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J Patrick

Publications and source records attributed to J Patrick.

At least 37 records · Page 2Linked to original sources
PubMed1994

alpha-Bungarotoxin blocks the nicotinic receptor mediated increase in cell number in a neuroendocrine cell line.

Exposure of H69 small cell lung carcinoma cells to nicotinic agonists resulted in a significant increase (up to 100%) in cell number after 6 to 12 days. The effect of nicotine (10(-8) M to 10(-4) M) was both dose and time dependent as was that of another nicotinic agonist cytisine (10(-6) M to 10(-4) M). Interestingly, both the nicotine and cytisine induced increases in H69 cell number were blocked by alpha-bungarotoxin, as well as d-tubocurarine a nicotinic blocker which appears to interact with most nicotinic receptors. These results suggest that the nicotine induced increase in cell number is mediated through an interaction at the nicotinic alpha-bungarotoxin receptor. This idea is further supported by experiments which show (1) that H69 cells possess high affinity alpha-bungarotoxin sites (Kd = 25 nM, Bmax = 10.4 fmol/10(6) cells) with the characteristics of a nicotinic alpha-bungarotoxin receptor and (2) that the potencies of nicotinic receptor ligands in the alpha-bungarotoxin binding assay were similar to those observed in the functional studies. Northern analysis showed that mRNA for alpha 7, a putative nicotinic alpha-bungarotoxin binding subunit, and for alpha 5 were present in H69 cells. The present data provide further evidence that nicotine increases cell number in small cell lung carcinoma and are the first to show that this effect is mediated through an interaction at the nicotinic alpha-bungarotoxin receptor population. These results suggest that the alpha-bungarotoxin site may be involved in modulating proliferative responses in neuroendocrine derived SCLC cells.

Alkaloids↗
PubMed1994

Prolyl isomerase requirement for the expression of functional homo-oligomeric ligand-gated ion channels.

Ligand-gated ion channel subunits show a striking abundance of highly conserved proline residues. We, therefore, tested the hypothesis that peptidyl-prolyl isomerases may be involved in the maturation of these channels. Cyclosporin A, a selective blocker of a ubiquitous isomerase cyclophilin, reduced the surface expression in Xenopus oocytes of functional homo-oligomeric receptors containing nicotinic acetylcholine receptor subunit alpha 7 without blocking alpha 7 polypeptide synthesis. This effect could be generalized to the homo-oligomeric 5-hydroxytryptamine type 3 receptor but not to the hetero-oligomeric muscle nicotinic receptor. An alpha 7 receptor could be rescued from cyclosporin A blockade by coexpressed muscle non-alpha subunits. The effect of cyclosporin A was reversed by overexpression of exogenous rat brain cyclophilin. These findings indicate that cyclophilins may play a critical role in the maturation of homo-oligomeric receptors, acting directly or indirectly as prolyl isomerases or as molecular chaperones.

Amino Acid Isomerases↗
PubMed1994

Neuropathology of the near-term and midgestation ovine fetal brain after sustained in utero hypoxemia.

OBJECTIVE: The neuropathologic mechanisms of the ovine fetal brain in response to several hours of sustained hypoxemia with variable degrees of metabolic acidemia was investigated in both the preterm and near-term ovine fetus. STUDY DESIGN: Three groups of fetuses were studied in each of the near-term and midgestation groups: a hypoxic group, a control group, and an uninstrumented control group. Histopathologic studies were performed after a 40-hour recovery period after experimentation. RESULTS: Pathologic findings consisted of predominately white matter damage with some adjacent cortical necrosis but no selective neuronal injury. In the near-term group the hypoxia group fetuses demonstrated significantly higher white matter injury scores than did control group fetuses (p < 0.05). Periventricular white matter injury was the predominant pattern seen in the midgestation group. CONCLUSIONS: In spite of normalization of biophysical and biochemical parameters after hypoxemia both midgestation and near-term fetuses sustained pathologic changes. Presence or extent of injury did not correlate with the degree of hypoxemia or metabolic acidosis achieved.

Acidosis↗
PubMed1994

Recovery of the ovine fetus from sustained hypoxia: effects on endocrine, cardiovascular, and biophysical activity.

OBJECTIVE: The purpose of this study was (1) to determine the ability of the ovine fetus to recover from a self-limiting asphyxial insult and (2) to monitor cardiovascular and biophysical activity as potential markers of such an insult or underlying neurologic impairment. STUDY DESIGN: Nineteen fetal sheep were studied (12 hypoxia and 7 control) at 0.9 of gestation during a 24-hour control period, up to 8 hours of either sustained hypoxemia or room air, and for a 40-hour recovery period. Fetal heart rate, blood pressure, electrocortical activity, electroocular activity, and breathing movements were monitored continuously. Fetal arterial blood was sampled at set times for blood gases, pH, lactate, and catecholamine levels. RESULT: Induced fetal hypoxemia resulted in a lactic metabolic acidosis that progressively worsened, with death occurring in three of the animals during the early recovery period. The remaining animals showed a rapid metabolic and endocrine normalization of values by 24 hours. Fetal cardiovascular and biophysical measurements likewise returned to control values during the early recovery period, although three animals had seizure-like activity. CONCLUSION: The near-term ovine fetus surviving a sustained asphyxial insult sufficient to induce neuropathologic change within the brain demonstrates a normalization of biophysical activity during the early period of recovery, although seizure-like activity may subsequently be evident.

Animals↗
PubMed1993

Validation of the MCMI-I Borderline Personality Disorder Scale with a well-defined criterion sample.

This study examined the MCMI-I BPD scale's accuracy in assigning borderline personality disorder as a primary diagnosis. Clinicians with particular expertise in Axis II pathology diagnosed borderline patients in two groups in this sample. Results indicate that the MCMI-I BPD scale has very limited utility as a screening instrument for individual diagnoses when a well-defined borderline sample is-used as a criterion. This study further suggests that at present only clinicians with particular expertise in the diagnosis of personality disorders can assess the degree and type of Axis II pathology present in a given patient. Because most structured interview and self-report validation studies have not included well-defined criterion groups, diagnostic validity of particular measures generally has not been established beyond the level of concordance.

Adult↗
PubMed1993

Management of lentigo maligna and lentigo maligna melanoma with paraffin-embedded tangential sections: utility of immunoperoxidase staining and supplemental vertical sections.

BACKGROUND: The use of frozen sections in the management of lentigo maligna and lentigo maligna melanoma has been the focus of some controversy. OBJECTIVE: Our purpose was to utilize paraffin-embedded tangential sections in the management of two cases of lentigo maligna and three cases of lentigo maligna melanoma. METHODS: A modification of Mohs micrographic surgery using rush paraffin-embedded sections with adjunctive immunoperoxidase staining (HMB-45) and supplemental vertical sections was employed. RESULTS: This method resulted in enhanced histologic evaluation of section margins and did not compromise the diagnosis of the primary invasive melanoma or Breslow measurements. CONCLUSION: Mohs micrographic surgery modified by the use of rush paraffin-embedded sections allows adjunctive immunoperoxidase staining and supplemental vertical sections that may be helpful in the management of lentigo maligna and lentigo maligna melanoma.

Aged↗
PubMed1993

Mapping of ligand binding sites of neuronal nicotinic acetylcholine receptors using chimeric alpha subunits.

We constructed a series of chimeric neuronal nicotinic acetylcholine (ACh) receptor (nAChR) alpha subunits to map the location of amino acid residues that determine the pharmacological properties of these receptors. The alpha 2 and alpha 3 subunits form pharmacologically distinct nAChRs upon expression, in combination with the beta 2 subunit, in Xenopus oocytes. The alpha 2 beta 2 subunit combination is insensitive to the nicotinic antagonist neuronal bungarotoxin (NBT) and is much more sensitive to nicotine than to ACh. In contrast, the alpha 3 beta 2 subunit combination is potently inhibited by NBT and is much less sensitive to nicotine than to ACh. Chimeric subunits were constructed by replacing portions of alpha 2 or alpha 3 with the analogous portion of the other alpha subunit. Pharmacological analysis of receptors formed by these chimeric subunits, in combination with beta 2, revealed that amino acid residues involved in determining NBT sensitivity were located within sequence segments 84-121, 121-181, and 195-215. Amino acid residues that determine agonist sensitivity were located within sequence segments 1-84 and 195-215. Within region 195-215, we used site-directed mutagenesis to demonstrate the importance of Gln-198 of alpha 3 (proline in alpha 2) in determining both the antagonist sensitivity and the agonist sensitivity of neuronal nAChRs.

Acetylcholine↗
PubMed1993

Borderline disorder and attachment pathology.

In this paper, the authors investigate the theoretical and empirical association between dysfunctions of the attachment system and borderline personality disorder. Attachment theory focuses on the maintenance of a sense of safety and security through a close personal relationship with a particular person. Based on a biological behavioural system, functional attachment relationships in adulthood rely on experiences and expectations of security within the relationship. These issues are also important to the definition and dynamics of borderline personality disorder. The dimensions and patterns of reciprocal attachment were compared with other scales measuring components of psychopathology and interpersonal relationships. In a sample of 85 female outpatients, only four of the attachment scales--feared loss, secure base, compulsive care-seeking and angry withdrawal--identified patients with high scores on a measure of borderline disorder. Of these four scales, feared loss had the predominant effect. These empirical results support the hypothesized relationship between dysfunctions of the attachment system and borderline disorder.

Adult↗
PubMed1993

The integration of the self-psychological and cognitive-behavioural models in the treatment of borderline personality disorder.

The major focus of the non pharmacological treatment of borderline personality disorders is rapidly shifting from long term, psychodynamically oriented therapies to highly structured and explicitly operationalized cognitive-behavioural treatment models. The goal of these models is changing targeted maladaptive coping behaviour. This paper examines possible limiting factors to Linehan's model of dialectical behaviour therapy, based on the implications of self-definition-seeking behaviour which is commonly observed in these patients. The extent to which borderline patients' self-definition-seeking behaviour is exaggerated and unremitting in a therapeutic context identifies the primacy of these individuals' striving for self-cohesion. If this need is unrecognized and treatment strategies which address it are not incorporated, the success of cognitive-behavioural treatment models can be unnecessarily (and sometimes severely) compromised. A solution to this problem may lie in the integration of therapeutic principles derived from self-psychology. An outline of this theoretical model and its application in brief therapy on increasing self-cohesion are presented.

Adult↗
PubMed1992

Gene transcripts for the nicotinic acetylcholine receptor subunit, beta4, are distributed in multiple areas of the rat central nervous system.

Previous in situ hybridization experiments reported that beta4 (beta 4) neuronal nicotinic acetylcholine receptor (nAChR) transcripts were found only in the medial habenula (MHB). Co-expression in Xenopus oocytes of the beta 4 subunit and any one of three ligand-binding or alpha subunits results in the formation of functional nAChRs. Comparisons between the pharmacology of nAChRs expressed in oocytes and the pharmacology of nAChRs found in the rat CNS prompted a further investigation of the localization of transcripts encoding the beta 4 nAChR subunit. Using two beta 4-specific cRNA probes, in situ hybridization was performed in rat brain. beta 4 mRNA was detected at high levels in the presubiculum, parasubiculum, subiculum and dentate gyrus of the hippocampal formation, in layer IV of the isocortex, in the medial habenula, in the interpeduncular nucleus, and in the trigeminal motor nerve nucleus. Moderate hybridization signals were seen in the isocortex (layers I-III), in olfactory regions, in fields CA1 through CA4 of Ammon's horn and the entorhinal cortex of the hippocampal formation, in the supramammillary nucleus, in the pontine nucleus, in the cerebellum, and in the locus coeruleus. No hybridization above background was detected in the septum, basal ganglia, sensory portions of the brainstem, or spinal cord.

Animals↗
PubMed1992

Calcium modulation and high calcium permeability of neuronal nicotinic acetylcholine receptors.

Two properties were found to distinguish neuronal from muscle nicotinic acetylcholine receptors (nAChRs). First, neuronal nAChRs have a greater Ca2+ permeability. The high Ca2+ flux through neuronal nAChRs activates a Ca(2+)-dependent Cl- conductance, and the Ca2+ to Cs+ permeability ratio (PCa/PCs) is 7 times greater for neuronal than for muscle nAChRs. A second difference between the receptor types is that neuronal nAChRs are potently modulated by physiological levels of external Ca2+. Neuronal nAChR currents are enhanced by external Ca2+ in a dose-dependent manner. The results indicate that changes in extracellular Ca2+ modulate neuronal nAChRs and may modulate cholinergic synapses in the CNS. Also, activation of neuronal nAChRs produces a significant influx of Ca2+ that could be an important intracellular signal.

Adrenal Glands↗
PubMed1992

Effects of sustained hypoxemia on the sheep fetus at midgestation: endocrine, cardiovascular, and biophysical responses.

OBJECTIVE: The purpose of our study was to examine the effects of induced hypoxia on endocrine, cardiovascular, and biophysical measurements of the ovine fetus at 0.6 (83 to 93 days) of gestation and to compare the fetal responses at this earlier gestation with those reported near term. STUDY DESIGN: Fourteen fetal sheep were studied (9 in the hypoxia group and 5 in the control group) at 0.6 of gestation during a 24-hour control period, 8 hours of either sustained hypoxemia or room air, and a 40-hour recovery period. RESULTS: Induced fetal hypoxemia resulted in a progressive lactic metabolic acidosis; however, all fetuses had recovered within 24 hours. The fetal endocrine response was variable with norepinephrine, the only measured hormone showing a significant hypoxia-related increase (p less than 0.05). Fetal heart rate and mean arterial blood pressure showed little hypoxia-induced change, although fetal heart rate was significantly increased over the first 2 hours (p less than 0.05). The percent time fetal breathing movements, electroocular activity, and nuchal muscle activity likewise showed little hypoxia-induced change. CONCLUSION: The cardiovascular and biophysical response of the preterm fetus to induced hypoxemia is thus much less pronounced than that of the older gestational-aged fetus; this difference may impact on survival and the success of antenatal assessment protocols.

Animals↗
PubMed1992

Effect of ethanol on the release of prostaglandins from ovine fetal brain stem during gestation.

Prostaglandins (PGs) have been implicated as mediators of the ethanol-induced suppression of ovine fetal breathing movements (FBM). The objectives of the present study were to determine the ontogeny of the in vitro efflux of PGE2 and 6-keto PGF1 alpha in ovine fetal brain stem during the second half of gestation and to determine the effect of in vitro ethanol exposure on the efflux of these PGs. Ovine fetal brain stem tissue was obtained at mean gestational ages of 80 days (n = 6), 105 days (n = 10), and 135 days (n = 16) by rapid excision following maternal euthanization. Tissue slices (400 microM thickness) were prepared from the lower pons-medulla region of the brain stem. After a 1-hr equilibration period in artificial cerebrospinal fluid, efflux of PGE2 and 6-keto PGF1 alpha in the brain stem was determined using the brain slice-superfusion method, and the PGE2 and 6-keto PGF1 alpha concentrations in the superfusate were determined by specific radioimmunoassay. The mean spontaneous efflux of PGE2 and 6-keto PGF1 alpha expressed as pmol PG/gram wet weight of tissue/5-min collection period was, respectively, 31.9 +/- 4.2 and 26.6 +/- 2.4 at 80 days, 38.3 +/- 5.2 and 29.6 +/- 2.2 at 105 days, and 57.4 +/- 3.1 and 27.1 +/- 1.1 at 135 days of gestation. In vitro exposure to 20, 40, and 80 mM ethanol did not affect PG efflux in the brain stem at 80 and 105 days of gestation. In vitro ethanol exposure decreased PGE2 and 6-keto PGF1 alpha efflux at 135 days of gestation to 36.8 +/- 5.3% and 41.6 +/- 4.3% of spontaneous efflux within 15 min, respectively; this effect of ethanol was not dose-dependent. The data do not support the hypothesis that ethanol increases PG efflux in the ovine fetal brain stem. In view of these findings and the data implicating PGs in the mechanism of ethanol-induced suppression of FBM, it is possible that ethanol acts at either central sites rostral to the brain stem (i.e., upstream CSF) or peripheral sites to increase the synthesis of PGs and their efflux into the systemic circulation, with subsequent transfer to the respiratory control region(s) of the brain stem.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Effects of ethanol exposure on the embryo-fetus: experimental considerations, mechanisms, and the role of prostaglandins.

The purpose of this review is to critically examine the effects of ethanol on the embryo-fetus. There has been a tremendous amount of human epidemiological and experimental animal research on the characterization of the anomalies produced by chronic prenatal ethanol exposure and the identification of critical periods of vulnerability and critical amounts of ethanol necessary to produce fetal effects and (or) abnormal development. Few studies have examined the underlying mechanism(s) of the action of ethanol, and even fewer studies have examined the effects of single-dose ethanol exposure on the embryo-fetus. In this review, the current state of knowledge of the effects of chronic use of ethanol on the embryo-fetus is summarized. The primary focus of the review is on the embryonic-fetal effects of acute ethanol exposure, with particular emphasis on the ethanol-induced suppression of fetal breathing movements, as this effect appears to be a very sensitive index of acute exposure of the near-term fetus to ethanol. Factors to be considered in the selection of experimental animals to investigate the mechanism of action of ethanol and to study the acute effects of ethanol are discussed. Postulated mechanisms of action of ethanol on the embryo-fetus are evaluated with a focus on the role of prostaglandins. Finally, future directions in this field of research are proposed.

Animals↗