PubMed Health⌕ Search

Biomedical subjects

D Frey

Publications and source records attributed to D Frey.

At least 19 recordsLinked to original sources
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↗
PubMed1998

[Chronic back pain].

Low-back pain is a very common disease in Switzerland as elsewhere, with a prevalence of 65%. The pain is usually due to degeneration of the motion segment, but subsides spontaneously in some 95% of cases irrespective of the treatment. Only 5% of patients still have pain after one year; but account for over 80% of the costs due to low-back pain. Some patients can be helped by surgical fusion; however; preoperative identification of the pain source is mandatory. Since there is no consistent correlation between pain and the degree of degeneration of motion segments as seen on plain radiographs, functional radiographs, CT scan or MRI, other diagnostic methods such as facet blocks, discography and external diagnostic fixation must be used. After careful patient selection a fusion operation may be considered. Good results after fusion operations are reported in 60-80% of patients. The operative techniques are described.

Cost-Benefit Analysis↗
PubMed1997

[Treatment of chronic polyarthritis].

Rheumatoid arthritis (RA) is a chronic autoimmune disease involving progressive destruction of multiple joints and, in the later stages, significant mortality. Worldwide, 1% of the population is afflicted. Despite new insights into the autoimmune mechanisms during the last decade a cure has not been found, although pain, disability and general suffering can be alleviated via several therapeutic approaches when carefully coordinated. Early use of immunosuppressive therapy with DMARDs (disease modifying antirheumatic drugs), while avoiding their side effects, is critical for disease control. Counselling within a good doctor-patient relationship, with the additional help of physiotherapy and ergotherapy, increases the patient's capacity to cope with the disease. Hand and joint surgery, skillfully performed, decreases pain and disability. Newer strategies of immunosuppression, while encouragingly effective, are only short term. These experimental agents are more expensive, they are associated with side effects and their future place in RA therapy has yet to be defined.

Antirheumatic Agents↗
PubMed1997

Comparative results of early and delayed cannulation of arteriovenous graft in haemodialysis.

OBJECTIVE: To determine whether arteriovenous graft (AVG) can be cannulated for haemodialysis 24-48 h following placement. DESIGN AND MATERIALS: Thirty-six upper extremity Gore-Tex PTFE arteriovenous grafts were cannulated for haemiodialysis 24-36 h (n = 18) and at 10-14 days (n = 18) following insertion. The determinant parameters were compression time to control bleeding, venous back pressure, haematoma, infection and occlusion. MAIN RESULTS: In a 40 day follow-up, there were no significant difference in cannulation of AVG at 24-36 h vs. 10-14 days using the predetermined parameters. CONCLUSION: Early graft cannulation produced no adverse results than late cannulation when the diameter of the tunneller matched the diameter of the graft. Early graft cannulation was safe and recommended.

Arm↗
PubMed1997

Molecular analysis of HLA-DR polymorphism in polymyalgia rheumatica. Swiss Group for Research on HLA in Polymyalgia Rheumatica.

OBJECTIVE: To analyze by molecular typing possible associations of HLA-DRB1 alleles with polymyalgia rheumatica (PMR) compared to controls and patients with rheumatoid arthritis (RA) in Switzerland. METHODS: In a multicenter survey, we recruited 100 patients with PMR with and without signs of giant cell arteritis (GCA), 198 with RA, and 200 controls (volunteer bone marrow donors). HLA-DR generic typing was performed by microtiter plate oligotyping and DR4 subtypes analyzed by dot blot hybridization with sequence specific oligonucleotides or by polymerase chain reaction sequence specific primers. RESULTS: DR4 and DR1 tended to be increased in PMR, compared to controls (36 vs 30%, p = 0.30; and 19 vs 12%, p = 0.16, respectively). Frequencies of all RA associated DR4 and DR1 subtypes tended to be increased in PMR as well. Frequency of the HLA-DR beta 1 70-74 shared motif (QK/RRAA) was significantly higher in PMR than in controls [50 vs 36%, odds ratio (OR) = 1.8, p = 0.018], although lower than in RA (77 vs 36%, OR = 6.0, p < 0.0001), and slightly out of the range of significance if a Bonferroni correction was applied (p = 0.1). At double dose, this epitope was also increased in PMR, but not significantly (5 vs 2%, OR = 2.6, p = 0.17), while it was markedly augmented in RA (22 vs 2%, OR = 14, p = < 0.0001). In patients with the shared epitope, the frequency of clinical signs of GCA tended to be increased (19 vs 10%, p = 0.25). Frequency of the HLA-DR beta 1 DRYF 28-31 motif was identical in PMR (95%) and controls (93%). CONCLUSION: PMR may be associated with the HLA-DR beta 1 70-74 shared epitope. This association, however, would be much weaker for PMR than for RA, particularly with the shared epitope at double dose. PMR is clearly not associated with the HLA-DR beta 1 DRYF 28-31 motif.

Aged↗
PubMed1996

Use of c7E3 Fab in conjunction with primary coronary stenting for acute myocardial infarctions complicated by cardiogenic shock.

Although use of thrombolytic therapy during primary angioplasty is controversial, the development of a monoclonal antibody (c7E3 Fab) to the platelet glycoprotein IIb/IIIa receptor has been a tremendous breakthrough in the field of interventional cardiology. Use of the antibody during high-risk angioplasty or atherectomy procedures has been shown to significantly reduce the incidence of death, MI, or emergent repeat revascularization. We describe four cases in which c7E3 Fab was used as an adjunct to coronary stenting in the peri-infarct period in patients with cardiogenic shock. To our knowledge, no other reports have addressed the use of glycoprotein IIb/IIIa receptor inhibitors with coronary stent implantation. Our experience in this small population suggests that coronary stenting for myocardial infarctions may be a feasible option in selected patients to allow maximal luminal dilation and successful reperfusion. We emphasize that our results are preliminary, and we eagerly await the results of the EPILOG study which will provide more definitive data on the safety and efficacy of c7E3 Fab and coronary stenting from the perspective of a large, randomized trial.

Abciximab↗
PubMed1995

The risks, benefits, and costs of expanding donor criteria. A collaborative prospective three-year study.

The study purpose was to identify risks, benefits and costs associated with an expanded donor protocol. The protocol design evaluated organs rescued using expanded donor criteria and weighed all costs associated with doing so. Costs were measured against conditions experienced with expanded and traditional criteria and recipient outcome. Traditional donors were between 5 and 55, with negative serologies, and no history of hypertension or diabetes. "Expanded donors" were between 55 and 75 or less than 5, with a history of hypertension, diabetes and/or sero-positive for Hepatitis C. During this study 73 donors met criteria from which 200 organs were transplanted. Defined costs and outcomes for recipients were tracked. Using expanded criteria: costs averaged 20% more per organ; OPO personnel spent an average of 6 hours more time on-site; an additional 12-14 hours in placement activity; and average organs per donor decreased. Heart patient and graft survival rates for traditional and expanded donor organs were comparable. Kidney patients transplanted from this pool experienced a decrease in patient (P = .14) and a significant decrease in graft (P = .02) survival rates. Patient (P = .05) and graft (P = .01) survival rates were significantly lower in liver patients transplanted with expanded donor organs. Two hundred transplants occurred using expanded donor criteria. Costs for the OPO increased appreciably. Heart and kidney utilization from these donors seems justified. It is thought that liver recipients' results were due to utilizing them in sicker patients. Recovery of organs from donors using expanded criteria appears to be a reasonable way of increasing organ supply.

Adolescent↗
PubMed1994

Effect of bed compression on high-performance liquid chromatography columns with gigaporous polymeric packings.

The behavior of chromatographic columns packed with gigaporous, highly cross-linked styrenic particles was investigated for use in protein separation by reversed-phase chromatography at high flow velocities. Stainless-steel columns which were 3.5 or 7.5 cm long and had an inner diameter of 0.46 mm were slurry packed with 8 or 20 mm diameter spherical particles of 4000 A mean pore size by using methanol as the packing fluid. It was found that the conditions employed during the packing process have a dramatic effect on the properties of such columns and that this can be attributed in part to the deformability of the particles. An increase in the packing pressure to approximately 6000 p.s.i. (41 MPa) resulted in a higher mass-transfer efficiency for the column with a concomitant decrease in permeability. This is ascribed to a decrease in the interstitial porosity with increasing packing pressure since the experimentally measured plate heights for these columns were found to agree quantitatively with theoretical predictions that relate changes in the interstitial porosity to intraparticle mass transfer. However, the theoretically derived relationship between porosity, permeability, and efficiency does not hold for columns packed at pressures higher than 6000 p.s.i., in which case the total column porosity was found to be high while the permeability and column efficiency were low. This behavior is explained by the formation of a low-porosity layer of highly compressed particles at the downstream end of the column during high pressure packing so that the assumption of axially uniform column properties used in the theoretical approach leads to very large errors.

Chromatography, High Pressure Liquid↗