Concerns about possible drug interactions.
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Animals↗
Biomedical subjects
G Davidson
Publications and source records attributed to G Davidson.
Differential regulation of melatonin receptors in sheep, chicken and lizard brains by cholera and pertussis toxins and guanine nucleotides.
G-proteins define both the pharmacological characteristics and the signalling pathways of G-protein-coupled receptors. Melatonin receptors have been shown to belong to this class of receptors through their sensitivity to modulators of G-protein function. This study reveals that 2-125I-iodomelatonin (125I-MEL) binding to different target tissues is differentially affected by agents which disrupt the G-protein cycle. GTP gamma S, pertussis (PTX) and cholera (CTX) toxins each reduce 125I-MEL binding to ovine pars tuberalis (oPT) and lizard brain membranes, whereas chicken brain is affected only by GTP gamma S (guanosine 5'-O-(3-thiotriphosphate)) and CTX. In contrast, high affinity binding of 125I-MEL in the ovine hippocampus was not affected by any of these agents. This finding, together with the fact that neural binding sites of the sheep brain were found to have markedly lower molecular mass than those of the oPT on native gel electrophoresis (365 vs 525 kDa), suggests that the neural 125I-MEL binding sites in sheep may not be G-protein coupled. Pharmacologically, however, the binding sites in the hippocampus and oPT could not be distinguished using 11 analogues of melatonin. Therefore, these data support the notion not only of multiple forms of melatonin receptor/G-protein complex, but of high affinity binding sites for 125I-MEL which do not display sensitivity to guanine nucleotides.
Animals↗
Intraluminal micromanometry: an evaluation of the dynamic performance of micro-extrusions and sleeve sensors.
Conventional manometric techniques are unsuitable for studies in premature infants and small laboratory animals. We have therefore developed silicone rubber 5-lumen and 10-lumen micromanometric extrusions with an o.d. 2.0 mm and lumina of 0.35 mm i.d. This study evaluates the suitability of microextrusions for intraluminal perfusion manometry. Pressure offset, post-occlusion pressure rise rate and sphincter model studies were used to assess the manometric performance of the extrusions and a miniature sleeve sensor (25 mm long) at infusion rates of 0.01-0.1 mL min-1. Micro-extrusions (5-lumen/10-lumen, respectively) had offsets (per 100 cm of length) of 3.8/5.0 mmHg at 0.01 mL min-1 and 25.6/26.2 mmHg at 0.1 mL min-1 and rise rates (in 160 cm lengths) of 64/43 mmHg sec-1 at 0.01 mL min-1 and 330/224 mmHg sec-1 at 0.1 mL min-1. Infusion rates 0.025 mL min-1 produced rise rates 100 mmHg sec-1. The miniature sleeve sensor had minimal resistance to perfusion, rise rates of 3 mmHg sec-1 at 0.01 mL min-1 and 23 mmHg sec-1 at 0.1 mL min-1 and recorded pressure as accurately as a side hole. We conclude that the performance of micromanometric extrusions and sleeves is sufficient for intraluminal perfusion manometry.
Animals↗
Low blood pressure in Down's syndrome, A link with Alzheimer's disease?
Low blood pressure is reported in Down's syndrome (DS). To assess this and determine whether low pressure results from the disease or from long-term residence in hospital, we measured blood pressure with a random-zero sphygmomanometer in three groups of patients: 52 DS inpatients, 62 DS outpatients, and 60 outpatients with other forms of mental handicap. Relative to normal reference populations, blood pressure was low in both DS inpatients (systolic, score -33 mm Hg, P < .0001) and DS outpatients (-25 mm Hg, P < .0001). It was normal in non-DS outpatients (-4.0 mm Hg, P = .3). Blood pressure rose normally with age in the non-DS group but not in the DS group. We conclude that blood pressure is low in DS and that this is a feature of the disease rather than of the protected environment in which patients live. A mechanism related to trisomy 21 is likely, and there may be a link with Alzheimer's disease (AD) because blood pressure is also low in Alzheimer's and a high proportion of Ds patients develop this disease. If, as is likely, blood pressure is lowered in Alzheimer's by the neuropathy, the same neuropathy developing early in DS may also reduce blood pressure.
Adult↗
Regulation of the Mel 1a melatonin receptor mRNA and protein levels in the ovine pars tuberalis: evidence for a cyclic adenosine 3',5'-monophosphate-independent Mel 1a receptor coupling and an autoregulatory mechanism of expression.
The Mel 1a receptor gene has recently been cloned and sequenced, and its product has been found to represent a new class of the G protein-coupled receptor superfamily. A unique aspect of its endogenous hormonal ligand, melatonin, is the prolonged duration (16 h) required to initiate appropriate photoperiodic responses in the animal. This study provides the first data on the transcriptional and translational regulation of this receptor in primary cultures of its native tissue, the pars tuberalis of the ovine pituitary. Using RNAse protection assays we show Mel 1a mRNA expression is rapidly induced through changes in intracellular cAMP levels. Forskolin enhances Mel 1a mRNA expression, whereas melatonin reverses this effect. RNA stability is also a factor, as Mel 1a mRNA expression decreases rapidly in the presence of actinomycin D. Although the expression of receptor protein is sensitive to forskolin stimulation, the lag between induction of mRNA and protein suggests that other factors (e.g. RNA splicing) contribute to functional receptor expression. Furthermore we observed that both mRNA and receptor protein levels increase spontaneously during primary culture, and these rises could be blocked by melatonin. A spontaneous rise in Mel 1a mRNA can also occur in serum-depleted cultures. In the absence of corresponding changes in cAMP, these results suggest not only that the Mel 1a receptor can autoregulate its own expression by an undefined pathway, but also they provide the first evidence that melatonin can act via a cAMP-independent signal transduction pathway to repress transcription in this tissue.
Animals↗
Rapid and simultaneous quantification of rhamnose, mannitol, and lactulose in urine by HPLC for estimating intestinal permeability in pediatric practice.
Determination of intestinal permeability by measuring nonmetabolized sugars has been used to assess the integrity of intestinal mucosa. We have developed and validated a modified HPLC method for determining the concentration of L-rhamnose, mannitol, and lactulose in urine, using an amine-modified silica column and refractive index detection. Probe sugars are simultaneously resolved within 18 min. The calibration curve for each sugar is linear to 20 mmol/L. The minimum detectable concentration of lactulose is 0.05 mmol/L. Recovery of probe sugars is between 99.3% and 105.1%. Overall precision (CV) of estimation of probe sugars ranges from 4.2% to 6.5%. In 14 urine samples from healthy children who ingested the test solution containing 1 g of L-rhamnose, 1 g of mannitol, and 5 g of lactulose, the 5-h urinary excretion ratios of lactulose/rhamnose and lactulose/mannitol were 0.047 +/- 0.018 and 0.021 +/- 0.010 (mean +/- SD), respectively. This method presents a rapid, convenient, and practical technique for determining intestinal permeability in clinical pediatric practice.
Adolescent↗
Esophageal body and lower esophageal sphincter function in healthy premature infants.
BACKGROUND & AIMS: Gastroesophageal reflux is a common problem in premature infants. The aim of this study was to use a novel manometric technique to measure esophageal body and lower esophageal sphincter pressures in premature infants. METHODS: Micromanometric feeding assemblies (OD, < or = 2 mm) incorporating 4-9 manometric channels were used in 49 studies of 27 premature neonates. Esophageal body motility was recorded at three sites for 20 minutes after feeding. Twenty attempts (one per minute) were made to stimulate swallowing via facial stimulation (Santmyer reflex). In 32 studies lower esophageal sphincter pressures were recorded (sleeve) for 15 minutes before and after feeding. RESULTS: Peristaltic motor patterns were less common than non-peristaltic motor patterns (26.6% vs. 73.4%; P < 0.0001) that comprised 31.1% synchronous, 34.6% incomplete, and 6.3% retrograde pressure waves. Reflex swallowing was elicited more frequently in neonates older than 34 weeks postconceptional age than in younger infants (33.4% vs. 20.4%; P < 0.05). Mean lower esophageal sphincter pressure was 20.5 +/- 1.7 mm Hg before and 13.7 +/- 1.3 mm Hg after feeding (P < 0.0005). CONCLUSIONS: Premature infants show nonperistaltic esophageal motility that may contribute to poor clearance of refluxed material. In contrast, the lower esophageal sphincter mechanisms seem well developed.
Deglutition↗
Autoimmune enteropathy with anti-goblet cell antibodies.
A 9-year-old boy with a 5-year history of severe protracted diarrhea requiring home parenteral nutrition and a 1 year history of abnormal liver function tests was admitted for duodenal, rectal, and liver biopsy. Duodenal biopsy results showed mild villus blunting, a mild lymphocytic infiltrate, and absent goblet cells. Paneth cells and endocrine cells could not be identified. Review of several previous biopsies showed an almost total absence of goblet cells by light microscopy. Anti-goblet cell antibodies of the immunoglobulin (Ig)G class were shown by immunofluorescence with a titer of 1:512. Histological examination of rectal mucosa also showed a total lack of goblet cells, orderly surface epithelial cells, and infiltration of the colonic crypts by lymphocytes. Immunoperoxidase staining of rectal mucosa showed increased numbers of lymphocytes with an excess of CD3+, CD45RO+ T cells, and increased numbers of B cells labeling with B1 and L26. Increased numbers of CD25+ (activated) lymphocytes were also observed. HLA/DR expression was striking and observed in both the crypt and surface enterocytes, as well as in the lamina propria. Immunological assessment of the patient showed an inverted CD4/CD8 ratio and IgA/IgG4 deficiency. The liver biopsy and radiological investigation were in keeping with chronic sclerosing cholangitis. Although a slight and transient improvement in histological appearances was observed with prednisolone there was no significant improvement of diarrhea. Trials of azothiaprine and oral cyclosporin did not result in clinical or histological improvement.
Autoantibodies↗
Melatonin receptors couple through a cholera toxin-sensitive mechanism to inhibit cyclic AMP in the ovine pituitary.
The nature of melatonin receptor-G-protein coupling in ovine pars tuberalis (PT) cells of the pituitary was addressed using cholera (CTX) and pertussis (PTX) toxins. ADP-ribosylation of ovine PT membrane proteins using 32P-NAD in the presence of CTX radiolabelled several substrates including 44, 51, and 60 kD proteins. Each were clearly distinct from the 40 kD substrate radiolabelled in the presence of PTX. Acute incubation of PT membranes with either toxin reduced the number of high affinity binding sites for 125I-MEL, although the magnitude of the inhibition was much greater for CTX (56%) than for PTX (20%). A CTX-sensitive component also mediates the inhibition of forskolin-stimulated cyclic AMP accumulation as pre-treatment of PT cells with CTX (5 micrograms/ml) for 16 h blocked this response. Gs alpha is a major substrate for ADP-ribosylation by CTX, and 16 h pre-treatment of PT cells with CTX (5 micrograms/ml) caused a down-regulation of Gs alpha. Northern analysis showed only one major transcript of Gs alpha of about 2 kb, which would encompass all of the known splice variants of the Gs gene. Screening of a cDNA library from ovine PT for Gs-related genes and sequencing of clones, combined with RT-PCR of PT mRNA, revealed no novel products. On this basis it is concluded that the CTX substrate is unlikely to be a novel splice variant or related gene product of the Gs class of G-protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Diphosphate Ribose↗
Phospholipases and melatonin signal transduction in the ovine pars tuberalis.
The potential role of phospholipases in mediating melatonin-dependent inhibition of adenylyl cyclase was investigated in pars tuberalis (PT) cultures. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated the release of choline metabolites and increased the transphosphatidylation reaction. The calcium ionophore A23187 stimulated the release of arachidonic acid from cultures. These observations demonstrate phospholipase A and D activities within PT. Phosphatidic acid inhibited forskolin-stimulated production of cyclic AMP both in PT cells and in membrane preparations. This indicates that melatonin could inhibit adenylyl cyclase by increasing phosphatidic acid levels through activation of cellular phospholipases. Melatonin did not stimulate the release of arachidonic acid or choline from PT cultures, nor did it increase intracellular levels of hydrophobic second messengers or stimulate transphosphatidylation. Therefore melatonin does not stimulate phospholipase A and D pathways in PT cells. However, these pathways are present in the PT and their activation could potentially modulate the cellular actions of melatonin.
Adenylyl Cyclases↗
Intervening in animal health care.
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Animals↗
p72, a marker protein for melatonin action in ovine pars tuberalis cells: its regulation by protein kinase A and protein kinase C and differential secretion relative to prolactin.
The function of the pars tuberalis as a mediator of the action of melatonin remains elusive. As a direct method of assessing the potential role of secretory proteins, ovine pars tuberalis cells have been cultured and radiolabelled with 35S-methionine, and the accumulation of specific radioactive products in the medium, measured after separation by SDS-PAGE and fluorography. The synthesis and secretion of a number of labelled proteins are increased by forskolin (1 microM) and inhibited dose dependently by melatonin (IC50, 300 pM), although consistently a 72-kD protein (p72), is the most intensely labelled of these. Thus, 72 acts as a useful marker of cellular activity for melatonin, whereas prolactin (p23) provides a melatonin non-responsive marker in ovine pars tuberalis cell cultures. The synthesis and secretion of p72 and other melatonin-sensitive proteins is regulated through the cyclic AMP/protein kinase A second-messenger pathway, as analogues of cyclic AMP mimic the action of forskolin, yet 1,9-dideoxyforskolin, a forskolin analogue that is not active on adenylate cyclase, has no effect. However, the phorbol ester, phorbol-12,13-myristate acetate, also regulates the synthesis and secretion of the same profile of proteins as forskolin indicating a potential role for protein kinase C, which occurs through an independent rather than a synergistic pathway. The differential effects of nocadazole (1 microM) and extracellular calcium depletion upon p72 and prolactin secretion indicates that p72 is secreted by a calcium and microtubule independent pathway, in contrast to prolactin. These observations in conjunction with the absence of dense-core storage vesicles in melatonin-responsive cells of the ovine PT are consistent with constitutive secretion of p72 from the latter and regulated secretion of prolactin from melatonin non-responsive cells. Using immunoprecipitation de novo synthesis and secretion of either LH or LH-like proteins from ovine pars tuberalis cells could not be detected under the conditions used. The absence of 125I-(Des-Gly10[D-Ala6]-LHRH-ethylamide) binding over most, but not all, of the ovine pars tuberalis supports the contention that the majority of the cells of the ovine pars tuberalis are not gonadotrophs. These results provide further support for the unique function for the pars tuberalis.
Animals↗
Cloning and expression of a new member of the melanocyte-stimulating hormone receptor family.
A new member of the G protein-coupled receptor superfamily has been isolated from an ovine genomic library with a probe generated by the application of the PCR technique, using cDNA synthesized on a mRNA template isolated from the ovine pars tuberalis. This genomic clone encodes a novel receptor of 325 amino acids with seven transmembrane domains. These domains share homology with other members of this family, but the best homology is with the recently cloned human MC-1 (50% in the transmembrane domains) and MC-3 (69% in the transmembrane domains) MSH receptors and the human ACTH (42% in the transmembrane domains) receptor. When this receptor was expressed in Cos7 cells, it was able to bind a potent analogue of alpha-MSH, [Nle4,D-Phe7]-alpha-MSH (NDP-MSH), with high affinity. This binding could be displaced by pro-opiomelanocortin-derived and related peptides, with the order of potency NDP-MSH > alpha-MSH = ACTH > beta-MSH and with no effect of gamma-MSH, delta-MSH or beta-endorphin. The expressed receptor was demonstrated to be functionally coupled to the adenylate cyclase second messenger pathway, with alpha-MSH, beta-MSH and ACTH stimulating cyclic AMP production. The amount of the mRNA for this receptor was found to be very low. The tissue distribution of this receptor could only be observed using the reverse transcription-PCR technique and the receptor was found to be present in a number of somatic tissues. These data indicate that this is a new and distinct member of the melanocortin receptor family.
Amino Acid Sequence↗
Necrosis in a meningioma following systemic chemotherapy. Case report.
Radiological and clinical evidence of acute necrosis in a meningioma following one cycle of chemotherapy with 5-fluorouracil, folinic acid, and levamisole was observed in a patient being treated for invasive rectal carcinoma. The possible mechanisms and implications of this occurrence are discussed.
Adenocarcinoma↗
Administration of total parenteral nutrition in pigeons.
Venous access devices connected to jugular vein catheters were implanted SC in 2 groups of 6 White Carneau pigeons (Columba livia). Total parenteral nutrition (TPN), or a control solution (lactated Ringer's solution) was infused as a bolus 4 times daily. Physiologic, hematologic, and biochemical variables were monitored over 5 days. Complications in the TPN-treated pigeons included 8.7% weight loss during the 5-day trial, hyperglycemia for up to 90 minutes after infusion, and glucosuria after infusion. Control pigeons lost 1.3% of their body weight and did not become hyperglycemic or glucosuric after infusion. Hematocrit in both groups of pigeons decreased to a value slightly below published reference values for pigeons. Five pigeons developed venous thrombosis in the proximal part of the cranial vena cava. Results indicated that intermittent administration of TPN is possible in birds; however, further research is required to develop better techniques for administration of TPN solutions. Additionally, it is important to determine, more specifically, the caloric and nutrient requirements of pigeons under stress and receiving TPN.
Animals↗
Intracranial arterial occlusion associated with high-activity iodine-125 brachytherapy for glioblastoma.
We describe two patients who developed devastating strokes due to intracranial arterial occlusion 15 weeks and 97 weeks following high dose stereotactic iodine-125 brachytherapy for glioblastoma multiforme. In both cases the occlusion was within the implant volume at points receiving 110-281 Gy and there was no other evidence of significant atherosclerosis in the patients. We therefore conclude that these complications were a direct result of the brachytherapy. The phenomenon of radiation-induced occlusion of large cerebral arteries is reviewed.
Arterial Occlusive Diseases↗
Relationship of maternal substance abuse to subsequent sudden infant death syndrome in offspring.
To assess the possible relationship between maternal drug use during pregnancy and subsequent sudden infant death syndrome (SIDS), we identified 1760 cases of SIDS from a population of more than 1.2 million infants (1.45/1000) born in New York City between 1979 and 1989. The SIDS rate in drug-exposed infants was 5.83 per 1000 infants, compared with 1.39 per 1000 infants who were not drug exposed. With control for known associated high-risk variables, the risk ratio for SIDS in each individual drug group (methadone, 3.6; heroin, 2.3; methadone and heroin, 3.2; cocaine, 1.6; cocaine and methadone or heroin, 1.1) was higher than in the non-drug-exposed group. Higher rates of SIDS were found in infants exposed to opiates alone than in cocaine-exposed infants, but increasing rates of SIDS in cocaine-exposed infants toward the end of the decade suggested that "crack" cocaine may be linked to these increasing rates. Declines in the overall rate of SIDS during the decade were observed for both the drug-exposed (11.28 to 4.09 per 1000) and the nonexposed groups (1.70 to 1.05 per 1000). Differences in rates of SIDS between major racial-ethnic groups in nonexposed infants were not apparent if the mothers used drugs during pregnancy. Seasonal variation and distribution of ages at time of SIDS death did not differ between the drug-exposed group and the nonexposed group, suggesting that drug-associated SIDS may provide clues as to the cause or causes of SIDS.
Adult↗
Deferoxamine attenuates ischemia-induced reperfusion injury in the skin and muscle of myocutaneous flaps in the pig.
The dose effect of deferoxamine treatment in attenuation of ischemia-induced reperfusion injury in the skin and muscle of latissimus dorsi myocutaneous flaps was studied in pigs weighing 19.7 +/- 0.5 kg. The latissimus dorsi myocutaneous flaps were subjected to 4, 6, or 8 hours of warm global ischemia. The length and area of viable and nonviable skin and muscle were assessed 48 hours after the ischemic insult by using the fluorescein and nitroblue tetrazolium dye tests, respectively. It was observed that perioperative deferoxamine treatment (250 mg/kg IV) was effective (p < 0.05) in attenuation of ischemia-induced reperfusion injury in the skin but not in the muscle of latissimus dorsi myocutaneous flaps subjected to 4, 6, or 8 hours (n = 10) of ischemia compared with the saline-treated control (n = 10). In a separate study, it was observed that preoperative deferoxamine treatment (250 mg/kg per day x 2 days, IM) plus perioperative deferoxamine treatment (250 mg/kg IV) was effective (p < 0.05) in attenuation of muscle ischemia-induced reperfusion injury in latissimus dorsi myocutaneous flaps subjected to 4 hours of ischemia and 48 hours of reperfusion (n = 10) compared with the saline treated control (n = 10). Morphologic studies with light and electron microscopy also provided evidence to indicate that preoperative plus perioperative deferoxamine treatment, but not perioperative deferoxamine treatment alone, remarkably reduced ischemia-induced reperfusion injury in the skeletal muscle of latissimus dorsi myocutaneous flaps compared with the saline-treated control. It is concluded that deferoxamine is effective in the attenuation of ischemia-induced reperfusion injury in the skin and muscle of pig latissimus dorsi myocutaneous flaps, but a longer period and/or higher dose of deferoxamine treatment is required for the muscle than for the skin. The pharmacologic actions and metabolism of deferoxamine relating to mitigation of ischemia-induced reperfusion injury in the pig skin and muscle are discussed.
Animals↗