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Biomedical subjects

E Roberts

Publications and source records attributed to E Roberts.

At least 19 recordsLinked to original sources
PubMed1992

Amide bond replacements incorporated into CCK-B selective "dipeptoids".

This paper describes the chemical synthesis and CCK-B and CCK-A receptor binding affinities of a series of compounds in which the central amide bond of the CCK-B "dipeptoid" ligand tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,S*)]-[2-[[1-(hydroxymethyl)- 2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]carb amate (4) (CCK-B IC50 = 852 nM), and tricyclo[3.3.1.1(3,7)]dec-2-yl (R)-[1-(1H-indol-3-ylmethyl)-1-methyl- 2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate (23) (CCK-B IC50 = 32 nM) is replaced by 11 different amide replacements. These replacements are the methyleneamino (CH2NH), the reverse amide (NHCO), the ester (COO), the N-methylamide (CONMe), the thioamide (CSNH), the N-acetylmethyleneamino (CH2NAc), the cis double bond (CHCH), the ethylene (CH2CH2), the thiolester (COS), the hydroxyethylene (CHOHCH2), and a 4,5-dihydro-1,3-thiazole. Most of the replacements have weaker affinity and reduced selectivity for the CCK-B receptor than the parent amide. However, this affinity can be improved by appending a fumarate side chain to the phenethyl group, e.g. tricyclo[3.3.1.1(3,7)]dec-2-yl-3-(1H-indol-3-yl-methyl)-3-methyl-4 ,9- dioxo-7-phenyl-5,13-dioxa-2,8-diazatetradec-10-enoate (36) (CCK-B IC50 = 38.8 nM). Replacement of the amide of compound 4 with a 4,5-dihydro-1,3-thiazole gives tricyclo[3.3.1.1(3,7)]dec-2-yl [1-[4,5-dihydro-4-(phenylmethyl)-2- thiazolyl]-2-(1H-indol-3-yl)ethyl]carbamate (5), which is selective for the CCK-A receptor (CCK-A IC50 = 125 nM, CCK-B IC50 = 2580 nM, ratio = 21). The methyleneamino and hydroxyethylene replacements, which have been used elsewhere as transition-state inhibitors of enzymes, are poor mimics of the amide in these CCK-B receptor ligands. Some of the steric, lipophilic, and hydrogen bonding properties of amide replacements incorporated into the simple amide, N-methylacetamide, have been quantified with the aid of molecular modeling. These data will contribute to the rational selection of amide bond replacements in other substrates.

Amides↗
PubMed1992

Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it.

Immediate post-training intracerebroventricular administration to male mice of pregnenolone (P), pregnenolone sulfate (PS), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, dihydrotestosterone, or aldosterone caused improvement of retention for footshock active avoidance training, while estrone, estradiol, progesterone, or 16 beta-bromoepiandrosterone did not. Dose-response curves were obtained for P, PS, DHEA, and testosterone. P and PS were the most potent, PS showing significant effects at 3.5 fmol per mouse. The active steroids did not show discernible structural features or known membrane or biochemical effects that correlated with their memory-enhancing capacity. The above, together with the findings that DHEA acted even when given at 1 hr after training and that P, PS, and DHEA improved retention over a much wider dose range than do excitatory memory enhancers, led to the suggestion that the effects of the active steroids converge at the facilitation of transcription of immediate-early genes. P and PS, for which receptors have not yet been demonstrated, may exert their effects by serving as precursors for the formation of a panoply of different steroids, ensuring near-optimal modulation of transcription of immediate-early genes required for achieving the plastic changes of memory processes. Low serum levels of P in aging and the increases of cancer and behavioral disorders in individuals receiving drugs that block synthesis of cholesterol, the immediate precursor of P, suggest possible clinical utility for P.

Animals↗
PubMed1992

Identification of a nonsense mutation in the amelogenin gene (AMELX) in a family with X-linked amelogenesis imperfecta (AIH1).

A family with X-linked amelogenesis imperfecta (XAI) is described in which the disease is associated with a nonsense mutation in exon 5 of the amelogenin gene. This mutation involves a single base deletion (CCCC-->CCC) in the exon in an affected male, his sister and his mother. The effect of this deletion is to alter the reading frame and to introduce an inappropriate TGA stop codon (an opal mutation) into the exonic sequence of the amelogenin gene immediately 3' of the mutation. The clinical features in the examined members of this family indicate that, in some individuals, the most noticeable defect is of enamel hypoplasia. In others, the hypoplastic changes are subtle and might have been overlooked on cursory examination; the most noticeable change is of enamel colour, indicating a degree of hypomineralisation. We propose that the amelogenin gene is implicated in both the formation of enamel of normal thickness and in the normal mineralisation process.

Adolescent↗
PubMed1992

The ligand binding site of the synaptosomal choline transporter: a provisional model based on inhibition studies.

A topographic model of the ligand binding site of the choline transporter was deduced from inhibition studies with the help of CPK molecular models. It is posited that there are two identical or closely similar hydrophilic anionic sites separated from each other by an hinged, essentially planar but conformationally flexible cationic hydrophobic domain. Subsequently to attachment of external choline to either one of the anionic sites, both sites cooperate in enveloping the ligand by a Venus fly-trap mechanism. This leads to rapid configurational changes by which the closed-liganded form of the transporter opens up to the interior to release the bound choline. Intracellular K+, a ligand for the choline-binding site, is proposed to be counter-transported by a reversal of the above mechanism.

Binding Sites↗
PubMed1992

Genetic heterogeneity in X-linked amelogenesis imperfecta.

The AMELX gene located at Xp22.1-p22.3 encodes for the enamel protein amelogenin and has been implicated as the gene responsible for the inherited dental abnormality X-linked amelogenesis imperfecta (XAI). Three families with XAI have been investigated using polymorphic DNA markers flanking the position of AMELX. Using two-point linkage analysis, linkage was established between XAI and several of these markers in two families, with a combined lod score of 6.05 for DXS16 at theta = 0.04. This supports the involvement of AMELX, located close to DXS16, in the XAI disease process (AIH1) in those families. Using multipoint linkage analysis, the combined maximum lod score for these two families was 7.30 for a location of AIH1 at 2 cM distal to DXS16. The support interval around this location extended about 8 cM proximal to DXS92, and the AIH1 location could not be precisely defined by multipoint mapping. Study of recombination events indicated that AIH1 lies in the interval between DXS143 and DXS85. There was significant evidence against linkage to this region in the third family, indicating locus heterogeneity in XAI. Further analysis with markers on the long arm of the X chromosome showed evidence of linkage to DXS144E and F9 with no recombination with either of these markers. Two-point analysis gave a peak lod score at DXS144E with a maximum lod score of 2.83 at theta = 0, with a peak lod score in multipoint linkage analysis of 2.84 at theta = 0. The support interval extended 9 cM proximal to DXS144E and 14 cM distal to F9.(ABSTRACT TRUNCATED AT 250 WORDS)

Amelogenesis Imperfecta↗
PubMed1992

Head injury: impact on the wives.

Wives of head-injured patients often need considerable support because of the myriad of role transitions and role changes they experience. The impact of the head injury on the wife of a survivor is presented in this article. Content analysis was used to analyze data with the themes of role changes, emotional impact of the injury, hope and need for support emerging. Implications for practice and research include need for support groups with nurses as facilitators, the importance of fostering hope, and need for education of health care professionals.

Adaptation, Psychological↗
PubMed1991

Three distinct DNA ligases in mammalian cells.

The major DNA ligase of proliferating mammalian cells, DNA ligase I, catalyzes the joining of single strand breaks in double stranded DNA and is active on a synthetic substrate of oligo(dT) hybridized to poly(dA). DNA ligase I does not catalyze the joining of an oligo(dT).poly(rA) substrate. Two additional DNA ligases, II and III, which can act on the latter substrate have been purified from calf thymus. DNA ligase II, which has been described previously, is a 72-kDa protein. DNA ligase III migrates as a 100-kDa protein in denaturing gel electrophoresis. Structural, immunochemical, and catalytic studies on the three DNA ligase activities strongly indicate that they are the products of three different genes.

Adenosine Monophosphate↗
PubMed1991

Control of blood gas measurements in intensive-care units.

The frequency of blood gas measurement in two adult intensive-care units was assessed for 7 months before and 12 months after introduction of a protocol of indications for such investigation. Demographic, diagnostic, outcome, and intervention data were collected prospectively. There were no differences in demographic characteristics, severity or type of illness, survival, or frequency of arterial or pulmonary artery catheter use between the two observation periods, but the frequency of blood gas analysis fell by 44% (p less than 0.001) after the protocol was introduced.

Aged↗
PubMed1991

Amnestic effects in mice of four synthetic peptides homologous to amyloid beta protein from patients with Alzheimer disease.

Immediate post-training intracerebroventricular administration of a synthetic peptide homologous to beta protein of brain amyloid, [Gln11]beta-(1-28), caused amnesia for footshock active avoidance training in mice in a dose-dependent fashion. This effect was specific to memory processing since the peptide did not cause amnesia when injected 24 hr after training nor did it disturb storage or retrieval of older memories. Shorter fragments of the amyloid beta protein consisting of residues 12-28, 18-28, and 12-20 also were amnestic when given intracerebroventricularly, residues 12-20 being least effective. The hippocampus, a brain structure importantly involved in learning and memory, consistently shows severe pathological changes and deposition of amyloid in patients with Alzheimer disease. Immediate post-training bilateral intrahippocampal injection of [Gln11]beta-(1-28) produced amnesia at much lower doses than did [Gln11]beta-(1-28) injected intracerebroventricularly. Thus these experimental results suggest a possible direct role of amyloid beta protein or fragments thereof in an aspect of the spectrum of cognitive deficit in Alzheimer disease.

Alzheimer Disease↗
PubMed1991

Syncytial giant-cell hepatitis. Sporadic hepatitis with distinctive pathological features, a severe clinical course, and paramyxoviral features.

BACKGROUND AND METHODS: We describe a new form of hepatitis, occurring in 10 patients over a period of six years, characterized clinically by manifestations of severe hepatitis, histologically by large syncytial giant hepatocytes, and ultrastructurally by intracytoplasmic structures consistent with paramyxoviral nucleocapsids. RESULTS: The patients ranged in age from 5 months to 41 years. The tentative clinical diagnosis before biopsy was non-A, non-B hepatitis in five patients and autoimmune chronic active hepatitis in the others. Five patients underwent liver transplantation; the others died. The diagnosis of syncytial giant-cell hepatitis was established pathologically. The liver cords were replaced in all 10 patients by syncytial giant cells with up to 30 nuclei. In 8 of the 10 the cytoplasm contained pleomorphic particles of 150 to 250 microns, filamentous strands, and particles of 14 to 17 nm with peripherally disposed spikes resembling paramyxoviral nucleocapsids. Structures resembling degenerated forms were found in the other two patients. One of two chimpanzees injected with a liver homogenate from the index patient had an increase in the titer of paramyxoviral antibodies, probably an anamnestic reaction to previous paramyxoviral infection, suggesting that a paramyxoviral antigen but not viable virus was present in the liver homogenate. CONCLUSIONS: Although further virologic studies will be required for precise classification, we believe that paramyxoviruses should be considered in patients with severe sporadic hepatitis.

Acute Disease↗
PubMed1991

Living systems are tonically inhibited, autonomous optimizers, and disinhibition coupled to variability generation is their major organizing principle: inhibitory command-control at levels of membrane, genome, metabolism, brain, and society.

It is proposed that the major organizing principle in living systems is disinhibition coupled to variability generation. Facile traverse of adaptive functional ranges is made possible by activities of inhibitory (attenuating and/or time-delaying) influences. These maintain barriers to physicochemical perturbations, so that interactions between the external environment and living systems produce transient local changes (signals) that are transduced by a variety of devices at hand to release activities within them. Coupling exists between the driving force (forcing function) and the generation of variability (information-processing capacity) among subunits of particular systems, i.e., there is expansible capacity for processing information in relation to demand. Metaphorically, metabolically generated energy is used to wind the biological springs. Hierarchical nesting of inhibitory command-control is discussed at levels of membrane, metabolism, genomic expression, brain function, and internalization of societal prohibitions (conscience).

Animals↗
PubMed1991

Rationally designed "dipeptoid" analogues of CCK. alpha-Methyltryptophan derivatives as highly selective and orally active gastrin and CCK-B antagonists with potent anxiolytic properties.

This paper describes the synthesis and structure-activity relationships (SAR) leading to the first rational design of "dipeptoid" analogues of the neuropeptide cholecystokinin (CCK). Compounds [R-(R*,S*)]-4-[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo [3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-3- phenylpropyl]-amino]-4-oxo-2-butenoic acid, [R-(R*,R*)]-4-[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo [3.3.1.1(3,7)]dec-2-oxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxo-2-butenoic acid, and [R-(R*,R*)]-4-[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo [3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxobutanoic acid (29d) have CCK-B binding affinities of IC50 = 0.8, 0.7, and 1.7 nM with a CCK-A/CCK-B ratio of 550, 1100, and 2500, respectively. Compound 27 is well-absorbed and is equiactive by the subcutaneous (sc) and intravenous (iv) routes of administration in the Ghosh and Schild test in rats in inhibiting pentagastrin stimulated gastric acid secretion with ED50 = 0.07 (0.01-0.34) mumol/kg. Compound 29d is anxiolytic in mice in the black-white test box over the range 0.0001-30 mg/kg sc, comparable in activity to diazepam over the range 0.125-1 mg/kg ip), and also active in this test when dosed orally over a wide range from 0.0001 to 10 mg/kg.

Animals↗
PubMed1990

Prenatal diagnosis of trisomy for the distal two-thirds of the long arm of chromosome 14 (q21----qter).

A de novo case of 'pure' trisomy 14q21----qter is described which was detected at amniocentesis following an abnormal ultrasound scan of a 25-year-old woman. This is apparently the largest distal 14q duplication reported in a case surviving beyond the first trimester. The infant appeared to have an association of clinical abnormalities previously observed in distal 14q trisomy and proximal 14q trisomy/mosaic trisomy 14.

Adult↗