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Biomedical subjects

L J Miller

Publications and source records attributed to L J Miller.

At least 73 records · Page 4Linked to original sources
PubMed1998

Mentally ill mothers who have killed: three cases addressing the issue of future parenting capability.

Many parents with severe and chronic mental illness lose custody of their children due to child abuse or neglect. These children may linger in foster care for long periods of time until decisions about custody are made. Recent proposals to shorten the time that children remain in the foster care system include the use of categories of abuse to guide decisions about custody. One proposal has been to "fast-track" cases involving parents with long-standing mental disorders by automatically terminating parental rights. This approach assumes that a severe and chronic mental disorder is incompatible with safe parenting. This report describes three cases of mentally ill mothers who lost custody of their children after they killed someone. The mothers were nonetheless found to be at low risk for future child maltreatment and violence according to evaluation with two current methodologies, Parenting Risk Assessment and Risk of Violence Assessment. The cases question the assumption that mental illness is incompatible with safe parenting and underscore the fact that evaluation of the parenting competency of mentally ill parents is rarely clear-cut.

Adolescent↗
PubMed1998

Brief cognitive behavioral interventions in mild traumatic brain injury.

Postconcussion syndrome is a common and persisting consequence of mild traumatic head injury. The development of treatments for the syndrome has been hampered by a lack of consensus in diagnostic criteria, confusion about the relative contribution of psychological and neurologic etiological factors, and a paucity of controlled treatment outcome studies. In this article, we review the literature relevant to prevention and treatment of persisting postconcussive symptoms. Studies in adults and children suggest that although symptoms may initially have a neurologic basis, the syndrome persists because of psychological factors. Brief psychological treatment appears to significantly reduce the severity and duration of symptoms following mild head trauma. The attribution of persisting symptoms to organic factors conversely appears to be iatrogenic. Potentially useful diagnostic and treatment protocols are outlined.

Journal Article↗
PubMed1998

Family planning knowledge, attitudes and practices in women with schizophrenic spectrum disorders.

This study set out to test three hypotheses about family planning in women with schizophrenic spectrum disorders, as compared to demographically comparable non-mentally ill control women: that they (1) report at least as much unprotected intercourse while not desiring pregnancy; (2) have less knowledge about contraception; and (3) perceive more, and different, obstacles to obtaining or using birth control. A semistructured Family Planning Interview was administered to subjects (n = 44) with Research Diagnostic Criteria diagnoses of schizophrenia and schizoaffective disorder, and to non-mentally ill control subjects (n = 50). The participants had high rates of unprotected intercourse, as did non-mentally ill controls. They had significantly less reproductive and contraceptive knowledge than the control subjects, and were more likely to perceive birth control as difficult to obtain. The most common reason women with schizophrenic spectrum disorders gave for failing to use birth control was that they did not expect to have sex, while that given by non-mentally ill subjects related to side-effects of birth control. Important obstacles to family planning in women with schizophrenic spectrum disorders include relative lack of knowledge and difficulty planning ahead. Although many women with schizophrenia could benefit from long-acting, reversible contraception, many may be unaware of those options and/or may find them difficult to obtain. Integrating family planning with mental health care might better address the unique needs of this population.

Adolescent↗
PubMed1998

Propofol for the long-term sedation of a critically ill patient.

OBJECTIVE: To report a case in which propofol was used successfully in an intubated patient on a prolonged basis and to review the literature that discusses long-term infusions (> 7 days) of propofol. METHODS: Information was retrieved from a MEDLINE search of the English-language literature. Reports of clinical trials and case reports that compared the safety and efficacy of long-term propofol and midazolam were included in this review. Information about the study design and the efficacy and adverse effects of the drugs was collected, and the data were synthesized. RESULTS: Clinical reports indicate that a long-term infusion of propofol is comparable in safety and efficacy to a long-term infusion of midazolam. The distinct adverse-effect profile of long-term use of propofol, including hypertriglyceridemia, was evaluated and reported as significant. CONCLUSION: The limited data available suggest that long-term infusion of propofol is a practical alternative to use of standard agents for sedation of intubated patients. Adverse effects such as cardiovascular depression, respiratory depression, and hypertriglyceridemia may limit the routine use of propofol.

Adult↗
PubMed1998

Protean effects of a natural peptide agonist of the G protein-coupled secretin receptor demonstrated by receptor mutagenesis.

G protein-coupled receptors initiate signaling cascades after associating with heterotrimeric G proteins. This is typically initiated by agonist binding, but can also occur spontaneously, particularly in receptors bearing distinct missense mutations. Two such mutations in the parathyroid hormone receptor are associated with constitutive activity, manifesting clinically as Jansen's metaphyseal chondroplasia. We introduce analogous mutations separately and together into the secretin receptor to explore their impact on another family member. Constructs were expressed transiently in COS cells, and had binding and signaling (cAMP generation) studied. Each construct was processed appropriately to lead to cell surface expression and signaling. Secretin bound to the wild-type receptor with two affinity states recognized, 1% of sites in the high affinity state (Ki = 0.5 +/- 0.1 nM) and 99% in the low affinity state (Ki = 23 +/- 3 nM). Mutant receptor binding best fit a single affinity state, having values for Ki of 5 +/- 1 nM (H156R), 8 +/- 1 nM (T322P) and 6 +/- 1 nM (H156R/T322P), with each of these demonstrating a shift to higher affinity than the predominent low affinity state of the wild-type receptor. Each mutant receptor expressed small to moderate constitutive activity, with basal levels of cAMP activity greater than control (P < .01): H156R, 1.4-fold; T322P, 4.5-fold and H156R/T322P, 6.8-fold. The level of basal activity of even the most active construct was only 15% of the maximal response of wild-type receptor. Although each of the single site mutants responded to secretin by increasing their cAMP levels in a concentration-dependent manner, the dual mutant decreased its cAMP in response to hormone (EC50 = 13 nM). Thus, a natural agonist had become an inverse agonist at this unique construct. Because this could reflect reduced normal coupling with Gs or increased aberrant coupling with Gi, the mechanism was further explored using pertussis toxin and a stable analogue of GTP. Although ligand-binding determinants were retained in the dual receptor mutant, the conformation of this receptor upon secretin binding effected a reduction in its basal coupling with Gs, thereby resulting in inverse agonism.

Animals↗
PubMed1997

Direct identification of a distinct site of interaction between the carboxyl-terminal residue of cholecystokinin and the type A cholecystokinin receptor using photoaffinity labeling.

Mechanisms of ligand binding and activation of G protein-coupled receptors are particularly important, due to their ubiquitous expression and potential as drug targets. Molecular interactions between ligands and these receptors are best defined for small molecule ligands that bind within the transmembrane helices. Extracellular domains seem to be more important for peptide ligands, based largely on effects of receptor mutagenesis, where interference with binding or activity can reflect allosteric as well as direct effects. We now take the more direct approach of photoaffinity labeling the active site of the cholecystokinin (CCK) receptor, using a photolabile analogue of CCK having a blocked amino terminus. This probe, 125I-desaminotyrosyl-Gly-[Nle28,31, pNO2-Phe33]CCK-(26-33), binds specifically, saturably, and with high affinity (Ki = 3.3 nM) and has full agonist activity. This makes likely its being sited in a natural position within the receptor. As substrate, we used CHO-CCK receptor cells overexpressing functional recombinant rat type A CCK receptor. Covalent labeling of the appropriate Mr = 85,000-95,000 plasma membrane glycoprotein with core of Mr = 42,000 was established by SDS-polyacrylamide gel electrophoresis and autoradiography. A single domain adjacent to transmembrane 1 was labeled, as established by cyanogen bromide cleavage and separation by gel and/or high pressure liquid chromatography. The site of interaction was further defined by additional proteolysis with trypsin, with purification of the labeled fragment, followed by manual Edman degradation and radiochemical sequencing. This demonstrated that Trp39 was specifically labeled and likely resides proximate to the carboxyl-terminal pNO2-Phe33 residue of the probe. A model of this ligand-bound receptor has been constructed and will be used to plan future experiments to refine our understanding of this interaction.

Affinity Labels↗
PubMed1997

Neuroanatomical distribution of vasotocin in a urodele amphibian (Taricha granulosa) revealed by immunohistochemical and in situ hybridization techniques.

Immunohistochemical and in situ hybridization techniques were used to investigate the neuroanatomical distribution of arginine vasotocin-like systems in the roughskin newt (Taricha granulosa). Vasotocin-like-immunoreactive neuronal cell bodies were identified that, based on topographical position, most likely, are homologous to groups of vasopressin-immunoreactive neuronal cell bodies described in mammals, including those in the bed nucleus of the stria terminalis, medial amygdala, basal septal region, magnocellular basal forebrain-including the horizontal limb of the diagonal band of Broca, paraventricular and supraoptic nuclei, suprachiasmatic nucleus, and dorsomedial hypothalamic nucleus. Several additional vasotocin-like-immunoreactive cell groups were observed in the forebrain and brainstem regions; these observations are compared with previous studies of vasotocin- and vasopressin-like systems in vertebrates. Arginine vasotocin-like-immunoreactive fibers and presumed terminals also were widely distributed with high densities in the basal limbic forebrain, the ventral preoptic and hypothalamic regions, and the brainstem ventromedial tegmentum. Based on in situ hybridization studies with synthetic oligonucleotide probes for vasotocin and the related neuropeptide mesotocin, as well as double-labeling studies with combined immunohistochemistry and in situ hybridization, we conclude that the vasotocin immunohistochemical procedures used identify vasotocin-like, but not mesotocin-like, elements in the brain of T. granulosa. The distribution of arginine vasotocin-like systems in T. granulosa is greater than the distribution previously reported for any other single vertebrate species; however, it is consistent with an emerging pattern of distribution of vasotocin- and vasopressin-like peptides in vertebrates. Complexity in the vasotocinergic system adds further support to the conclusion that this peptide regulates multiple neurophysiological and neuroendocrinological functions.

Animals↗
PubMed1997

Quantitative dynamic multicompartmental analysis of cholecystokinin receptor movement in a living cell using dual fluorophores and reconstruction of confocal images.

Receptor regulation is a key component of the phenomenon of desensitization in response to agonist stimulation which protects cells from overstimulation. Receptor internalization is one part of this response, often quantified by the portion of saturable ligand binding which becomes resistant to acidic washes. It is now clear that this can include receptor in multiple distinct cellular compartments. We have developed a morphological technique involving dual fluorescent probes to delineate the plasmalemma and the ligand-occupied receptor using confocal microscopy, with analysis involving three-dimensional reconstruction and quantitation of receptor movement through each compartment. When a radioiodinated cholecystokinin (CCK) analogue occupied its receptor on the CHO-CCKR cell line, it became progressively more resistant to dissociation with acidic medium. Quantitation of receptor internalization in these cells over time using this dynamic morphological technique correlated with the acid-resistant receptor fraction, and provided the additional information of the cellular compartments traversed. This technique will have multiple applications to explore the cell-specific handling of this and other ligand-occupied receptors.

Animals↗
PubMed1997

Hydrophobic peptide mapping of clinically relevant heptathelical membrane proteins by capillary electrophoresis.

The structural investigation of G protein-coupled receptors has been hindered by the lack of techniques to effectively resolve the hydrophobic peptides obtained by chemical or proteolytic cleavage, as well as the minute amounts of protein typically isolated. We have developed a capillary electrophoresis method for efficient separation of hydrophobic peptides using a cyanogen bromide digest of bacteriorhodopsin as a model for these clinically important membrane proteins. This procedure includes (i) solubilization of the protein digest in acetic acid; and (ii) electrophoresis using an acetic acid-based buffer system augmented by acetonitrile and hexane sulfonic acid, in a Polybrene-coated fused silica capillary. The potential for detection sensitivity to be increased at least 100-fold by use of on-line solid-phase extraction on C18-silica is shown. This approach is potentially useful for peptide fingerprinting of sparse and extremely hydrophobic membrane receptors.

Bacteriorhodopsins↗
PubMed1997

Assessing parenting competency in individuals with severe mental illness: a comprehensive service.

Determining the parenting capabilities of individuals with severe mental disorders who are alleged perpetrators of child abuse or neglect is a profoundly difficult task. This article discusses the methodological shortcomings of some widely used assessment strategies and outlines the components of a comprehensive parenting competency evaluation for individuals with severe mental illness. Procedures identifying both risk factors associated with abuse or neglect and protective influences against child maltreatment are summarized. These procedures are illustrated by describing a Chicago-based parenting assessment team for parents with severe mental disorders.

Adult↗
PubMed1997

Postconcussion syndrome occurs in children.

The consensus of evidence published since 1924 suggests that parents report attention deficits, hyperactivity, or conduct disorder after pediatric head injury rather than postconcussion syndrome. In this study, the symptoms reported by children after mild (n = 38) and moderate-severe (n = 27) head trauma were compared to those reported after orthopedic injury (n = 47) and to adults matched for injury severity and chronicity by using a structured interview based on diagnostic criteria for postconcussion syndrome. Pediatric head trauma caused significantly more subjective symptoms after 6 weeks than orthopedic injury. These symptoms were related to head injury severity and the child's anxiety level. When assessed in a similar manner, children report postconcussion syndrome similar to that seen in adults.

Adolescent↗
PubMed1997

Cholecystokinin-induced desensitization, receptor phosphorylation, and internalization in the CHP212 neuroblastoma cell line.

Agonist stimulation of cells often results in desensitization of the response, to protect the cell from overstimulation. We have previously shown that the type A cholecystokinin (CCK) receptor on the pancreatic acinar cell and on the model CHO-CCKR cell line undergoes desensitization in response to CCK, with receptor phosphorylation and internalization playing key roles. Although these mechanisms contribute in a cell-specific manner, no analogous information exists for the CCK receptor expressed on neuronal cells, where in vivo data demonstrate a particularly sensitive response to CCK. The present study was designed to explore CCK receptor desensitization in the CHP212 neuroblastoma cell line, focusing on inositol 1,4,5-trisphosphate (IP3) responses to CCK and on recognized molecular and cellular mechanisms of desensitization. CCK promptly stimulated IP3 responses in these cells, with hormonal responsiveness rapidly and completely desensitized. Both receptor phosphorylation and internalization were observed to occur, with the former occurring most rapidly and likely being responsible for the earliest desensitization observed. Although the time course of receptor phosphorylation and dephosphorylation, and the groups of kinases involved in the neuroblastoma cell line, were most similar to those in the pancreatic cell, the movement of the agonist-bound receptor in these cells was quite different from that in the pancreatic cell and most similar to that in the CHO-CCKR cell line. This hybrid response supports the cell-specific nature of CCK receptor regulation and provides an important system to explore the molecular determinants of these processes.

Dose-Response Relationship, Drug↗
PubMed1997

Sexuality, reproduction, and family planning in women with schizophrenia.

This article reviews data about how schizophrenia affects sexuality, pregnancy, the puerperium, parenting, and family planning. Women with schizophrenia have high rates of coerced sex, sexual risk behavior, and unwanted pregnancies. High rates of obstetric complications and custody loss increase morbidity for women and their offspring. Since untreated psychosis increases these problems, the risks of withholding pharmacotherapy must be weighed against the risks of prescribing medications during pregnancy. The puerperium is a time when women are especially vulnerable to exacerbations of schizophrenia. Mothers with schizophrenia may have a reduced ability to read children's cues, and they often have weak social support networks. Their children may be more difficult to raise than other children. Parenting rehabilitation can address some of these problems. Often, women with schizophrenia who are sexually active and do not wish to become pregnant do not use contraception. Incorporating family planning measures into mental health care delivery systems may reduce unwanted pregnancies.

Antipsychotic Agents↗
PubMed1997

Roles of cholecystokinin receptor phosphorylation in agonist-stimulated desensitization of pancreatic acinar cells and receptor-bearing Chinese hamster ovary cholecystokinin receptor cells.

Receptor phosphorylation has been implicated in desensitization responses to some agonist ligands, in which receptors may become uncoupled from G proteins and move into cellular compartments inaccessible to hydrophilic ligands. Understanding of the linkage between these processes, however, has come largely from recombinant receptor-bearing cell systems with consensus sites of kinase action mutagenized. We recently established methodology permitting direct assessment of sites of phosphorylation of the cholecystokinin receptor (CCKR) in its native milieu in the pancreatic acinar cell and in a Chinese hamster ovary (CHO)-CCKR cell line (1, 2). Although CCK binding leads to phosphorylation of serine residues within the third intracellular loop of the receptor in both cell types, there are clear differences in the time course of phosphorylation, in the balance of action of kinases and a receptor phosphatase, and in a few of the distinct sites phosphorylated. In this work, we have directly assessed the inositol 1,4,5-triphosphate responses to CCK and desensitization of these responses in both cells. CHO cell lines expressing receptor mutants with protein kinase C consensus sites modified were also studied. CCK-stimulated inositol 1,4,5-triphosphate responses in both cells expressing wild-type receptors were rapidly and completely desensitized, associated with the onset of receptor phosphorylation. However, despite maintenance of the phosphorylated state of the receptor in the CHO-CCKR cell and its dephosphorylation returning the receptor to its basal state in the acinar cell, desensitization continued to be present in both. Mutagenesis of Ser260 and Ser264 to alanines individually reduced receptor phosphorylation by approximately 50%, whereas the dual mutant completely eliminated agonist-stimulated phosphorylation. Because other sites of phosphorylation were still intact in this construct, this raises the possibility of hierarchical phosphorylation with these two sites key in making other sites accessible to kinases. Constructs modifying Ser264 delayed the onset of desensitization, whereas all constructs proceeded to achieve complete desensitization by 10 min. Receptor internalization occurred independent of its phosphorylation state in the CHO cell lines, explaining the desensitization observed. In the acinar cell in which the receptor remains on the cell surface after agonist occupation, we postulate that receptor insulation achieves similar uncoupling from G protein association as is achieved by receptor phosphorylation early after agonist occupation.

Animals↗
PubMed1997

Molecular and functional heterogeneity of cholangiocytes from rat liver after bile duct ligation.

Cholangiocytes, the epithelial cells that line intrahepatic bile ducts, participate in bile secretion via basal and agonist-stimulated transport of solutes and water. On the basis of subtle structural differences between cholangiocytes lining small vs. large bile ducts, as well as known phenotypic variations among transporting epithelia in other organs, we demonstrated that cholangiocytes are functionally heterogeneous along the intrahepatic biliary tree of normal rats. In studies reported here, we confirm and extend the concept of functional heterogeneity of cholangiocytes by employing the bile duct-ligated (BDL) rat model of cholestasis associated with selective cholangiocyte proliferation. Using novel isolation and separatory techniques, we prepared subpopulations of pure small, medium, and large cholangiocytes from BDL rats and compared them with regard to gene expression and basal or agonist-responsive transport activities. Although transcripts for gamma-glutamyl transpeptidase and cytokeratin 19, two cholangiocyte-specific proteins, and glyceraldehyde-3-phosphate dehydrogenase, a housekeeping gene, were in all three subpopulations, genes for several proteins involved in solute transport [Cl-/HCO3- exchanger, cystic fibrosis transmembrane conductance regulator (CFTR), and secretin receptor] were expressed only in medium and large cholangiocytes. Consistent with these findings, secretin increased intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) and 36Cl- efflux rates in medium and large cholangiocytes but not in small cholangiocytes. Also, forskolin/8-(4-chlorophenylthio)-cAMP stimulated 36Cl- efflux rates only in medium and large cholangiocytes, consistent with selective functional expression of CFTR in these subpopulations. These results support the molecular and functional heterogeneity of cholangiocytes within the intrahepatic biliary ductal system and are consistent with the notion that hormone-regulated transport of solutes after BDL occurs principally in medium and large cholangiocytes in a fashion similar to that observed in normal rat liver.

Animals↗
PubMed1997

Cellular handling of unoccupied and agonist-stimulated cholecystokinin receptor determined by immunolocalization.

Cellular handling of receptor molecules is an important mechanism for the regulation of appropriately sensitive hormone-stimulated signaling. Until now, our understanding of the cellular handling of the cholecystokinin (CCK) receptor has been largely limited to following a tagged ligand through the cell. In the present work, we report the application of unique CCK receptor antisera directed toward intracellular domains, which permitted the immunolocalization of this molecule independently of its occupation with ligand. The CCK receptor antisera were also useful in Western blotting and immunoprecipitation of this receptor. Unstimulated CCK receptors remained on the surface of both recombinant stable rat CCK-A receptor-bearing Chinese hamster ovary cell line (CHO-CCKR) cells and native rat pancreatic acinar cells and did not constitutively internalize. Agonist stimulation of the CHO-CCKR cells resulted in the prompt internalization of a subset of surface receptors, representing those that were occupied with ligand. Unoccupied receptors remained on the surface, uninfluenced by the stimulated signaling pathways. Consistent with this, CCK receptor phosphorylation induced by 12-O-tetradecanoylphorbol-13-acetate treatment did not stimulate receptor internalization. After internalization, we observed substantial receptor recycling to the plasma membrane. These insights provide the first evidence that CCK receptor internalization occurs as a direct result of an induced conformational change and presumed bimolecular interaction, rather than as an effect of a signaling event.

Amino Acid Sequence↗
PubMed1997

Antagonist-stimulated internalization of the G protein-coupled cholecystokinin receptor.

Receptor-mediated endocytosis has been observed after agonist occupation of several G protein-coupled receptors, which contributes to the desensitization response to agonist stimulation; however, the cellular signals required to initiate this process are unclear. In this study, we developed and characterized a new antagonist analogue of cholecystokinin (D-Tyr-Gly-[(Nle28,31,D-Trp30)cholecystokinin-26-32]-phen eth yl ester) that can be tagged with a fluorescent rhodamine and radioiodinated. This has permitted us to demonstrate that antagonist occupation of the cholecystokinin receptor also results in receptor internalization, which dissociates this response from second messenger signaling activities and receptor phosphorylation. Immunolocalization of this receptor after occupation with an established nonpeptidyl antagonist confirmed this phenomenon. Antagonist-induced receptor internalization probably results from stabilization of the receptor in a conformation that exposes a domain critical to directing it into the clathrin-dependent endocytic pathway. This work provides evidence for a new and independent mechanism for receptor internalization, provides a mechanism for the rarely observed phenomenon of antagonist-induced desensitization, and raises important issues regarding the approach to establish optimal treatment regimens for antagonist drugs.

Binding, Competitive↗