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L O'Connell

Publications and source records attributed to L O'Connell.

At least 19 recordsLinked to original sources
PubMed2001

Experimental models for the investigation of female sexual function and dysfunction.

There have been limited anatomic and physiological investigations of the female sexual arousal response. A broader understanding of the physiologic mechanisms of female sexual arousal function is required to improve the management of women with sexual dysfunction. Three experimental test systems have been developed to understand better the biochemical and physiological mechanisms of female sexual arousal response. An in vivo animal model was developed to record physiological and hemodynamic changes in the clitoris and vagina following pelvic nerve stimulation and administration of vasoactive agents and physiological modulators. In vitro organ baths of clitoral and vaginal tissue were utilized to investigate mechanisms involved in the regulation of smooth muscle contractility. In addition, primary cell cultures of human and animal clitoral and vaginal smooth muscle cells were developed to investigate signal transduction pathways modulating smooth muscle tone. In vivo studies revealed hemodynamic changes in vagina and clitoris in response to pelvic nerve stimulation, vasodilators and physiological modulators. Organ bath studies have demonstrated that clitoral and vaginal smooth muscle tone is affected by non-adrenergic and non-cholinergic neurotransmitters, and the presence of functional alpha 1 and alpha 2 adrenergic receptors in these tissues has been established through biochemical studies. These changes are regulated by the tone of vascular and non-vascular smooth muscle in the vagina and clitoris. Primary cell culture studies have suggested that several physiological modulators such as vasoactive intestinal polypeptide (VIP), nitric oxide (NO), and prostaglandin E (PGE) regulate vaginal smooth muscle contractility. Data from experimental models have provided a preliminary understanding of the mechanisms of the female sexual arousal response.

Animals↗
PubMed2000

TrkA amino acids controlling specificity for nerve growth factor.

Neurotrophins are important for the development and maintenance of the vertebrate nervous system, mediating their signal into the cell by specific interaction with tyrosine kinase receptors of the Trk family. The extracellular portion of the Trk receptors has been previously proposed to consist of a cysteine-rich motif, a leucine-rich motif, a second cysteine-rich motif followed by two immunoglobulin-like domains. Earlier studies have shown that a major neurotrophin-binding site in the Trk receptors resides in the second immunoglobulin-like domain. Although the individual amino acids in TrkA involved in binding to nerve growth factor (NGF) and those in TrkC involved in binding to neurotrophin-3 have been mapped in this domain, the Trk amino acids that provide specificity remained unclear. In this study, a minimum set of residues in the human TrkC second immunoglobulin-like domain, which does not bind nerve growth factor (NGF), were substituted with those from human TrkA. The resulting Trk variant recruited binding of NGF equivalent to TrkA, maintained neurotrophin-3 binding equivalent to TrkC, and also bound brain-derived neurotrophin, although with lower affinity compared with TrkB. This implies that the amino acids in the second immunoglobulin-like domain that determine Trk specificity are distinct for each Trk.

Amino Acid Sequence↗
PubMed1998

High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors.

Neurotrophic factors are important for survival and maintenance of neurons during developmental and adult stages of the vertebrate nervous system. The neurotrophins mediate their signal into the cell by specific interaction with tyrosine kinase receptors of the Trk family. The extracellular immunoglobulin-like domain of the Trk receptors adjacent to the membrane has previously been shown to be the dominant element for specific neurotrophin binding. Using computer graphics models of the human TrkA and TrkC immunoglobulin-like domains as a guide, the residues involved in binding to their respective neurotrophins were mapped by mutational analysis. TrkC primarily utilizes loop EF, between beta-strands E and F, for binding. In contrast, TrkA utilizes the EF loop as well as additional residues, the latter being prime candidates for determining the specificity of TrkA versus TrkC. When selected TrkC and TrkA mutants with reduced binding were expressed on NIH3T3 cells, neurotrophin-induced autophosphorylation was strongly reduced or absent.

Amine Oxidase (Copper-Containing)↗
PubMed1997

Specificity determinants in neurotrophin-3 and design of nerve growth factor-based trkC agonists by changing central beta-strand bundle residues to their neurotrophin-3 analogs.

Neurotrophic factors mediate their signal by binding to specific cell surface receptors of the trk family. The binding sites of neurotrophin-3 (NT-3) and nerve growth factor (NGF) to their preferred receptors trkC and trkA, respectively, were previously determined by mutational analyses. These and other studies showed that trkA can discriminate between NGF and NT-3 primarily by recognition of their N-terminal residues. The mechanism of trkC discrimination, however, remained unclear especially since the most important residue in NT-3 involved in binding to trkC, R103, is conserved in all neurotrophins. In this study residues that are part of the central beta-strand bundle of NT-3 and are not conserved among the neurotrophins were grafted onto NGF and tested for recruitment of trkC affinity. Exchange of NGF residues at positions 18, 20, 23, 29, 84, and 86 by their NT-3 counterparts resulted in NGF variants that bound to trkC, while maintaining their affinity to trkA, and were able to induce autophosphorylation and differentiation of PC12 cells expressing trkC. These variants show that the amino acid at position 23 (glycine in NGF, threonine in NT-3) is critical for trkC recognition while other residues fine tune the specificity of NT-3 for trkC. The results demonstrate the importance of nonconserved residues of the central beta-strand bundle region for the interaction of NT-3 with trkC and emphasize the different mechanism of specificity determination that is employed in the NT-3/trkC and NGF/trkA ligand/receptor pairs.

Amino Acid Sequence↗
PubMed1995

An immunoglobulin-like domain determines the specificity of neurotrophin receptors.

The neurotrophins influence survival and maintenance of vertebrate neurons in the embryonic, early post-natal and post-developmental stages of the nervous system. Binding of neurotrophins to receptors encoded by the gene family trk initiates signal transduction into the cell. trkA interacts preferably with nerve growth factor (NGF), trkB with brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) and trkC with neurotrophin-3 (NT-3). By constructing 17 different chimeras and domain deletions of the human trk receptors and analyzing their binding affinities to the neurotrophins we have shown that an immunoglobulin-like domain located adjacent to the transmembrane domain is the structural element that determines the interaction of neurotrophins with their receptors. Chimeras of trkC where this domain was exchanged for the homologous sequences from trkB or trkA gained high affinity binding to BDNF or NGF respectively, while deletion of this domain in trkC or trkA abolished binding to NT-3 or NGF respectively. This domain alone retained affinities to neurotrophins similar to the full-length receptors and when expressed on NIH 3T3 cells in fusion with the kinase domain showed neurotrophin-dependent activation.

3T3 Cells↗
PubMed1994

The binding site on human immunoglobulin E for its high affinity receptor.

Immunoglobulin (Ig) E antibodies mediate allergic responses by binding to specific high affinity receptors, Fc epsilon RI, on mast cells and basophils. Previous studies have shown that the principal Fc epsilon RI binding site is located on the third constant domain, Fc epsilon 3, of IgE. Based on a model of the IgE Fc epsilon 3 (which is homologous to the second constant domain of IgG), homology scanning mutagenesis and replacement of individual residues were used to determine the specific amino acids of human IgE involved in binding to human Fc epsilon RI. The amino acids are localized in three loops, which form a putative ridge on the most exposed side of the Fc epsilon 3 domain of IgE and include Arg-408, Ser-411, Lys-415, Glu-452, Arg-465, and Met-469. The preponderance of charged residues suggests that IgE-Fc epsilon RI binding is mediated primarily by electrostatic interaction. Furthermore, it is possible to confer Fc epsilon RI binding to an IgG molecule by introducing these three IgE loops into the IgG C gamma 2 domain.

Amino Acid Sequence↗
PubMed1991

X-ray structure of human relaxin at 1.5 A. Comparison to insulin and implications for receptor binding determinants.

The X-ray crystal structure of relaxin at 1.5 A resolution is reported for the physiologically active form of the human hormone. Relaxin is a small, two-chain polypeptide that is a member of the protein hormone family that also includes insulin and the insulin-like growth factors IGF-I and IGF-II. These hormones have biologically diverse activities but are structurally similar, sharing a distinctive pattern of cysteine and glycine residues. The predicted structural homology of relaxin to insulin is confirmed by this structural analysis; however, there are significant differences in the terminal regions of the b-chain. Although relaxin, like insulin, crystallizes as a dimer, the orientation of the molecules in the respective dimers is completely different. The region of the relaxin molecule proposed to be involved in receptor binding is part of the dimer interface, suggesting that some of the other residues contained in the dimer contact surface might be receptor binding determinants as well. The proposed receptor binding determinants for insulin likewise include residues at its dimer interface. However, because the dimer contacts of relaxin and insulin are quite different, it appears that these two structurally related hormones have evolved somewhat dissimilar mechanisms for receptor binding.

Amino Acid Sequence↗
PubMed1991

Conditions not attributable to a mental disorder: an epidemiological study of family problems.

OBJECTIVE: The objective of this research was to identify and measure the differences among three groups of psychiatric outpatients: those with family problems but without mental disorders, those with both family problems and mental disorders, and those with a mental disorder but without family problems. DSM-III V code conditions (conditions not attributable to a mental disorder) other than family problems do occur, but family problems were chosen because of their importance. METHOD: All patients admitted to an outpatient psychiatric clinic during a 2-year period were studied (N = 382). Of these, 92 had V code conditions unrelated to family problems and were excluded. Data are presented on the remaining 290 patients. Sociodemographic variables, DSM-III diagnoses, source of referral, previous and subsequent use of outpatient services, and type of family problem were examined. Patients were from a low-income population and came from three ethnic groups (white, black, and Hispanic). RESULTS: Among whites, more men than women had family problems without mental disorders; among blacks, more women than men had family problems with and without mental disorders. Marital problems occurred most frequently in the group with family problems without mental disorders, and married subjects were more likely to have a V code condition. Professional referrals were more common than other referral sources in all three groups. However, family problems without mental disorders were more likely to occur among those who were referred by their families and had never had psychiatric treatment; patients with family problems and mental disorders were more likely to be self-referred and to have been previously treated; those with a mental disorder but without family problems were usually referred by professionals and almost always had been previously treated. There appeared to be underreporting of family problems among those with family problems and mental disorders and among black men with family problems with and without mental disorders. CONCLUSIONS: More research is needed on the patterns of use of outpatient psychiatric services by individuals with family problems and other V code conditions.

Adult↗
PubMed1985

Effect of gamma-irradiation on the healing of gastric biopsy sites in monkeys. An experimental model for peptic ulcer disease and gastric protection.

The acute effects of gamma-irradiation on the gastric mucosa have been studied in a primate model. Fiberoptic gastroscopies were performed in 6 rhesus monkeys in the basal state as well as 3 h and 3, 7, and 9 days after total body irradiation (800 rads). Gastric biopsy specimens (diameter 1 mm) obtained during each session were examined using light microscopy and scanning electron microscopy; in addition, subsequent healing of the biopsy sites was assessed visually. Gastric biopsy sites were completely healed in 3 days in the basal state; in contrast, ulcer craters (diameter 1 mm) were still present at the site of the biopsies 3, 7, and 9 days after the biopsies were performed in irradiated animals. Light microscopic examination of the biopsy specimens demonstrated only lymphocytic infiltration of the lamina propria. In contrast, scanning electron microscopic examination revealed that the size and number of microvilli of the gastric surface epithelial cells were increased on the day of irradiation compared to basal; 3-9 days later, numerous gastric surface epithelial cells were damaged or had disappeared so that bare areas of the lamina propria were visible in the specimens taken outside of the ulcer craters. These changes may reflect inadequate protection of insufficient regeneration of gastric mucosal cells which, in turn, would explain the persistence of ulcers after gastric biopsies were performed in irradiated monkeys.

Animals↗
PubMed1983

Rorschach norms for inner city children.

Rorschach data for 272 Black children are presented in age groups from 3 to 12. The Rorschach characteristics presented are F+%, A%, Fabulized Combinations, Perseverations, Color Naming, Rejections, Wholes, Details, Small Details (Dd), R, M, and P. Comparisons with Ames and Exner reveal a lower form accuracy level, and a lower percentage of Wholes, with a higher D level. Response rate, rate of development of the M response, rate of development of the P response, and of the Animal response are very similar to the other normative samples.

Child↗
PubMed1980

Effects of lead poisoning on cognitive test performance.

47 lead-poisoned children, treated and without encephalopathy, are compared with sibling controls on perceptual-verbal pattern comparisons of subtests of the Wechsler Intelligence Scale for Children to determine whether there has been brain damage. Both groups of children do not differ significantly from each other on comparisons of these patterns, and they appear to be similar to each other in WISC functioning. The conclusion is that lead-poisoning, treated, and without encephalopathy, does not result in detectable brain damage by means of these pattern analyses.

Adolescent↗
PubMed1978

IQ following treatment of lead poisoning: a patient-sibling comparison.

Forty-seven children treated for lead poisoning (PbB 50 to 365 microgram/dl) were compared to siblings next in age (PbB less than 40 microgram/dl) by a battery of psychologic tests. Symptoms were present in 18 but none had frank encephalopathy. Physical and neurologic examinations revealed no residual damage. Mean psychologic test scores showed no significant difference between patients and controls except in the arithmetic subtest, in which patients' scores were not related to lead concentration. Intelligence tests failed to distinguish children successfully treated from their sibling controls.

Child↗
PubMed1977

Cold agglutinins in a case of chronic lymphatic leukaemia. A study of the lymphocyte surface.

A case of chronic lymphatic leukaemia with cold agglutinins is presented in which peripheral blood lymphocytes of varying maturity appeared to possess T- and B-cell markers. A cold agglutinin IgM in type is identified in the serum and at the cell surface. This seems to be responsible for the spontaneous rosetting of sheep red blood cells (SRBC); A single clonal origin of these cells is suggested with maturation arrest. It is also suggested that with configurational change in lymphocyte surface cryoglobulins may sometimes produce spontaneous rosetting with SRBC.

Agglutinins↗
PubMedDate not supplied

Childhood sexual abuse, psychological distress, and medical use among women.

OBJECTIVE: This study examined the relationships between reported history of childhood sexual abuse (CSA), psychological distress, and medical utilization among women in a health maintenance organization (HMO) setting. METHODS: Participants were 206 women aged 20 to 63 years who were recruited from an HMO primary care clinic waiting area. Participants were classified, using screening questionnaires and the revised Symptom Checklist 90, as 1) CSA-distressed, 2) distressed only, 3) CSA only, or 4) control participants. Medical utilization rates were generated from the computerized database of the HMO for 1) nonpsychiatric outpatient, 2) psychiatric outpatient, 3) emergency room (ER), and 4) inpatient admissions. RESULTS: CSA-distressed and distressed only groups both used significantly more nonpsychiatric outpatient visits than CSA only and control participants but were not different from one another. CSA only and control participants did not differ on nonpsychiatric outpatient utilization. CSA-distressed participants used significantly more ER visits and were more likely to visit the ER for pain-related complaints than other participants. Among CSA-distressed participants, those who met criteria for physical abuse had significantly more ER visits than those who did not. There were no differences among the four groups in inpatient utilization rates. CONCLUSIONS: Psychological distress is associated with higher outpatient medical utilization, independent of CSA history. History of CSA with concomitant psychological distress is associated with significantly higher ER visits, particularly for those with a history of physical abuse. History of CSA without distress is not associated with elevated rates of medical utilization. Screening for psychological distress, CSA, and physical abuse may help to identify distinct subgroups with unique utilization patterns.

Adult↗
PubMedDate not supplied

Inhibition of allergic reactions with antibodies to IgE.

Numerous clinical studies show that direct interference with the IgE response leads to a decrease or elimination of allergic symptoms. The aim of these studies was to design a therapy aimed at decreasing IgE levels in order to ameliorate atopic disease. To this end, a murine monoclonal antibody, MAE11, directed against IgE was identified, which had all the properties necessary to interfere with IgE responses, but lacked the harmful side effects of inducing receptor cross-linking. The antibody was selected on the basis of its ability to bind circulating IgE at the same site as the high-affinity receptor, thus blocking the binding of IgE to mast cells and basophils. To allow for possible chronic administration and to avoid the problems of antigenicity, MAE11 was humanized. The best of several humanized variants, version 25 (rhumAb-E25) was selected since it possessed binding affinity and biological activity comparable to MAE11. Clinical studies are underway to determine the safety and efficacy of this treatment for allergic rhinitis and asthma.

Allergens↗