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Biomedical subjects

S L Dixon

Publications and source records attributed to S L Dixon.

17 recordsLinked to original sources
PubMed2001

One-dimensional molecular representations and similarity calculations: methodology and validation.

Drug discovery research is increasingly dedicated to biological screening on a massive scale, which seems to imply a basic rejection of many computer-assisted techniques originally designed to add rationality to the early stages of discovery. While ever-faster and more clever 3D methodologies continue to be developed and rejected as alternatives to indiscriminant screening, simpler tools based on 2D structure have carved a stable niche in the high-throughput paradigm of drug discovery. Their staying power is due in no small part to simplicity, ease of use, and demonstrated ability to explain structure-activity data. This observation led us to wonder whether an even simpler view of structure might offer an advantage over existing 2D and 3D methods. Accordingly, we introduce 1D representations of chemical structure, which are generated by collapsing a 3D molecular model or a 2D chemical graph onto a single coordinate of atomic positions. Atoms along this coordinate are differentiated according to elemental type, hybridization, and connectivity. By aligning 1D representations to match up identical atom types, a measure of overall structural similarity is afforded. In extensive structure-activity validation tests, 1D similarities consistently outperform both Daylight 2D fingerprints and Cerius(2) pharmacophore fingerprints, suggesting that this new, simple means of representing and comparing structures may offer a significant advantage over existing tried-and-true methods.

Drug Design↗
PubMed1999

LASSOO: a generalized directed diversity approach to the design and enrichment of chemical libraries.

Pharmaceutical discovery relies on the screening of chemical libraries that are as diverse as possible yet constrained in favor of compounds possessing attributes that are normally associated with successful drug candidates. We describe a new algorithm for simultaneously addressing both objectives, providing an effective means to increase structural diversity in a chemical library while maintaining a bias toward compounds that retain the desirable properties of drugs. The LASSOO algorithm exploits differences in descriptor distributions to identify novel compounds that are most dissimilar to the members of an existing screening library and most similar to members of a target library with desirable characteristics. We illustrate the LASSOO technique using publicly available compound databases and bit string descriptors. The architecture of the algorithm is general enough to allow any set of descriptors or similarity measures to be employed, and it is easily adaptable to other means of directing diversity, such as the avoidance of toxicity and/or poor pharmacokinetic properties.

Algorithms↗
PubMed1999

The hidden component of size in two-dimensional fragment descriptors: side effects on sampling in bioactive libraries.

We have carried out a number of sampling experiments in libraries of bioactive compounds to illustrate how size biases introduced by two-dimensional (2D) fragment distance functions may provide misleading information about the diversity of compound subsets. The number of different biological targets covered by a given subset is used as a measure of bioactive diversity, and it is considered to be the relevant property with which 2D diversity should correlate. Since the nature of the size biases depends on the way in which 2D distance is computed, we investigated three different methods of calculating distance. Use of 1-Tanimoto as a dissimilarity measure leads to the spurious conclusion that collections of structurally small compounds are inherently more diverse than other collections which may cover a broader range of sizes and more biological targets. XOR or squared Euclidean distance, by contrast, shows a preference for subsets of structurally larger compounds, but this does not appear to have as many adverse consequences in terms of target coverage. A simple product of 1-Tanimoto and XOR tends to equalize the opposing size effects of the two component distance functions and leads to a relatively unbiased means of comparing structures. Results here suggest that careful consideration should be given to the way in which chemical structures are compared whenever 2D fragment descriptors are used.

Drug Design↗
PubMed1999

Investigation of classification methods for the prediction of activity in diverse chemical libraries.

Classification methods based on linear discriminant analysis, recursive partitioning, and hierarchical agglomerative clustering are examined for their ability to separate active and inactive compounds in a diverse chemical database. Topology-based descriptions of chemical structure from the Molconn-X and ISIS programs are used in conjunction with these classification techniques to identify ACE inhibitors, beta-adrenergic antagonists, and H2 receptor antagonists. Overall, discriminant analysis misclassifies the smallest number of active compounds, while recursive partitioning yields the lowest rate of misclassification among inactives. Binary structural keys from the ISIS package are found to generally outperform the whole-molecule Molconn-X descriptors, especially for identification of inactive compounds. For all targets and classification methods, sensitivity toward active compounds is increased by making repetitive classification using training sets that contain equal numbers of actives and inactives. These balanced training sets provide an average numerical class membership score which may be used to select subsets of compounds that are enriched in actives.

Adrenergic beta-Antagonists↗
PubMed1999

Do health professionals' attitudes interfere with the treatment of depression?

Might the attitudes of health care professionals help to explain why most persons with a depressive disorder do not receive adequate care? To assess this question, the authors surveyed the faculty and staff of a midwestern university. One hundred percent of the social workers who responded found psychotherapy or counseling to be extremely or quite effective in treating persons with a major depressive episode, compared to 55% of the psychologists and 31% of the psychiatrists. For medication, the corresponding figures were 88% of psychiatrists, 64% of psychologists, and 46% of social workers. Many respondents noted problems with interprofessional communication, while most psychiatrists felt that individuals treated by two or more professionals for their depression usually receive poorer care. If future studies indicate that nonmedical therapists who view antidepressants as relatively ineffective are less likely to refer depressed clients for medication evaluation, these findings might help to explain why many depressed individuals who could benefit from medication do not receive it. Concerns about interprofessional communication, as well as psychiatrists' beliefs about the quality of care received by persons treated by more than one professional, might also explain why joint treatment occurs less often than would be desirable. The authors discuss some of the implications that these findings may have for the education of health care professionals.

Attitude to Health↗
PubMed1990

Hypergammaglobulinemic purpura of Waldenström.

Hypergammaglobulinemic purpura of Waldenström is characterized by hypergammaglobulinemia, recurring purpura, an elevated erythrocyte sedimentation rate, and the presence of rheumatoid factor indicative of circulating immune complexes. There is a significant association with autoimmune diseases, especially Sjögren's syndrome and lupus erythematosus. Hypergammaglobulinemic purpura is considered primary when there is no other associated disease or secondary when associated with other diseases, usually autoimmune. Immune derangements are fundamental in its pathogenesis, although its cause is still unknown. Therapy is unrewarding and is probably unnecessary for this usually benign condition. Three cases are presented that are representative of patients with hypergammaglobulinemic purpura.

Adult↗
PubMed1989

Schwannomatosis. An unusual variant of neurofibromatosis or a distinct clinical entity?

Multiple schwannomas have frequently been seen in patients with neurofibromatosis. Recently, the association of multiple cutaneous schwannomas, central nervous system tumors, and various neurologic deficits has been described in Japanese patients as a condition called schwannomatosis. We describe the first non-Japanese cases of schwannomatosis and compare and contrast this unusual condition with the well-known variants of neurofibromatosis. We conclude that the features of schwannomatosis are distinct and define a condition that does not fit into the current classification scheme of neurofibromatosis. The occurrence of multiple cutaneous schwannomas in the absence of cardinal features of neurofibromatosis may indicate the presence of central nervous system tumors or various neurologic deficits.

Adolescent↗
PubMed1989

Fulminant transfusion-associated graft-versus-host disease in a premature infant.

A fatal case of transfusion-associated graft-versus-host disease developed in a premature infant after receiving several blood products, including nonirradiated white blood cells. Transfusion-associated graft-versus-host disease can be prevented. Irradiation of blood products is the least controversial and most effective method. Treatment was unsuccessful in most reported cases of transfusion-associated graft-versus-host disease. Therefore irradiation of blood products before transfusing to patients susceptible to transfusion-associated graft-versus-host disease is strongly recommended.

Blood↗
PubMed1989

Erythema dyschromicum perstans and lichen planus: are they related?

A 53-year-old woman initially had lichen planus primarily on her extremities. Approximately 1 year later, lesions consistent with erythema dyschromicum perstans were observed. Both diseases cleared with griseofulvin therapy but returned after discontinuation of the drug. Retreatment with griseofulvin again resulted in clearing.

Biopsy↗
PubMed1986

Pustular folliculitis associated with Demodex folliculorum.

A 49-year-old man presented with an acute onset of folliculitis on his right cheek. The folliculitis was unresponsive to antibiotics. A potassium hydroxide preparation of a scraping from the affected area revealed the presence of numerous Demodex mites. The patient was treated with topical crotamiton (Eurax) cream resulting in rapid resolution of the folliculitis. We believe that this case represents a localized pustular folliculitis resulting from a heavy infestation with Demodex folliculorum. In spite of more than 50 years of investigation, the role of D. folliculorum in human cutaneous disease remains controversial.

Folliculitis↗
PubMed1985

Allergic contact dermatitis to dyclonine hydrochloride simulating extensive herpes simplex labialis.

Two patients developed allergic contact dermatitis to 1% dyclonine hydrochloride gel, a nonprescription topical anesthetic widely marketed for the symptomatic treatment of herpes simplex labialis. Both patients mistakenly believed that the eruption was expanding herpes simplex labialis, which resulted in their more frequent application of the dyclonine hydrochloride and a delay in diagnosis. Dermatologists should recognize that 1% dyclonine hydrochloride gel can cause allergic contact dermatitis that can masquerade as widespread herpes simplex labialis.

Adult↗
PubMed1984

Occlusion amblyopia secondary to a mixed capillary-cavernous hemangioma.

We report a case of amblyopia that developed in an infant and was secondary to occlusion of the visual axis by a capillary-cavernous hemangioma. In addition to occlusion amblyopia, hemangiomas can cause astigmatic and myopic refractive errors, which usually persist throughout life. Indications for treatment and therapeutic modalities are discussed. Patients with cavernous and/or capillary hemangiomas of the periorbital region need ophthalmologic consultation and close follow-up during the first year of life. Therapy should be started promptly if growth of the hemangioma threatens to occlude vision or induce refractive error.

Amblyopia↗
PubMedDate not supplied

Bioactive diversity and screening library selection via affinity fingerprinting.

The Similarity Principle provides the conceptual framework behind most modern approaches to library sampling and design. However, it is often the case that compounds which appear to be very similar structurally may in fact exhibit quite different activities toward a given target. Conversely, some targets recognize a wide variety of molecules and thus bind compounds that have markedly different structures. Affinity fingerprints largely overcome the difficulties associated with selecting compounds on the basis of structure alone. By describing each compound in terms of its binding affinity to a set of functionally dissimilar proteins, fundamental factors relevant to binding and biological activity are automatically encoded. We demonstrate how affinity fingerprints may be used in conjunction with simple algorithms to select active-enriched diverse training sets and to efficiently extract the most active compounds from a large library.

Algorithms↗