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Biomedical subjects

M Ebeling

Publications and source records attributed to M Ebeling.

At least 19 recordsLinked to original sources
PubMed2002

Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms.

Osteoporosis is a common disease characterized by a decrease in bone mass, architectural deterioration of the bone tissue, and an increased risk of fracture. The condition is under strong genetic control, involving a large variety of gene products, but to date the genes responsible remain poorly defined. Although population-based studies have identified polymorphisms in several candidate genes that are associated with bone mineral density (BMD), these account for only a small proportion of the population variance in bone mass. In this study, we looked for evidence of an allelic association between polymorphisms in the SOST gene and BMD. This gene was analyzed because loss-of-function mutations in SOST cause sclerosteosis, a sclerosing bone dysplasia associated with increased bone mass due to increased bone formation. We identified 26 different polymorphisms in the SOST gene and selected 5 of these for association analysis in a case-control study of 619 women with either high or low BMD, drawn from a random population-based survey of 5119 perimenopausal white women. The high BMD group comprised 326 women in whom lumbar spine BMD values adjusted for age, height, and weight were in the highest 16% of the population distribution, and the low BMD group comprised 293 women in whom BMD values were in the lowest 16% of the population distribution. The distribution of genotypes and alleles for each Single Nucleotide Polymorphism (SNP) examined did not differ in the low and high BMD groups. We conclude that, in this population, common allelic variations in the SOST gene do not contribute significantly to the regulation of high or low BMD.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease.

Van Buchem disease is an autosomal recessive skeletal dysplasia characterised by generalised bone overgrowth, predominantly in the skull and mandible. Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients. These features are very similar to those of sclerosteosis and the two conditions are only differentiated by the hand malformations and the tall stature appearing in sclerosteosis. Using an extended Dutch inbred van Buchem family and two inbred sclerosteosis families, we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and sclerosteosis are caused by mutations in the same gene. In a previous study, we positionally cloned a novel gene, called SOST, from the linkage interval and identified three different, homozygous mutations in the SOST gene in sclerosteosis patients leading to loss of function of the underlying protein. The present study focuses on the identification of a 52 kb deletion in all patients from the van Buchem family. The deletion, which results from a homologous recombination between Alu sequences, starts approximately 35 kb downstream of the SOST gene. Since no evidence was found for the presence of a gene within the deleted region, we hypothesise that the presence of the deletion leads to a down regulation of the transcription of the SOST gene by a cis regulatory action or a position effect.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Identification and characterization of human taste receptor genes belonging to the TAS2R family.

The sense of taste is a chemosensory system responsible for basic food appraisal. Humans distinguish between five primary tastes: bitter, sweet, sour, salty and umami. The molecular events in the perception of bitter taste are believed to start with the binding of specific water-soluble molecules to G-protein-coupled receptors encoded by the TAS2R/T2R family of taste receptor genes. TAS2R receptors are expressed at the surface of taste receptor cells and are coupled to G proteins and second messenger pathways. We have identified, cloned and characterized 11 new bitter taste receptor genes and four new pseudogenes that belong to the human TAS2R family. Their encoded proteins have between 298 and 333 amino acids and share between 23 and 86% identity with other human TAS2R proteins. Screening of a mono-chromosomal somatic cell hybrid panel to assign the identified bitter taste receptor genes to human chromosomes demonstrated that they are located in chromosomes 7 and 12. Including the 15 sequences identified, the human TAS2R family is composed of 28 full-length genes and 16 pseudogenes. Phylogenetic analyses suggest a classification of the TAS2R genes in five groups that may reflect a specialization in the detection of specific types of bitter chemicals.

Amino Acid Sequence↗
PubMed2001

Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST).

Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

H-BloX: visualizing alignment block entropies.

H-BloX is a web-based JavaScript application that allows the calculation and visualization of Shannon information content or relative entropy (Kullback-Leibler 'distance') within sequence alignment blocks. The application was designed for use in both teaching and research. Amino acid, nucleic acid sequences, or any other type of aligned chemical structures may serve as the input. Various interpretations of the meaning of 'entropy' or 'information content' are possible, including treatment as a chemical diversity measure or the degree of feature conservation. For analysis of numerical data by H-BloX, values must be converted to a user-defined character alphabet before computation of entropy or information content. H-BloX was successfully applied to feature identification in Escherichia coli signal peptides and their cleavage sites. Characteristics known features became visible, e.g., the hydrophobic core region and the well-known '-3,-1' cleavage site pattern. Based on the H-BloX analysis, the hydrophobic core is centered at amino acid residue position 13, counting from the N-terminal end of the protein precursor sequence. This result was obtained by using a built-in feature of H-BloX that enables conversion of amino acid sequences to a different alphabet that is based on hydrophobicity assignments. H-BloX can be accessed online or downloaded as HTML/JavaScript at http://bopwww.biologie.uni-freiburg.de/~bioinfo/HBloX/html/index.html.

Bacterial Proteins↗
PubMed2001

Effects of systemic interleukin-10 therapy on psoriatic skin lesions: histologic, immunohistologic, and molecular biology findings.

Interleukin-10 is an important anti-inflammatory and immunosuppressive cytokine with major impact on several immune reactions, including regulatory mechanisms in the skin. Recently, we performed a phase II trial in psoriatic patients receiving subcutaneously interleukin-10 over 7 wk. The clinical response suggested that interleukin-10 might represent a novel anti-psoriatic drug. In order to understand better the mode of action and to elucidate the effects of systemic interleukin-10 treatment on the skin immune system, skin punch biopsies from sites different from interleukin-10 injection were analyzed. Biopsies were obtained from the patients before, at the end, and 3 wk after interleukin-10 therapy. The results are reported here. Histologic examination showed a decrease of several parameters reflecting the psoriatic disease activity as acanthosis and extension of the horny layer. Immunohistologic examination demonstrated decreasing numbers of infiltrating T cells, dermal CD1a+ cells, and a diminished proliferation of epidermal cells. Using a novel, quantitative reverse transcriptase-polymerase chain reaction approach a significant shift within the cytokine pattern was found. Interleukin-10 therapy led to a decrease of cutaneous interleukin-8 and interleukin-10 mRNA expression. Whereas no significant changes of interleukin-6, tumor necrosis factor-alpha, and interferon-gamma expression were found, interleukin-4 was strongly upregulated suggesting a shift from a type 1 towards a type 2 cytokine pattern. The changes within the local cytokine pattern seem to be disease-related, as an inverse course was found in a single interleukin-10 nonresponding patient. Our findings demonstrate considerable effects of systemic interleukin-10 application on the skin immune systems, which might contribute to the anti-psoriatic activity of interleukin-10.

Adult↗
PubMed2001

Time required for blood lead levels to decline in nonchelated children.

OBJECTIVE: To determine the time for a decline in blood lead to less than 10 microg/dL in nonchelated children who are enrolled in case management. STUDY DESIGN: Retrospective analysis of venous blood lead data of lead-poisoned children followed in a case management program designed to decrease lead exposure. Children were excluded if their blood lead had not yet declined to less than 10 microg/dL, if they received chelation therapy, or if they had not received follow-up for more than 15 months. We calculated the time between peak elevation of lead and decline to less than 10 microg/dL. Data were categorized based on the child's peak blood lead and season in which their peak blood lead occurred. Data were analyzed using ANOVA and linear regression. Kaplan-Meier survival analysis was used to describe data in population form. RESULTS: 579 patients were included in the analysis. Blood leads of 25-29, 20-24, 15-19, and 10-14 microg/dL required 24.0, 20.9, 14.3, and 9.2 months, respectively, to decline to less than 10 microg/dL. For continuous data, a linear relationship was described by the following equation: Time (# of months required to achieve a blood lead less than 10 microg/dL) = 0.845 x peak lead; p < 0.0001. Kaplan-Meier curves complement the findings in a population-based fashion. CONCLUSIONS: The mean time for blood lead to decline was linearly related to the peak in blood lead. The time for 50% of the blood lead to decline to less than 10 microg/dL was not linear and varied with peak lead.

Chelation Therapy↗
PubMed2001

Effects of a weaning protocol on ventilated pediatric intensive care unit (PICU) patients.

As part of a learning collaborative sponsored by the Center for the Evaluative Clinical Sciences (CECS) at Dartmouth College, a multidisciplinary pediatric intensive care unit (PICU) group began meeting in 1997 to evaluate potential performance improvement (PI) opportunities. A reduction in mechanical ventilation (MV) hours was the initial team focus. The multidisciplinary team developed and implemented protocols and physician order sets outlining care for MV weaning, neuromuscular blockade/therapeutic paralyzation, and enteral feedings. Since the initiation of our protocols in July 1997, we have significantly reduced the number of hours our PICU patients receive MV.

Algorithms↗
PubMed1999

Interleukin 10 treatment of psoriasis: clinical results of a phase 2 trial.

OBJECTIVE: To determine the safety and clinical effects of interleukin 10 (IL-10) treatment of psoriasis. DESIGN AND METHODS: In an open-label phase 2 trial, 10 patients with psoriasis subcutaneously received recombinant human IL-10 over a 7-week period in a dosage of 8 microg/kg daily (n=5) or 20 microg/kg 3 times per week (n=5). Patients were followed up for an additional 5 weeks. RESULTS: The treatment was well tolerated. Antipsoriatic effects were found in all but 1 patient. A significant decrease of the psoriasis area and severity index by 55.3% +/- 11.5% (mean +/- SEM) was observed (P<.02). The antipsoriatic efficiency was confirmed by histological examination. Heterogeneity in the effectiveness was found among the patients, but seems to be independent of the dosage regimen. However, a tendency to a better response was found in the patients who received 20-microg/kg IL-10 3 times per week. Decreasing response in the delayed-type hypersensitivity reaction against recall antigens indicated immunosuppressive effects. Moderate effects on hematopoietic cells were observed. CONCLUSIONS: Our data suggest that IL-10 therapy for psoriasis is safe and possibly clinically effective. Consequently, its value in psoriasis and similar immune diseases should be further determined. Dose-finding, placebo-controlled, double-blind trials are necessary now.

Adult↗
PubMed1999

[Interleukin-10 in dermatology].

In recent years the investigation of cytokines has been a focus of scientific interest in order to understand the pathogenesis of a variety of diseases. In additions cytokines are increasingly being used for therapeutic purposes, including dermatologic disorders. IL-10 is a recently described cytokine with anti-inflammatory and immunosuppressive qualities which plays an important role in immunoregulation. The overexpression of this mediator has been proven in some inflammatory dermatoses as well as in various skin tumors. These observations help to understand down regulatory events in hyper-inflammatory conditions such as allergic or toxic dermatitis on the one hand and the suppression of an adequate anti-tumor response and thereby the progression of malignant tumors on the other hand. Recent investigations indicate a relative IL-10 deficiency in psoriasis. Initial therapeutic applications of IL-10 in psoriasis underline the pathophysiological importance of this cytokine.

Humans↗
PubMed1999

Risk factors for neonatal death in twin gestations in the state of South Carolina.

OBJECTIVE: The aim of the study was to describe risk factors for neonatal death among twins born in South Carolina. STUDY DESIGN: South Carolina publicly accessible live birth and infant death cohort files for live-born twins >500 g were reviewed for the years 1988 through 1993. Infants with lethal anomalies were deleted from the cohort before analysis. Risk factors for neonatal death were determined for the entire cohort and for the birth weight categories of 500 to 999 g, 1000 to 1499 g, 1500 to 2499 g, and >/=2500 g. Statistical comparisons were performed with the Mantel-Haenszel chi2 test and multivariate logistic regression. RESULTS: Of 7833 live-born twins, 263 (3.4%) died during the neonatal period. The mean birth weight was 2357 +/- 650 g (range 500-5358 g) at a mean gestational age of 35.7 +/- 3.5 weeks. Overall neonatal mortality rates were significantly increased (P <.001) for twins whose mothers were nonwhite (4.2 vs 2.8%), were <20 years old (6.0 vs 3.2%), or received no prenatal care (14.7 vs 3.1%). After we controlled for population characteristics with multivariate techniques, analysis revealed birth weight <2500 g and residence in the most populous urban areas to be associated with increased neonatal mortality rates. After stratification into birth weight categories, race was no longer a significant variable; in fact, nonwhite twins had a survival advantage at birth weights <1500 g, but this was not significant. Maternal age <20 years was associated with a higher neonatal mortality rate for infants with birth weights between 1500 and 2499 g. Absence of prenatal care significantly increased the neonatal mortality rate for twins >/=1500 g but not for those who were smaller. For infants weighing 500 to 999 g neonatal mortality rates were significantly lower at hospitals with >/=2000 deliveries/y than at hospitals with lower delivery volumes (P =.005). CONCLUSIONS: Although the overall neonatal mortality rate for twins continues to improve, increased rates are still seen among blacks, teenagers, and women who receive no prenatal care. Twins between 500 and 999 g have significantly reduced neonatal mortality rates when delivered at hospitals with a high obstetric volume.

Adult↗
PubMed1998

A qualitative field method for monitoring pesticides in the edge-of-field runoff.

A field method is described, which allows the qualitative estimation of pesticide contamination in the edge-of-field runoff. The method employs cheap and easy-to-use runoff sampling bottles, which were installed in an agricultural stream catchment over a period of three growing seasons. During this time 18 runoff events were detected, in nine of which insecticide contamination was measured (maximum concentrations: lindane 0.7 microgram l-1 and 12.7 micrograms kg-1, parathion 20 micrograms l-1 and 728 micrograms kg-1, fenvalerate 18.4 micrograms l-1 and 924 micrograms kg-1). These insecticides were detected mainly as particle-bound chemicals. On about 80% of the occasions the presence or absence of runoff measured in the field was in agreement with a simulation of runoff presence or absence using the runoff model KINEROS.

Agriculture↗
PubMed1998

A new method to examine very low birth weight fetal and hebdomadal mortality in a regionalized system of perinatal care.

OBJECTIVE: Aggressive maternal transport of very low birth weight (VLBW) live births from community hospitals to regional perinatal centers may artificially increase community fetal death rates. By allocating maternal transports according to the location of antepartum and intrapartum care and separately computing antepartum and intrapartum fetal mortality rates, a more appropriate measure of hospital-based mortality may be determined. METHOD: Delivery charts were reviewed for 568 VLBW deliveries (including 97 fetal deaths and 77 hebdomadal deaths) occurring between 1990 and 1992 in a geographically defined perinatal region. Maternal transports were analyzed with community hospitals for antepartum mortality rates and with the regional center for intrapartum mortality rates. RESULTS: Using traditional methods, the fetal mortality rates for community hospitals and the regional center were antepartum 385.1 vs. 45.2, respectively, and intrapartum 120.9 vs. 24.9, respectively. When regional center live births (maternal transports) are placed with community hospitals for analysis of antepartum mortality, the new antepartum mortality rates were 185.7 vs. 72.8, respectively. The hebdomadal mortality rate for community hospitals was 250.0 as compared to 145.8 for the regional center. CONCLUSION: Maternal transports to a regional center represent successful antepartum management by community care providers. Even though they delivered in the regional center, they should be analyzed with community hospitals for antepartum fetal mortality comparisons. Therefore, antepartum and intrapartum fetal mortality should be examined separately in a functioning regionalized perinatal care program where the location of patient care differs from location of delivery.

Adolescent↗
PubMed1997

Protein folding: optimized sequences obtained by simulated breeding in a minimalist model.

For a minimalist model of protein folding, which we introduced recently, we investigate various methods to obtain folding sequences. A detailed study of random sequences shows that, for this model, such sequences usually do not fold to their ground states during simulations. Straight-forward techniques for the construction of folding sequences, based solely on the target structure, fail. We describe in detail an optimization algorithm, based on genetic algorithms, for the "simulated breeding" of folding sequences in this model. We find that, for any target structure studied, there is not only a single folding sequence but a patch of sequences in sequence space that fold to this structure. In addition, we show that, much as in real proteins, nonhomologous sequences may fold to the same target structure.

Amino Acid Sequence↗
PubMed1996

Prognostic significance of prior preterm twin delivery on subsequent singleton pregnancy.

OBJECTIVE: Our purpose was to determine whether preterm birth of twins is associated with an increased risk of preterm birth in a subsequent singleton pregnancy. STUDY DESIGN: The Medical University of South Carolina perinatal database was accessed to identify a cohort of patients who were delivered of twins followed by a singleton gestation (1981 to 1993). Maternal transports were excluded to minimize referral bias. Preterm birth was defined as < 37 weeks' gestation. Relative risks with 95% confidence intervals were calculated. RESULTS: One hundred forty-four patients were identified who were delivered of twins followed by a singleton gestation. Preterm delivery occurred in 86 (59.7%) of the twins and 21 (14.6%) of the subsequent singletons. Preterm birth of twins was associated with a significantly increased risk of preterm delivery in a subsequent singleton pregnancy (relative risk 2.87, 95% confidence interval 1.02 to 8.09). In the subset of women who were delivered of twins at < 30 weeks' gestation, 42% of the subsequent singletons were delivered preterm (relative risk 6.11, 95% confidence interval 2.07 to 18.02). The relative risk of preterm birth of a singleton after delivery of twins between 30 and 34 weeks' gestation was 3.63 (95% confidence interval 1.02 to 12.92). However, if the preceding twins delivered between 34 and 37 weeks' gestation, the relative risk of preterm birth of the subsequent singleton was not significantly increased (relative risk 1.42, 95% confidence interval 0.40 to 5.01). CONCLUSIONS: Preterm birth of twins before 34 weeks' gestation is associated with a significant risk for preterm delivery in a subsequent singleton pregnancy. The magnitude of risk increases with decreasing gestational age of the preceding twin delivery.

Adult↗