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Biomedical subjects

Paul Miller

Publications and source records attributed to Paul Miller.

At least 19 recordsLinked to original sources
PubMed2007

Efficacy and safety of rosuvastatin 40 mg versus atorvastatin 80 mg in high-risk patients with hypercholesterolemia: results of the POLARIS study.

POLARIS investigated the efficacy and safety of rosuvastatin 40 mg and atorvastatin 80 mg in high-risk patients with hypercholesterolemia. Patients (n=871) were randomized to rosuvastatin 40 mg/day or atorvastatin 80 mg/day for 26 weeks. The primary endpoint was percentage change in LDL-C levels at 8 weeks. Secondary assessments included safety and tolerability, NCEP ATP III LDL-C goal achievement, change in other lipids and lipoproteins at 8 and 26 weeks, and health economics. Mean LDL-C levels were reduced significantly more with rosuvastatin 40 mg than with atorvastatin 80 mg at 8 weeks (-56% versus -52%, p<0.001). The proportion of patients achieving the NCEP ATP III LDL-C goal at 8 weeks was significantly higher in the rosuvastatin 40 mg group (80% versus 72%, p<0.01). Significant differences in the change from baseline in high-density lipoprotein cholesterol (HDL-C) (+9.6% versus +4.4%) and apolipoprotein (Apo)A-I levels (+4.2 versus -0.5) were observed between rosuvastatin and atorvastatin (all p<0.05). Both treatments were well tolerated. Based on a US analysis, rosuvastatin used fewer resources and delivered greater efficacy. Intensive lipid-lowering therapy with rosuvastatin 40 mg/day provided greater LDL-C-lowering efficacy than atorvastatin 80 mg/day, enabling more patients to achieve LDL-C goals. Rosuvastatin may therefore improve LDL-C goal achievement in high-risk patients with hypercholesterolemia.

Aged↗
PubMed2007

The role of spoken and sign languages in the retention of written words by prelingually deafened native signers.

The purpose of this study was to determine the nature and efficiency of the strategies used by prelingually deafened native signers for the temporary retention of written words with reference to a primary language-coding hypothesis (M. A. Shand, 1982). For the gathering of the data, participants were shown lists of serially presented written target words that they were asked to recognize according to their presentation order from within word pools that contained different types of code-specific distracter words. Three performance dimensions were examined: (a) false recognition of target words, (b) correct recognition of target words, and (c) retention of target word presentation order. Participants were prelingually deafened native signers (n=11, average grade level=8.18 [1.17]) and a hearing control group (n=25, average grade level=9.00 [0.76]). Findings from the analysis of the nature of false recognition and the number of correctly recognized words show convincingly that formationally similar distracter words interfered with the memory performance of the native signers and phonologically similar distracter words with that of the hearing control group. It was concluded that the participants decoded written words into a code reflecting their primary language experience for their temporary retention in working memory.

Adolescent↗
PubMed2007

Long-term control of bone turnover in Paget's disease with zoledronic acid and risedronate.

UNLABELLED: A single 5-mg infusion of zoledronic acid restores biochemical markers of bone turnover into the reference range in the majority of patients with Paget's disease and maintains biochemical remission for at least 2 years. This effect is largely independent of pretreatment disease activity and prior bisphosphonate therapy. INTRODUCTION: Zoledronic acid (ZOL) is a potent bisphosphonate that produces a rapid and complete control of the increased bone turnover of Paget's disease. Long-term control of disease activity is an important aim of treatment in the hope that this will reduce the risk of complications such as deformity, fracture, and degenerative joint disease. MATERIALS AND METHODS: This study compares the ability of ZOL 5 mg given as a 15-minute intravenous infusion with risedronate (RIS) 30 mg daily by mouth for 60 days to maintain long-term control of bone turnover. No bisphosphonate was given during the extension study. All patients (n = 296) who achieved a therapeutic response, defined as normalization or a >75% reduction in the total alkaline phosphatase (total ALP) excess above the midpoint of the reference range, were eligible for inclusion. RESULTS: ZOL maintained the mean level of total ALP at the middle of the reference range, whereas those treated with risedronate showed a linear increase in total ALP from the 6-month post-treatment time-point. Both treatments resulted in a linear relationship between the 6-month nadir and 24-month total ALP. The relationship for RIS was shifted upward, showing that for a given level of post-treatment biochemical activity, bone turnover increased with time. This was in contrast to the ZOL-treated patients where total ALP generally remained unchanged over this 18-month extension period. A similar pattern of response was seen with the other bone turnover markers. CONCLUSIONS: ZOL maintains bone turnover within the reference range over 24 months from the initiation of treatment. A reduction in the incidence and severity of long-term complications may require persistent normalization of bone turnover over many years, and this now seems a realistic possibility with ZOL.

Administration, Oral↗
PubMed2006

Phosphorothioate oligonucleotides reduce mitochondrial outer membrane permeability to ADP.

G3139, an antisense Bcl-2 phosphorothioate oligodeoxyribonucleotide, induces apoptosis in melanoma and other cancer cells. This apoptosis happens before and in the absence of the downregulation of Bcl-2 and thus seems to be Bcl-2-independent. Binding of G3139 to mitochondria and its ability to close voltage-dependent anion-selective channel (VDAC) have led to the hypothesis that G3139 acts, in part, by interacting with VDAC channels in the mitochondrial outer membrane (21). In this study, we demonstrate that G3139 is able to reduce the mitochondrial outer membrane permeability to ADP by a factor of 6 or 7 with a K(i) between 0.2 and 0.5 microM. Because VDAC is responsible for this permeability, this result strengthens the aforesaid hypothesis. Other mitochondrial respiration components are not affected by [G3139] up to 1 microM. Higher levels begin to inhibit respiration rates, decrease light scattering and increase uncoupled respiration. These results agree with accumulating evidence that VDAC closure favors cytochrome c release. The speed of this effect (within 10 min) places it early in the apoptotic cascade with cytochrome c release occurring at later times. Other phosphorothioate oligonucleotides are also able to induce VDAC closure, and there is some length dependence. The phosphorothioate linkages are required to induce the reduction of outer membrane permeability. At levels below 1 microM, phosphorothioate oligonucleotides are the first specific tools to restrict mitochondrial outer membrane permeability.

Adenosine Diphosphate↗
PubMed2006

Bcl-2 protein in 518A2 melanoma cells in vivo and in vitro.

PURPOSE: Bcl-2 is an apoptotic protein that is highly expressed in advanced melanoma. Several strategies have been employed to target the expression of this protein, including G3139, an 18-mer phosphorothioate oligodeoxyribonucleotide targeted to the initiation region of the Bcl-2 mRNA. This compound has recently completed phase III global clinical evaluation, but the function of Bcl-2 as a target in melanoma has not been completely clarified. To help resolve this question, we have permanently and stably down-regulated Bcl-2 protein and mRNA expression in 518A2 cells by two different technologies and evaluated the resulting clones both in vitro and in vivo. EXPERIMENTAL DESIGN: 518A2 melanoma cells were transfected with plasmids engineered to produce either a single-stranded antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA or a short hairpin RNA also targeted to the Bcl-2 mRNA. In vitro growth, the apoptotic response to G3139, and the G3139-induced release of cytochrome c from isolated mitochondria were evaluated. Cells were then xenografted into severe combined immunodeficient mice and tumor growth was measured. RESULTS: In vitro, down-regulation of Bcl-2 expression by either method produced no change either in the rate of growth or in sensitivity to standard cytotoxic chemotherapeutic agents. Likewise, the induction of apoptosis by G3139 was entirely Bcl-2 independent. In addition, the G3139-induced release from isolated mitochondria was also relatively independent of Bcl-2 expression. However, when xenografted into severe combined immunodeficient mice, cells with silenced Bcl-2, using either technology, either failed to grow at all or grew to tumors of low volume and then completely regressed. In contrast, control cells with "normal" levels of Bcl-2 protein expression expanded to be large, necrotic tumors. CONCLUSIONS: The presence of Bcl-2 protein profoundly affects the ability of 518A2 melanoma cells to grow as human tumor xenografts in severe combined immunodeficient mice. The in vivo role of Bcl-2 in melanoma cells thus differs significantly from its in vitro role, and these experiments further suggest that Bcl-2 may be an important therapeutic target even in tumors that do not contain the t14:18 translocation.

Animals↗
PubMed2006

A pharmacologic target of G3139 in melanoma cells may be the mitochondrial VDAC.

G3139, an 18-mer phosphorothioate antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA, can induce caspase-dependent apoptosis via the intrinsic mitochondrial pathway in 518A2 and other melanoma cells. G3139-mediated apoptosis appears to be independent of its ability to down-regulate the expression of Bcl-2 protein, because the release of mitochondrial cytochrome c precedes in time the down-regulation of Bcl-2 protein expression. In this study, we demonstrate the ability of G3139 and other phosphorothioate oligonucleotides to bind directly to mitochondria isolated from 518A2 cells. Furthermore, we show that this interaction leads to the release of cytochrome c in the absence of a mitochondrial membrane permeability transition. Our data further demonstrate that there is an interaction between G3139 and VDAC, a protein that can facilitate the physiologic exchange of ATP and ADP across the outer mitochondrial membrane. Evidence from the electrophysiologic evaluation of VDAC channels reconstituted into phospholipid membranes demonstrates that G3139 is capable of producing greatly diminished channel conductance, indicating a closed state of the VDAC. This effect is oligomer length-dependent, and the ability of phosphorothioate homopolymers of thymidine of variable lengths to cause the release of cytochrome c from isolated mitochondria of 518A2 melanoma cells can be correlated with their ability to interact with VDAC. Because it has been suggested that the closure of VDAC leads to the opening of another outer mitochondrial membrane channel through which cytochrome c can transit, thus initiating apoptosis, it appears that VDAC may be an important pharmacologic target of G3139.

Base Sequence↗
PubMed2006

Influence of surgical strategies on outcome after the Norwood procedure.

OBJECTIVE: The study objective was to identify how the evolution of surgical strategies influenced the outcome after the Norwood procedure. METHODS: From 1992 to 2004, 367 patients underwent the Norwood procedure (median age, 4 days). Three surgical strategies were identified on the basis of arch reconstruction and source of pulmonary blood flow. The arch was refashioned without extra material in group A (n = 148). The arch was reconstructed with a pulmonary artery homograft patch in groups B (n = 145) and C (n = 74). Pulmonary blood flow was supplied by a modified Blalock-Taussig shunt in groups A and B. Pulmonary blood flow was supplied by a right ventricle to pulmonary artery conduit in group C. Early mortality, actuarial survival, and freedom from arch reintervention or pulmonary artery patch augmentation were analyzed. RESULTS: Early mortality was 28% (n = 102). Actuarial survival was 62% +/- 3% at 6 months. Early mortality was lower in group C (15%) than group A (31%) or group B (31%; P <.05). Actuarial survival at 6 months was better in group C (78% +/- 5%) than group A (59% +/- 5%) or group B (58% +/- 4%; P <.05). Fifty-three patients (14%) had arch reintervention. Freedom from arch reintervention was 76% +/- 3% at 1 year, with univariable analysis showing no difference among groups A, B, and C (P =.71). One hundred patients (27%) required subsequent pulmonary artery patch augmentation. Freedom from patch augmentation was 61% +/- 3% at 1 year, and was lower in group C (3% +/- 3%) than group A (80% +/- 4%) or group B (72% +/- 5%; P <.05). CONCLUSIONS: Survival after the Norwood procedure improved after the introduction of a right ventricle to pulmonary artery conduit, but a greater proportion of patients required subsequent pulmonary artery patch augmentation. The type of arch reconstruction did not affect the incidence of arch reintervention.

Aorta↗
PubMed2006

Processing unpointed Hebrew: what can we learn from determining the identicalness of monosyllabic and bisyllabic nouns.

The aim of this study was to determine whether Hebrew readers reference phonological information for the silent processing of unpointed Hebrew nouns. A research paradigm in which participants were required to perform consecutive same/different judgments regarding the identicalness of members of stimulus pairs was used for answering this question. Twenty-eight students (mean grade 4.9) participated in the study. The nouns used in preparing the word stimulus pairs were comprised of various amounts of syllabic information (monosyllabic versus bisyllabic) and differed in the degree this information was represented by their letter graphemes. The main findings suggest that the processing of the identicalness of unpointed Hebrew words may not involve the referencing of their phonological information.

Child↗
PubMed2006

Experience with intraoperative ultrasound in paediatric cardiac surgery.

OBJECTIVE: Intraoperative ultrasound was introduced to evaluate the adequacy of repair after surgical repair of congenital cardiac malformations. Our purpose was to review the evolution of this technique at our centre. METHODS: We evaluated all intraoperative ultrasound studies undertaken between 1997 and 2002, reviewing the data from 1997 through 2001 retrospectively, but undertaking a prospective audit of studies undertaken from 2002 onwards. In all, we carried out a total number of 639 intraoperative ultrasound studies, from a possible 2737 cardiac operations (23.3%), using the epicardial approach in 580 (90.7%), and transoesophageal ultrasound in the other 59 patients (9.3%). Median age was 0.6 years, with an interquartile range from 0.06 to 3.6 years. RESULTS: The findings obtained using intraoperative ultrasound influenced the surgical management in 63 of the 639 patients (9.9%), suggesting the need for additional surgery in 26, adjustment of the band placed round the pulmonary trunk in 16, preoperative assessment of the cardiac malformation in 5, and confirming the need for prolonged support with cardiopulmonary bypass for impaired ventricular function in 16. There were 18 early reoperations, 5 of which may have been predicted by intraoperative ultrasound. Of the 183 studies reviewed prospectively in 2002, it was not possible to obtain the complete range of views in 8 (4.4%), while in 27 patients (14.7%), the postoperative findings using transthoracic interrogation differed from the findings obtained immediately following bypass. CONCLUSION: Intraoperative ultrasound is an important technique for monitoring the results of complex congenital cardiac surgery. The immediate recognition of significant lesions, together with multidisciplinary discussion, allows for improved management and prevention of early surgical reintervention.

Adolescent↗
PubMed2006

Stability of discrete memory states to stochastic fluctuations in neuronal systems.

Noise can degrade memories by causing transitions from one memory state to another. For any biological memory system to be useful, the time scale of such noise-induced transitions must be much longer than the required duration for memory retention. Using biophysically-realistic modeling, we consider two types of memory in the brain: short-term memories maintained by reverberating neuronal activity for a few seconds, and long-term memories maintained by a molecular switch for years. Both systems require persistence of (neuronal or molecular) activity self-sustained by an autocatalytic process and, we argue, that both have limited memory lifetimes because of significant fluctuations. We will first discuss a strongly recurrent cortical network model endowed with feedback loops, for short-term memory. Fluctuations are due to highly irregular spike firing, a salient characteristic of cortical neurons. Then, we will analyze a model for long-term memory, based on an autophosphorylation mechanism of calcium/calmodulin-dependent protein kinase II (CaMKII) molecules. There, fluctuations arise from the fact that there are only a small number of CaMKII molecules at each postsynaptic density (putative synaptic memory unit). Our results are twofold. First, we demonstrate analytically and computationally the exponential dependence of stability on the number of neurons in a self-excitatory network, and on the number of CaMKII proteins in a molecular switch. Second, for each of the two systems, we implement graded memory consisting of a group of bistable switches. For the neuronal network we report interesting ramping temporal dynamics as a result of sequentially switching an increasing number of discrete, bistable, units. The general observation of an exponential increase in memory stability with the system size leads to a trade-off between the robustness of memories (which increases with the size of each bistable unit) and the total amount of information storage (which decreases with increasing unit size), which may be optimized in the brain through biological evolution.

Action Potentials↗
PubMed2006

Analysis of spike statistics in neuronal systems with continuous attractors or multiple, discrete attractor States.

Attractor networks are likely to underlie working memory and integrator circuits in the brain. It is unknown whether continuous quantities are stored in an analog manner or discretized and stored in a set of discrete attractors. In order to investigate the important issue of how to differentiate the two systems, here we compare the neuronal spiking activity that arises from a continuous (line) attractor with that from a series of discrete attractors. Stochastic fluctuations cause the position of the system along its continuous attractor to vary as a random walk, whereas in a discrete attractor, noise causes spontaneous transitions to occur between discrete states at random intervals. We calculate the statistics of spike trains of neurons firing as a Poisson process with rates that vary according to the underlying attractor network. Since individual neurons fire spikes probabilistically and since the state of the network as a whole drifts randomly, the spike trains of individual neurons follow a doubly stochastic (Poisson) point process. We compare the series of spike trains from the two systems using the autocorrelation function, Fano factor, and interspike interval (ISI) distribution. Although the variation in rate can be dramatically different, especially for short time intervals, surprisingly both the autocorrelation functions and Fano factors are identical, given appropriate scaling of the noise terms. Since the range of firing rates is limited in neurons, we also investigate systems for which the variation in rate is bounded by either rigid limits or because of leak to a single attractor state, such as the Ornstein-Uhlenbeck process. In these cases, the time dependence of the variance in rate can be different between discrete and continuous systems, so that in principle, these processes can be distinguished using second-order spike statistics.

Action Potentials↗
PubMed2005

Inhibitory control by an integral feedback signal in prefrontal cortex: a model of discrimination between sequential stimuli.

The prefrontal cortex (PFC) is known to be critical for inhibitory control of behavior, but the underlying mechanisms are unclear. Here, we propose that inhibitory control can be instantiated by an integral signal derived from working memory, another key function of the PFC. Specifically, we assume that an integrator converts excitatory input into a graded mnemonic activity that provides an inhibitory signal (integral feedback control) to upstream afferent neurons. We demonstrate this scenario in a neuronal-network model for a temporal discrimination task. The task requires the working memory of the vibrational frequency (f1) of an initial stimulus (stimulus 1), followed by comparison of the frequency (f2) of a second stimulus (stimulus 2) with the stored f1 and a binary decision (f2 > f1 or f2 < f1). The integral feedback signal generated by stimulus 1 gates the later inputs based on the amplitude difference (f2 - f1). The feedback control signal enables a subset of neurons to reverse their tuning to f1 between stimulus 1 and stimulus 2, when they become tuned to the difference, f2 - f1. These neurons maintain a lower firing rate during the delay compared with their peak rate during stimulus 1. A second subset of neurons, tuned to f1 during the delay, reaches a rate during stimulus 2 that depends on the maximum of f1 and f2. Our work suggests a circuit mechanism for discrimination across time and predicts neuronal behavior that can be tested experimentally.

Discrimination, Psychological↗
PubMed2005

Power-law neuronal fluctuations in a recurrent network model of parametric working memory.

In a working memory system, persistent activity maintains information in the absence of external stimulation, therefore the time scale and structure of correlated neural fluctuations reflect the intrinsic microcircuit dynamics rather than direct responses to sensory inputs. Here we show that a parametric working memory model capable of graded persistent activity is characterized by arbitrarily long correlation times, with Fano factors and power spectra of neural activity described by the power laws of a random walk. Collective drifts of the mnemonic firing pattern induce long-term noise correlations between pairs of cells, with the sign (positive or negative) and amplitude proportional to the product of the gradients of their tuning curves. None of the power-law behavior was observed in a variant of the model endowed with discrete bistable neural groups, where noise fluctuations were unable to cause long-term changes in rate. Therefore such behavior can serve as a probe for a quasi-continuous attractor. We propose that the unusual correlated fluctuations have important implications for neural coding in parametric working memory circuits.

Action Potentials↗
PubMed2005

What the processing of real words and pseudohomophones can tell us about the development of orthographic knowledge in prelingually deafened individuals.

This study represents an attempt to determine the nature and efficiency of the strategies used by prelingually deafened individuals for the recognition of written words with reference to an orthographic self-teaching concept (D. L. Share, 1995). A research paradigm asking the participants to make categorical judgments for real words and pseudohomophones of the real words was used for gathering the data. Participants were prelingually deafened, native signers (n = 11, age = 14.18) and a hearing control group (n = 25, age = 15.00). In general, findings suggest that, although the participants with deafness were very impaired in their phonological decoding abilities, their efficiency in recognizing and categorizing written words was similar to that of their hearing counterparts. This suggests that they must have developed strategies for the acquisition of orthographic knowledge that do not rely on phonology.

Adolescent↗
PubMed2005

Body odor similarity in noncohabiting twins.

There is currently considerable interest in biometric approaches using human odor as a marker of disease or genetic individuality. Body odor is also thought to be used during mate choice to select genetically compatible mates. The idea that body odor reveals information about both genetic identity and genetic similarity is most readily tested by examining odor in twin pairs. However, although this idea can be traced back 130 years to Francis Galton in 1875, most studies using dogs fail to control for shared environmental effects associated with cohabitation. Here we show that odors of identical twins (but not dizygotic twins) can be matched by human sniffers at rates better than chance, even when the twins are living apart. In addition, matching frequencies for identical twin odors were not significantly different from those for duplicate odors from the same individual. These results indicate an important genetic influence on body odor and the potential for developing technologies for human odor printing in relation to underlying genotype.

Adult↗
PubMed2005

Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease.

BACKGROUND: The advent of bisphosphonates advanced therapy for Paget's disease, but more effective and convenient agents are needed to increase adherence. Zoledronic acid, a bisphosphonate administered as a single intravenous infusion, might meet these needs. METHODS: In two identical, randomized, double-blind, actively controlled trials of 6 months' duration, we compared one 15-minute infusion of 5 mg of zoledronic acid with 60 days of oral risedronate (30 mg per day). The primary efficacy end point was the rate of therapeutic response at six months, defined as a normalization of alkaline phosphatase levels or a reduction of at least 75 percent in the total alkaline phosphatase excess. The results of the studies were pooled. RESULTS: At six months, 96.0 percent of patients receiving zoledronic acid had a therapeutic response (169 of 176), as compared with 74.3 percent of patients receiving risedronate (127 of 171, P<0.001). Alkaline phosphatase levels normalized in 88.6 percent of patients in the zoledronic acid group and 57.9 percent of patients in the risedronate group (P<0.001). Zoledronic acid was associated with a shorter median time to a first therapeutic response (64 vs. 89 days, P<0.001). Higher response rates in the zoledronic acid group were consistent across all demographic, disease-severity, and treatment-history subgroups and with changes in other bone-turnover markers. The physical-component summary score of the Medical Outcomes Study 36-item Short-Form General Health Survey, a measure of the quality of life, increased significantly from baseline at both three and six months in the zoledronic acid group and differed significantly from those in the risedronate group at three months. Pain scores improved in both groups. During post-trial follow-up (median, 190 days), 21 of 82 patients in the risedronate group had a loss of therapeutic response, as compared with 1 of 113 patients in the zoledronic acid group (P<0.001). CONCLUSIONS: A single infusion of zoledronic acid produces more rapid, more complete, and more sustained responses in Paget's disease than does daily treatment with risedronate.

Administration, Oral↗
PubMed2005

The stability of a stochastic CaMKII switch: dependence on the number of enzyme molecules and protein turnover.

Molecular switches have been implicated in the storage of information in biological systems. For small structures such as synapses, these switches are composed of only a few molecules and stochastic fluctuations are therefore of importance. Such fluctuations could potentially lead to spontaneous switch reset that would limit the lifetime of information storage. We have analyzed a model of the calcium/calmodulin-dependent protein kinase II (CaMKII) switch implicated in long-term memory in the nervous system. The bistability of this switch arises from autocatalytic autophosphorylation of CaMKII, a reaction that is countered by a saturable phosphatase-1-mediated dephosphorylation. We sought to understand the factors that control switch stability and to determine the functional relationship between stability and the number of molecules involved. Using Monte Carlo simulations, we found that the lifetime of states of the switch increase exponentially with the number of CaMKII holoenzymes. Switch stability requires a balance between the kinase and phosphatase rates, and the kinase rate must remain high relative to the rate of protein turnover. Thus, a critical limit on switch stability is set by the observed turnover rate (one per 30 h on average). Our computational results show that, depending on the timescale of fluctuations in enzyme numbers, for a switch composed of about 15 CaMKII holoenzymes, the stable persistent activation can span from a few years to a human lifetime.

Calcium-Calmodulin-Dependent Protein Kinase Type 2↗