin-inhibitable activation of NF-kappaB; i.e. , (E)-capsaicin restored etoposide sensitivity. Interleukin 4 had no effect on Bcl-x(L) protein levels but accelerated the increase in Bcl-x(L) protein associated with CD40 activation. VCAM-1- and interleukin 4-mediated signals diminished conformational changes in Bax protein and prevented the etoposide-induced disruption of constitutive Bax-Bcl-x(L) binding.Conclusions: Microenvironmental factors reduce the sensitivity of a B-cell lymphoma to etoposide in vitro by modulating the expression and functions of Bax and Bcl-x(L). This interaction may provide a paradigm for epigenetically induced drug resistance in other tumors. [ABSTRACT FROM AUTHOR]

Background: Observational studies indicate that oophorectomy at about age 40 reduces breast cancer risk by approximately a half in high risk women. Widespread use of risk reducing oophorectomy is unlikely to be acceptable to these women. We explored the feasibility of giving goserelin to produce reversible ovarian suppression together with raloxifene to maintain bone mineral density (BMD). Objectives: The primary study objective was adherence to treatment. Secondary objectives were uptake of randomisation, side effects/quality of life and measures of effect on bone and in serum. Methods: Recruitment was from 3 UK Family History Clinics. Consenting women at ≥1 in 3 lifetime risk of breast cancer were randomised to control or monthly subcutaneous goserelin 3.6 mg and raloxifene 60 mg/d orally for two years. Questionnaires (Endocrine Symptom Checklist, Trait & State Anxiety, Sexual Activity & Cancer Worry) measuring toxicity/quality of life were administered by nurses. Dual energy X-ray absorptiometry (DXA) BMD measurements were performed in the treatment arm annually. Lipids and collagen breakdown products were measured by standard methods. Results: 75 of 511 (14.7%) women approached agreed to randomisation (38 to treatment and 37 to control). The major reason for non-entry was fear of side effects (85%). Median age was 37 and 35 years, for the experimental (A) and control arm (B), respectively. Median follow up is 8.8 years. 20/38 in arm A and 27/37 of controls completed the 24 m study. 18/38 women in arm A withdrew (13 [34%] because of side effects) and 10/37 in arm B for various reasons including the desire for risk reducing surgery (n = 4). No significant differences were seen in the Endocrine Symptom Sub-scale, State or Trait anxiety or Cancer Worry. However, Hot flushes, night and cold sweats (together p <0.005), vaginal dryness (p = 0.006); loss of interest in sex, dyspareunia and reduced sexual pleasure (together p < 0.005) were significantly more in arm A. Despite this, 11 of 23 women in arm A when asked would have been happy to complete a potential five years of treatment. BMD declined by 3-7% and Ctx significantly increased (p < 0.005 each) but both returned to baseline by year 3. Lipids were unchanged. 4 women later developed breast cancer in arm B and 2 in arm A. Conclusions: Uptake and adherence to treatment was relatively low in this group of women at high risk. The major reason for low uptake was fear of side effects and these were the major reason for drop out from treatment. Raloxifene did not maintain BMD. This approach to breast cancer prevention induced significant symptoms and bone loss, thus methods to ameliorate these need to be developed if ovarian suppression is to play a role in breast cancer prevention. [ABSTRACT FROM AUTHOR]

Bcl-2 homologues (such as Bcl-xL) promote survival in part through sequestration of "activator" BH3-only proteins (such as Puma), preventing them from directly activating Bax. It is thus assumed that inhibition of interactions between activators and Bcl-xL is a prerequisite for small molecules to antagonize Bcl-xL and induce cell death. The biological properties, described here of a terphenyl-based alpha-helical peptidomimetic inhibitor of Bcl-xL attest that displacement of Bax from Bcl-xL is also critical. Terphenyl 14 triggers Bax-dependent but Puma-independent cell death, disrupting Bax/Bcl-xL interactions without affecting Puma/Bcl-xL interactions. In cell-free assays, binding of inactive Bax to Bcl-xL, followed by its displacement from Bcl-xL by terphenyl 14, produces mitochondrially permeabilizing Bax molecules. Moreover, the peptidomimetic kills yeast cells that express Bax and Bcl-xL, and it uses Bax-binding Bcl-xL to induce mammalian cell death. Likewise, ectopic expression of Bax in yeast and mammalian cells enhances sensitivity to another Bcl-xL inhibitor, ABT-737, when Bcl-xL is present. Thus, the interaction of Bcl-xL with Bax paradoxically primes Bax at the same time it keeps Bax activity in check, and displacement of Bax from Bcl-xL triggers an apoptotic signal by itself. This mechanism might contribute to the clinical efficiency of Bcl-xL inhibitors. [ABSTRACT FROM AUTHOR]