Biomedical subjects

T J McDonald

Publications and source records attributed to T J McDonald.

At least 19 recordsLinked to original sources

PubMed2006

Fetal fornix transection and gestation length in sheep.

Experiments in several species indicate that the hippocampus influences hypothalamo-pituitary-adrenal (HPA) axis function. In fetal sheep, simultaneous ACTH and cortisol rises over the last 30 days of gestation peak at term and are necessary for birth. We hypothesized that if the fetal hippocampal formation is functional in late gestation, loss of hippocampal input to the HPA axis following fetal fornix transection would change gestation length in comparison to controls. At 118-121 days of gestation (dG), stereotaxic technique was used in fetal sheep to sham transect (SHAM; n = 8) or transect (FXTX; n = 6) the dorsal fornix at the level of the hippocampal commissure. No differences were found between SHAM and FXTX fetuses in daily hormone profiles over the last week of gestation or in gestation length (148.0 +/- 1.2 vs. 149.0 +/- 0.4 dG, respectively). We conclude that the fetal hippocampus is immature in late gestation and we speculate that an immature hippocampus is necessary for the loss of negative feedback control that gives rise to the long term, simultaneous increases in ACTH and cortisol that are indispensable for labor and delivery at term in sheep.

Acetylcholinesterase↗

PubMed2006

Effect of 30 per cent maternal nutrient restriction from 0.16 to 0.5 gestation on fetal baboon kidney gene expression.

Previous studies in rodents and sheep show that maternal nutrient restriction during pregnancy alters fetal renal development. To date, no studies using fetal baboon RNA with human Affymetrix gene chips have been published. In the present study we have (1) evaluated the specificity of the Affymetrix human gene array 'Laboratory on a Chip' system for use with fetal baboon mRNA and (2) investigated the effects of moderate maternal global nutrient restriction (NR; 70% of ad libitum animals) from early (30 days gestation (dG)) to mid-gestation (90 dG; term = 184 dG) on the fetal baboon kidney. Morphometric and blood measurements were made on 12 non-pregnant baboons before they were bred. All baboons were fed ad libitum until 30 days pregnant, at which time six control baboons continued to feed ad libitum (control - C) while six received 70% of the C diet on a weight adjusted basis. Fetal kidneys were collected following caesarean section at 90 dG, with samples flash frozen and fixed for histological assessment. Fetal hip circumference was decreased in the NR group (68 +/- 2 versus 75 +/- 2 mm), while fetal body weight and all other measurements of fetal size were not different between C and NR at 90 dG. Maternal body weight was decreased in the NR group (12.16 +/- 0.34 versus 13.73 +/- 0.55 kg). Having established the specificity of the Affymetrix system for fetal baboon mRNA, gene expression profiling of fetal kidneys in the context of our maternal nutrient restriction protocol shows that NR resulted in a down-regulation of genes in pathways related to RNA, DNA and protein biosynthesis, metabolism and catabolism. In contrast, genes in cell signal transduction, communication and transport pathways were up-regulated in the NR group. These changes indicate that even a moderate level of maternal global NR impacts fetal renal gene pathways. Our histological assessment of renal structure indicates decreased tubule density within the cortex of NR kidneys compared with controls. The number of glomerular cross-sections per unit area were unaffected by NR, suggesting that tubule tortuosity and/or tubule length was decreased in the NR kidney. Taken together the changes indicate that NR results in accelerated fetal renal differentiation. The negative impact of poor maternal nutrition on the fetal kidney may therefore be in part due to shortening of critical phases of renal growth resulting in decreased functional capacity in later life. These findings may have important implications for postnatal renal function, thereby contributing to the observed increased predisposition to hypertension and renal disease in the offspring of nutrient restricted mothers.

Aging↗

PubMed2006

A pragmatic protocol for I-131 rhTSH-stimulated ablation therapy in patients with renal failure.

PURPOSE: Ablation of thyroid remnants in patients with differentiated thyroid carcinoma and renal failure can be challenging because of the altered and variable clearance rates of iodine from the blood secondary to variations in dialysis protocols, which complicate the selection of the appropriate I-131 dose. The advent of recombinant human TSH allows a simpler approach to dosimetry and ablation without rendering the patient hypothyroid. Avoidance of hypothyroidism may be an important consideration for patients who are experiencing various morbidities from conditions associated with renal failure. METHOD: Three patients on dialysis, who had undergone total thyroidectomy and were euthyroid on L-thyroxine replacement, were given diagnostic doses of I-131 followed by blood and whole-body retention measurements through serial dialyses to determine individual blood clearance rates. After administration of rhTSH, each patient received an ablative dose of I-131 calculated to keep total body dose below 1 Gy. RESULTS: The treatments were administered without complications, and in follow-up imaging of 2 available patients, the ablations were demonstrated to be complete. CONCLUSION: Dosimetry performed on euthyroid dialysis patients permits I-131 dose selection and avoids the additional morbidity of hypothyroidism.

Adult↗

PubMed2004

Partitioning and desorption behavior of polycyclic aromatic hydrocarbons from disparate sources.

Contaminated sediments pose a unique challenge for risk assessment or remediation because the overlying water column may transport contaminants offsite or to ecological receptors. This research compares the behavior of polycyclic aromatic hydrocarbons (PAHs) on marine sediments from two sites. The first site was affected by shipping activities and the second was impacted by a creosote seep. Organic carbon:water partitioning coefficients (Koc values) were measured with three solutions. Desorption was measured using Tenax beads. PAHs from the ship channel had lower Koc values than those from the creosote facility. For example, the average logKoc value of ship channel pyrene was significantly lower than that of creosote facility pyrene (4.39 +/- 0.35 and 5.29 +/- 0.09, respectively, when tested in 5 mM calcium chloride). These results were consistent with the greater desorption of pyrene, phenanthrene and benzo(a)pyrene from the ship channel than from the creosote facility sediments. Organic compound desorption from sediments can be considered to be a two-stage process, with a labile fraction that desorbs quickly and a refractory fraction that desorbs much more slowly. In both sediments, more than 75% of the benzo(a)pyrene was found to have partitioned into the refractory phase. The amounts of phenanthrene and pyrene that partitioned into the refractory phase were lower. Linear correlations of logKoc with log(CR/CL) (where CR and CL are the fractions of the compound in the refractory and labile phases, respectively, at time zero) showed that partitioning measurements made with the US EPA's Toxicity Characteristic Leaching Procedure fluid (US EPA, 1996) most closely matched predictions of desorption behavior. The data imply that with a larger data set, it may be possible to relate simple partitioning measurements to desorption behavior. Partitioning measurements were used to predict water concentrations. Despite having higher concentrations of carcinogenic PAHs [cPAHs, the seven PAHs categorized by the US EPA (2004) as class B2 carcinogens], creosote facility sediments were predicted to produce lower aqueous concentrations of cPAHs. These results indicate that both sediment and contaminant characteristics will impact contaminant release from sediments.

Adsorption↗

PubMed2004

Effect of betamethasone administration to the pregnant baboon at 0.75 gestation on placental eNOS distribution and activity.

Betamethasone is frequently administered to pregnant women at risk of premature labor to accelerate fetal lung maturation. Maternally administered betamethasone produces pronounced changes in the fetal peripheral vasculature, raises fetal blood pressure and produces fetal growth restriction. Endothelial nitric oxide synthase (eNOS) plays an important role in regulating vascular tone. We hypothesized that effects of betamethasone on the fetal vasculature include decreased eNOS activity. We determined a significant depression of total placental eNOS protein measured by ELISA (betamethasone treated vs control, 0.48 +/- 0.28 vs 1.57 +/- 0.45, p < 0.05) and immunohistochemistry in both syncytiotrophoblast and vascular endothelium. Following betamethasone exposure, eNOS mRNA and enzyme activity showed decreasing trends which were not statistically significant. eNOS protein was higher in the placentas of both control and betamethasone treated baboons in the presence of a female fetus compared with a male fetus. The same effect of the sex of the fetus was observed in the betamethasone group for eNOS mRNA. In conclusion, maternally administered betamethasone produces a consistent decrease in several indices of placental eNOS function that may play a role in the altered cardiovascular dynamics and fetal growth retardation produced by betamethasone administration in late pregnancy.

Animals↗

PubMed2004

Abdominal pregnancy in a baboon: a first case report.

The abdominal pregnancy is a rare, but life threatening complication of ectopic embryo implantation. Only three cases of abdominal pregnancy have been previously described in primates: in a squirrel monkey, owl monkey and in a rhesus macaque. A 14-year-old wild-caught olive baboon (Papio cynocephalus anubis) was diagnosed at the ultrasound examination with advanced gestational age extrauterine pregnancy. At the initial laparotomy and necropsy the diagnosis of abdominal pregnancy was made on Studdiford's criteria. This case indicates the possibility of developing a model for further study of different types of ectopic pregnancy and indicates a cesarean section as a risk factor for abdominal pregnancy.

Animals↗

PubMed2004

Normal concentrations of essential and toxic elements in pregnant baboons and fetuses (Papio species).

Heavy metals are essential for the normal progression of maternal and fetal tissue growth and metabolism in pregnancy. Considerable data have been collected for concentrations of various elements in pregnant women, but no comprehensive evaluation of element concentrations in any non-human primate model has been performed. Baboons were studied at the second half of pregnancy. Forty essential and toxic element concentrations were analyzed by absorption spectrophotometry in paired maternal and fetal blood samples; hair and nail samples in pregnant baboons; in placenta, amniotic fluid; and fetal femur, lymph nodes, and liver. Concentrations demonstrated an excellent correlation with concentrations reported in late human pregnancy. Twenty-four elements were below detectable limits in various specimens. We conclude that the pregnant baboon offers unique opportunities to study both normal maternal, fetal, and placental physiology as well as the environmental toxicology of these elements. This information and the ability to use the pregnant baboon as a model is important because essential and toxic elements are key components of the diet as well as major products of manufacturing processes within our industrialized society.

Amniotic Fluid↗

PubMed2004

White monkey syndrome in infant baboons (Papio species).

Over 23 months, zinc toxicosis was diagnosed in 35 baboons aged 5-12 months in one galvanized metal and concrete cage complex with conditions that led to excessive exposure to environmental zinc. Clinical signs included reduced pigmentation of hair, skin, and mucous membranes (whiteness), alopecia, dehydration, emaciation, cachexia, dermatitis, diarrhea and, in six cases, severe gangrenous dermatitis of extremities. The syndrome was characterized by pancytopenia, elevated zinc and low copper serum concentrations, low vitamin D and bone-specific alkaline phosphatase levels, and atypical myelomonocytic proliferation of bone marrow. This syndrome emphasizes the importance of proper husbandry and cage design and indicates the potential of infant baboons as a model to study the effects of excessive zinc on development. This is the first report describing the epidemiologic and clinical presentation of zinc toxicosis in infant baboons in captivity.

Alopecia↗

PubMed2003

Connexin 43 ontogeny in fetal sheep adrenal glands.

We examined fetal sheep adrenal glands from 99 to 130 days of gestational age (dGA) to see how connexin 43 (Cx43), the major if not the only adult adrenal gap junction protein, changes expression as the adrenal cortex emerges from the well-documented refractory period to participate in labor and delivery. Immunocytochemical technique and Western blot were used to examine changes in the quantity and quality of Cx43. In addition, adrenal glands of ACTH infused fetuses or of fetuses from dexamethasone injected ewes underwent image analysis quantification after Cx43 immunostaining. Finally, fetal adrenal glands, from fetuses splanchnic nerve sectioned (SPLX) at 125 dGA, were examined for the pattern of Cx43 immunostaining at 131 days of gestation. From 100 to 130 dGA, the amount of Cx43 in cells of the adrenal cortex increased steadily while the pattern of immunoreactivity changed from predominantly cytoplasmic to membrane bound. At 100-103 dGA, ACTH infusion increased the size of the cortex, but decreased the expression of Cx43 per unit area while dexamethasone had no effect on either parameter. Lastly, the expression of Cx43 as a membrane bound protein was not delayed or reversed by SPLX. We conclude that the described changes in Cx43 are most intriguing given their temporal relationship to the described preparturient increases in ACTH and cortisol in peripheral fetal plasma as term approaches and deserve further investigation.

Adrenal Cortex↗

PubMed2003

Porous organoclay composite for the sorption of polycyclic aromatic hydrocarbons and pentachlorophenol from groundwater.

Complex mixtures of hazardous chemicals such as polycyclic aromatic hydrocarbons (PAHs) in contaminated soil and groundwater can have severe and long-lasting effects on health. The evidence that these contaminants can cause adverse health effects in animals and humans is rapidly expanding. The frequent and wide-spread occurrence of PAHs in groundwater makes appropriate intervention strategies for their remediation highly desirable. The core objective of this research was to assess the ability of a clay-based composite to sorb and remove toxic contaminants from groundwater at a wood-preserving chemical waste site. Treatment efficiencies were evaluated using either effluent from an oil-water separator (OWS) or a bioreactor (B2). The effluent water from these units was passed through fixed bed columns containing either an organoclay composite or granular activated carbon. The sorbent columns were placed in-line using existing sampling ports at the effluent of the OWS or B2. Individual one-liter samples of treated and untreated effluent were collected in Kimax bottles over the course of 78 h (total of 50 samples). Subsequently each sample was extracted by solid phase extraction methodology, and pentachlorophenol (PCP) and PAH concentrations were quantitated via GC/MS. Columns containing porous organoclay composite, i.e. sand-immobilized cetylpyridinium-exchanged low-pH montmorillonite clay (CP/LPHM), were shown to reduce the contaminant load from the OWS effluent stream by 97%. The concentrations of benzo[a]pyrene (BaP) and PCP were considerably reduced (i.e. >99%). An effluent stream from the bioreactor was also filtered through columns packed with composite or an equivalent amount of GAC. Although the composite reduced the majority of contaminants (including BaP and PCP), it was less effective in diminishing the levels of lower ring versus higher ring PAHs. Conversely, GAC was more effective in removing the lower ring PAHs, except for naphthalene and PCP. The effectiveness of sorption of PCP from the OWS effluent by the composite was confirmed using a PCP-sensitive adult hydra bioassay previously described in our laboratory. The findings of this initial study have delineated differences between CP/LPHM and GAC for groundwater remediation, and suggest that GAC (instead of sand) as the solid support for organoclay may be more effective for the treatment of contaminated groundwater under field conditions than GAC or CP/LPHM alone. Further work is ongoing to confirm this conclusion.

Adsorption↗

PubMed2003

Betamethasone in the last week of pregnancy causes fetal growth retardation but not adult hypertension in rats.

We tested the hypotheses that (1) maternal betamethasone (betaM) treatment over the range of clinical doses for prevention of prematurity-related pathologies from day 15 to 21 of rat gestation would produce growth retardation, and (2) the lowest betaM dose to produce growth retardation would result in hypertension in adult offspring. In experiment 1, pregnant Sprague-Dawley rats were administered betaM (0, 50, 100, 200, 400, or 600 microg/kg per day, subcutaneously) on days 15-21 of pregnancy and necropsied on day 21.5, with fetal lung and placental weights recorded. In experiment 2, two more groups of rats (0 or 100 microg/kg per day, subcutaneously) were allowed to deliver, and offspring were instrumented at 100 +/- 4 days of postnatal life with indwelling left carotid arterial catheters. After 48 hours of recovery, blood pressure was recorded continuously for 24 hours. In experiment 1, all newborn rats treated with betaM, and their placentas, except those receiving 50 microg/kg per day, were growth retarded in comparison with controls (P <.05). All treated lungs were smaller than those of controls (P <.05). In experiment 2, no differences were found in the mean arterial blood pressure of adult offspring given the lowest effective dose of betaM (100 microg/kg per day) compared with controls (114.2 +/- 5.3 mmHg versus 114.6 +/- 3.4 mmHg, respectively). These data suggest that glucocorticoids given in the last week of rat pregnancy in the lowest human clinical dose do not cause hypertension and somatic growth retardation. However, the presence of lung growth restriction at this dose argues for more studies on the efficacy of even lower concentrations for their ability to improve lung and other organ and tissue function while avoiding unwanted side effects.

Animals↗

PubMed2002

Local, exendin-(9-39)-insensitive, site of action of GLP-1 in canine ileum.

Glucagon-like peptide-1 (GLP-1) modulates glucose levels following a meal, including by inhibition of gastric emptying and intestinal transport. Intra-arterial injection of GLP-1 into the gastric corpus, antrum, or pylorus of anesthetized dogs had no effect on the contractile activity of the resting or neurally activated stomach. GLP-1 injected intra-arterially inhibited intestinal segments when activated by enteric nerve stimulation but not by acetylcholine. Isolated ileum segments were perfused intra-arterially, instrumented with strain gauges to record circular muscle activity and with subserosal electrodes to stimulate enteric nerves. GLP-1 caused concentration-dependent inhibition of nerve-stimulated phasic but not tonic activity. This was absent during TTX-induced activity and partly prevented by N(G)-nitro-L-arginine. Exendin-(9-39), the GLP-1 antagonist, had no intrinsic activity and did not affect the actions of GLP-1. Capsaicin mimicked the effects of GLP-1 and may have reduced the effect of subsequent GLP-1. GLP-1 may mediate paracrine action on afferent nerves in the canine ileal mucosa using an unusual receptor.

Animals↗

PubMed2002

Neonatal ovine adrenal cortical and medullary Cell H+ responses to ACTH and prostaglandin E(2).

The microphysiometric technique was used to evaluate 1- and 3-day-old lamb adrenal gland H+ production in response to ACTH or PGE(2). ACTH stimulated cortical, but not medullary H+ production; maximal H+ by combined cortical and medullary cells was greater than by cortical cells alone (p < 0.05). In contrast, the magnitude of the H+ response to PGE(2) was greater with medullary than with cortical cells alone or with cortical and medullary cells combined (p < 0.05). The H+ response to ACTH was greater in 3-day-old compared to 1-day-old lambs while the potency of PGE(2) was not different at the ages studied. We conclude that in neonatal sheep: (1) ACTH and PGE(2) are potentially important in adrenal regulation, and (2) paracrine communication appears to be functioning as has been shown for adults.

Adrenal Cortex↗

PubMed2001

Cerebrospinal fluid gastrin releasing peptide in the diagnosis of leptomeningeal metastases from small cell carcinoma.

BACKGROUND: The clinical diagnosis of leptomeningeal metastases is often difficult to substantiate. Patients with an underlying malignancy typically present with neurologic symptoms referable to multiple levels of the neuraxis. Although most patients have an abnormal cerebrospinal fluid (CSF), less than 60% have evidence of malignant cells on cytologic examination from a single lumbar puncture, and the disease is usually advanced in patients with positive results. An elevated serum level of gastrin releasing peptide (GRP) in patients with small cell carcinoma has emerged as one of the most useful markers for disease activity. METHODS: A patient with small cell carcinoma presented with signs of meningitis and an abnormal CSF. However, the CSF gave repeatedly negative cytologic results. Hence, serum and CSF were analyzed for GRP. RESULTS: The CSF GRP level was elevated by more than six orders of magnitude above the serum level. An autopsy demonstrated extensive meningeal and parenchymal brain involvement by small cell carcinoma. CONCLUSIONS: The diagnosis of leptomeningeal metastases in patients with small cell carcinoma can be established by CSF GRP testing, even when cytologic examination is negative.

Biomarkers, Tumor↗

PubMed2001

Evaluation of methods for predicting the toxicity of polycyclic aromatic hydrocarbon mixtures.

Risk assessments of polycyclic aromatic hydrocarbon mixtures are hindered by a lack of reliable information on the potency of both mixtures and their individual components. This paper examines methods for approximating the toxicity of polycyclic aromatic hydrocarbon (PAH) mixtures. PAHs were isolated from a coal tar and then separated by ring number using HPLC. Five fractions (A-E) were generated, each possessing a unique composition and expected potency. The toxicity of each fraction was measured in the Salmonella/mutagenicity assay and the Chick Embryo Screening Test (CHEST). Their abilities to induce ethoxyresorufin-O-deethylase and to inhibit gap junction intercellular communication in rat liver Clone 9 cells were also measured. In the Salmonella/mutagenicity assay, fractions were predicted to have potencies in the order C > D > E > B > A. Toxic equivalency factors (TEFs) for fractions A-E were in the order E > or = D > C > B > A. TEF values were 20,652, 20,929, 441, 306, and 74.1 micrograms of BaP equiv/g, respectively. A lack of agreement between assay-predicted potencies and chemical analysis-predicted potencies was observed with other assays and other methods of calculation. The results demonstrate the limitations of using a single method to predict the toxicity of a complex PAH mixture.

Animals↗

PubMed2001

Impacts of aging on in vivo and in vitro measurements of soil-bound polycyclic aromatic hydrocarbon availability.

Ingestion of contaminated soil is an exposure pathway at approximately one-half of the Superfund sites in the United States. This study was designed to evaluate the impacts of aging in soil on the availability of polycyclic aromatic hydrocarbons (PAHs). Two coal tar (CT)-amended soils were prepared. One was aged for 270 days and the other was not aged. Both of these treatments were incorporated into pellets and fed to male Fischer 344 rats. Excretion of 1-hydroxypyrene (1-OHP) in urine and PAH concentrations in the liver were monitored as end points. Additionally, soil:water partitioning and desorption were measured as comparisons to the in vivo results. After 5 days of ingesting their respective treatments, rats in the aged soil group excreted 4.41 +/- 1.67 ppm 1-OHP/mg of pyrene ingested while rats in the unaged soil group excreted 5.27 +/- 1.37 ppm/mg of pyrene ingested. Animals fed aged CT soil had 0.051 +/- 0.011 ppm carcinogenic PAHs in livers/mg ingested while rats fed unaged CT soil had 0.063 +/- 0.037 ppm carcinogenic PAHs in livers/mg ingested. Partitioning and desorption results revealed a similar results. These results indicate that, at high application rates, soil contact time may not play as significant a role in determining availability as simple dispersion and sorption on soil.

Animals↗

PubMed2001

Open trial of methotrexate as treatment for autoimmune hearing loss.

OBJECTIVE: To assess the efficacy of low-dose methotrexate (MTX) administered for the treatment of autoimmune hearing loss. METHODS: This was a prospective, 12-month, open-label study of 17 patients with refractory autoimmune hearing loss. All patients had ongoing episodic worsening of hearing in one or both ears prior to enrollment despite traditional medical therapy. The MTX dose was 7.5-25 mg/week. Hearing loss and vertigo were evaluated at baseline and at completion of the study. Hearing improvement was defined as an improvement in pure tone threshold (PT) average of >10 dB or an increase in speech discrimination (SD) of >15%; worsening was defined as a decrease of >10 dB in PT or a decrease of >15% in SD in at least one ear. RESULTS: MTX was well tolerated. Among patients with Meniere's disease, 5 of 9 had improvement or resolution of vertigo. Equilibrium improved in all 3 patients with Cogan's syndrome and improved in 2 out of 3 patients with idiopathic hearing loss and this symptom. According to the parameters defined above, hearing improved in 11 patients (65%), was unchanged in 4 patients (23%), and worsened in 2 patients (12%). CONCLUSION: Long-term low-dose MTX therapy may be a useful therapy for at least some patients who have hearing loss with a presumptively autoimmune-mediated component that is refractory to traditional therapies.

Adult↗

PubMed2001

Response of Wegener's granulomatosis to anti-CD20 chimeric monoclonal antibody therapy.

We report on the successful, compassionate use of the anti-CD20 chimeric monoclonal antibody rituximab in a patient with chronic, relapsing cytoplasmic antineutrophil cytoplasmic antibody (cANCA)-associated Wegener's granulomatosis (WG). The patient initially responded to treatment with glucocorticoids and cyclophosphamide. However, bone marrow toxicity during cyclophosphamide treatment of a relapse precluded its further use. Azathioprine and mycophenolate mofetil treatment had failed to maintain remission of the WG, and methotrexate was contraindicated. Because the patient's 5-year course was characterized by close correlation of cANCA levels with disease activity, selective elimination of cANCA was deemed a treatment option for his latest relapse. He was given 4 infusions of 375 mg/M2 of rituximab and high-dose glucocorticoids. Complete remission was associated with the disappearance of B lymphocytes and cANCA. Glucocorticoid treatment was then discontinued. After 11 months, the cANCA recurred, and rituximab therapy was repeated, without glucocorticoids. At 8 months after the second course of rituximab (18 months after the first course), the patient's WG has remained in complete remission. Elimination of B cells by rituximab therapy may prove to be an effective and safe new treatment modality for ANCA-associated vasculitis and possibly other autoimmune diseases. This modality warrants closer examination in a carefully conducted clinical trial.

Aged↗