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B Dreyer

Publications and source records attributed to B Dreyer.

10 recordsLinked to original sources
PubMed2001

A common ancestral origin of the frequent and widespread 2299delG USH2A mutation.

Usher syndrome type IIa is an autosomal recessive disorder characterized by mild-to-severe hearing loss and progressive visual loss due to retinitis pigmentosa. The mutation that most commonly causes Usher syndrome type IIa is a 1-bp deletion, described as "2299delG," in the USH2A gene. The mutation has been identified in several patients from northern and southern Europe and from North America, and it has been found in single patients from South America, South Africa, and China. Various studies have reported a range of frequencies (.16-.44) among patients with Usher syndrome, depending on the geographic origin of the patients. The 2299delG mutation may be the one that most frequently causes retinitis pigmentosa in humans. Given the high frequencies and the wide geographic distribution of the mutation, it was of interest to determine whether the mutation resulted from an ancestral mutational event or represented a mutational hotspot in the USH2A gene. Haplotype analysis was performed on DNA samples from 116 unrelated patients with Usher syndrome type IIa; the patients were from 14 countries and represented 148 2299delG alleles. On the basis of six single-nucleotide polymorphisms within the USH2A gene, 12 core haplotypes were observed in a panel of normal chromosomes. However, in our analysis, only one core haplotype was found to be associated with the 2299delG mutation. The data indicate that the widespread geographic distribution of the 2299delG mutation is the result of an ancestral mutation that has spread throughout Europe and into the New World as a result of migration.

Alleles↗
PubMed2001

Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development.

Prior reports have demonstrated that both parathyroid hormone-related protein (PTHrP) and the type I PTH/PTHrP receptor are necessary for the proper development of the embryonic mammary gland in mice. Using a combination of loss-of-function and gain-of-function models, we now report that PTHrP regulates a series of cell fate decisions that are central to the survival and morphogenesis of the mammary epithelium and the formation of the nipple. PTHrP is made in the epithelial cells of the mammary bud and, during embryonic mammary development, it interacts with the surrounding mesenchymal cells to induce the formation of the dense mammary mesenchyme. In response, these mammary-specific mesenchymal cells support the maintenance of mammary epithelial cell fate, trigger epithelial morphogenesis and induce the overlying epidermis to form the nipple. In the absence of PTHrP signaling, the mammary epithelial cells revert to an epidermal fate, no mammary ducts are formed and the nipple does not form. In the presence of diffuse epidermal PTHrP signaling, the ventral dermis is transformed into mammary mesenchyme and the entire ventral epidermis becomes nipple skin. These alterations in cell fate require that PTHrP be expressed during development and they require the presence of the PTH/PTHrP receptor. Finally, PTHrP signaling regulates the epidermal and mesenchymal expression of LEF1 and (&bgr;)-catenin, suggesting that these changes in cell fate involve an interaction between the PTHrP and Wnt signaling pathways.

Animals↗
PubMed2001

Temporally regulated overexpression of parathyroid hormone-related protein in the mammary gland reveals distinct fetal and pubertal phenotypes.

We have previously demonstrated that overexpression of parathyroid hormone-related protein (PTHrP) in the mammary glands of transgenic mice results in defects in ductal elongation and branching during puberty and in lobuloalveolar development during pregnancy. In addition, we have shown that PTHrP is necessary for the formation of the initial ductal tree during embryonic mammary development. In order to examine the effect of varying the timing of PTHrP overexpression on mammary development, we created tetracycline-regulated, K14-tTA/Tet(O)-PTHrP double transgenic mice. In this report, we document that this 'tet-off' system directs transgene expression to the mammary gland and that it is fully repressed in the presence of tetracycline. Using these mice, we demonstrate that transient overexpression of PTHrP before birth causes defects in ductal branching during puberty and that overexpression of PTHrP during puberty decreases the rate of ductal elongation. Furthermore, we demonstrate that if PTHrP overexpression is initiated after ductal morphogenesis is completed, lobuloalveolar development is unaffected. Finally, we demonstrate that the impairment in ductal elongation caused by PTHrP is associated with an increase in the basal rate of epithelial cell apoptosis in terminal end buds and a failure to increase end bud cell proliferation and decrease apoptosis in response to estrogen and progesterone.

Animals↗
PubMed2000

Identification of novel USH2A mutations: implications for the structure of USH2A protein.

Usher syndrome type II is an autosomal recessive disorder, characterised by stable hearing impairment from childhood and progressive retinitis pigmentosa from the late teens. Mutations in the USH2A gene, located on 1q41, were recently shown to be responsible for Usher syndrome type IIa. We have investigated the molecular pathology of Usher type II by screening the USH2A gene for mutations in 31 unrelated patients from Denmark and Norway. Besides the frequent 2299delG mutation, which accounted for 44% of the disease alleles, a heterogeneous spectrum of mutations was identified. Sixteen new, putative disease-causing mutations were detected, of which 12 were private and four were shared by unrelated patients. The disease-causing mutations were scattered throughout the gene and included six nonsense and seven missense mutations, two deletions and one small insertion. In addition, six non-pathogenic polymorphisms were identified. All missense mutations resulted in major amino acid side-chain alterations. Four missense mutations affected the N-terminal part of USH2A, whereas three missense mutations affected the laminin-type epidermal growth factor-like (LE) domain. The structural consequences of the mutations affecting the LE domain are discussed in relation to the three-dimensional structure of a LE-module of the mouse laminin gamma1 chain.

Adolescent↗
PubMed1998

Pediatric ambulance utilization in a large American city: a systems analysis approach.

BACKGROUND: Research on utilization of ambulances by pediatric patients lacks an objective, reproducible tool for the evaluation of patterns of ambulance use by both the providers and the users of this resource. OBJECTIVES: 1) To develop an objective, diagnosis-based measure of appropriateness of ambulance utilization. 2) To use the measure to evaluate whether Municipal Ambulance Service dispatchers assign ambulances appropriately, and whether parents/caretakers request ambulances appropriately. STUDY DESIGN: 1) Development of the pediatric ambulance need evaluation (PANE) tool: The consensus of an expert panel was used to assign patients arriving by ambulance to three levels of prehospital transport need based upon their ultimate hospital discharge diagnoses, and were as follows: required advanced life support ambulance (ALS); required basic life support ambulance (BLS); required a less acute mode of transport (LAT). 2) Assessment of appropriateness of ambulance assignments by EMS call-receiving operators (CRO) and of ambulance requests by parents/caretakers: Comparison of actual type of ambulance assigned and of need for ambulance, using the PANE tool and hospital admission rates as gold standards. DATA COLLECTION: Level of prehospital transport provided (ALS vs BLS), ultimate ED diagnosis, and ED disposition (admission vs discharge) was collected for each patient from information abstracted from the prehospital and ED records. SETTING: Bellevue Hospital Center and Harlem Hospital Center, two level I trauma centers in New York City, both with Pediatric Emergency Departments staffed 24 hours a day by attending physicians and residents. PATIENT SELECTION: Consecutive sample of 2633 patients, birth to 18 years of age, who arrived to either hospital by ambulance as primary transports from the field over a one-year period. RESULTS: 1) Development of PANE tool: At Bellevue Hospital, 7% of ED visits arrived by ambulance; at Harlem Hospital, 5% arrived by ambulance. Using these ambulance arrivals, 215 diagnoses were identified for inclusion in the PANE tool. An expert panel categorized each diagnosis as requiring ALS, BLS, or LAT, with a high level of interobserver agreement (weighted kappa = 0.793). As a measure of external validity of the PANE, admission rates were highest in the ALS group, next highest in the BLS group, and lowest in the LAT group (chi2 for trend, P < 0.05). 2) Assessment of ambulance assignments and requests: According to the PANE tool, the sensitivity of dispatcher assignment of ALS ambulances was 72 %. Therefore, 28 % of patients who required an ALS ambulance received BLS care. 50% of patients assigned to an ALS ambulance did not require that level of care, and 1/3 of these were categorized by the PANE as not requiring an ambulance at all. CONCLUSIONS: The PANE tool compared favorably to admission rates as a measure of the severity of illness of patients arriving by ambulance. Applying the PANE tool, we conclude that the majority of requests for ambulances are appropriate, and that the majority of the time dispatchers were able to dispatch the appropriate level of care. However, there is room for significant improvement in utilization of ambulances, and tools like the PANE will be useful in achieving this goal.

Adolescent↗
PubMed1984

Plasma contact activation and decrease of factor V activity on negatively-charged polyelectrolytes.

The effect of negatively-charged polymers, used in some artificial devices, on plasma clotting and kinin systems was studied in vitro using polyelectrolyte complexes. Contact activation was observed as an immediate, transient and surface-dependent phenomenon. After incubation of the plasma with the polymer a small decrease of factor XII activity was noticed, which corresponded to a greater reduction of prekallikrein activity and to a marked kinin release. No significant decrease of factor XII, prekallikrein, HMW kininogen could be detected immunologically. Only the initial contact of the plasma with the polyelectrolyte lead to activation, subsequently the surface became inert. Beside contact activation, factor V activity also decreased in the plasma. The decrease was surface and time-dependent. It was independent of contact factor activation, and appeared to be related to the sulfonated groups of the polymer. If purified factor V was used instead of plasma factor V, inactivation was immediate and not time-dependent suggesting a direct adsorption on the surface. A second incubation of the plasma-contacted polymer with fresh plasma resulted in a further loss of Factor V activity.

Electrolytes↗
PubMed1980

The collagenous components of the subendothelium. Correlation of structure and function.

Endothelial cells provide a continuous nonthrombogenic lining for the vascular tree. Once the endothelium is denuded platelet adhesion and aggregation occur. One postulated mechanism for the nonthrombogenic properties of the endothelial surface is PGI2 production by endothelial cells, which strongly inhibits platelet aggregation. We propose here that the collagen type(s) associated with the endothelial cell surface may also play an important role in these phenomenon. We found that endothelial cells in culture produce types IV and AB2 collagen (both do not aggregate platelets in vitro) and that type AB2 collagen is uniformly distributed on the endothelial cell surface. We have shown this by immunofluorescence microscopy, immunoelectron microscopy, biosynthetic incorporation, and specific immunoprecipitation techniques. Platelets will not aggregate on monolayers of endothelium while they will aggregate on monolayers of other cells cultured from the vascular wall which produce collagen types that aggregate platelets in vitro. Thus, a specific cell surface-associated collagen (type AB2) may be an important determinant in the ability of the endothelial cell to present a nonthrombogenic surface to the blood.

Animals↗