Sequential Regime Research Articles

Application of a sequential regime shift detection method to the Bering Sea ecosystem

Abstract A common problem of existing methods for regime shift detection is their poor performance at the ends of time-series. Consequently, shifts in environmental and biological indices are usually detected long after their actual appearance. A recently introduced method based on sequential t-test analysis of regime shifts (STARS) treats all incoming data in real time, signals the possibility of a regime shift as soon as possible, then monitors how perception of the magnitude of the shift changes over time. Results of a STARS application to the eastern Bering Sea ecosystem show how the 1989 and 1998 regime shifts manifest themselves in biotic and abiotic indices in comparison with the 1977 shift.

Androgen Receptor Is Targeted to Distinct Subcellular Compartments in Response to Different Therapeutic Antiandrogens

Antiandrogens are routinely used in the treatment of prostate cancer. Although they are known to prevent activation of the androgen receptor (AR), little is known about the mechanisms involved. This report represents the first study of the localization of wild-type AR following expression at physiologic relevant levels in prostate cells and treatment with androgen and antiandrogens. We have characterized a cellular model for prostate cancer using in situ cellular fractionation, proteomics, and confocal microscopy and investigated the effect of antiandrogens in clinical use on the subcellular localization of the AR. Different antiandrogens have diverse effects on the subcellular localization of the AR. Treatment with androgen results in translocation from the cytoplasm to the nucleoplasm, whereas the antiandrogens hydroxyflutamide and bicalutamide lead to reversible association with the nuclear matrix. In contrast, treatment with the antiandrogen cyproterone acetate results in AR association with cytoplasmic membranes and irreversible retention within the cytoplasm. In addition, we demonstrate that AR translocation requires ATP and the cytoskeleton, regardless of ligand. These results reveal that not all antiandrogens work via the same mechanism and suggest that an informed sequential treatment regime may benefit prostate cancer patients. The observed subnuclear and subcytoplasmic associations of the AR suggest new areas of study to investigate the role of the AR in the response and resistance of prostate cancer to antiandrogen therapy.

Clinical trial of sequential antiviral therapy for patients with chronic hepatitis B in China

To establish a sequential antiviral regime and evaluate its efficacy in patients with chronic hepatitis B using a controlled trial. Seventy-four patients with chronic hepatitis B were divided into 3 groups: 30 cases were enrolled in the sequential antiviral group in which patients received eight-week treatment with thymosin alpha1 (1.6 mg/time, subcutaneous injection, 2 times/week), six-month treatment with interferon (500 MU/ times, muscle inject, every other day) begun in the fifth week of the therapeutic course, and lamivudine treatment (100 mg/days) begun 2 months later after HBeAg seroconversion or just after the withdrawal of interferon to more than eighteen months. Fourteen cases were enrolled in combination group in which patients received six-month treatment with interferon and thymosin alpha1 simultaneously in the same manner as in sequential antiviral group. Thirty cases were enrolled in lamivudine group in which patients received more than eighteen-month treatment with lamivudine. The temporary rates of HBeAg seroconversion and normalization of alanine aminotransferase (effective rate) in sequential antiviral group, combination group and lamivudine group were 76.7%, 78.6% and 13.3%, respectively. The effective rates of sequential group and combination group were very similar, and significantly higher than that of lamivudine group (P less than 0.01). Long-term efficacy rates were 76.7%, 57.1% and 16.7% among the three groups, respectively. The long-term effective rate of sequential group was relatively higher. The rate of liver damage sensitive period in sequential antiviral group and combination group was 47.7%. The time of onset was from 2 to 8 weeks after the treatment begun, earlier than that from 6 to 8 weeks after the beginning of interferon alone in the literature. Sequential antiviral therapy had much higher rates of long-term HBeAg seroconversion, undetectable HBV DNA and normalization of alanine aminotransferase with good cost-effectiveness. Its mechanism to promote the antiviral effect might be dependent on the immunoregulatory action of thymosin alpha1 in the earlier period and the specific inhibition of HBV DNA replication by lamivudine in the later period of the therapeutic course.

The effect of hormone replacement therapy on Ca2+ mobilization and P-selectin (CD62P) expression in platelets examined under flow cytometry.

A series of events, such as increase of cytoplasmic free calcium (Ca2+) and expression of P-selectin (CD62P), an adhesion molecule, on the platelet surface, are significant indicators of platelet activation. We have used flow cytometry to examine Ca2+ mobilization and CD62P expression in platelets in whole blood obtained in women prior to, and after, different forms of hormone replacement therapy. Thirty-two women completed a protocol consisting of two consecutive 1-month periods under oestradiol (E2), administered orally (2 mg/day) or transdermally (50 microg/day) in random order, followed by a 4-week transdermal sequential regime, in which, during the last 14 days, either progesterone (300 mg/day) or medroxyprogesterone acetate (5 mg/day) was added to the 50 microg/day E2, administered orally in random order. None of the hormonal combinations determined significant changes in Ca2+ mobilization or CD62P expression in non-stimulated platelets. However, stimulation of platelets with adenosine diphosphate, but not with thrombin, caused a significant increase in cytoplasmic Ca2+ concentration during treatment with transdermal E2 plus progesterone. Also when stimulating with thrombin, transdermal E2 was more active than oral E2 in increasing CD62P expression, a difference that was not reduced by the addition of progestogens. In conclusion, hormone replacement therapy only increased Ca2+ mobilization or CD62P expression in stimulated platelets, and then followed a varied pattern that was dependent on the stimulant and on the specific hormonal formulation.

Prospective randomized trial to assess caloric and protein needs of critically Ill, anuric, ventilated patients requiring continuous renal replacement therapy

Objectives We measured the energy and protein needs in 50 sequential, critically ill, ventilated patients requiring continuous renal replacement therapy (CRRT) for renal failure by using indirect calorimetry and three sequential isocaloric protein-feeding regimes of 1.5, 2.0, and 2.5 g · kg −1 · d −1. We also assessed the compliance of actual feeding with target feeding and correlated the predictive energy requirements of the formulae with the actual energy expenditure (EE) measured by indirect calorimetry. We also determined whether these feeding regimes affected patient outcome. Methods The energy and protein needs of 50 consecutive, critically ill patients (31 male; age 53.3 ± 17.4 y; Acute Physiology and Chronic Health Evaluation (APACHE II) score: 26.0 ± 8.0; Acute Physiology and Chronic Health Evaluation score predicted risk of death: 50.0 ± 25.0%) were assessed by using indirect calorimetry and ultrafiltrate nitrogen loss. Entry into this study was on commencement of CRRT. To eliminate any beneficial effect from the passage of time on nitrogen balance, 10 of the 50 patients were randomized to receive 2.0 g · kg −1 · d −1 throughout the study, and the others received an escalating isocaloric feeding regime (1.5, 2.0, and 2.5 g · kg −1 · d −1) at 48-h intervals. Enteral feeding was preferred, but if this was not tolerated or unable to meet target, it was supplemented or replaced by a continuous infusion of total parenteral nutrition. Energy was given to meet caloric requirements as predicted by the Schofield equation corrected by stress factors or based on the metabolic cart readings of EE and was kept constant for all patients throughout the trial. Patients were stabilized on each feeding regime for at least 24 h before samples of dialysate were taken for nitrogen analysis at 8-h intervals on the second day. CRRT was performed by using a blood pump with a blood flow of 100 to 175 mL/min. Dialysate was pumped in and out counter-currently to the blood flow at 2 L/h. A biocompatible polyacrylonitrile hemofilter was used in all cases. Results EE was 2153 ± 380 cal/d and increased by 56 ± 24 cal/d ( P < 0.0001) throughout the 6-d study period to 2431 ± 498 cal/d. At study entry, the mean predicted (Schofield) caloric requirement was 2101 ± 410. Patients received 99% of the predicted energy requirements. However, the mean EE was 11% higher at 2336 ± 482 calories. This difference was not uniform. If the predicted caloric requirement was less than 2500, the EE exceeded the predicted by an average of 19%. If the predicted caloric requirement was greater than 2500, the EE on average was 6% less than predicted. This relation was significant ( P = 0.025) and has not been described previously. Nitrogen balance was inversely related to EE ( P = 0.05), positively related to protein intake ( P = 0.0075), and more likely to be attained with protein intakes larger than 2 g · kg −1 · d −1 ( P = 0.0001). Nitrogen balance became positive in trial patients over time but were negative in control patients over time ( P = 0.0001). Nitrogen balance was directly associated with hospital outcome ( P = 0.03) and intensive care unit outcome ( P = 0.02). For every 1-g/d increase in nitrogen balance, the probability of survival increased by 21% ( P = 0.03; odds ratio, 1.211; 95% confidence limits, 1.017,1.443). Further, although enterally and parenterally fed patients had lower mortalities than predicted, the presence of enteral feeding, even after adjusting for predicted risk of death, had a statistically significant benefit to patient outcome ( P = 0.04). Conclusions This study found that a metabolic cart can improve the accuracy of energy provision and that a protein intake of 2.5 g · kg −1 · d −1 in these patients increases the likelihood of achieving a positive nitrogen balance and improving survival. Enteral feeding is preferable, but if this is not possible or does not achieve the target, then it should be supplemented by parenteral feeding.

Charge transfer in duplex DNA containing mismatch

A theory for charge transfer between the electrode and the donor/acceptor molecule coupled through a DNA bridge in solution is developed. We explore the crossover between the coherent tunneling and the incoherent sequential transfer regimes by varying the electrode potential and discuss the effects of single-base mismatches in DNA duplex in both regimes. In the former regime a single-base mismatch in DNA duplex causes a reduction in the charge transfer rate simply by decreasing the electron tunneling matrix element, however, in the latter regime the effects are rather complicated.

Ovarian cancer: progress and continuing controversies in management

Ovarian cancer is the most lethal of the gynaecological cancers, affecting approximately 1 in 75 women in the developed world. In most cases (>75%), the disease is disseminated beyond the ovary at diagnosis. For patients with stage III–IV disease, many clinicians agree that standard treatment should comprise six cycles of paclitaxel–carboplatin. Randomised trials over the past 10 years have indicated the superiority of paclitaxel-based treatment and that carboplatin is equivalent to cisplatin, but better tolerated. A recent trial has suggested that docetaxel may be a better option than paclitaxel, with reduced neurotoxicity and comparable efficacy. Overall treatment results remain unsatisfactory, since the median survival for these patients is 2–3 years. Future progress may be made by addressing the following issues: Would sequential regimes be more effective? Intriguing results from two large randomised trials (ICON-3 and GOG-132) indicate that single agent platinum might well be incorporated into such regimes. Additionally, a range of other agents could be tested as part of first-line regimes, having demonstrated activity in relapsed patients; these include topotecan, gemcitabine and liposomal doxorubicin. Newer agents, such as cell signalling inhibitors have shown potential as single agents, but may be particularly effective in combination with current drugs. Real progress can be expected when a better understanding is achieved of the mechanisms underlying clinical drug resistance in ovarian cancer, and a close laboratory–clinical interaction is crucial.

Transdermal estradiol reduces plasma myeloperoxidase levels without affecting the LDL resistance to oxidation or the LDL particle size

This study was designed to investigate the effects of different therapeutic range doses of transdermal estradiol (E(2)), alone or in combination with progesterone (P) or medroxyprogesterone acetate (MPA), on plasma lipoprotein levels and on three parameters related with LDL oxidizability, the resistance of LDL to oxidation by copper, the LDL particle size, and the myeloperoxidase levels. Thirty-five healthy postmenopausal women who had been amenorrheic for at least 1 year received two consecutive, 2-month doses of transdermal estrogen (25-microg and 50-microg E(2) patch). Thereafter, they were randomly assigned to receive a 2-month treatment of either a 100-microg E(2) patch or a 50-microg E(2) patch combined with P (300 mg/day) or MPA (5 mg/day) during the last 14 days. Neither transdermal E(2) alone nor transdermal E(2) plus progestogen modified the lipoprotein profile, the LDL resistance to oxidation, or the LDL particle size. However, all treatments similarly reduced the myeloperoxidase protein levels. Different dosages of transdermal E(2) within the therapeutic range were equally effective in reducing myeloperoxidase protein levels. The effect remained after addition of P or MPA in a sequential regime.

Mining and sustainable development: considerations for minerals supply

AbstractSustainable development involves meeting the needs of human societies while maintaining viable biological and physical Earth systems. The needs include minerals: metals, fuels, industrial and construction materials. There will continue to be considerable demand for virgin mineral resources, even if levels of recycling and efficiency of use are optimal, and rates of population growth and globalisation decrease significantly. This article aims to stimulate debate on strategic issues for minerals supply. While the world has considerable stocks of mineral resources overall, international considerations of the environmental and social aspects of sustainable development are beginning to result in limitations on where mining will be conducted and what types of deposits will be mined. Current and emerging trends favour large mines in parts of the world where mining can be conducted within acceptable limits of environmental and social impact. Finding new deposits that meet such criteria will be all the more challenging given a disturbing global decline in the rate of discovery of major economic resources over the last decade, and the decreasing land area available for exploration and mining.To attract responsible exploration and mining, governments of mining nations will need to provide: regional‐scale geo‐scientific datasets as required to attract and guide future generations of exploration; resource access through multiple and sequential land use regimes, and frameworks for dealing with indigenous peoples' issues; and arrangements for consideration of mining proposals and regulation of mines that ensure responsible management of environmental and social issues.The minerals industry will need to continue to pursue advances in technologies for exploration, mining, processing, waste management and rehabilitation, and in public reporting of environmental and social performance.

F03Transvaginal sonographic detection of endometrial pathology in postmenopausal women on HRT

BackgroundThe aim of this study was to assess the sonographic aspect of the endometrium in postmenopausal patients receiving hormone replacement therapy (HRT) at different phases of the treatment and to identify endometrial pathologies on the basis of abnormal sonographic findings.MethodThe study group was composed of 103 women treated with sequential (82) or combined (21) HRT for at least 6 months. All patients underwent transvaginal sonography (TVS) with evaluation of endometrial thickness and echopattern. Patients on seqential regimes underwent TVS subsequently in the estrogen (phase E) and progestogen phases (phase P) and after withdrawal bleeding or immediately 5 days after the last progestogen administration (phase 0). Patients with an endometrial thickness &gt; 5 mm (in phase 0 for patients on sequential HRT) or with TVS anomalies of the endometrial pattern underwent sonohysterography and/or hysteroscopy.ResultsIn the 82 women on sequential HRT regimes mean endometrial thickness was significantly lower in phase 0 (3.8 ± 1.2 mm) compared to phase E (5.8 ± 1.7 mm) and phase P (6.2 ± 2.1 mm). On 20 patients with TVS abnormal endometrial findings sonohysterography identified 8 benign endometrial polyps which were removed by hysteroscopy and 2 simple hyperplasia were diagnosed by histeroscopically guided biopsy.ConclusionsSonohysterography is useful in HRT patients to detect endometrial polyps. In case of diffuse or focal endometrial thickness on sonohysterography an office hysteroscopy with guided biopsy could be useful.

Methane activation by surface oxygen in calcia-stabilized zirconia

Methane activation at 450–700°C by 14 mol% calcia-stabilized zirconia was studied by the transient reaction of pure methane with the oxidized material. Three distinct sequential reaction regimes are observed. Initially, methane oxidation rates are similar to those in cofed methane–oxygen mixtures. After a small amount of oxygen (amount) is removed from the material, the reactivity of the material suddenly increases while a larger amount of oxygen, roughly equivalent to 1 surface layer, is removed. Finally, after this reductive phase, methane continues to react rapidly to deposit a surface layer of carbonaceous material which can be removed by reoxidation. This cycle can be repeated.

Biophysical Integration of Effects of Epidermal Growth Factor and Fibronectin on Fibroblast Migration

Cell migration is regulated simultaneously by growth factors and extracellular matrix molecules. Although information is continually increasing regarding the relevant signaling pathways, there exists little understanding concerning how these pathways integrate to produce the biophysical processes that govern locomotion. Herein, we report the effects of epidermal growth factor (EGF) and fibronectin (Fn) on multiple facets of fibroblast motility: locomotion speed, membrane extension and retraction activity, and adhesion. A surprising finding is that EGF can either decrease or increase locomotion speed depending on the surface Fn concentration, despite EGF diminishing global cell adhesion at all Fn concentrations. At the same time, the effect of EGF on membrane activity varies from negative to positive to no-effect as Fn concentration and adhesion range from low to high. Taking these effects together, we find that EGF and Fn regulate fibroblast migration speed through integration of the processes of membrane extension, attachment, and detachment, with each of these processes being rate-limiting for locomotion in sequential regimes of increasing adhesivity. Thus, distinct biophysical processes are shown to integrate for overall cell migration responses to growth factor and extracellular matrix stimuli.

Solvent Reorganization in Long-Range Electron Transfer: Density Matrix Approach

The dynamics of charge transfer from a photoexcited donor to an acceptor coupled through a bridge is investigated by using a correlation-function approach in Liouville space that takes into account solvent dynamics with an arbitrary distribution of time scales. The time- and frequency-resolved fluorescence spectrum from the acceptor is used to probe the scaling of the ET rate with bridge size. The crossover between the coherent tunneling (transfer) and the incoherent sequential (transport) regimes and its implications on the nature of ET processes in DNA are discussed.

A sampling plan for egg batches ofChilospp. (Lepidoptera: Pyralidae) on maize

Abstract The spatial distribution of egg batches of Chilo spp. on maize, Zea mays was described using Taylor's power law and the slope, b, was found to be 1.036. This value was not statistically different from 1 and the distribution of egg batches was therefore judged to be random. Using this Information, optimal sample sizes were calculated for both direct and binomial sampling plans. A presence‐absence sequential sampling regime based on an economic threshold of 15% of plants with egg batches is presented. A minimum of 40 plants should be inspected within 2–3 weeks of planting.

Growth Factors: Therapeutic Advances in Wound Healing

Polypeptide growth factors regulate cellular processes involved in wound healing. Application of exogenous growth factors can modify the healing process and, with recombinant DNA technology, growth factors can now be made in sufficient quantity to be used therapeutically. Several growth factors are showing promising results in clinical trials, especially in cases of impaired healing, such as chronic ulcers. Preclinical studies indicate that further growth factors may have therapeutic potential in a wide range of wound-healing applications. The use of specifically designed and modified growth factors, growth-factor inhibitors, and sequential and combinatorial dosing regimes offer further possibilities for enhancing wound healing.

A comparison of pregnancy rates for 131 donor oocyte transfers using either a sequential or fixed regime of steroid replacement therapy

This study describes the overall results of 131 donor oocyte transfers between 1982 and 1989 when 30 pregnancies resulted (23% pregnancy rate/transfer). A retrospective comparison of results between an earlier sequential hormone replacement regime and a more recent low dosage, variable length oestrogen replacement shows that the latter offers greater flexibility and a promising trend towards higher pregnancy rates.

Flow Regimes During Cyclic Steam Stimulation At Cold Lake

Abstract From the analyses of production data from thousands of cyclic steam stimulation (CSS) cycles at Cold Lake, a conceptual model of the flow regimes has been developed. It indicates that the traditional reservoir flow conceptualization of bitumen and water slipping past each other according to the relative permeability curves is, to a large extent, inapplicable at Cold Lake, and very likely inappropriate to visualizing steam stimulation in general. Upon completion of steam injection, three distinct and sequential flow regimes characterize the production phase: type I, free water with little if any bitumen production: type II, slugs of free water alternating with slugs of water in bitumen emulsion, resulting in scattered production rates; and type III, a single phase flow condition comprising of water in bitumen emulsion with very smooth, slowly varying production rates. In early cycles the majority of the bitumen production occurs during type III flow, with the type II regime being small. Over time, as the cycle number increases, the water content of the emulsion in type III flow reaches a maximum of about 50%; the flow then increasingly remains in type II condition, corresponding to a decline in the well's OSR and increase III the wafer/oil ratio (WOR) as the well begins to approach its economic limit. The swelling of the bitumen by the entrained water permits the emulsion to occupy essentially the whole pore space during type III flow, incorporating an otherwise continuous free water that could compete for production at the wellbore. This may be the physical reason for the need to introduce hysteresis to depress the water relative permeability during numerical stimulations of the production phase of CSS. Introduction Using cyclic steam stimulation (CSS), Esso Resources Canada Limited produces in excess of 14,000 m3/day of 10 API gravity bitumen from the Clearwater formation at Cold Lake, Alberta(l). A significant technological effort supports this large commercial thermal recovery project. Progress has been made in delineating the relative importance of key recovery mechanisms of CSS, such as formation recompaction, solution gas drive and gravity drainage(2). This paper reports the reservoir flow regimes during the production phase of CSS deduced from the analyses of production data from thousands of cycles. This analysis leads to the view-point that the traditional reservoir flow conceptualization of bitumen and water slipping past each other according to the relative permeability curves is, to a large extent, inapplicable at Cold Lake, and very likely inappropriate to visualizing steam stimulation in general. Perusal of the production data shows that the water and bitumen production rates often track each other with considerable coherence; this is most striking when the WOR is one. This is illustrated in Figure 1 for well A in its fourth cycle production. Note that in the later half of the cycle, for a period of 150 days, the WOR persists as one even during wide variations in fluid rates. During this period the reservoir is cooling, with the viscosity of the bitumen increasing much faster than that of the water; by the end of the period, it is estimated that the ratio of bitumen to water viscosity has increased at least by a factor of two.

Coherent and sequential tunneling in double barriers with transverse magnetic fields.

Coherent and sequential processes in resonant tunneling through a double barrier are theoretically analyzed by means of a magnetic field parallel to the interfaces. The use of a simple model for describing scattering effects and a generalized transfer Hamiltonian method allow us to conclude that presently available experimental information is restricted to the sequential regime. We show that, for systems with barriers narrower than the ones used in the published experiments, coherent tunneling becomes dominant on the sequential mechanism.

Clinical applications of antiandrogens

Antiandrogens, substances that prevent androgens from expressing their activity at target cells, play an important role in the treatment of prostate cancer. The most frequently used substances have either a steroidal structure (cyproterone acetate) or a non-steroidal structure (Flutamide or Anandron). Antiandrogens have been tested both alone and in combination with treatments aimed at inhibiting testicular secretion (castration, LH-RH analogs), thereby producing complete blockade of androgen secretion and action. Patients treated by such combination protocols have often shown an improvement in the percentage of remissions and, less often, improvement in survival. Administration of antiandrogens improves the clinical symptoms of patients with benign prostatic hypertrophy, but the exact mechanism of their action requires further investigation. Cutaneous manifestations due to hyperandrogenicity (hirsutism, alopecia, acne) have also been improved by cyproterone acetate, which is often given together with estrogens (reversed sequential regime), by spironolactone or topically applied products. Finally, antiandrogens have been successfully used to treat breast cancer in men, early puberty, hypersexuality and sexual deviations.

Test of sequential feeding regimes for larvae of Elminius modestus Darwin (Cirripedia: Balanomorpha)

The larvae of the intertidal barnacle Elminius modestus Darwin were reared using six different feeding regimes comprising a large and/or a small flagellate fed to the larvae at different times during the course of their development. The relative value of the feeding regimes was ascertained by using the rate of development, survival, and size attained by the larvae as a measure of success or failure. The best feeding regime was found to be that providing a unialgal diet of the small flagellate initially followed by a unialgal diet of the large flagellate in later stages of development, while the reverse situation gave the worst results. The increase in mesh size of the antennal filter during growth of the nauplii is suggested as a reason for the varying success of feeding regimes employing foods of different sizes during development. This is seen as confirmation of the idea that cirriped nauplii collect their food by means of filtering appendages rather than by localized currents alone.