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Biomedical subjects

D M Scott

Publications and source records attributed to D M Scott.

At least 19 recordsLinked to original sources
PubMed2004

Design, synthesis, and analysis of a polyethelene glycol-modified (PEGylated) small molecule inhibitor of integrin {alpha}4{beta}1 with improved pharmaceutical properties.

Integrin alpha4beta1 plays an important role in inflammatory processes by regulating the migration of leukocytes into inflamed tissues. Previously, we identified BIO5192 [2(S)-{[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino}-4-[4-methyl-2(S)-(methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-pentanoylamino]-butyric acid], a highly selective and potent (K(D) of 9 pM) small molecule inhibitor of alpha4beta1. Although BIO5192 is efficacious in various animal models of inflammatory disease, high doses and daily treatment of the compound are needed to achieve a therapeutic effect because of its relatively short serum half-life. To address this issue, polyethylene glycol modification (PEGylation) was used as an approach to improve systemic exposure. BIO5192 was PEGylated by a targeted approach in which derivatizable amino groups were incorporated into the molecule. Two sites were identified that could be modified, and from these, five PEGylated compounds were synthesized and characterized. One compound, 2a-PEG (K(D) of 19 pM), was selected for in vivo studies. The pharmacokinetic and pharmacodynamic properties of 2a-PEG were dramatically improved relative to the unmodified compound. The PEGylated compound was efficacious in a rat model of experimental autoimmune encephalomyelitis at a 30-fold lower molar dose than the parent compound and required only a once-a-week dosing regimen compared with a daily treatment for BIO5192. Compound 2a-PEG was highly selective for alpha4beta1. These studies demonstrate the feasibility of PEGylation of alpha4beta1-targeted small molecules with retention of activity in vitro and in vivo. 2a-PEG, and related compounds, will be valuable reagents for assessing alpha4beta1 biology and may provide a new therapeutic approach to treatment of human inflammatory diseases.

Animals↗
PubMed2003

An assessment of the mechanistic differences between two integrin alpha 4 beta 1 inhibitors, the monoclonal antibody TA-2 and the small molecule BIO5192, in rat experimental autoimmune encephalomyelitis.

Integrin alpha 4 beta 1 plays an important role in inflammatory processes by regulating the migration of lymphocytes into inflamed tissues. Here we evaluated the biochemical, pharmacological, and pharmacodynamic properties and efficacy in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, of two types of alpha 4 beta 1 inhibitors, the anti-rat alpha 4 monoclonal antibody TA-2 and the small molecule inhibitor BIO5192 [2(S)-[[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino]-4-[4-methyl-2(S)-(methyl-[2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl]-amino)-pentanoylamino]-butyric acid]. TA-2 has been extensively studied in rats and provides a benchmark for assessing function. BIO5192 is a highly selective and potent (KD of <10 pM) inhibitor of alpha 4 beta 1. Dosing regimens were identified for both inhibitors, which provided full receptor occupancy during the duration of the study. Both inhibitors induced leukocytosis, an effect that was used as a pharmacodynamic marker of activity, and both were efficacious in the EAE model. Treatment with TA-2 caused a decrease in alpha 4 integrin expression on the cell surface, which resulted from internalization of alpha 4 integrin/TA-2 complexes. In contrast, BIO5192 did not modulate cell surface alpha 4 beta 1. Our results with BIO5192 indicate that alpha 4 beta 7 does not play a role in this model and that blockade of alpha 4 beta 1/ligand interactions without down-modulation is sufficient for efficacy in rat EAE. BIO5192 is highly selective and binds with high affinity to alpha 4 beta 1 from four of four species tested. These studies demonstrate that BIO5192, a novel, potent, and selective inhibitor of alpha 4 beta 1 integrin, will be a valuable reagent for assessing alpha 4 beta 1 biology and may provide a new therapeutic for treatment of human inflammatory diseases.

Animals↗
PubMed2000

Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.

Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the structures of the T. gondii apo AK, AK:adenosine complex and the AK:adenosine:AMP-PCP complex to 2.55 A, 2.50 A and 1.71 A resolution, respectively. These structures reveal a novel catalytic mechanism that involves an adenosine-induced domain rotation of 30 degrees and a newly described anion hole (DTXGAGD), requiring a helix-to-coil conformational change that is induced by ATP binding. Nucleotide binding also evokes a coil-to-helix transition that completes the formation of the ATP binding pocket. A conserved dipeptide, Gly68-Gly69, which is located at the bottom of the adenosine-binding site, functions as the switch for domain rotation. The synergistic structural changes that occur upon substrate binding sequester the adenosine and the ATP gamma phosphate from solvent and optimally position the substrates for catalysis. Finally, the 1.84 A resolution structure of an AK:7-iodotubercidin:AMP-PCP complex reveals the basis for the higher affinity binding of this prodrug over adenosine and thus provides a scaffold for the design of new inhibitors and subversive substrates that target the T. gondii AK.

Adenosine↗
PubMed2000

Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.

Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the structures of the T. gondii apo AK, AK:adenosine complex and the AK:adenosine:AMP-PCP complex to 2.55 A, 2.50 A and 1.71 A resolution, respectively. These structures reveal a novel catalytic mechanism that involves an adenosine-induced domain rotation of 30 degrees and a newly described anion hole (DTXGAGD), requiring a helix-to-coil conformational change that is induced by ATP binding. Nucleotide binding also evokes a coil-to-helix transition that completes the formation of the ATP binding pocket. A conserved dipeptide, Gly68-Gly69, which is located at the bottom of the adenosine-binding site, functions as the switch for domain rotation. The synergistic structural changes that occur upon substrate binding sequester the adenosine and the ATP gi phosphate from solvent and optimally position the substrates for catalysis. Finally, the 1.84 A resolution structure of an AK:7-iodotubercidin:AMP-PCP complex reveals the basis for the higher affinity binding of this prodrug over adenosine and thus provides a scaffold for the design of new inhibitors and subversive substrates that target the T. gondii AK.

Adenosine↗
PubMed2000

Lymphangioma-like Kaposi's sarcoma: etiology and literature review.

Much confusion surrounds a rare and occasionally described variant of Kaposi's sarcoma (KS) known as lymphangioma-like or bullous KS. We describe the typical clinical and histologic features and elucidate the etiologic cell in lymphangioma-like KS. A computer-based review of the English-language literature was performed. Routine histologic and immunoperoxidase techniques were performed on formalin-fixed tissue. Immunoperoxidase staining for anti-CD31, anti-CD34, and anti-factor VIII-related antigen suggests that the etiologic cell of origin is the vascular endothelial cell. Lymphangioma-like KS has been described for more than a century and given various names. Dilated vascular spaces correlate with the clinically bullous lesions, which are veritable KS and not a secondary reaction to it.

Adult↗
PubMed2000

Anaesthetic management of a parturient with a colloid cyst of the third ventricle.

A colloid cyst in the third ventricle near the foramen of Monroe can obstruct cerebrospinal fluid (CSF) flow from the lateral ventricles. Any change in the CSF pressure on either side of the cyst can lead to displacement and thus precipitate acute hydrocephalus. Management of the confinement of a patient with a colloid cyst must therefore aim to minimize changes in CSF pressure. We describe our management of a patient with a small colloid cyst who was permitted to labour with the assistance of patient-controlled epidural analgesia. The available alternatives are discussed.

Adult↗
PubMed1999

Fibrous hamartoma of infancy.

Fibrous harmartoma of infancy is a benign soft tissue tumor that occurs in the first few years of life. Although the lesion is not distinctive clinically, it has a characteristic microscopic appearance. Only 12 cases of fibrous hamartoma of infancy have been reported in the dermatology literature.

Female↗
PubMed1999

Effectiveness of student assistance programs in Nebraska schools.

BACKGROUND: This study investigated whether Nebraska schools with Student Assistance Programs (SAP) are associated with reduced adolescent alcohol use and a higher level of academic achievement than students from schools without a SAP. METHODS: In 1992, the Toward a Drug Free Nebraska (TDFN) survey was administered to 3,454 students in grades seven to twelve at eighty-three Nebraska schools. A second survey, the TDFN "team activity report" collected from each school's team, the presence of a SAP (n = 34 schools) or absence of a SAP (n = 49 schools). Student responses for alcohol use and academic achievements were linked with the presence of a SAP through use of a school identification number on both surveys. RESULTS: Students from schools with a SAP reported a lower use of alcohol in the last thirty days, compared with students from schools without a SAP program (p < 0.05), and they also reported a significant difference in academic achievement (p < 0.05). CONCLUSIONS: While this study used post hoc analysis of data, the results suggest lower alcohol use and higher academic achievement among students from SAP schools. Given SAPs' popularity, these trends suggest that further research should be conducted to demonstrate the effectiveness of student assistance programs.

Adolescent↗
PubMed1998

Crystal structures of Toxoplasma gondii uracil phosphoribosyltransferase reveal the atomic basis of pyrimidine discrimination and prodrug binding.

Uracil phosphoribosyltransferase (UPRTase) catalyzes the transfer of a ribosyl phosphate group from alpha-D-5-phosphoribosyl-1-pyrophosphate to the N1 nitrogen of uracil. The UPRTase from the opportunistic pathogen Toxoplasma gondii is a rational target for antiparasitic drug design. To aid in structure-based drug design studies against toxoplasmosis, the crystal structures of the T.gondii apo UPRTase (1.93 A resolution), the UPRTase bound to its substrate, uracil (2.2 A resolution), its product, UMP (2.5 A resolution), and the prodrug, 5-fluorouracil (2.3 A resolution), have been determined. These structures reveal that UPRTase recognizes uracil through polypeptide backbone hydrogen bonds to the uracil exocyclic O2 and endocyclic N3 atoms and a backbone-water-exocyclic O4 oxygen hydrogen bond. This stereochemical arrangement and the architecture of the uracil-binding pocket reveal why cytosine and pyrimidines with exocyclic substituents at ring position 5 larger than fluorine, including thymine, cannot bind to the enzyme. Strikingly, the T. gondii UPRTase contains a 22 residue insertion within the conserved PRTase fold that forms an extended antiparallel beta-arm. Leu92, at the tip of this arm, functions to cap the active site of its dimer mate, thereby inhibiting the escape of the substrate-binding water molecule.

Amino Acid Sequence↗
PubMed1998

Cytologic-pathologic correlations: fine needle aspiration of three cases of steatocystoma multiplex.

Steatocystoma multiplex is a rare condition characterized by multiple subcutaneous nodules classically located on the anterior chest. Diagnosis usually is made clinically or by biopsy. The lesions may be numerous, and surgical treatment may not be practical or the results may be unsatisfactory. Three patients with multiple subcutaneous nodules underwent fine needle aspiration, which produced smears with acellular debris. A diagnosis was possible in the first patient because of close collaboration with a dermatologist. The lesions in the other patients were recognized clinically and were confirmed cytologically by fine needle aspiration. A syringe holder allows the use of thin needles (22-gauge) to aspirate very small lesions (4 to 5 mm). Fine needle aspiration may provide a useful alternative to surgical methods in the treatment of these lesions because it is inexpensive, well-tolerated by the patients, and has no associated morbidity.

Adult↗
PubMed1998

Characterization of genes encoding translation initiation factor eIF-2gamma in mouse and human: sex chromosome localization, escape from X-inactivation and evolution.

The Delta Sxrb interval of the mouse Y chromosome is critical for spermatogenesis and expression of the male-specific minor transplantation antigen H-Y. Several genes have been mapped to this interval and each has a homologue on the X chromosome. Four, Zfy1 , Zfy2 , Ube1y and Dffry , are expressed specifically in the testis and their X homologues are not transcribed from the inactive X chromosome. A further two, Smcy and Uty , are ubiquitously expressed and their X homologues escape X-inactivation. Here we report the identification of another gene from this region of the mouse Y chromosome. It encodes the highly conserved eukaryotic translation initiation factor eIF-2gamma. In the mouse this gene is ubiquitously expressed, has an X chromosome homologue which maps close to Dmd and escapes X-inactivation. The coding regions of the X and Y genes show 86% nucleotide identity and encode putative products with 98% amino acid identity. In humans, the eIF-2gamma structural gene is located on the X chromosome at Xp21 and this also escapes X-inactivation. However, there is no evidence of a Y copy of this gene in humans. We have identified autosomal retroposons of eIF-2gamma in both humans and mice and an additional retroposon on the X chromosome in some mouse strains. Ark blot analysis of eutherian and metatherian genomic DNA indicates that X-Y homologues are present in all species tested except simian primates and kangaroo and that retroposons are common to a wide range of mammals. These results shed light on the evolution of X-Y homologous genes.

Amino Acid Sequence↗
PubMed1998

A preliminary study of immunologic and hematologic profiles of peripheral blood from Nebraska farmers who apply pesticides to their fields.

OBJECTIVE: Laboratory studies have documented a wide range of pesticide-induced changes in the hematopoietic and lymphoreticular systems. Some of these are expressed as altered serum values, blood cell counts, and leucocyte functions. The goal of the present study was to determine whether these alterations were evident in peripheral blood of Nebraska farmers who applied pesticides to their fields. METHODS: An invitation to participate was mailed to 100 residents (70 farmers; 30 controls) of Butler County, Nebraska. All respondents (51 farmers and 21 controls) were enrolled and surveyed by written questionnaire for health status and pesticide use. Our analysis included 45 farmers and 18 controls. The farmers were divided into a high (n = 23) and a low (n = 22) pesticide use group. Statistical correlations of ten blood values with both pesticide use and age were evaluated, since pesticide use correlated with age. RESULTS: Four of the ten blood values correlated with pesticide use and age (Spearman Rho). In a multiple regression model, pesticide use (not age) proved to be a predictor of red blood cell count and hematocrit. In the same model, pesticide use was not a predictor of mean red cell volume or candida antigen-induced T-lymphocyte proliferation. Serum complement activity did not correlate with pesticide use among the farmers (n = 45) but was significantly reduced (ANOVA) in the high pesticide use group, compared to controls. CONCLUSIONS: A preliminary study of blood values in a small cohort of Nebraska farmers found no pesticide-associated effects on 1) leucocyte count, 2) antigen- and mitogen-stimulated T-cell proliferation, 3) mitogen-stimulated B-cell proliferation, and 4) concentrations of serum IgG and IgM. The study found small but statistically significant pesticide-associated effects on red blood cells and serum complement.

Adult↗
PubMed1997

Why do some females reject males? The molecular basis for male-specific graft rejection.

The male-specific minor histocompatibility antigen H-Y plays an important role in both graft rejection and graft-versus-host disease following transplantation of male tissue into females that are completely matched at the major histocompatibility loci. The recent identification of two peptides that, in association with the mouse H-2Kk or human HLA B7 major histocompatibility class I molecules, are recognised by H-Y-specific T cells, has provided evidence for the molecular basis for such anti-H-Y responses. These peptides are encoded by the mouse and human homologues of a ubiquitously expressed Y chromosome gene, Smcy, whilst the equivalent peptides encoded by the X chromosome homologues of this gene fail to be recognised. Genetic studies have demonstrated that, as is the case for other minor histocompatibility antigens, peptide epitopes from several closely linked genes may be required to interact in order to elicit a response against H-Y. Definition of the peptides and the genes that encode these epitopes will allow the development of tolerogenic protocols that could specifically down-modulate the response to H-Y and perhaps even other minor histocompatibility antigens.

Amino Acid Sequence↗
PubMed1996

Anabolic steroid use among adolescents in Nebraska schools.

The extent of anabolic steroid use among adolescent sports participants and nonparticipants in Nebraska schools was studied. The Nebraska Secondary School Survey administered in 1991 contained 19 new items designed to determine rates of use of anabolic steroids and to measure participation in school sports. Schools participating in the survey are part of the Toward a Drug Free Nebraska training project; when the 1991 survey was conducted, training did not address ergogenic drug use. The survey was administered on a voluntary and confidential basis to Nebraska students in grades 7 through 12. A total of 4722 students in 62 secondary schools were surveyed; 3183 (67.4%) identified themselves as participants in school-sponsored sports. Of all the respondents, 117 (2.5%) reported having used anabolic steroids in the preceding 30 days. Some 4.5% of all the male respondents were steroid users, versus 0.8% of all the females. Of the students who reported using anabolic steroids, 72.6% were sports participants. Steroid users, whether they participated in sports or not, were more likely to use alcohol, tobacco, and other drugs than were nonusers of steroids. Among sports participants and nonparticipants, anabolic steroid users were more likely than nonusers to report acting violently. Nebraska students (grades 7 through 12) who participated in school-sponsored sports were more likely than non-participants to use anabolic steroids. Steroid-using athletes were more likely to use alcohol, tobacco, and other drugs than athletes who did not use steroids.

Adolescent↗
PubMed1996

Respiratory sensation during bronchial challenge testing with methacholine, sodium metabisulphite, and adenosine monophosphate.

BACKGROUND: There is some evidence that the perception of bronchoconstriction may very according to the nature of the provoking stimulus. The aims of this study were, firstly, to develop a method for measuring dyspnoea during induced bronchoconstriction in patients with asthma and, secondly, to apply this method to testing differences between directly and indirectly acting bronchoconstricting stimuli. METHODS: Descriptive terms suitable for quantifying respiratory discomfort due to bronchoconstriction in patients with asthma were identified in a preliminary investigation. The relation between reduction in forced expiratory volume in one second (FEV1) and respiratory discomfort, measured using a visual analogue scale (VAS), was then studied during challenges with three different inhaled stimuli: methacholine (MCH), sodium metabisulphite (MBS), and adenosine monophosphate (AMP). Three indices were calculated to describe the relation: the VAS value associated with a 20% fall in FEV1 (FEV20 VAS); the ratio of the final VAS value to the final percentage fall in FEV1 (VAS-FEV1 ratio); and the regression coefficient for predicting VAS from the percentage fall in FEV1 within each challenge (beta VAS FEV1). RESULTS: "Difficulty in breathing" and "chest tightness" were selected as suitable terms for quantifying respiratory discomfort. There were no differences between the three agonists in the qualitative aspects of the respiratory sensation. In paired challenges with the same agonist the three indices were all found to be reproducible for both sensations measured. MCH induced less intense difficulty in breathing and chest tightness for a given fall in FEV1 than did AMP. There was a trend in the same direction for the comparison between MCH and MBS. There were no differences between AMP and MBS. FEV20 VAS was less powerful in discriminating between agonists than the two slope indices. CONCLUSIONS: The relation between induced reduction in FEV1 and the intensity of respiratory discomfort can be measured reliably. The indirectly acting bronchoconstricting agonists AMP and MBS induced more intense respiratory discomfort for a given fall in FEV1 than the direct agonist MCH. This may be due to differences in unmeasured mechanical changes in the lungs or to an additional action on airway sensory nerves.

Adenosine Monophosphate↗
PubMed1996

Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma.

Asthma and chronic obstructive pulmonary disease are characterized by chronic airway inflammation. Studies using bronchoalveolar lavage (BAL) have shown an increased proportion of eosinophils in the BAL fluid from asthmatics compared with that from normal subjects, whereas studies of chronic obstructive pulmonary disease (COPD) have shown increased numbers of neutrophils. Induced sputum allows sampling of respiratory tract secretions from patients and control subjects, providing a noninvasive method of studying airway secretions and allowing characterization of cells and measurement of soluble markers. We investigated whether induced sputum was a useful method of studying airway fluid from patients with moderate to severe COPD and whether it could be used to compare inflammation in this condition with that in asthma. An initial reproducibility study was undertaken. Sputum was induced twice in 13 patients with severe COPD at a 14-d interval. Total and differential cell counts were carried out and were found to be reproducible over this period. Sputum was then induced in 14 patients with COPD, 23 patients with asthma, 12 healthy cigarette smokers, and 16 normal nonsmoking control subjects. We found a significant increase in neutrophils and increased concentrations of tumor necrosis factor-alpha (TNF alpha) and interleukin-8 (IL-8) in the patients with COPD compared with the smoking and nonsmoking control subjects. Interleukin-8, but not TNF alpha, was significantly higher in the COPD group than in the asthmatic group. We conclude that the cytokines TNF alpha and IL-8 may be involved in the inflammation in COPD.

Adult↗