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Biomedical subjects

M P Gillam

Publications and source records attributed to M P Gillam.

At least 19 recordsLinked to original sources
PubMed2005

Molecular analysis of the PDS gene in a nonconsanguineous Sicilian family with Pendred's syndrome.

OBJECTIVE: The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the Pendred's syndrome (PDS) gene that encodes pendrin, a chloride/iodide transporter expressed in the thyroid, the inner ear, and the kidney. In this study we performed clinical and molecular analyses in three siblings from a nonconsanguineous Sicilian family who presented with the clinical features of Pendred's syndrome. PATIENTS AND MOLECULAR ANALYSES: In two sisters and one brother, the clinical diagnosis of Pendred's syndrome was established based on the findings of sensorineural hearing loss and large goiters. Thyroid function tests, perchlorate discharge tests, thyroid ultrasound, and scintigraphy were performed in all affected individuals. Exons 2 to 21 of the PDS gene were amplified by polymerase chain reaction (PCR) and both strands were submitted to direct sequence analysis. RESULTS: The clinical diagnosis of Pendred's syndrome was supported by a positive perchlorate discharge test in the three afflicted siblings. Direct sequence analysis of the PDS gene revealed that all three harbored one allele with a novel mutation 890delC leading to a frameshift mutation and premature stop codon at position 302 (FS297 > 302X). On the other allele, two of the siblings had a previously described transition 1226G > A, which results in the substitution of arginine by histidine at position 409 (R409H). In the index patient, no mutation could be identified on the other allele. In functional studies, these mutants lose the ability of pendrin to mediate iodide efflux. CONCLUSIONS: All three patients included in this study presented with the classic Pendred syndrome triad. Two siblings were compound heterozygous for mutations in the coding region of the PDS gene. The third individual could have an unidentified mutation in a regulatory or intronic region of the PDS gene, or an identical phenotype caused by distinct pathogenic mechanisms.

Adolescent↗
PubMed2001

Genetic regulation of thyroid development.

Normal thyroid function is essential for development, growth, and metabolic homeostasis. The prerequisites for an euthyroid metabolic state include a normally developed thyroid gland, a properly functioning system for thyroid hormone synthesis, and sufficient iodine intake. Defects in any of the essential steps in thyroid development or thyroid hormone synthesis may result in morphologic abnormalities and impaired hormonogenesis. These defects can be partial or complete, leading to varying degrees of hypothyroidism. Morphologic alterations associated with congenital hypothyroidism include the absence of detectable thyroid tissue, ectopic tissue, thyroid hypoplasia, or a goitrous thyroid. However, in some patients with hypothyroidism, the thyroid is of normal size. This article focuses on defects in thyroid development. Recent insights into the developmental regulation of the calcitonin-producing C cells will not be discussed, and defects in hormone synthesis are discussed in an accompanying article.

Animals↗
PubMed2001

Genetic defects in thyroid hormone synthesis.

Thyroid hormone synthesis requires a normally developed thyroid gland, a properly functioning hypothalamic-pituitary-thyroid axis, and sufficient iodine intake. This article focuses on genetic defects in this axis. Defects that are primarily of developmental origin are discussed in our associated article in this issue. Defects in hormone synthesis usually are associated with the development of a goiter, provided that the bioactivity and action of thyrotropin (TSH) are not impaired. In contrast, hypoplasia of the gland may be caused by developmental defects, bioinactive TSH, or resistance to TSH at the level of the receptor or its signaling pathway. At the other end of the spectrum, hyperthyroidism may result from gain of function mutations in genes regulating growth and function.

Congenital Hypothyroidism↗
PubMed2000

Transplacental pharmacokinetics and fetal distribution of 2', 3'-didehydro-3'-deoxythymidine (d4T) and its metabolites in late-term rhesus macaques.

BACKGROUND: The overall goal of human immunodeficiency virus (HIV) therapy during pregnancy is to maintain maternal health and reduce the probability of vertical transmission during gestation and delivery, while keeping toxicity risks low. Azidothymidine (AZT) is currently recommended for pregnant women infected with HIV; however, many pregnant women are unable to tolerate AZT because of toxicity. In the present study, the placental transfer and fetal accumulation of the anti-HIV compound 2',3'-didehydro-3'-deoxythymidine (d4T) and its active (triphosphorylated) and inactive (thymine and beta-aminoisobutyric acid) metabolites were examined at steady state in late-term rhesus macaques. METHODS: On the day of the hysterotomy, the mother was administered an intravenous loading dose of d4T, followed by a 3-hr steady-state intravenous infusion that also included [(3)H]d4T as a tracer. After 3 hr of infusion, the fetus was delivered by cesarean section under halothane/N(2)O anesthesia. Plasma, amniotic fluid, and tissues were analyzed for d4T and its inactive metabolites by HPLC; tissue samples were analyzed for d4T and active (phosphorylated) metabolites by strong anion-exchange HPLC. RESULTS: Maternal steady-state plasma concentrations of d4T were 1-2 microg/ml, with a fetal-to-maternal plasma ratio of 0.85 +/- 0.09. The fetal tissue distribution of radioactivity was highest in the kidney and lowest in the brain. D4T, thymine, and beta-aminoisobutyric acid were detected in all fetal tissues examined. CONCLUSIONS: Our data indicate that d4T readily crosses the placenta and is present in the fetus as parent compound or its inactive metabolites after maternal infusion. Although fetal plasma concentrations of d4T were similar to clinical d4T concentrations, no phosphorylated metabolites were detected. Teratology 62:93-99, 2000. Published 2000 Wiley-Liss, Inc.

Aminoisobutyric Acids↗
PubMed1998

The effects of cocaine on nonhuman primate brain function are age dependent.

The effects of acute intravenous (i.v.) cocaine (COC) on several complex brain functions were studied in rhesus monkeys at 1.5, 3 and 10-11 years of age. Subjects performed several operant tasks (for food) that were used to model learning, short-term memory, color and position discrimination, and motivation, and disruption of performance of these tasks was used to quantitate drug effect. Drug effects were age dependent: The youngest subjects were 3 to 10 times less sensitive than the oldest. Presuming the observed behavioral effects of cocaine were caused primarily via its interaction with dopamine (DA) systems, changes in sensitivity to its effects with age are likely a reflection of the functional status of the DA system. These data, along with preliminary data on levels of DA transporters, suggest that the age-related differences in sensitivity to cocaine lie in, 'downstream' from, the dopamine receptor.

Aging↗
PubMed1998

Acute effects of dexfenfluramine (d-FEN) and methylenedioxymethamphetamine (MDMA) before and after short-course, high-dose treatment.

The acute behavioral effects of methylenedioxymethamphetamine (MDMA) and dexfenfluramine (d-FEN) were assessed in six rhesus monkeys using performance in the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB); three additional animals served as controls for neurochemical endpoints. The OTB consists of five food-reinforced tasks designed to model aspects of learning, short-term memory and attention, time estimation, motivation, and color and position discrimination. Shortly after the acute effects of each drug were determined, three of the monkeys received a short-course, high-dose exposure (2x /day x 4 days, intramuscular (i.m.) injections) of MDMA (10 mg/kg), while three monkeys were exposed to an identical regimen of d-FEN (5 mg/kg). Approximately one month later, the acute effects of each drug were again determined. In monkeys exposed to high-dose d-FEN, the sensitivities of the OTB tasks to acute disruption by either MDMA or d-FEN were essentially unchanged. Conversely, monkeys treated with high-dose MDMA were less sensitive to the acute behavioral effects of both drugs, although such an effect was seen more frequently for d-FEN and was OTB task specific. Thus a residual behavioral tolerance to the acute behavioral effects of MDMA and d-FEN was noted after high-dose MDMA exposure, but not after high-dose d-FEN exposure. These findings are surprising, as similar neurochemical effects (i.e., significant decreases of ca. 50% in serotonin in frontal cortex and hippocampus) were observed in all monkeys approximately six months after short-course, high-dose MDMA or d-FEN treatment.

Animals↗
PubMed1997

Acute effects of LSD on rhesus monkey operant test battery performance.

The acute effects of LSD were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation, short-term memory and attention, motivation, learning, and color and position discrimination. The end points monitored included percent task completed, response rate, and accuracy. LSD (0.0003-0.03 mg/kg intravenously) significantly decreased percent task completed and accuracy in the time estimation task at doses < or = 0.003 mg/kg, but did not significantly affect response rate in this task at any dose tested. Accuracy in the short-term memory task was significantly decreased at the highest dose tested (0.03 mg/kg), but no other end points were affected in this task. Response rate was decreased in both the motivation and learning tasks at doses (0.01 and 0.003 mg/kg, respectively) lower than those affecting other end points. In the color and position discrimination task, only response rate was affected (0.01 and 0.03 mg/kg). These data demonstrate that in rhesus monkeys, performance of tasks believed to depend on aspects of time estimation and motivation are more sensitive to the acute disruptive effects of LSD than are tasks thought to model learning, short-term memory, and color and position discrimination.

Animals↗
PubMed1997

Transplacental pharmacokinetics and fetal distribution of azidothymidine, its glucuronide, and phosphorylated metabolites in late-term rhesus macaques after maternal infusion.

3'-Azido-3'-deoxythymidine (AZT) is currently prescribed to pregnant women infected with human immunodeficiency virus to reduce the risk of vertical transmission of the virus to the fetus. Consequently, more information is needed concerning the placental transfer and tissue distribution of AZT and its metabolites. In the present study, the placental transfer and fetal accumulation of AZT, its glucuronide metabolite [3'-azido-3'-deoxythymidine-beta-D-glucuronide (AZTG)], and phosphorylated metabolites were examined at steady-state in near-term rhesus macaques. One to 2 weeks before a chronic infusion, an intravenous bolus of 8 mg/kg AZT was administered to pregnant animals to determine the dose of AZT needed to reach steady-state plasma concentrations. On the day of hysterotomy, the mother was administered an intravenous loading dose of AZT, followed by a 3-hr steady-state intravenous infusion that also included a trace of [3H]AZT. After 3 hr of infusion, the mother was anesthetized, and the fetus was delivered. Plasma and amniotic fluid were analyzed for AZT and AZTG by HPLC, and tissue samples were analyzed for AZT, AZTG, and phosphorylated metabolites by strong anion exchange HPLC. Maternal steady-state plasma concentrations were 1.3-2.2 micrograms/ml for AZT and 2.3-8.0 micrograms/ml for AZTG. Fetal AZT and AZTG plasma concentrations were both lower (0.98-2.3 micrograms/ml and 1.3-5.4 micrograms/ml, respectively) than maternal concentrations, with fetal-to-maternal plasma ratios of 0.63-1.0 for AZT. Fetal tissue distribution of tritium was highest in the kidney and lowest in the brain. Although the active triphosphorylated metabolite was not detected in the fetus, the AZT-monophosphate was detected in almost all fetal tissues examined. Our data indicate that AZT is rapidly converted to the glucuronide and monophosphate metabolites in the fetus after maternal infusion.

Animals↗
PubMed1995

Acute effects of physostigmine on complex operant behavior in rhesus monkeys.

The effects of physostigmine were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation [temporal response differentiation (TRD)], short-term memory [delayed matching-to-sample (DMTS)], motivation [progressive ratio (PR)], learning [incremental repeated acquisition (IRA)], and color and position discrimination [conditioned position responding (CPR)]. The endpoints monitored included percent task completed, response rate, and accuracy. Physostigmine sulphate (0.001-0.056 mg/kg) significantly decreased the percentage of task completed and response rate in each task at 0.03 and 0.056 mg/kg. Accuracy in the TRD task was significantly decreased at 0.03 and 0.056 mg/kg, whereas accuracy in the CPR and IRA tasks was significantly decreased only at 0.056 mg/kg. DMTS accuracy was not significantly affected at any dose tested. A significant increase in accuracy was noted in learning task performance at the 0.01 mg/kg dose, although only for one-lever response sequences. Performance enhancements were not seen in any other task. These results indicate that in monkeys, low doses of physostigmine may facilitate acquisition or learning of simple one-lever spatial tasks while not significantly altering the acquisition of similar but more complex tasks. Impaired task performance at high doses may be more reflective of cholinomimetic side effects (tremor and hypothermia) that affect response rate than a central or "cognitive" impairment.

Animals↗
PubMed1995

Acute behavioral effects of phencyclidine on rhesus monkey performance in an operant test battery.

The effects of phencyclidine (PCP; a noncompetitive NMDA antagonist) were assessed in rhesus monkeys using performance in an operant test battery (OTB) consisting of five food-reinforced tasks thought to engender responses dependent upon aspects of time estimation, short-term memory, motivation, learning, and color and position discrimination. End-points included percent task completed (PTC), response rate or latency, and response accuracy. Testing occurred 15 min after IV injections of PCP (0.00, 0.003, 0.01, 0.03, 0.1, 0.13, 0.18, and 0.3 mg/kg). PCP disrupted performance of all tasks at 0.30 mg/kg. PTC was significantly decreased in the time estimation, motivation, and learning tasks at doses > or = 0.13 mg/kg. PTC for the short-term memory and color and position discrimination tasks was significantly decreased at 0.18 mg/kg and above. Response rate was significantly decreased at 0.13 mg/kg and above in the motivation and learning tasks and at 0.18 mg/kg and above in the time estimation, short-term memory, and color and position discrimination tasks. Response accuracy was significantly decreased in the time estimation, short-term memory, and learning tasks at doses > or = 0.13 mg/kg, while accuracy in the color and position discrimination task was decreased only at 0.30 mg/kg. PCP's effects on OTB performance were generally nonspecific, in that the time estimation, short-term memory, learning, and motivation tasks were all equally sensitive, with the color and position discrimination task being the least sensitive. These results are different than those obtained from earlier studies on the effects of MK-801, a more selective noncompetitive NMDA antagonist.

Animals↗
PubMed1994

Acute behavioral effects of MK-801 in rhesus monkeys: assessment using an operant test battery.

The acute effects of MK-801, a selective, noncompetitive NMDA receptor antagonist, were assessed using an operant test battery (OTB) of complex food-reinforced tasks that are thought to depend upon relatively specific brain functions such as motivation to work for food (progressive ratio, PR), learning (incremental repeated acquisition, IRA), color and position discrimination (conditioned position responding, CPR), time estimation (temporal response differentiation, TRD), and short-term memory and attention (delayed matching-to-sample, DMTS). Endpoints included response rates (RR), accuracies (ACC), and percent task completed (PTC). MK-801 (0.003-0.075 mg/kg, IV), given 15 min pretesting, produced significant dose-dependent decreases in measures of IRA and TRD performance at doses > or = 0.03 mg/kg. In both tasks, MK-801 produced significant decreases in accuracy at doses lower than those required to affect response rate. MK-801 also produced statistically significant decreases in PR, CPR, and DMTS measures, but only at higher doses (> or = 0.056 mg/kg) that caused significant decreases in both response rates and accuracies. These results indicate that, in monkeys, performance of operant tasks designed to model learning and time estimation is more sensitive to the disruptive effects of MK-801 than performance of tasks that model motivation, color, and position discrimination, and short-term memory and attention.

Animals↗
PubMed1993

Acute effects of caffeine on several operant behaviors in rhesus monkeys.

The acute effects of 1,3-trimethylxanthine (caffeine) were assessed using an operant test battery (OTB) of complex food-reinforced tasks that are thought to depend upon relatively specific brain functions, such as motivation to work for food (progressive ratio, PR), learning (incremental repeated acquisition, IRA), color and position discrimination (conditioned position responding, CPR), time estimation (temporal response differentiation, TRD), and short-term memory and attention (delayed matching-to-sample, DMTS). Endpoints included response rates (RR), accuracies (ACC), and percent task completed (PTC). Caffeine sulfate (0.175-20.0 mg/kg, IV), given 15 min pretesting, produced significant dose-dependent decreases in TRD percent task completed and accuracy at doses > or = 5.6 mg/kg. Caffeine produced no systematic effects on either DMTS or PR responding, but low doses tended to enhance performance in both IRA and CPR tasks. Thus, in monkeys, performance of an operant task designed to model time estimation is more sensitive to the disruptive effects of caffeine than is performance of the other tasks in the OTB.

Animals↗
PubMed1992

Effects of atropine on operant test battery performance in rhesus monkeys.

The acute behavioral effects of atropine sulfate were assessed using a battery of complex food-reinforced operant tasks that included: temporal response differentiation (TRD, n = 7); delayed matching-to-sample (DMTS, n = 6), progressive ratio (PR, n = 8), incremental repeated acquisition (IRA, n = 8), and conditioned position responding (CPR, n = 8). Performance in these tasks is thought to depend primarily upon specific brain functions such as time perception, short-term memory and attention, motivation, learning, and color and position discrimination, respectively. Atropine sulfate (0.01-0.56 mg/kg iv), given 15-min pretesting, produced significant dose-dependent decreases in the number of reinforcers obtained in all tasks. Response rates decreased significantly at greater than or equal to 0.03 mg/kg for the learning and discrimination tasks, at greater than or equal to 0.10 mg/kg for the motivation and short-term memory and attention tasks, and at greater than or equal to 0.30 mg/kg for the time perception task. Response accuracies were significantly decreased at doses greater than or equal to 0.10 mg/kg for the learning, discrimination, and short-term memory and attention tasks, and at greater than or equal to 0.30 mg/kg for the time perception task. Thus, the order of task sensitivity to any disruption by atropine is learning = color and position discrimination greater than time perception = short-term memory and attention = motivation (IRA = CPR greater than TRD = DMTS = PR). Thus in monkeys, the rates of responding in operant tasks designed to model learning and color and position discrimination were the most sensitive measures to atropine's behavioral effects. Accuracy in these same task was also disrupted but at higher doses. These data support the hypothesis that cholinergic systems play a greater role in the speed (but not accuracy) of performance of our learning and discrimination tasks compared to all other tasks. Accuracy of responding in these and the short-term memory task, all of which involve the use of lights as visual stimuli, was more sensitive to disruption by atropine than those tasks which did not utilize such strong visual stimuli.

Animals↗
PubMedDate not supplied

Acute effects of methylenedioxymethamphetamine (MDMA) on several complex brain functions in monkeys.

The effects of MDMA were assessed in rhesus macaques using behavior in an operant test battery (OTB) consisting of five food-reinforced tasks designed to model aspects of time estimation, short-term memory, and attention, motivation, learning, and color and position discrimination. Testing occurred 30 min after intramuscular, injections of MDMA (0.0, 0.1, 0.3, and 1.0 mg/kg). The behavioral endpoints monitored included percent task completed, response rate or latency, and response accuracy. Percent task completed was significantly decreased in the time estimation, learning, and motivation tasks at 1.0 mg/kg as compared to saline controls. Response accuracies in the time estimation and learning tasks were also decreased at 1.0 mg/kg. Response rate was decreased at 1.0 mg/kg in the motivation task but was not significantly affected in any other tasks. No behavioral endpoints were significantly affected in the short-term memory and attention and color and position discrimination tasks at any dose tested. Results indicate that time estimation, motivation, and learning are more sensitive to the acute effects of MDMA than are short-term memory and attention and color and position discrimination.

Animals↗
PubMedDate not supplied

Pharmacokinetics of cocaine in pregnant and nonpregnant rhesus monkeys.

To determine pharmacokinetic parameters for cocaine in rhesus monkey plasma, samples were taken over several hours after i.m. administration of cocaine plus a tritiated cocaine tracer. Cocaine and its metabolites, benzoylecgonine and norcocaine, were isolated via HPLC and quantitated using liquid scintillation spectrometry. Pregnant subjects were dosed with cocaine at 0.3 (n = 3) or 1.0 (n = 3) mg/kg, whereas nonpregnant female subjects were dosed with 1.0 mg/kg (n = 3). For the pregnant subjects, pharmacokinetic studies were conducted on about gestational day 125 and areas under the concentration versus time curve (AUCs, ng/mL x h) were 64 +/- 26 (+/- SEM) and 143 +/- 12; half-lives (t1/2s, h) were 1.9 +/- 0.6 and 1.1 +/- 0.1 after 0.3 and 1.0 mg/kg i.m., respectively. For nonpregnant subjects dosed acutely with 1.0 mg/kg, the AUC was 262 +/- 63 and the t1/2 was 1.4 +/- 0.3. There appear to be few differences in the pharmacokinetic parameters of cocaine and benzoylecgonine between pregnant and nonpregnant monkeys in this study.

Animals↗