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D Frey

Publications and source records attributed to D Frey.

At least 19 recordsLinked to original sources
PubMed2004

Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B.

Previous experiments have demonstrated the stable expression of factor IX (FIX) protein in mice and canine models of hemophilia B following portal vein gene transfer with a recombinant adeno-associated virus (rAAV) vector encoding FIX. Here, we present the results of studies that further optimized the rAAV vector transgene cassette used to express FIX and explored the use of the less-invasive intravenous (i.v.) route of vector administration for the treatment of hemophilia B. First, a liver-specific promoter was evaluated in conjunction with cis-acting regulatory elements in mice. Constructs that included both the beta-globin intron and the woodchuck hepatitis virus post-transcriptional regulatory element resulted in the highest level of FIX expression in vivo. Using this optimized vector, we demonstrate that i.v. injection was feasible for hepatic gene transfer in mice, achieving 70-80% of portal vein expression levels of FIX. In further studies using the Chapel Hill strain of hemophilia B dogs, we demonstrate for the first time FIX expression and partial correction of the bleeding disorder following i.v. administration of an AAV vector.

Animals↗
PubMed2003

Hormone replacement therapy: what is the evidence today?

Based on the most recent studies, it clearly appears that long-term hormone replacement therapy (HRT) prevents fractures but does not improve established coronary artery disease. In addition, HRT leads to a small increase in breast cancer incidence and to a decrease in colorectal cancer incidence. HRT increases the incidence of venous thrombosis, pulmonary embolisms and strokes. As a consequence, HRT can no longer be recommended for primary or secondary prevention of cardiovascular diseases. In addition, it was also demonstrated that HRT was not able to improve cognitive functions and prevent dementia. Therefore regarding daily clinical practice, HRT certainly remains useful to control the symptoms of oestrogen deficiency in recently menopausal patients, but it should definitively no longer be recommended for long-term treatment.

Aged↗
PubMed2003

[Therapy of osteoporosis: bisphosphonates, SERM's, teriparatide and strontium].

The therapy of osteoporosis is mostly based upon the use of drugs which inhibit bone resorption. Among these, the bisphosphonate family is the best known and mostly used by clinicians. Both second and third generation bisphosphonates, like alendronate and risedronate, are now available as weekly tablets which have facilitated the patient compliance to treatment together with a decreased occurrence of gastrointestinal side effects. These compounds are used efficiently to treat postmenopausal osteoporosis and osteoporosis of men as well. Their use did provide good evidence of increased bone mineral density (BMD) and a reduction in fracture rates. The use of intravenous bisphosphonates such as Zoledronate, Ibandronate and Pamidronate remains in most of the cases limited to special indications such as intolerance to the oral formulations and treatment of patients with bone metastases. The selective estrogen modulators (SERM's) family is limited to a single product on the market as of now, Raloxifene, which does inhibit bone resorption and is well documented by postmenopausal women to increase BMD and reduce vertebral fractures. In addition, a large range of positive nonosseous effects have been documented such as the reduction of the incidence of breast cancer. Other substances do have a strong anabolic effect such as Teriparatide, a recombinant human formulation of PTH 1-34. This compound has demonstrated good efficacy in postmenopausal women, increasing vertebral and hip BMD and reducing the incidence of fractures at both sites. The exact role of Teriparatide in the clinical setting is still open but its overall impact in the therapy of osteoporosis could be major due to its major efficiency over shorter periods of time. Strontium ranelate, a new divalent Strontium salt taken orally, acts both as an anti-catabolic and anabolic agent. The first results provided with strontium ranelate are very promising due to its major effect on the increase in BMD both at the vertebral and hip sites and its ability to reduce the incidence of fractures at both locations. Additional data are awaited to confirm these initial positive results.

Aged↗
PubMed2001

p27-p16 fusion gene inhibits angioplasty-induced neointimal hyperplasia and coronary artery occlusion.

Inhibition of proliferative neointima formed by vascular smooth muscle cells is a potential target in preventing angioplasty-induced restenosis. We have created a potent antiproliferative by fusing the active regions of the p27 and p16 cell cycle inhibitors. Intravascular delivery of a replication-deficient adenoviral vector (AV) encoding this p27-p16 fusion protein, named W9, inhibited balloon injury-induced neointimal hyperplasia in rabbit carotid arteries. In a therapeutically more relevant model, AV-W9 was delivered to balloon-injured porcine coronary arteries in vivo using an infusion catheter. Of the three coronary arteries, two were injured with a 15-mm balloon catheter and either were left untreated or were treated with 10(12) viral particles of either AV-W9 or a control null virus. AV-W9 treatment significantly inhibited neointimal hyperplasia in this porcine arterial balloon injury model compared with untreated or control virus-treated vessels. The average intimal area of the AV-W9-treated group 10 days after balloon injury and treatment was 0.42+/-0.36 mm(2), whereas the AV-null group demonstrated an intimal area of 0.70+/-0.52 mm(2). At day 10 the average intimal thickness of the AV-W9-treated vessels was 9.1 microm (n=5, x 20 magnification) compared with 21.2 microm (n=5, x 20 magnification) in control virus-treated vessels. This trend was also observed at 28 days after balloon injury and gene transfer during which AV-W9-treated vessels demonstrated an average intimal thickness of 4.7 microm (n=8, x 20 magnification) compared with 13.3 microm (n=3, x 20 magnification) in control virus-treated vessels and 7.3 microm (n=5, x 20 magnification) in the sham-treated vessels. The AV-W9 treatment was safe and well tolerated. These data suggest that AV-W9 gene therapy may be useful in preventing angioplasty-induced intimal hyperplasia in the coronary artery.

Adenoviridae↗
PubMed2001

Stability of adenoviral vectors following catheter delivery.

Adenoviral vectors have shown promise in a variety of preclinical vascular disease models. Intravascular infusion is one methodology to introduce the adenoviral vector into the affected area of the blood vessel. The biocompatibility of the infusion catheter with the adenoviral vector is key for successful local transfer. It has been recently suggested that catheter-based delivery of adenoviral vectors may result in the loss of vector infectivity. We demonstrate here a catheter capable of delivering adenoviral vectors without the loss of viral particle or infectious titers. First- (DeltaE1) and second- (DeltaE1/DeltaE4) generation adenoviral vectors were tested for their biocompatibility with the Crescendo microporous infusion catheter, which is designed for local infusion of therapeutic agents to human coronary or peripheral arteries. We found that incubation of either the DeltaE1 or the DeltaE1/DeltaE4 viral vectors for up to 30 min in the catheter at 37 degrees C did not result in a loss of viral particles or of viral infectivity. Here, we show that the Crescendo catheter is biocompatible with adenoviral vectors and suitable for vascular gene therapy.

Adenoviridae↗
PubMed2001

Confirmation bias in sequential information search after preliminary decisions: an expansion of dissonance theoretical research on selective exposure to information.

Research on selective exposure to information consistently shows that, after having made a decision, people prefer supporting over conflicting information. However, in all of these experiments participants were given an overview of all available pieces of information, selected them simultaneously, and did not process the requested information during the selection phase. In the present research the authors show that an even stronger preference for supporting information arises if information is presented and processed sequentially instead of simultaneously (Experiment 1), and they demonstrate that this stronger confirmation bias is due to sequential presentation and not to sequential processing of information (Experiment 2). The authors provide evidence that the increase in confirmation bias under sequential presentation is caused by heightened commitment due to the participants' increased focusing on their decision (Experiments 3 and 4).

Adult↗
PubMed2001

Possible medication errors in home healthcare patients.

OBJECTIVE: To determine the frequency of possible medication errors in a population of older home healthcare patients according to expert panel objective criteria. DESIGN: A cross-sectional survey. SETTING: Two of the largest urban home healthcare agencies in the United States. PARTICIPANTS: Home healthcare patients age 65 and older admitted to selected offices of these agencies between October 1996 and September 1998. MEASUREMENTS: We used two sets of consensus-based expert panel criteria to define possible medication errors. The Home Health Criteria identify patients with patterns of medication use and signs and symptoms that indicate sufficient likelihood of a medication-related problem to warrant reevaluating the patient. The Beers criteria identify medications that experts have deemed generally inappropriate for older patients. RESULTS: The 6,718 study subjects took a median of five drugs; 19% were taking nine or more medications. A possible medication error was identified for 19% of patients according to Home Health Criteria, 17% according to the Beers criteria, and 30% according to either. Possible errors increased linearly with number of medications taken. When patients taking one to three medications were compared with those taking nine or more drugs, the percentages with possible errors were, respectively, 10% and 32% for the Home Health Criteria, 8% and 32% for the Beers criteria, and 16% and 50% for both. CONCLUSION: Nearly one-third of the home healthcare patients surveyed had evidence of a potential medication problem or were taking a drug considered inappropriate for older people. More-effective methods are needed to improve medication use in this vulnerable population.

Aged↗
PubMed2001

[Psychological satiation: a new experimental study of an old construct].

The present experiment on the phenomenon of psychic satiation expands on the work of Karsten (1928) and Lewin (1928). Psychic satiation denotes a loss of intrinsic motivation when the same action is performed repeatedly. Although many studies have shown the high theoretical and practical relevance of this phenomenon, the conditions which lead to or reinforce psychic satiation have rarely been investigated empirically. Based on the concept of psychic satiation as formulated by Karsten and Lewin and refined by Schulz-Hardt, Rott, Meinken, and Frey (in press), we predicted that psychic satiation will increase if the task does not lend itself to being carried out "peripherally" (i.e., as an almost unconscious incidental action) and if it has high personal relevance. These predictions were investigated in an experiment with 66 high-school students who performed different versions of the "Konzentrations-Leistungs-Test" (concentration-performance-test, KLT). The results are largely in line with our predictions. In addition, the results indicate that the relation between satiation and performance is moderated by personal relevance and the induced task characteristic.

Adolescent↗
PubMed2001

[Confirmatory information search in simultaneous vs. sequential information presentation].

After having made a preliminary or final decision, people prefer information that supports their chosen alternative to information that conflicts with their choice. Jonas, Schulz-Hardt, Frey, and Thelen (in press) found that sequential presentation of information leads to an even stronger preference for supporting information than the traditional form of simultaneous presentation. Their proposed explanation for this effect was that sequential presentation induces a focus on the prior decision, thereby increasing commitment to this decision. The present experiment was designed to rule out an alternative explanation: Being repeatedly confronted with pieces of information to select from could induce the participants to search for more information than they consider to be necessary, and because less effort is required to process supporting information the additional information requests are predominantly for these supporting pieces of information. To test this alternative explanation, in the present experiment--as in the Jonas et al. (in press) experiments--simultaneous vs. sequential information presentation following a preliminary decision was manipulated. In contrast to the former experiments, this time the number of information requests was fixed: Participants in both conditions had to choose 8 out of 16 pieces of information. The results show that once again a stronger preference for supporting information arises when the information is presented sequentially compared to simultaneously. The alternative explanation mentioned above could thus be ruled out.

Adolescent↗
PubMed2000

Shared and unique roles of CAP23 and GAP43 in actin regulation, neurite outgrowth, and anatomical plasticity.

CAP23 is a major cortical cytoskeleton-associated and calmodulin binding protein that is widely and abundantly expressed during development, maintained in selected brain structures in the adult, and reinduced during nerve regeneration. Overexpression of CAP23 in adult neurons of transgenic mice promotes nerve sprouting, but the role of this protein in process outgrowth was not clear. Here, we show that CAP23 is functionally related to GAP43, and plays a critical role to regulate nerve sprouting and the actin cytoskeleton. Knockout mice lacking CAP23 exhibited a pronounced and complex phenotype, including a defect to produce stimulus-induced nerve sprouting at the adult neuromuscular junction. This sprouting deficit was rescued by transgenic overexpression of either CAP23 or GAP43 in adult motoneurons. Knockin mice expressing GAP43 instead of CAP23 were essentially normal, indicating that, although these proteins do not share homologous sequences, GAP43 can functionally substitute for CAP23 in vivo. Cultured sensory neurons lacking CAP23 exhibited striking alterations in neurite outgrowth that were phenocopied by low doses of cytochalasin D. A detailed analysis of such cultures revealed common and unique functions of CAP23 and GAP43 on the actin cytoskeleton and neurite outgrowth. The results provide compelling experimental evidence for the notion that CAP23 and GAP43 are functionally related intrinsic determinants of anatomical plasticity, and suggest that these proteins function by locally promoting subplasmalemmal actin cytoskeleton accumulation.

Actins↗
PubMed2000

GAP43, MARCKS, and CAP23 modulate PI(4,5)P(2) at plasmalemmal rafts, and regulate cell cortex actin dynamics through a common mechanism.

The dynamic properties of the cell cortex and its actin cytoskeleton determine important aspects of cell behavior and are a major target of cell regulation. GAP43, myristoylated alanine-rich C kinase substrate (MARCKS), and CAP23 (GMC) are locally abundant, plasmalemma-associated PKC substrates that affect actin cytoskeleton. Their expression correlates with morphogenic processes and cell motility, but their role in cortex regulation has been difficult to define mechanistically. We now show that the three proteins accumulate at rafts, where they codistribute with PI(4,5)P(2), and promote its retention and clustering. Binding and modulation of PI(4, 5)P(2) depended on the basic effector domain (ED) of these proteins, and constructs lacking the ED functioned as dominant inhibitors of plasmalemmal PI(4,5)P(2) modulation. In the neuron-like cell line, PC12, NGF- and substrate-induced peripheral actin structures, and neurite outgrowth were greatly augmented by any of the three proteins, and suppressed by DeltaED mutants. Agents that globally mask PI(4,5)P(2) mimicked the effects of GMC on peripheral actin recruitment and cell spreading, but interfered with polarization and process formation. Dominant negative GAP43(DeltaED) also interfered with peripheral nerve regeneration, stimulus-induced nerve sprouting and control of anatomical plasticity at the neuromuscular junction of transgenic mice. These results suggest that GMC are functionally and mechanistically related PI(4,5)P(2) modulating proteins, upstream of actin and cell cortex dynamics regulation.

Actins↗
PubMed2000

Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases.

The addition or loss of synapses in response to changes in activity, disease, or aging is a major aspect of nervous system plasticity in the adult. The mechanisms that affect the turnover and maintenance of synapses in the adult are poorly understood and are difficult to investigate in the brain. Here, we exploited a unique anatomical arrangement in the neuromuscular system to determine whether subtypes of synapses can differ in anatomical plasticity and vulnerability. In three genetic mouse models of motoneuron disease of diverse origin and severity, we observed a gradual and selective loss of synaptic connections that begun long before the onset of clinical deficits and correlated with the timing of disease progression. A subgroup of fast-type (fast-fatiguable) neuromuscular synapses was highly vulnerable and was lost very early on. In contrast, slow-type synapses resisted up to the terminal phase of the disease. Muscle-specific differences were also evident. Similar selective losses were detected in aged mice. These selective vulnerability properties of synapses coincided with hitherto unrecognized major differences in stimulus-induced anatomical plasticity that could also be revealed in healthy mice. Using paralysis and/or growth-associated protein 43 overexpression to induce synaptic sprouting, we found that slow-type, disease-resistant synapses were particularly plastic. In contrast, fast-type synapses with the highest vulnerability failed to exhibit any stimulus-induced change. The results reveal pronounced subtype specificity in the anatomical plasticity and susceptibility to loss of neuromuscular synapses and suggest that degenerative motoneuron diseases involve a common early pathway of selective and progressive synaptic weakening also associated with aging.

Aging↗
PubMed2000

Biased information search in group decision making.

Research has shown that people prefer supporting to conflicting information when making decisions. Whether this biased information search also occurs in group decision making was examined in three experiments. Experiment 1 indicated that groups as well as individuals prefer supporting information and that the strength of this bias depends on the distribution of the group members' initial decision preferences. The more group members had chosen the same alternative prior to the group discussion (group homogeneity), the more strongly the group preferred information supporting that alternative. Experiment 2 replicated these results with managers. Experiment 3 showed that the differences between homogeneous and heterogeneous groups reflect group-level processes. Higher commitment and confidence in homogeneous groups mediated this effect. Functional and dysfunctional aspects of biased information seeking in group decision making are discussed.

Adolescent↗