Biomedical subjects

J L Hill

Publications and source records attributed to J L Hill.

At least 19 recordsLinked to original sources

PubMed1999

Stage-dependent effects of epidermal growth factor on Ca2+ efflux in mouse oocytes.

Epidermal growth factor (EGF) has received much attention recently for its positive effects on mammalian oocyte maturation and embryo development and its potential importance in cytoplasmic maturation of oocytes. Calcium (Ca2+) homeostasis in germinal vesicle stage oocytes has also been suggested to play a role in cytoplasmic maturation. This study examined the effects of EGF on Ca2+ mobilization as measured by its efflux from mouse oocytes at three time periods throughout maturation (0-4 hr, 4-8 hr, and 12 hr). Immature cumulus oocyte complexes (COCs) removed from the ovary for less than 4 hr exhibit oscillations in Ca2+ efflux that initiated 5-30 min following EGF stimulation. This response was not observed in COCs matured for 4-8 hr or 12 hr or in unstimulated 0-4 hr COCs. Denuded oocytes and cumulus cells did not show the same response to EGF (8.2 nM and 16.4 nM). Immunohistochemistry for detection of the EGF receptor along with EGF internalization studies showed that receptors are present both on cumulus cells and the oocyte but EGF appears to be internalized mainly by the cumulus cells. These data demonstrate that EGF induces oscillations in Ca2+ efflux in COCs 0-4 hr old and this response is mediated by the cumulus cells.

Animals↗

PubMed1999

Behavioral and physiological effects of remifentanil and alfentanil in healthy volunteers.

BACKGROUND: The subjective and psychomotor effects of remifentanil have not been evaluated. Accordingly, the authors used mood inventories and psychomotor tests to characterize the effects of remifentanil in healthy, non-drug-abusing volunteers. Alfentanil was used as a comparator drug. METHODS: Ten healthy volunteers were enrolled in a randomized, double-blinded, placebo-controlled, crossover trial in which they received an infusion of saline, remifentanil, or alfentanil for 120 min. The age- and weight-adjusted infusions (determined with STANPUMP, a computer modeling software package) were given to achieve three predicted constant plasma levels for 40 min each of remifentanil (0.75, 1.5, and 3 ng/ml) and alfentanil (16, 32, and 64 ng/ml). Mood forms and psychomotor tests were completed, and miosis was assessed, during and after the infusions. In addition, analgesia was tested at each dose level using a cold-pressor test. RESULTS: Remifentanil had prototypic micro-like opioid subjective effects, impaired psychomotor performance, and produced analgesia. Alfentanil at the dose range tested had more mild effects on these measures, and the analgesia data indicated that a 40:1 potency ratio, rather than the 20:1 ratio we used, may exist between remifentanil and alfentanil. A psychomotor test administered 60 min after the remifentanil infusion was discontinued showed that the volunteers were still impaired, although they reported feeling no drug effects. CONCLUSIONS: The notion that the pharmacodynamic effects of remifentanil are extremely short-lived after the drug is no longer administered must be questioned given our findings that psychomotor effects were still apparent 1 h after the infusion was discontinued.

Adult↗

PubMed1998

Acute intravenous administration of ondansetron and m-CPP, alone and in combination, in patients with obsessive-compulsive disorder (OCD): behavioral and biological results.

Obsessive-compulsive disorder (OCD) has been linked to abnormal function of brain serotonin (5-HT) pathways. Since ondansetron is a highly selective 5-HT3 receptor antagonist, the present study was undertaken to investigate 5-HT3 function in OCD. We administered m-CPP (0.08 mg/kg i.v.) and the potent 5-HT3 antagonist, ondansetron (0.15 mg/kg i.v.), to 11 OCD patients. All of the subjects received four separate challenges (m-CPP + placebo, m-CPP + ondansetron, ondansetron + placebo and placebo + placebo). In comparison to placebo, administration of m-CPP was associated with significant behavioral effects, particularly self-rated measures of anxiety, altered self-reality, functional deficit and OCD symptoms. Pretreatment with ondansetron did not affect any of the self-rated behavioral symptoms. After administration of m-CPP relative to placebo, significant increases in plasma cortisol and prolactin were found. These changes were not affected by ondansetron. In conclusion, our results do not support the hypotheses that 5-HT3 receptor-mediated mechanisms modulate m-CPP's behavioral and neuroendocrine effects in patients with OCD.

Adult↗

PubMed1998

Comparing the subjective, psychomotor and physiological effects of intravenous pentazocine and morphine in normal volunteers.

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of pentazocine in non-drug-abusing volunteers and to compare and contrast the effects of pentazocine with those of morphine. Sixteen subjects without histories of opiate dependence were injected in an upper extremity vein with 0, 7.5, 15 or 30 mg/70 kg pentazocine or 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. Pentazocine increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of "nodding," "sweating" and "turning of stomach" and increased visual analog scale ratings of "difficulty concentrating," "drunk" and "having unpleasant bodily sensations." Pentazocine (30 mg) had a greater propensity to increase ratings associated with dysphoria than did 10 mg of morphine. Pentazocine produced impairment on four measures of psychomotor performance. Ten milligrams of morphine produced minimal psychomotor impairment. Both pentazocine and morphine induced miosis, but 10 mg of morphine had a greater magnitude of effect than 30 mg of pentazocine. The results of the present study demonstrate that 7.5 to 30 mg of pentazocine had orderly, dose-related effects on subjective, psychomotor and physiological variables. Further, a clinically relevant dose of pentazocine, 30 mg, produced a greater magnitude of dysphoric subjective effects than did 10 mg of morphine, which is consistent with the literature reporting that pentazocine has a greater likelihood of inducing psychotomimesis than do other opioids.

Adult↗

PubMed1997

Redox-dependent conformational changes are common structural features of cytochrome c from various species.

Discrepant results from X-ray crystallographic and physicochemical studies on the conformations of the two redox states of cytochrome c raise important questions about the nature of redox-dependent conformational changes and whether differences are common structural features of various cytochrome c species. Comparative studies of cytochrome c from 10 species (horse, cow, sheep, pig, dog, rabbit, chicken, pigeon, tuna, and baker's yeast) in aqueous solutions were carried out using Fourier transform infrared (FT-IR) spectroscopy. The second-derivative analysis revealed similar conformational changes in all 10 species upon reduction of the heme iron regardless of the differences in the amino acid sequences. The redox-dependent changes involve the amide I regions ascribed to extended beta-structure, beta-turn, and alpha-helix structures. Three species (cow, sheep, and pig) with identical amino acid sequences displayed nearly identical infrared spectra for the oxidized and reduced states, which rules out the possible contribution of experimental error. These results show unequivocally that redox-dependent conformational changes are common structural feature of various cytochrome c species and demonstrate the usefulness of FT-IR spectroscopy as a quick and inexpensive tool in comparative studies of functionally related conformational changes of proteins.

Animals↗

PubMed1997

Influence of ovine oviducal amino acid concentrations and an ovine oestrus-associated glycoprotein on development and viability of bovine embryos.

This study examined the effects of incorporating an ovine oviducal oestrus-associated glycoprotein (oEGP) and amino acids, at the concentrations present in the ovine oviduct around the time of oestrus, on in vitro production and subsequent viability of bovine embryos. The first experiment compared the influence of ovine oviducal concentrations of amino acids with MEM and BME amino acids. There was no treatment effect on cleavage rate (74.9% vs. 75.5%), but there was a higher (P < 0.05) blastocyst yield (30.4 vs. 25.2) and a shorter time (P < 0.05) to blastocyst formation (7.16 +/- 0.64 vs. 7.27 +/- 0.56 days) following use of oviducal concentrations of amino acids. Experiment 2 examined the influence of oEGP in combination with each of the amino acid treatments. oEGP had no effect on cleavage or blastocyst yield within amino acid treatments. Day of blastocyst formation significantly influenced nuclei numbers (P < 0.001) with higher numbers being obtained on day 7 than on either day 6 or day 8. There was also a significant (P < 0.01) interaction between day of blastocyst formation and amino acid treatment on blastocyst nuclei numbers. The third experiment studied the effects of the amino acid treatments on embryo viability. There was no effect of amino acid treatment of embryos on pregnancy rates (34.5 vs. 44.4%) following transfer of days 6 and 7 blastocysts to synchronized recipients. oEGP did not influence any of the parameters of bovine embryo development that were measured, suggesting that effects of this protein observed on ovine embryos are species specific. It is concluded that ovine oviducal amino acid concentrations are beneficial to blastocyst development in vitro but do not have any further beneficial effect following transfer of blastocysts to recipients.

Amino Acids↗

PubMed1997

Behavioral, physiological and neuroendocrine responses in healthy volunteers to m-chlorophenylpiperazine (m-CPP) with and without ondansetron pretreatment.

Several serotonin3 (5-HT3) antagonists have been shown to attenuate the anxiogenic effects of the serotonergic agent, m-chlorophenylpiperazine (m-CPP), in animal models, but little data regarding possible effects of 5-HT3 antagonists on responses to m-CPP are available from studies in humans. Therefore, we studied the behavioral, physiological and neuroendocrine responses of 12 healthy volunteers to i.v. administered placebo and m-CPP (0.08 mg/kg), with and without i.v. pretreatment with the selective 5-HT3 antagonist, ondansetron (0.15 mg/kg). Compared to placebo, m-CPP given alone significantly increased ratings of anxiety and several other behavioral measures. m-CPP also produced statistically significant increases in temperature, systolic and diastolic blood pressure, heart rate, and in plasma concentrations of adrenocorticotropic hormone, cortisol, prolactin and norepinephrine. Responses to ondansetron given alone were no different from those of placebo. Pretreatment with ondansetron did not affect peak behavioral responses to m-CPP, but was associated with a significantly earlier return to baseline levels of ratings of anxiety and functional deficit as well as a summary measure of overall behavioral effects. Following ondansetron pretreatment, the increases produced by m-CPP in systolic and diastolic blood pressure and heart rate were no longer significantly different from placebo. Ondansetron pretreatment significantly reduced their plasma cortisol response to m-CPP without affecting the other plasma hormone responses. Plasma concentrations of m-CPP were unaffected by ondansetron pretreatment. These findings suggest that in normal human subjects some behavioral, cardiovascular and neuroendocrine effects of m-CPP may be partially modulated by 5-HT3 receptor-mediated mechanisms.

Adult↗

PubMed1996

Biological and behavioral responses to D-amphetamine, alone and in combination with the serotonin3 receptor antagonist ondansetron, in healthy volunteers.

Evidence that serotonin3 (5-hydroxytryptamine3, 5-HT3) antagonists attenuate behavioral responses to D-amphetamine and cocaine suggests that 5-HT3 receptors modulate brain dopamine in animals. This study examined the potential interactions of the 5-HT3 antagonist ondansetron and D-amphetamine in 10 healthy human volunteers. After the subjects were pretreated with placebo or ondansetron (0.15 mg/kg, i.v.), 5-h challenge tests with oral D-amphetamine (0.5 mg/kg) were performed. As animal studies and early clinical studies with ondansetron have suggested nonlinear dose-response relationships, three subjects also underwent pilot studies with three doses of ondansetron (0.15, 0.05, and 0.015 mg/kg) before they received D-amphetamine. Administration of D-amphetamine increased plasma levels of cortisol, prolactin, growth hormone; elevated blood pressure, pulse, and temperature; and tended to increase self-ratings of activation/euphoria and anxiety. Amphetamine-induced increases in plasma prolactin were significantly reduced by ondansetron pretreatment, but the other neuroendocrine responses were unchanged. Diastolic blood pressure elevations were also significantly attenuated after administration of the lower ondansetron doses, but the other physiologic responses were unchanged. In subjects with minimal or moderate activation/euphoria responses, ondansetron pretreatment only minimally affected these effects of D-amphetamine. Preliminary data, however, indicate that those subjects with robust activation-euphoria responses to D-amphetamine had attenuated responses after ondansetron pretreatment. Taken together, these results suggest that some but not most of D-amphetamine's biological and behavioral effects may be modified by a 5-HT3 antagonist in healthy human volunteers.

Administration, Oral↗

PubMed1996

Development of ovine embryos in synthetic oviductal fluid containing amino acids at oviductal fluid concentrations.

The effects of supplementing synthetic oviductal fluid (SOF) with amino acids, at oviductal fluid concentrations, on the development of ovine in vitro-matured/in vitro-fertilized embryos was examined in three experiments. In the first, embryo development in SOF, SOF + 2% human serum (HS), SOF + 20% HS, and SOF + BSA, with and without amino acid supplementation, was examined. Development of zygotes to the blastocyst and hatching blastocyst stages was highest in medium containing 20% HS (64.8% and 54.4%, respectively) irrespective of amino acid supplementation. However, supplementation was significantly beneficial in all other media, with up to 42.1% of zygotes developing into hatching blastocysts. In these media, supplementation also significantly increased the mean number of nuclei per newly formed blastocyst (up to a mean of 70.8) and reduced the time during which blastocysts formed. Experiment 2 was an examination of the effect on embryo development of three amino acid preparations (oviduct amino acid concentrations vs. Eagle's Basal Medium (BME) essential + Minimum Essential Medium (MEM) nonessential vs. MEM essential + MEM nonessential concentrations) and the presence or absence of BSA. Both the amino acid and BSA treatments significantly influenced the percentage of zygotes that developed to the hatching blastocyst stage but not to the blastocyst stage. The preferred medium contained amino acids at oviductal fluid concentrations and BSA (54.5% hatching rate). The amino acid treatments did not significantly influence the mean number of nuclei per newly formed blastocyst, but the addition of BSA had a significant effect (70.7 +/- 1.14 vs. 75.7 +/- 1.13). In experiment 3, embryo development to Day 13 was examined after culture in SOF containing amino acids at oviductal fluid concentrations. Embryos were cultured in the presence of either BSA, polyvinyl alcohol (PVA), or no additional supplement and were transferred to recipient ewes on either Day 0 (after in vitro fertilization), 3, or 5. The addition of BSA or PVA had no significant effect, but significantly more embryos developed to Day 13 following transfer on Day 0 (60.0%) than on either Day 3 or 5 (overall 45.4%). It is concluded that SOF containing oviductal fluid concentrations of amino acids 1) facilitates the development of a high percentage (57.5%) of blastocysts, 2) improves embryo morphology compared with that observed in medium containing HS, 3) significantly improves hatching rates compared with those obtained in SOF containing commercially available preparations of amino acids, and 4) produces embryos with relatively high levels of viability to Day 13 of pregnancy.

Amino Acids↗

PubMed1995

Evidence that 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia in rats is mediated by stimulation of 5-HT2A receptors.

The effects of various 5-HT receptor subtype-selective antagonists were studied on phenylisopropylamine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia in Wistar rats, in an attempt to characterize the 5-HT receptor subtype mediating DOI-induced hyperthermia. Intraperitoneal administration of DOI to rats produced hyperthermia with a peak effect at 60 min. Pretreatment with propranolol (beta-adrenoceptor antagonist that also has binding affinity for 5-HT1A, 5-HT1B and 5-HT2C sites), MDL-72222 or ondansetron (5-HT3 antagonists) did not attenuate DOI-induced hyperthermia. In contrast, pretreatment with metergoline (5-HT1/5-HT2 antagonist), ketanserin, LY53857, mesulergine, mianserin and ritanserin (5-HT2C/5-HT2A antagonists), as well as spiperone (5-HT1A/5-HT2A/D2 antagonist), significantly attenuated DOI-induced hyperthermia. Furthermore, daily administration of DOI (2.5 mg/kg per day) for 17 days did not produce either tolerance to its hyperthermic effect or modify m-CPP-induced hyperthermia in rats. These findings suggest that DOI-induced hyperthermia in rats is mediated by stimulation of 5-HT2A receptors.

Amphetamines↗

PubMed1995

Serotonergic modulation of anticholinergic effects on cognition and behavior in elderly humans.

Cholinergic neurotransmission is thought to be modulated by serotonin as documented in animal and human studies. We examined the effects of the muscarinic antagonist scopolamine (0.4 mg IV) given alone or together with the serotonin mixed agonist/antagonist m-chlorophenylpiperazine (m-CPP, 0.08 mg/kg IV), and the selective 5-HT3 receptor antagonist ondansetron (0.15 mg/kg IV). Ten normal elderly volunteers each received five separate pharmacologic challenges (placebo, ondansetron, scopolamine, scopolamine+ondansetron, and scopolamine+m-CPP). Cognitive, behavioral, and physiologic variables were analyzed using repeated measures analysis of variance. The acute effects of scopolamine in certain cognitive, behavioral, and physiological measures were significantly exaggerated by the addition of m-CPP. Scopolamine's cognitive effects were unaffected by ondansetron at the dose tested, nor did ondansetron given alone affect basal cognitive performance. This pilot study suggests that the serotonin mixed agonist/antagonist m-CPP may influence cholinergic neurotransmission. The changes associated with the combination of scopolamine and m-CPP do not appear to be secondary to simple pharmacokinetic alterations and suggest a complex interaction between the cholinergic and serotonergic systems centrally.

Aged↗

PubMed1995

Oviduct proteins in fertilization and early embryo development.

The oviduct controls the environment in which the gametes are transported and fuse, and in which embryonic development begins. The ultrastructural topography of the ampulla and isthmus is similar, consisting of ciliated and secretory cells, but a different array of proteins is secreted by each segment along with various serum components. Amino acids are selectively secreted by the oviduct; these amino acids probably interact with the gametes or embryo to facilitate the processes of fertilization and development. An oviduct-specific glycoprotein is synthesized by the ampulla of sheep and cattle in response to oestrogen and secreted mainly from day-1 to day 3 of the ovarian cycle. This oestrus-associated glycoprotein (EGP) has a variable molecular mass of 80-97 kDa and a pI value ranging from 4.7 to 5.5. The bovine (b) and ovine (o) EGP genes are 95.5% identical and consist of 1560 base pairs encoding 519 amino acids containing one N-linked and several O-linked glycosylation sites. The terminal glycosides are N-acetylglucosamine and galactose-N-acetylgalactosamine for bEGP, and fucose, galactose and sialic acid residues are also identified for oEGP. EGP binds to zona pellucida and blastomere membranes, but evidence for EGP binding to sperm membranes is equivocal. After in vitro fertilizaton the proportion of sheep oocytes cleaving was increased in the presence of oEGP, but when single-cell embryos were cultured with oEGP, these cleavage rates were reduced. In addition, consistent positive effects of oEGP were observed on blastocyst formation. Elaboration of the mechanism of synthesis of EGP, its action and its role in fertilization and embryo development is important for our understanding of the events of early pregnancy.

Amino Acids↗

PubMed1994

Serum antibody for somatostatin-14 and prodynorphin 209-240 in patients with obsessive-compulsive disorder, schizophrenia, Alzheimer's disease, multiple sclerosis, and advanced HIV infection.

Patients with obsessive-compulsive disorder (OCD) demonstrated significant levels of antibody for somatostatin-28, its C-terminal fragment somatostatin-14, and prodynorphin. In contrast there were lower levels of reactivity for somatostatin-28(1-14) (the N-terminal fragment of somatostatin-28) and negligible reactivity for several other peptides including beta-endorphin and corticotropin. Healthy volunteers and disease controls [schizophrenia, Alzheimer's disease, multiple sclerosis, and subjects with advanced human immunodeficiency virus (HIV) infection] exhibited negligible reactivity. These data raise the consideration of an autoimmune mechanism for some OCD.

Adult↗

PubMed1994

Co-culture, oviduct secretion and the function of oviduct-specific glycoproteins.

Co-cultures of embryos with somatic cells, usually in the form of monolayers, or conditioned medium from these somatic cells, results in development past the early stage blocks and the formation of hatched blastocysts. Optimum rates of development are not achieved, however, and the task is to investigate components of the oviduct that are obligatory or facilitative for embryo development. Glycine and alanine are amino acids present in much higher concentrations in oviduct fluid than in serum or culture media. Glycoproteins specifically produced by the oviduct around oestrus bind to embryos and aid development but are absent from most culture media. These glycoproteins are induced by oestrogen in vivo but not in vitro. It is our contention that co-cultures of mammalian embryos should include appropriate concentrations of amino acids and a source of embryotrophic glycoproteins as an additive or by including stromal cells in addition to epithelial cells.

Animals↗

PubMed1994

Scopolamine effects on the pressor response to thyrotropin-releasing hormone in humans.

Thyrotropin-releasing hormone (TRH) produces a marked pressor effect, which may be mediated by central cholinergic neurons, which in turn enhance sympathetic nervous system activity. In this study, 22 subjects (10 patients with Alzheimer's disease and 12 elderly controls) were administered IV scopolamine or placebo prior to administration of IV high-dose TRH (0.5 mg/kg). Systolic blood pressure was less on the day scopolamine was administered prior to TRH administration, as compared with placebo (F[1,20] = 6.12, p < 0.02). Results indicate that the pressor effect of TRH is attenuated by scopolamine, indicating a role of the cholinergic system in this response in humans.

Aged↗

PubMed1994

Functional and biochemical evidence for altered serotonergic function in the fawn-hooded rat strain.

Administration of various doses of DOI (a 5-HT2A/5-HT2C agonist) produced hyperthermia that was significantly less in the FH rat strain relative to the Wistar rat strain. Similarly, administration of various doses of ipsapirone (a 5-HT1A agonist) produced hypothermia that was significantly less in the FH rat strain relative to the Wistar rat strain. Furthermore, m-CPP (a 5-HT agonist)-induced increases in growth hormone levels were also significantly less in the FH rat strain relative to the Wistar rat strain. There was no significant difference in the levels of either 5-HT or 5-HIAA between the two rat strains in the frontal cortex, hippocampus, hypothalamus, and striatum. In the brain stem, however, both 5-HT and 5-HIAA levels were significantly lower in the FH rat strain relative to the Wistar rat strain. On the other hand, 5-HT turnover rate was significantly higher in the hypothalamus and striatum and significantly lower in the hippocampus in the FH rat strain relative to the Wistar rat strain. These findings provide further evidence for altered serotonergic function in the FH rat strain and, in addition, suggest that the FH rat strain may prove to be a useful genetic model for some neuropsychiatric disorders with possible abnormalities in serotonergic function such as depression, obsessive-compulsive disorder, and the eating disorders.

Amphetamines↗

PubMed1994

Enhanced anorexic responses to m-chlorophenylpiperazine during lithium administration to fawn-hooded rats.

In the present study, we investigated whether functional adaptational changes in the serotonergic neurotransmitter mechanisms regulating food intake following long-term lithium treatment in Fawn-Hooded rats (a rat strain suggested to represent a genetic model of depression) were different or similar to those previously observed in Wistar rats. Long-term (21-25 days) lithium treatment accentuated m-chlorophenylpiperazine (m-CPP, a 5-HT agonist) induced decreases in food intake. There was no significant difference in either brain m-CPP concentrations or hypothalamic norepinephrine, dopamine and 5-hydroxyindoleacetic acid concentrations between control and long-term lithium-treated rats following m-CPP. However, hypothalamic serotonin concentrations were significantly higher in long-term lithium-treated compared to saline-treated animals. This finding contrasts with our previous report demonstrating attenuation of m-CPP-induced anorexia in Wistar rats following similar long-term lithium treatment, and therefore suggests a differential adaptation in the serotonergic neurotransmitter mechanisms regulating food intake in a genetic animal model of depression.

Animals↗

PubMed1994

Lithium treatment restores clonidine's effect in an animal model of depression.

IP administration of various doses of clonidine produces significant increases in growth hormone levels in the Wistar rats but not in the Fawn-Hooded (FH) rats, a rat strain suggested to be a genetic model of depression. However, short-term lithium treatment restores clonidine's effect on growth hormone levels in the Fawn-Hooded rats. Potentiation of clonidine's effect on growth hormone levels following short-term lithium treatment appears most likely due to increased serotonergic function as a consequence of enhanced 5-HT concentrations at postsynaptic 5-HT1C receptor sites. Thus, the reversal of a deficit state in Fawn-Hooded rats by lithium treatment supports earlier studies suggesting this rat strain to represent a genetic model of depression.

Animals↗