Prevention of skin cancer in xeroderma pigmentosum: the physician as advocate.
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Child↗
Biomedical subjects
L J Roberts
Publications and source records attributed to L J Roberts.
Evidence for the existence of F2-isoprostane receptors on rat vascular smooth muscle cells.
The isoprostanes are nonenzymatically generated prostanoids synthesized in vivo in humans and rats through reactions catalyzed by free oxygen radicals. 8-Epi-prostaglandin F2 alpha (8-epi-PGF2 alpha), an F2-isoprostane, is a potent smooth muscle constrictor. A thromboxane A2 (TxA2) receptor antagonist, SQ 29548, blocks renal vasoconstriction during 8-epi-PGF2 alpha administration in rats. With the use of cultured rat aortic smooth muscle cells, we found specific binding sites for [3H]SQ 29548 and for [125I]BOP, a TxA2 agonist. Both ligands were displaced from these binding sites by 8-epi-PGF2 alpha, although with significantly lesser potency than nonlabeled SQ 29548, I-BOP, or U-46619, a TxA2 agonist. In contrast, 8-epi-PGF2 alpha stimulated inositol 1,4,5-trisphosphate production and DNA synthesis in these cells with significantly greater potency than any TxA2 agonist, effects only partially inhibited by SQ 29548. In human TxA2 receptor cDNA-transfected cells, competition by 8-epi-PGF2 alpha for specific [3H]SQ 29548 binding was negligible. Thus 8-epi-PGF2 alpha probably exerts its biological actions in vascular smooth muscle through activation of receptor sites related to but distinct from TxA2 receptors. The existence of such binding sites suggests novel avenues for investigation into the biology of TxA2 and of free radical-mediated tissue injury.
Animals↗
Airway and vascular effects of 8-epi-prostaglandin F2 alpha in isolated perfused rat lung.
The effects of 8-epi-prostaglandin (PG) F2 alpha, a recently discovered noncyclooxygenase free radical-catalyzed product of arachidonic acid, on pulmonary vascular and airway tone, its potency, and its mechanism of action were studied. Progressively increasing bolus doses (1.0, 5.0, 10.0, and 20.0 micrograms) of 8-epi-PGF2 alpha were injected into the pulmonary artery catheter of 18 isolated rat lungs, and a single dose (40.0 micrograms) was injected into 7 additional rat lungs. The lungs were perfused with Krebs-Henseleit buffer solution containing 3% bovine serum albumin at 50 ml.kg-1.min-1 during ventilation with 21% O2-5% CO2-74% N2. 8-Epi-PGF2 alpha caused rapid pulmonary vascular and airway constrictor responses, which were followed by a gradual return over 10 min to baseline levels. Double vascular occlusion at peak rise in pulmonary arterial pressure (Ppa) revealed a 28% increase in arterial resistance. The rise in Ppa with 20 micrograms of 8-epi-PGF2 alpha was approximately twofold greater than with 20 micrograms of the cyclooxygenase-derived prostaglandin PGF2 alpha. The addition of 100 microM N-nitro-L-arginine, a blocker of endothelium-derived relaxing factor, in the perfusate potentiated the rise in Ppa by 244%. Injection of 40 micrograms of rat atrial natriuretic factor at peak response to 20 micrograms of 8-epi-PGF2 alpha accelerated the return to baseline Ppa, resistance to airflow across the lung, and dynamic lung compliance values.(ABSTRACT TRUNCATED AT 250 WORDS)
Air Pressure↗
Collision-induced dissociation of F2-isoprostane-containing phospholipids.
Free radical-induced lipid peroxidation results in the production of metabolites of arachidonic acid isomeric with prostaglandin F2 alpha. The formation of these compounds, termed F2-isoprostanes, occurs independent of the enzyme cyclooxygenase. The discovery that F2-isoprostanes can exert potent biological activity has suggested that they may mediate, to some extent, the biological responses to oxidant injury. Collision-induced dissociation of the [M-CH3]- ions from oxidized phospholipids isolated by extraction and normal phase high performance liquid chromatography from livers of rats treated with CCl4 to induce lipid peroxidation revealed several molecular species of phospholipids that had the F2-isoprostane esterified to the glycerophosphocholine backbone. Collision-induced dissociation of the [M-CH2CHN(CH3)3]- ion revealed that the F2-isoprostanes were primarily esterified at the sn-2 position of the glycerophospholipid as expected. Furthermore, tandem mass spectrometry of the carboxylate anion from the F2-isoprostane (m/z 353) resulted in the unique loss of 44 u characteristic of a 1,2-cyclic diol moiety such as that found in the PGF2-ring. These observations indicate that intact phospholipids containing fatty acyl groups of the isoprostane structure can be readily detected with tandem mass spectrometry even when present as minor components in a biological extract. Although no specific isomer identification can be made from the complex mixture, these techniques establish the existence of these novel metabolites of arachidonic acid esterified to glycerophospholipids.
Animals↗
Non-cyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids.
We recently reported the discovery of a series of bioactive prostaglandin F2-like compounds (F2-isoprostanes) that are produced in vivo by free radical-catalyzed peroxidation of arachidonic acid independent of the cyclooxygenase enzyme. Inasmuch as phospholipids readily undergo peroxidation, we examined the possibility that F2-isoprostanes may be formed in situ on phospholipids. Initial support for this hypothesis was obtained by the finding that levels of free F2-isoprostanes measured after hydrolysis of lipids extracted from livers of rats treated with CCl4 to induce lipid peroxidation were more than 100-fold higher than levels in untreated animals. Further, increased levels of lipid-associated F2-isoprostanes in livers of CCl4-treated rats preceded the appearance of free compounds in the circulation, suggesting that the free compounds arose from hydrolysis of peroxidized lipids. This concept was supported by demonstrating that free F2-isoprostanes were released after incubation of lipid extracts with bee venom phospholipase A2 in vitro. When these lipid extracts were analyzed by HPLC, fractions that yielded large quantities of free F2-isoprostanes after hydrolysis eluted at a much more polar retention volume than nonoxidized phosphatidylcholine. Analysis of these polar lipids by fast atom bombardment mass spectrometry established that they were F2-isoprostane-containing species of phosphatidylcholine. Thus, unlike cyclooxygenase-derived prostanoids, F2-isoprostanes are initially formed in situ on phospholipids, from which they are subsequently released preformed, presumably by phospholipases. Molecular modeling of F2-isoprostane-containing phospholipids reveals them to be remarkably distorted molecules. Thus, the formation of these phospholipid species in lipid bilayers may contribute in an important way to alterations in fluidity and integrity of cellular membranes, well-known sequelae of oxidant injury.
Animals↗
A physiologic concept of exercise-induced pulmonary hemorrhage in horses.
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Animals↗
Effectively treating stimulant-abusing schizophrenics: mission impossible?
The development of effective treatment programs for dual diagnosis patients is in its initial stages, hampered by a variety of clinical, theoretical, administrative, and even sociopolitical obstacles. These patients are difficult to engage and treat effectively using standard systems of care. The Dual Diagnosis Treatment Program at the Brentwood VA Hospital integrates treatment for both stimulant abuse and chronic psychosis within one comprehensive program, emphasizing continuous treatment teams, optimal pharmacological management, behavior-shaping strategies, skills-training techniques, and assertive case management. The combination of these treatment approaches within one program appears to have helped some patients in our preliminary, one-year experience. Future publications will describe results from controlled outcome comparisons of DDTP with customary VA care.
Adult↗
The F2-isoprostane, 8-epi-prostaglandin F2 alpha, a potent agonist of the vascular thromboxane/endoperoxide receptor, is a platelet thromboxane/endoperoxide receptor antagonist.
F2-isoprostanes are a recently discovered series of prostaglandin (PG)F2-like compounds that are produced in vivo in humans by nonenzymatic free radical catalyzed peroxidation of arachidonic acid. One of the compounds that can be produced in abundance by this mechanism is 8-epi-PGF2 alpha. 8-epi-PGF2 alpha is a potent vasoconstrictor in the rat, an effect that has been shown to be mediated via interaction with vascular thromboxane (TxA2)/endoperoxide (PGH2) receptors. In an effort to further understand the biological properties of this prostanoid in relation to its ability to interact with TxA2/PGH2 receptors, we examined its effects on human and rat platelets. At concentrations of 10(-6) M and 10(-5) M, 8-epi-PGF2 alpha induced only a shape change in human platelets and at higher concentrations (10(-4) M) induced reversible but not irreversible aggregation. Both the shape change and reversible aggregation were unaffected by indomethacin but were inhibited by the TxA2/PGH2 receptor antagonist SQ29548. Conversely, 8-epi-PGF2 alpha inhibited platelet aggregation induced by the TxA2/PGH2 receptor agonists U46619 (10(-6) M) and IBOP (3.3 x 10(-7) M) with an IC50 of 1.6 x 10(-6) M and 1.8 x 10(-6) M, respectively. 8-epi-PGF2 alpha also inhibited platelet aggregation induced by arachidonic acid. Similarly, in rat platelets, 8-epi-PGF2 alpha alone induced only modest reversible aggregation but completely inhibited U46619-induced aggregation.
Animals↗
Identification of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans.
Oral administration of niacin (nicotinic acid) at pharmacologic doses that reduce serum cholesterol levels induces intense flushing in humans. We have recently shown that the vasodilation following ingestion of niacin is due to the release of prostaglandin (PG) D2. However, the site from which PGD2 is released is not known. It has previously been shown that topical application of methylnicotinate causes local cutaneous erythema. Thus, we investigated whether topical methylnicotinate causes a release of PGD2 locally from skin and the possibility that skin may be a major contributor to the release of PGD2 when niacin is administered by mouth. Topical administration of methylnicotinate (10(-1) M) to the forearms of human volunteers resulted in 58- to 122-times increases in levels of PGD2 and 25- to 33-times increases in levels of the metabolite of PGD2, 9 alpha,11 beta-PGF2, in blood drawn from the antecubital vein draining the treated sites. Increased levels of PGD2 and 9 alpha,11 beta-PGF2 were not found in blood drawn simultaneously from veins in the contralateral arm, indicating that the PGD2 was released from the site of methylnicotinate application. The release of PGD2 in response to topically applied methylnicotinate occurred in a dose-dependent manner over the concentration range of 10(-3) to 10(-1) M. The release of PGD2 was not accompanied by a release of histamine, suggesting that the release of PGD2 was not from the mast cell. Following oral ingestion of niacin, levels of PGD2 in superficial venous blood draining the skin were 14 to 1200 times higher than the level in arterial blood supplying the skin of the same arm. This finding indicates that the skin is a major site from which PGD2 is released following oral ingestion of niacin. These studies thus indicate that the cutaneous vasodilation that occurs following oral administration of niacin is primarily due to a release of PGD2 from a niacin responsive cell that resides in the skin.
Administration, Oral↗
The role of manometry, electromyography and radiology in the assessment of faecal incontinence.
The results of laboratory investigations in 156 patients presenting with faecal incontinence are reviewed to see if and how these investigations supplement a careful clinical evaluation, and in particular to see if they help in the practical management of the problem. All patients underwent anal manometry, and in addition 52 underwent anal sphincter electromyography and 27 defaecatory proctography. Anal manometry quantified sphincteric weakness, and proved superior to digital assessment in this regard. Resting and squeeze pressures were less in those with complete than those with partial incontinence but the differences were not statistically significant. The measurements of rectal sensation and compliance were not additionally helpful. Single fibre electromyography provided the best measure of denervation with re-innervation and was abnormal in about 85% of the group studied. Jitter studies were unhelpful. Most patients had some abnormality on defaecatory proctography but clinical significance could not be established. The choice of treatment was made on clinical grounds and was not influenced by these investigations.
Aged↗
The role of manometry, electromyography and radiology in the assessment of intractable constipation.
An analysis is made of functional studies performed in 96 constipated patients to see how these studies influenced the choice of surgical treatment. All patients underwent anal manometry, and other investigations included colonic transit studies (56), anal sphincter electromyography (42) and defaecatory proctography (34). Additionally nine patients underwent full thickness rectal biopsy. The resting anal canal pressures of the patients studied were lower than controls, and fibre density studies on electromyography were abnormal in half the patients studied suggesting a degree of denervation of the sphincter muscles, which possibly related to chronic straining on the toilet. There was evidence of reduced rectal sensation as shown by an increase in the least perceived volume on balloon distension of the rectum, and in those with megarectum and/or megacolon an increase in maximum tolerated volume. The recto-anal inhibitory reflex was used to screen for adult Hirschsprung's disease, but in one patient the reflex was present despite absence of ganglia on full thickness rectal biopsy indicating the need for biopsy as the definitive diagnostic procedure. Delayed colonic transit using radio opaque markers was a necessary requirement before recommending colectomy, and delayed transit was demonstrated in 34% of the patients studied. Anismus on electromyography was found in 20% of the patients but there was poor correlation with failure of the anorectal angle to widen when bearing down on proctography. The investigations helped in the choice of treatment, but were difficult to interpret. They should be used in severe constipation when surgery is being contemplated.
Adolescent↗
Effects of a novel prostaglandin, 8-epi-PGF2 alpha, in rabbit lung in situ.
We determined the effects of 8-epiprostaglandin (PG) F2 alpha, a noncyclooxygenase free radical-catalyzed product of arachidonic acid, on pulmonary vascular tone, its potency, and its mechanism of action. 8-Epi-PGF2 alpha (0.5-20 micrograms) was injected into the pulmonary artery (PA) catheter of 10 rabbits whose lungs were perfused in situ with Krebs-Henseleit buffer solution with 3% bovine serum albumin. PA pressure increased from a baseline of 13.5 +/- 0.6 to 25.6 +/- 2.0 cmH2O with 20 micrograms 8-epi-PGF2 alpha. 8-Epi-PGF2 alpha caused a rapid rise in PA pressure followed by a gradual decline over 40-60 min to baseline levels. Double vascular occlusion revealed a twofold increase in arterial resistance at peak rise in PA pressure. The rise in PA pressure with 20 micrograms 8-epi-PGF2 alpha was fivefold greater than with 20 micrograms of the cyclooxygenase-derived prostaglandin PGF2 alpha. The PA pressure response to 8-epi-PGF2 alpha was not altered by either cyclooxygenase block-ade with 150 microM meclofenamate or alpha-receptor blockade with 70 microM phentolamine, but was fully prevented by 40 microM SQ 29548, a thromboxane receptor antagonist. We conclude that in rabbits 8-epi-PGF2 alpha is a potent vasoconstrictor of the pulmonary vasculature, which appears to be due to the activation of SQ 29548-responsive thromboxane receptors.
Animals↗
Glomerular actions of a free radical-generated novel prostaglandin, 8-epi-prostaglandin F2 alpha, in the rat. Evidence for interaction with thromboxane A2 receptors.
8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) and related compounds are novel prostanoid produced by a noncyclooxygenase mechanism involving lipid peroxidation. Renal ischemia-reperfusion injury increased urinary excretion of these compounds by 300% over baseline level. Intrarenal arterial infusion at 0.5, 1, and 2 micrograms/kg per min induced dose-dependent reductions in glomerular filtration rate (GFR) and renal plasma flow, with renal function ceasing at the highest dose. Micropuncture measurements (0.5 microgram/kg per min) revealed a predominant increase in afferent resistance, resulting in a decrease in transcapillary hydraulic pressure difference, and leading to reductions in single nephron GFR and plasma flow. These changes were completely abolished or reversed by a TxA2 receptor antagonist, SQ 29,548. Competitive radioligand binding studies demonstrated that 8-epi-PGF2 alpha is a potent competitor for [3H]SQ 29,548 binding to rat renal arterial smooth muscle cells (RASM) in culture. Furthermore, addition of 8-epi-PGF2 alpha to RASM or isolated glomeruli was not associated with stimulation of arachidonate cyclooxygenase products. Therefore, 8-epi-PGF2 alpha is a potent preglomerular vasoconstrictor acting principally through TxA2 receptor activation. These findings may explain, in part, the beneficial effects of antioxidant therapy and TxA2 antagonism observed in numerous models of renal injury induced by lipid peroxidation.
Animals↗
Formation of novel non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in carbon tetrachloride hepatotoxicity. An animal model of lipid peroxidation.
These studies examine the in vivo formation of a unique series of PGF2-like compounds (F2-isoprostanes) derived from free radical-catalyzed nonenzymatic peroxidation of arachidonic acid. We have previously shown that levels of these compounds increase up to 50-fold in rats administered CCl4. To understand further the formation of these compounds in vivo, we carried out a series of experiments assessing factors influencing their generation. After CCl4 (2 ml/kg) was administered to rats, plasma F2-isoprostanes increased 55-fold by 4 h. Levels declined thereafter, but at 24 h, they were still elevated 21-fold, indicating continued lipid peroxidation. Pretreatment of rats with isonicotinic acid hydrazide and phenobarbital to induce cytochrome P-450 enhanced the production of F2-isoprostanes after CCl4 administration eightfold and fivefold, respectively, whereas inhibition of the cytochrome P-450 system with SKF-525A and 4-methylpyrazole decreased formation of F2-isoprostanes after CCl4 by 55 and 82%, respectively. Further, the glutathione-depleting agents buthionine sulfoximine and phorone augmented the F2-isoprostane response to CCl4 by 22- and 11-fold, respectively. F2-isoprostanes are formed in situ esterified to lipids and, in addition to increases in levels of free F2-isoprostanes in the circulation, levels of F2-isoprostanes esterified to lipids in various organs and plasma also increase sharply during CCl4 poisoning. The measurement of F2-isoprostanes may facilitate investigation of the role of lipid peroxidation in human diseases.
Acetaminophen↗
Evidence that histamine is the causative toxin of scombroid-fish poisoning.
BACKGROUND: The highest morbidity worldwide from fish poisoning results from the ingestion of spoiled scombroid fish, such as tuna and mackerel, and its cause is not clear. Histamine could be responsible, because spoiled scombroid fish contain large quantities of histamine. Whether histamine is the causative toxin, however, has remained in question. To address this issue, we investigated whether histamine homeostasis is altered in poisoned people. METHODS: The urinary excretion of histamine and its metabolite, N-methylhistamine, was measured in three persons who had scombroid-fish poisoning (scombrotoxism) after the ingestion of marlin. We measured 9 alpha, 11 beta-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid (PGD-M), the principal metabolite of prostaglandin D2, a mast-cell secretory product, to assess whether mast cells had been activated to release histamine. RESULTS: The fish contained high levels of histamine (842 to 2503 mumol per 100 g of tissue). Symptoms of scombrotoxism--flushing and headache--began 10 to 30 minutes after the ingestion of fish. In urine samples collected one to four hours after fish ingestion, the levels of histamine and N-methylhistamine were 9 to 20 times and 15 to 20 times the normal mean, respectively. During the subsequent 24 hours, the levels fell to 4 to 15 times and 4 to 11 times the normal values. Levels of both were normal 14 days later. PGD-M excretion was not increased at any time. Two persons treated with diphenhydramine had prompt amelioration of symptoms. CONCLUSIONS: Scombroid-fish poisoning is associated with urinary excretion of histamine in quantities far exceeding those required to produce toxicity. The histamine is most likely derived from the spoiled fish. These results identify histamine as the toxin responsible for scombroid-fish poisoning.
Adult↗
Quantification of the major urinary metabolite of prostaglandin D2 by a stable isotope dilution mass spectrometric assay.
Prostaglandin D2 (PGD2) has been found to be an important pathophysiological mediator in a number of human disorders. Thus a means to assess the endogenous production of PGD2 is of considerable clinical value. To accomplish this goal, we developed a method for the quantification of the major urinary metabolite of PGD2, 9 alpha, 11 beta-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid, by gas chromatography/negative ion chemical ionization mass spectrometry. This metabolite was chemically synthesized and converted to an 18O4-labeled derivative for use as an internal standard. Novel derivatization and purification procedures were incorporated in the assay taking advantage of the ability of the lower side chain of this molecule to undergo cyclization at acidic pH to form a hemiketal, gamma-lactone, and uncyclization with methoximation. Precision of the assay is +/- 7% and accuracy is 96%. The lower limit of sensitivity is approximately 50 pg. Normal levels for the urinary excretion of this metabolite in 18 normal adults was found to be 1.08 +/- 0.72 ng/mg creatinine (mean +/- 2SD). Substantial elevations in the urinary excretion of the metabolite were found in clinical situations in which prostaglandin D2 has been shown to be released in increased quantities. Thus, this assay provides a sensitive and accurate method to assess endogenous production of prostaglandin D2 as a means to explore the pathophysiological role of prostaglandin D2 in human disease.
Gas Chromatography-Mass Spectrometry↗
Urticaria pigmentosa. Systemic evaluation and successful treatment with topical steroids.
Nine patients with adult-onset urticaria pigmentosa were studied for the incidence of extracutaneous mast cell involvement and the efficacy of potent topical corticosteroid therapy for cutaneous lesions. Seven of the nine patients had increased mast cells in the marrow biopsy specimens, and five patients had focal aggregates of mast cells. The bone scan was abnormal in one patient. Liver-spleen scans revealed a shift of colloid uptake from liver to spleen in four patients. No abnormal gastrointestinal tract roentgenograms were obtained. Urinary histamine metabolites correlated with nodular bone marrow involvement, but not with other parameters. Results of the psychoneurologic testing revealed significant deviation from the norm with a verbal memory deficit in all nine patients and abnormalities on the Minnesota Multiphasic Personality Inventory in four patients. All nine patients were treated with 0.05% betamethasone dipropionate ointment under occlusion over half of the body nightly for 6 weeks. Seven of nine patients treated responded with almost complete resolution of their lesions. Hypothalamic pituitary adrenal axis suppression was evaluated with intramuscular cosyntropin stimulation and metyrapone administration during treatment. Only two patients, both of whom used the medication improperly, developed transient abnormalities. Slow return of lesions was noted 6 months after completion of therapy. Remissions could be lengthened with single weekly applications of topical steroids. Systemic involvement is frequent in patients with cutaneous mast cell disease and it is best demonstrated by bone marrow biopsy. Mast cell lesions can be safely and effectively treated with topical steroids in motivated patients.
Administration, Topical↗
Charting uncharted terrain: a behavioral observation system for mutual help groups.
Describes the development of a behavioral observation system for mutual help meetings and presents evidence supporting its reliability, validity, and utility. The MHOS-BIC (Mutual Help Observation System-Behavioral Interaction Codes) was used by 10 observers to record the sequential flow of group interaction in 527 meetings. Psychometric analyses indicate that the system performed consistently with measurement objectives. Mean kappas for each of the 12 coding categories ranged from .62 to .87; the system demonstrated sensitivity to setting and time differences; and a predictable pattern of correlations was found among BIC categories and conceptually related participant and observer ratings. Studies using the BIC to address substantive questions about mutual help are reviewed, providing further evidence for its validity and utility. An empirical description of mutual help is presented using BIC data, and the promises and limitations of the system are discussed.
Affective Symptoms↗