Biomedical subjects
Publications and source records attributed to K McCallum.
A novel series of 5,5-diaryl-2-amino-4-pentenoates was synthesized and found to be potent and selective glycine transporter type-2 reuptake inhibitors.
A novel series of 6-bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives was synthesized and found to be potent and selective 5-HT6 receptor antagonists.
A series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized, evaluated for their activity against the 5-HT2c and 5-HT2a, receptors and found to be agonists at 5-HT2c with selectivity over 5-HT2a.
Glucagon-like peptide 2 (GLP-2) is a 33-aa proglucagon-derived peptide produced by intestinal enteroendocrine cells. GLP-2 stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis. Moreover, GLP-2 prevents intestinal hypoplasia resulting from total parenteral nutrition. However, the mechanism underlying these actions has remained unclear. Here we report the cloning and characterization of cDNAs encoding rat and human GLP-2 receptors (GLP-2R), a G protein-coupled receptor superfamily member expressed in the gut and closely related to the glucagon and GLP-1 receptors. The human GLP-2R gene maps to chromosome 17p13.3. Cells expressing the GLP-2R responded to GLP-2, but not GLP-1 or related peptides, with increased cAMP production (EC50 = 0.58 nM) and displayed saturable high-affinity radioligand binding (Kd = 0.57 nM), which could be displaced by synthetic rat GLP-2 (Ki = 0.06 nM). GLP-2 analogs that activated GLP-2R signal transduction in vitro displayed intestinotrophic activity in vivo. These results strongly suggest that GLP-2, like glucagon and GLP-1, exerts its actions through a distinct and specific novel receptor expressed in its principal target tissue, the gastrointestinal tract.
A preliminary effort to validate the Junior Temperament and Character Inventory with a convenience sample of 322 children ages 9 to 12 years is described.
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We recently developed an approach which allows rapid generation of short, double-stranded oligonucleotides whereby one end of the duplex was joined and stabilized by a synthetic linker of specific design (miniduplexes)(6). Model miniduplexes based on the HIV-1 TAR RNA hairpin were shown to be thermodynamically stable and good substrates for binding by the HIV-1 Tat protein which normally bind to natural TAR (6). In this study, we have extended our studies to the design, synthesis and analysis of the binding properties of covalently closed, double-stranded, cyclic RNA miniduplexes. A strategy using automated chemical synthesis and T4 RNA ligase-catalyzed cyclization was employed to generate cyclic oligoribonucleotides. When both ends of a shortened, wild-type TAR RNA stem (9 bp) were covalently linked through either nucleotidic loops (4-6 nt) or synthetic linkers (derivatized from hexaethylene glycol), the resulting cyclic TAR RNA analogs were good substrates for binding by both Tat-derived peptide or full-length Tat protein. Interestingly, the cyclic TAR analogs failed to show any binding if the synthetic linker was reduced in length (e.g. derivatized from triethylene glycol), although such linkers are acceptable in the hairpin-shaped miniduplexes series (6). This implies that RNA conformational changes are required for Tat binding and that these changes are restricted in certain cyclic variants. Our findings suggest that covalently-closed nucleic acid miniduplexes may be useful both to study nucleic acid-protein interactions as well as to provide a basis for therapeutic intervention as transcription decoys.
The extent of the diversity of marine prokaryotes is not well known, primarily because of poor cultivability. However, new techniques permit the characterization of such organisms without culturing, via 16S rRNA sequences obtained directly from biomass. We performed such an analysis by polymerase chain reaction amplification with universal primers on five oligotrophic open-ocean samples: from 100-m (three samples) and 500-m depths in the western California Current (Pacific Ocean) and from a 10-m depth in the Atlantic Ocean near Bermuda. Of 61 clones, 90% were in clusters of two or more related marine clones obtained by ourselves or others. We report 15 clones related to clone SAR 11 found earlier near Bermuda (S. J. Giovannoni, T. B. Britschgi, C. L. Moyer, and K. G. Field, Nature [London] 345:60-63, 1990), 11 related to marine cyanobacteria, 9 clustered in a group affiliated with gram-positive bacteria, 9 in an archaeal cluster we recently described (mostly from the 500-m sample), 4 in a novel gamma-proteobacterial cluster, and 6 in three two-membered clusters (including other archaea). One clone was related to flavobacteria. Only the cyanobacteria plus one other clone, related to Roseobacter denitrificans (formerly Erythrobacter longus Och114), were within 10% sequence identity to any previously sequenced cultured organism in a major data base. We never found more than two occurrences of the same sequence in a sample, although four times we found identical sequences between samples, two of which were between oceans; one of these sequences was also identical to SAR 11.(ABSTRACT TRUNCATED AT 250 WORDS)
Marine bacteria often dominate the plankton biomass and are responsible for much of the cycling of organic matter, but bacterial diversity is poorly understood because conventional identification methods (requiring culturing) miss about 99% of the organisms. Recent advances permit characterization of microbial communities by analysis of 16S ribosomal RNA gene sequences directly from biomass without the need to culture the organisms; such studies from surface ocean samples have found only eubacteria, not archaebacteria (or Archaea), which are profoundly different. Here we report 16S rRNA sequences obtained from Pacific Ocean bacterioplankton samples collected from depths of 100 m and 500 m. Among these we found sequences only distantly related to those of any organisms previously characterized by 16S rRNA sequences, with similarities to the nearest such relatives (extreme thermophiles) approximately the same as those between animals and plants. We suggest that these sequences are from a previously undescribed archaebacterial group that may have diverged from the ancestors of characterized organisms very early in evolution.
The conception of personality disorders (PDs) as distinct units of mental disorders is neither precise nor useful. At least some PDs, classified as separate units, reflect different behavioral expression of the same personality deviation. In this article we describe structural, developmental, and clinical continuum between relatively distinct entities of antisocial PD and narcissistic PD. The two disorders represent different endpoints sharing a borderline level of personality organization and pathological narcissism. We propose a spectrum relation for antisocial and narcissistic PD because the disorders tend to co-occur in the same individual and to run in the same family more often than expected by chance.
Present classifications fall short of helping clinicians to systematically approach syndromes of antisocial (A-S) behavior. Various clinical forms of A-S behavior derive from different levels of personality organization (normal, neurotic, and borderline level) whereas certain personality disorders (PD) display specific antisocial "profiles" and form the horizontal continuum of antisocial behavior. The borderline level of personality and pathological narcissism stand behind A-S PD, Narcissistic PD, and Histrionic PD. The authors propose that the disorders should be regarded as spectrum disorders. Paranoid PD and "pure" Borderline PD complete the list of PDs manifesting A-S behaviors. Finally, diagnostic instruments for clinical approach to and research of A-S PD are presented.
This report provides a quantitative analysis of the distribution of helper-inducer T cells (H-I, LEU3A+) and cytotoxic-suppressor T cells (C-S, OKT8+) performed in a standardized fashion on material from 10 cases of multiple sclerosis. Particular attention was paid to cells at the plaque edge and to normal appearing white matter adjacent to plaques. Numbers of both the C-S and the H-I subset peaked directly at the edges of plaques, whether histopathologically active or inactive (P less than 0.01). Normal appearing areas outside active plaques had fewer C-S cells than equivalent areas outside inactive plaques (P less than 0.05). A study of three whole plaques showed that the sum of the two T cell subsets was significantly greater than the number of cells bearing the pan-T cell marker in two plaques and in two border regions. The present results support a crucial role for the balance of T cell subsets in the evolution of plaque margins. When taken together with similar findings in experimental allergic encephalomyelitis, they suggest that helper-inducer cell dominance at the border is necessary for plaque expansion while C-S dominance in non plaque areas is associated with controlled disease. In addition, they suggest either modulation of the OKT3 surface antigen or the presence of a non-T cell bearing OKT8 in association with the site of histopathological change.
A computerized version of the Diagnostic Interview for Children and Adolescents-Revised (DICA-R) has been developed. There are three versions of the interview, one for children aged 6 to 12, one for adolescents aged 13 to 18, and one for parents of children aged 6 to 18. Acceptability and reliability studies of the child and adolescent versions were performed on 93 subjects. The results show that children of all ages enjoyed the computer, and most were able to complete the interview with very little help. Reasonable reliability was found for both age groups despite difficulty with certain diagnostic criteria.
Milne Bay Province, Papua New Guinea, with a scattered population of 130,000 suffers from irregular health patrols in remote areas, and often inadequate supplies of contraceptive agents. A total of 694 tubal ligations were performed by hospital staff under local anaesthesia between 1978 and 1982 in the province, the number increasing each year. Detailed analysis of 324 operations from 1979 to 1981 showed an average age of 34, average parity of 7 (84% of women had five or more children) and the presence of one or more high risk factors other than multiparity in half the women operated upon. Tubal ligation decreases maternal mortality, and has proven to be a useful method of family planning for multiparous women living in remote villages in Milne Bay Province.