bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of organic nitrates on myocardial oxygen consumption in vitro
Authors: LEVY J. V.
Published: July 2012

Mannitol hexanitrate (MANHN), iditol hexanitrate and sorbitan tetranitrate, all at 442 μm, stimulate oxygen uptake by isolated rabbit atrial tissue.

At the same concentration, glyceryl trinitrate decreased oxygen uptake, while isosorbide dinitrate and erythrityl tetranitrate had no effect.

No simple correlation was found between the lipoid solubility or per cent nitration of these compounds and their effects on oxygen uptake.

The stimulating effect of MANHN and its possible role as an uncoupler of oxidative phosphorylation is discussed.
Local anaesthetic and anti‐arrhythmic actions of alprenolol relative to its effect on intracellular potentials and other properties of isolated cardiac muscle
Authors: SINGH B. N. , WILLIAMS E. M. VAUGHAN
Published: July 2012

Alprenolol, a β‐adrenoceptor blocking drug reported to have the same potency as propranololin vitroandin vivo, was found to be four times more active than procaine as a local anaesthetic on frog sciatic nerve.

At doses of 0·125 mg/kg and above alprenolol protected anaesthetized guinea‐pigs against ouabain‐induced ventricular fibrillation.

In isolated rabbit atria, resting potentials were unchanged, and the duration of the action potential was not prolonged, by concentrations of alprenolol up to 10·5 × 10−6m. The maximum rate of depolarization (MRD), however, was reduced by 30% at a concentration of 0·525 × 10−6m. This was 214 times less than the concentration which reduced the frog action potential height by 25%.

The concentration of alprenolol required to produce more than 15% decrease in contraction or maximum driven frequency was 3·5 × 10−6m.

As a test of the direct action of alprenolol on isolated cardiac muscle, MRD was also a more sensitive test than the measurement of electrical threshold or conduction velocity.
Selective depletion of noradrenaline: a proposed mechanism of the adrenergic neurone‐blocking action of bretylium
Authors: ABBS E. T. , ROBERTSON M. I.
Published: July 2012

The effects of bretylium have been investigated on the content and subcellular distribution of noradrenaline in cat spleen and on the overflow of noradrenaline in response to stimulation of the splenic nerve.

Bretylium, 15 min after its administration, produces a significant depletion of noradrenaline in only the supernatant fraction of an homogenate; at this time adrenergic neurone blockade is evident. This depletion of noradrenaline is apparent up to 18 h later but has disappeared 7 days after the administration of bretylium when nerve function is also restored.

Both the development of the neurone blockade and the depletion of noradrenaline are prevented by previous administration of (+)‐amphetamine.

In bretylium‐pretreated cats the noradrenaline content of the supernatant fraction is replenished and the neurone blockade is abolished after treatment with (+)‐amphetamine.

The depletion of noradrenaline, which is evident 30 min, 60 min and 18 h after treatment with bretylium, from other subcellular fractions—especially the high‐speed particulate fraction—appears to be unassociated with adrenergic neurone blockade.

It is concluded that bretylium produces its adrenergic neurone‐blocking activity by depleting noradrenaline from a “store” whose amine appears in the supernatant fraction after homogenization. Whilst bretylium is present this “store” cannot refill with noradrenaline.
The antagonism of adrenergic neurone blockade by amphetamine and dexamphetamine in the rat and guinea‐pig
Authors: FOLLENFANT M. J. , ROBSON R. D.
Published: July 2012

In isolated rat mesentery preparations, intra‐arterial injection of the following drugs rapidly suppressed vasoconstrictor responses to sympathetic nerve stimulation: bretylium (75–100 μg), guanethidine (10–20 μg) and bethanidine (20–30 μg); with phenoxypropylguanidine (15–30 μg) the onset of blockade was slower. The blockade caused by these or higher concentrations was rapidly abolished by intra‐arterial injection of amphetamine (100 μg) as also was the blockade caused by infusing bretylium or guanethidine for 10–20 min. Partial blockade was produced by 20 μg of reserpine and this was only slightly and briefly antagonized by amphetamine.

In mesentery preparations taken from rats 24 h after subcutaneous injection of bretylium 50 mg/kg, guanethidine 10 mg/kg, phenoxypropylguanidine 10 mg/kg or reserpine 0·1 mg/kg, responses to sympathetic nerve stimulation were greatly impaired. Only in the preparations from the bretylium‐treated rats did amphetamine antagonize the blockade. The adrenergic neurone blocking effect of bethanidine 10 mg/kg was evident at 12 h but not at 24 h after injection.

In rat mesentery amphetamine did not cause vasoconstriction but briefly potentiated the vasoconstrictor effect of sympathetic nerve stimulation. Responses to noradrenaline were not importantly affected.

The contractile responses of the rat inferior eyelid caused by stimulation of the cervical sympathetic nerve was greatly reduced 17–27 h after subcutaneous injection of bretylium 300 mg/kg, bethanidine 30 mg/kg, guanethidine 10 mg/kg or reserpine 0·3 mg/kg. Intravenous dexamphetamine (0·5 mg/kg) powerfully antagonized the effect of bretylium, weakly antagonized the blockade by bethanidine and guanethidine and caused no change in the response of reserpine‐treated animals.

The vas deferens taken from guinea‐pigs 24 h after subcutaneous injection of either bretylium or guanethidine showed greatly impaired responses to hypogastric nerve stimulation. Amphetamine largely restored the contractile response in bretylium‐treated rats but caused only weak antagonism in the guanethidine‐treated animals.
An ultrastructural and histochemical study of the short‐term effects of 6‐hydroxydopamine on adrenergic nerves in the domestic fowl
Authors: BENNETT T. , BURNSTOCK G. , COBB J. L. S. , MALMFORS T.
Published: July 2012

The effects of 6‐hydroxydopamine (6‐OHDA) on adrenergic nerves in the domestic fowl have been investigated with ultrastructural and fluorescence histochemical methods.

6‐OHDA depletes the nerves of catecholamine, initially by displacing it from the storage vesicles. 6‐OHDA enters large as well as small vesicles, indicating that large granular vesicles in adrenergic nerves are sites of amine storage.

Doses of 6‐OHDA, insufficient to cause degeneration, still cause loading of the vesicles.

The effects of various drugs on the action of 6‐OHDA indicate that this drug must be taken up by the nerves and reach a critical extragranular axoplasmic concentration before degeneration will occur; 6‐OHDA bound in the vesicles plays no part in the degenerative process.
The effect of amiodarone, a new anti‐anginal drug, on cardiac muscle
Authors: SINGH B. N. , WILLIAMS E. M. VAUGHAN
Published: July 2012

Amiodarone (2‐butyl, 3‐(4‐diethylaminoethoxy, 3,5‐diiodo, benzoyl) benzofuran hydrochloride), an anti‐anginal drug which causes coronary dilatation and depresses myocardial oxygen consumption, was found to protect anaesthetized guinea‐pigs against ouabain‐induced ventricular fibrillation.

A 5% (73·4 mm) solution of amiodarone had no local anaesthetic action on guinea‐pig skin.

Amiodarone, 20 mg/kg (29·4 μmol/kg) given daily for 6 weeks intraperitoneally, had no effect on the resting potential or action potential height, and only a small effect on the maximum rate of depolarization, of isolated rabbit atrial or ventricular muscle fibres as shown by intracellular recording. It caused a considerable prolongation of the action potential in both tissues.

Simultaneous administration of thyroxine (5 μg; 6·26 nmol), given daily for 3 weeks intraperitoneally, prevented the prolongation by amiodarone of the duration of the action potential.

Treatment of rabbits with 20 mg/kg of amiodarone daily intraperitoneally for 6 weeks had no effect on the weight of the thyroid gland, but was associated with a reduction in body growth rate.

Treatment of rabbits with 10 mg/kg (60·3 μmol/kg) of potassium iodide (equal in its iodine content to that of 20 mg/kg of amiodarone), given daily for 6 weeks intraperitoneally, had no effect on body growth rate or the duration of cardiac action potentials.

It was concluded that amiodarone had effects on cardiac action potentials similar to those which occur after thyroidectomy.
Noradrenaline and tyramine action on isolated atrial muscle of endotoxin‐treated guinea‐pigs
Authors: BHAGAT B. , CAVANAGH D. , MERRILD B. N. , RANA M. W. , RAO P. S.
Published: July 2012

Isolated left‐atrial strips of guinea‐pigs were driven electrically at a constant rate and log‐concentration curves were determined for the positive inotropic effect of noradrenaline and tyramine.

The atrial tissue from endotoxin‐treated animals had a reduced sensitivity to noradrenaline and tyramine.

After endotoxin, the sensitizing effect of cocaine on the response to noradrenaline was normal but accumulation of 3H‐noradrenaline in nerve terminals was markedly reduced.

Atrial tissue of endotoxin‐treated guinea‐pigs responded normally to stretch.
Effects of general depressant drugs on the electrical responses of isolated slabs of cat's cerebral cortex
Authors: FRANK G. B. , JHAMANDAS K.
Published: July 2012

In the neuronally isolated cortex of the cat, local application of diphenhydramine, promethazine, gammahydroxybutyrate, gammabutyrolactone, gamma aminobutyric acid, hyoscine and pethidine, and the intravenous injection of diazepam and meprobamate depressed or abolished the surface negative and surface positive response to direct stimulation and raised the stimulus threshold of the positive burst response. These effects were the same as previously demonstrated for general and local anaesthetics on the same preparation.

Chlorpromazine produced a similar depression in small concentrations but caused spontaneous activity in higher concentrations.

In contrast to local application, pethidine when given by intravenous injection in a high dose produced convulsant activity in the isolated cortical slab. The possibility was suggested that the convulsant activity was produced by a metabolite of pethidine.

The results of this investigation suggest that the central depression produced by a number of structurally unrelated drugs is indicative of an anaesthetic‐like property of these drugs.
The effects of histamine in malaria
Authors: MAEGRAITH B. G. , ONABANJO A. O.
Published: July 2012

Extracts of the blood of monkeys (Macaca mulatta) infected with Plasmodium knowlesi contain histamine. A mean total concentration of 0·15 μg/ml was present in the circulating blood.

No histamine was detected in the blood of healthy monkeys.

Vasodilatation and increased vascular permeability was observed at the site of injection of the extract into the skin and brain of guinea‐pigs.

Infiltration of the dermal layer by leucocytes was observed after intradermal injection of the histamine extract. A similar response was obtained in the brain.

The extract of the blood from the infected animal produced hypotension in rabbits when administered intravenously.

The pathophysiological significance of histamine in malaria is discussed.
Uptake, metabolism and release of [3H]‐adrenaline by human platelets
Authors: BORN G. V. R. , SMITH J. B.
Published: July 2012

Measurements were made of the uptake, metabolism and release of [3H]‐adrenaline by human platelets in citrated plasma or in an artificial medium.

Radioactive adrenaline was not taken up at 0–2° C. At 37° C there was a slow uptake which continued for at least 5 hours.

About half of the radioactivity in the platelets was intact adrenaline. The other half was an acidic metabolite from which adrenaline was released by acid hydrolysis.

The immediate uptake of adrenaline was proportional to its concentration in the plasma up to at least 1 × 10−5m. Uptake measured after 1 h also increased linearly with concentration up to about 1 × 10−4m but less with higher concentrations. The highest concentration ratio was about 12.

The concentration of metabolite in the platelets increased with the concentration of added adrenaline only up to about 2 × 10−4m.

The immediate uptake of adrenaline was partially inhibited by phentolamine and dihydroergotamine. Measurement of uptake both immediately and after 1 h showed that the inhibition produced was not increased beyond about 50% by these drugs or by (±)‐propranolol, chlorpromazine or amitriptyline up to 1 × 10−4m.

Formation of the metabolite was inhibited by pyrogallol, 8‐hydroxyquinoline, or tropolone. This inhibition was associated with a corresponding increase in the adrenaline accumulated intact. Formation of the metabolite was not inhibited by monoamine oxidase inhibitors.

Reserpine caused a small decrease in the uptake of adrenaline radioactivity in 1 h and a great increase in the proportion recovered as metabolite.

Thrombin caused the release from platelets of intact adrenaline but not of the metabolite.

Platelets of albino patients with spontaneous haemorrhages accumulated adrenaline radioactivity at the normal rate but this radioactivity was wholly accounted for by metabolite and not released by thrombin.

After taking up adrenaline, platelets resuspended in artificial medium at 37° C slowly released both adrenaline and its metabolite. At the same time, the intracellular adrenaline was slowly metabolized.

The results suggest that human platelets take up adrenaline by two processes, one of which is inhibited by both α‐ and β‐adrenoceptor blocking agents as well as by phenothiazines; and that in the platelets adrenaline is partly stored in organelles from which, like 5‐hydroxytryptamine, it can be specifically released.
Adrenoceptors of the chick rectum
Authors: BARTLET A. L. , HASSAN T.
Published: July 2012

The aim of the investigation was to determine whether the adrenoceptors of the chick rectum preparation complied with Ahlquist's classification; phentolamine (0·1 μg/ml) and propranolol (0·05 μg/ml) were used as specific antagonists of α‐ and β‐adrenoceptors, respectively.

Propranolol antagonized phenylephrine, isoprenaline and noradrenaline in the chick rectum preparation, although according to Ahlquist's classification phenylephrine stimulates α‐adrenoceptors selectively.

In the presence of propranolol, phenylephrine and noradrenaline produced small residual relaxations of the chick rectum preparation which were blocked by phentolamine. In the absence of propranolol, however, phentolamine did not antagonize relaxations to phenylephrine, isoprenaline or noradrenaline.

The adrenoceptors of the guinea‐pig colon preparation compiled with Ahlquist's classification in that they were like those generally present in intestine.
The protective actions of some anticholinergic drugs in sarin poisoning
Authors: BRIMBLECOMBE R. W. , GREEN D. M. , STRATTON JUNE A. , THOMPSON PAMELA B. J.
Published: July 2012

The central and peripheral anticholinergic activities of a series of drugs comprising atropine, hyoscine, caramiphen and one of its analogues, and three glycollic acid esters, have been measured.

The ability of the same drugs used alone, and in conjunction with N‐methyl pyridinium‐2‐aldoxime methanesulphonate (P2S), to protect mice, rats and guinea‐pigs from the lethal effects of sarin has been assessed.

No correlation was found to exist between central or peripheral anticholinergic activity and ability to protect from sarin.

On the indirectly stimulated isolated rat phrenic nerve‐diaphragm preparation all drugs with the exception of hyoscine caused potentiation of responses to low frequency stimulation but partial block of responses to high frequency stimulation. The drugs did not reverse the effects of sarin on the phrenic nerve‐diaphragm preparation.

It is concluded that a pharmacological action other than an anticholinergic one is involved, in part, in the protective actions against sarin of some of the drugs studied. Whether their effects on skeletal muscle are of any relevance in this respect is unresolved.
Iontophoretic release of acetylcholine, noradrenaline, 5‐hydroxytryptamine and d‐lysergic acid diethylamide from micropipettes
Authors: BRADLEY P. B. , CANDY J. M.
Published: July 2012

The in vitro iontophoretic release of tritium‐labelled acetylcholine and 5‐hydroxytryptamine from large and small micropipettes and noradrenaline and d‐lysergic acid diethylamide from small micropipettes was determined by liquid scintillation counting.

The release was directly proportional to the electrical charge passed in the range normally used in the iontophoretic study of these compounds. The transport numbers obtained for the large micropipettes were approximately double those with the small micropipettes. A very low transport number was found for d‐lysergic acid diethylamide.

The spontaneous leakage was small and did not vary appreciably with time.

The iontophoretic release of acetylcholine in vitro agreed with the in vitro measurements.

The brain‐stem tissue concentration of d‐lysergic acid diethylamide after intravenous injection into intact and decerebrate cats was determined.
Antagonism of 5‐hydroxytryptamine by LSD 25 in the central nervous system: a possible neuronal basis for the actions of LSD 25
Authors: BOAKES R. J. , BRADLEY P. B. , BRIGGS I. , DRAY A.
Published: July 2012

5‐Hydroxytryptamine (5‐HT), acetylcholine (ACh), noradrenaline (NA), glutamate, d,l‐homocysteic acid (DLH), glycine and γ‐aminobutyric acid (GABA) were applied to single neurones in the brain stem of decerebrate cats by microiontophoresis. The abilities of d‐lysergic acid diethylamide tartrate (LSD 25), methysergide maleate (UML 491) and 2‐bromo‐lysergic acid diethylamide (BOL 148) to antagonize the actions of these compounds were studied.

LSD 25 antagonized 5‐HT excitation of single neurones when applied iontophoretically or administered intravenously. LSD 25 also antagonized glutamate excitation of neurones which could be excited by 5‐HT. Inhibitory effects of 5‐HT, the action of glutamate on neurones which could be inhibited by 5‐HT and the actions of all the other compounds tested were unaffected by LSD 25.

Iontophoretically applied UML 491 was also a specific antagonist to 5‐HT and glutamate excitation but was less potent than LSD 25, and BOL 148 rarely exhibited antagonism.

It is suggested that antagonism to 5‐HT and glutamate excitation of brain stem neurones may be the basis of the psychotomimetic action of LSD 25. It is also suggested that there may be similarities in the mechanisms by which 5‐HT and glutamate produce excitation where they act on the same neurone.
A central site for the hypothermic effects of (+)‐amphetamine sulphate and p‐hydroxyamphetamine hydrobromide in mice
Authors: McCULLOUGH DEBORAH O. , MILBERG JANE N. , ROBINSON S. M.
Published: July 2012

In unanaesthetized mice, weighing 20–30 g, the effect of (+)‐amphetamine sulphate and p‐hydroxyamphetamine hydrobromide on rectal temperature was examined. The drugs were injected intraperitoneally or into the cerebral ventricles.

Amphetamine produced hypothermia when injected intraperitoneally in doses of 1–5 mg/kg and intraventricularly in doses of 0.5 to 25 μg. Injections of larger doses—10 mg/kg intraperitoneally and 400 μg intraventricularly—resulted in hyperthermia followed by hypothermia.

Hydroxyamphetamine produced hypothermia only when given by the intraventricular route; the effect was obtained with 0.5 to 25 μg. An intraventricular injection of 200 μg resulted in hyperthermia followed by hypothermia. When injected intraperitoneally the sole effect on temperature was hyperthermia, and this response was obtained with 5 and 10 mg/kg.

Hydroxyamphetamine injected intraperitoneally or intraventricularly in doses which produced hyperthermia reduced the noradrenaline but not the dopamine content of the brain. When injected intraventricularly in smaller doses which produced hypothermia no reduction in the noradrenaline content of the brain was obtained.

The hypothermia is attributed to an action on the anterior hypothalamus, and the possibility is discussed that it is brought about indirectly by the release of noradrenaline. The hyperthermia on the other hand is probably a peripheral effect.
Enhancement by potent diuretics of renal tubular necrosis induced by cephaloridine
Authors: DODDS M. G. , FOORD R. D.
Published: July 2012

Administration of frusemide or ethacrynic acid to cephaloridine‐treated mice increased both the incidence and extent of proximal renal tubular necrosis compared with that obtained in cephaloridine‐treated control mice.

Administration of frusemide to cephaloridine‐treated rats produced significant changes in urine output, electrolyte excretion and proteinuria, and plasma urea nitrogen and creatinine values were significantly increased compared with controls or rats that received frusemide or cephaloridine alone.

Histological examination of the kidneys showed a higher incidence and greater extent of tubular necrosis in rats that received both frusemide and cephaloridine.

It is suggested that this adverse drug interaction may have contributed to the deterioration in renal function observed in some patients treated with diuretics and cephaloridine concurrently.
Facilitation of the flexor reflex in the cat by intrathecal injection of catecholamines
Authors: DHAWAN B. N. , SHARMA J. N.
Published: July 2012

Effects of some α‐ and β‐adrenoceptor stimulants and antagonists were investigated on flexor reflex (FR) in chloralosed cats.

Noradrenaline (NA) produced facilitation of FR which was dose‐dependent and reproducible and was blocked by α‐adrenoceptor blocking agents.

Strychnine also produced facilitation of FR but the response was unaffected by α‐adrenoceptor blocking agents.

Metaraminol and α‐methyl‐noradrenaline had little effect on FR but blocked the NA response.

β‐adrenoceptor stimulants and antagonists had neither any effect on FR nor modified the NA response.

Vasopressin and histamine also failed to modify FR.

Possibility of α‐adrenoceptors in the neurones integrating FR is suggested.
A method of stimulating different segments of the autonomic outflow from the spinal column to various organs in the pithed cat and rat
Authors: GILLESPIE J. S. , MACLAREN A. , POLLOCK D.
Published: July 2012

A simple method of stimulating different segments of the autonomic outflow from the spinal column in the pithed cat and rat is described.

Using a movable Teflon‐shielded electrode inserted into the vertebral canal and an indifferent electrode under the skin, reproducible responses were obtained from the adrenals, the bladder, the blood vessels, the colon, the heart and the vas deferens. The level and number of segments stimulated was altered by varying the depth of insertion of the Teflon tube and the length of central steel electrode protruding from it.

The degree of localization of the stimulus seemed satisfactory since it was possible by stimulating the sacral parasympathetic outflow to the bladder and colon or the lumbar sympathetic outflow to the vas deferens, to elicit responses from these organs with little effect on the cardiovascular system. Stimulation at higher levels of the thoracic sympathetic outflow permitted discrimination between the pressor and cardio‐accelerator responses.

Hexamethonium (1 mg/kg) inhibited all the responses, but the colonic response, which occurred only after a latent period, was especially sensitive to ganglion blockade. Atropine (1 mg/kg) inhibited the bladder response by 50% but only prolonged the latency of the colonic response without affecting its magnitude. Physostigmine (1 mg/kg) enhanced the bladder and colonic responses and reversed the effects of hexamethonium on these organs. Phentolamine (1 mg/kg) abolished the pressor responses to stimulation of the thoracolumbar sympathetic outflow but did not affect the cardio‐accelerator response.
Synaptic potentials recorded by the sucrose‐gap method from the rabbit superior cervical ganglion
Authors: KOSTERLITZ H. W. , LEES G. M. , WALLIS D. I.
Published: July 2012

Compound ganglionic potentials evoked by stimulation of the preganglionic nerves to the superior cervical ganglion of the rabbit were recorded by the sucrose‐gap method.

When the distal part of the ganglion was bathed in flowing isotonic sucrose solution or sodium‐deficient solutions, ganglionic action potentials were no longer evoked, only large synaptic potentials.

The compound synaptic potential, which remained unaltered for more than 1 h, originated in a population of cells at the interface between the Krebs and sucrose solutions. Hexamethonium reduced the size but did not alter the time course of the synaptic potential.

It is suggested that a higher concentration of sodium ions is required for the generation of ganglionic action potentials than for either conduction in the postganglionic axons or production of synaptic potentials.

When lithium replaced sodium in the solution bathing the distal part of the ganglion, the synaptic potential was greatly reduced in amplitude. Impulse propagation in the postganglionic axons was only slightly impaired when lithium replaced sodium in the solution bathing the axons.

A quantitative assessment of the potency of the ganglion‐blocking drugs nicotine, pentolinium, hexamethonium and pempidine was made by measuring the depression of the synaptic potentials produced by bathing the distal part of the ganglion in flowing isotonic sucrose solution. The concentrations which produced a 50% depression were 8.1 μM nicotine, 26.5 μM pentolinium, 111 μM hexamethonium and 22.2 μM pempidine.
Effect of anti‐proteases and hexadimethrine bromide on the release of a bradykinin‐like substance during heating (46° C) of rat paws
Authors: LEME J. GARCIA , HAMAMURA L. , SILVA M. ROCHA E
Published: July 2012

The conditions in which the release of an active, bradykinin‐like agent occurred when rat paws were heated to 46° C were studied by means of the double coaxial perfusion of the subcutaneous spaces.

The active material thus released stimulated the isolated rat uterus, produced a relaxing effect on the isolated rat duodenum, was destroyed by incubation with chymotrypsin and was potentiated by bradykinin‐potentiating factor. LSD‐25, in doses sufficient completely to block 5‐hydroxytryptamine, did not affect the responses of the isolated uterus to the active material.

The effects on this release of anti‐proteases and hexadimethrine bromide, atropine and diphenhydramine were studied.

Soy‐bean trypsin inhibitor and hexadimethrine bromide added to the perfusion fluid produced a potent and reversible inhibition of the release of the active material; aprotinin and Kunitz inhibitor caused a temporary block.

When administered intravenously, much larger doses of the substances were necessary to produce a similar block.

Pretreatment of the animals with atropine plus diphenhydramine did not affect the release of the active kinin(s).

Ligature of one iliac artery was followed by disappearance of the active material in the perfusate from the corresponding paw.

These facts suggest that heating elicits a process leading to plasma extravasation and that the subcutaneous tissue is the chief site of release of the active material.
The autophagic inhibitor 3‐methyladenine potently stimulates PKA‐dependent lipolysis in adipocytes
Authors: Heckmann Bradlee L , Yang Xingyuan , Zhang Xiaodong , Liu Jun
Published: July 2012

BACKGROUND AND PURPOSE The class III PI3K inhibitor, 3‐methyladenine (3‐MA), is commonly used to selectively block autophagy. Recent findings suggest a strong relationship between autophagy and lipid turnover. Here, we explore the effect of 3‐MA on adipocyte lipolysis.

EXPERIMENTAL APPROACH Assays were performed in 3T3‐L1 cells. Cells were treated with 3‐MA and wortmannin, a pan PI3K and autophagy inhibitor. Pharmacological and genetic manipulation of endogenous autophagic and lipolytic pathways was used to ascertain the contribution of 3‐MA to the observed effects on lipolysis.

KEY RESULTS 3T3‐L1 cells that were exposed to 3‐MA showed a consistent increase in lipolysis, approximately 50% over basal levels. The effect of 3‐MA was not secondary to autophagic inhibition as treatment of 3T3‐L1 cells with wortmannin yielded no such changes. Dosing and time course experiments showed that 3‐MA's ability to activate lipolysis was more sensitive than its inhibitory effect on autophagy. Knockdown of adipose triglyceride lipase (ATGL) negated the stimulatory effect of 3‐MA by >90%, indicating that 3‐MA enhanced ATGL‐dependent hydrolysis of triacylglycerols. Additionally, the lipolytic effect of 3‐MA was dependent on the activation of PKA and 3‐MA induced a rapid and potent elevation of intracellular cAMP levels in adipocytes.

CONCLUSIONS AND IMPLICATIONS Cumulatively, we show that 3‐MA potently modulated a cellular mechanism and its underlying signalling pathways not associated with autophagy. Furthermore, we describe a novel stimulatory effect on a major signalling pathway. Our findings provide valuable information to studies employing 3‐MA as a specific inhibitor for PI3K and autophagy.
Heart repair and regeneration: Recent insights from zebrafish studies
Authors: Lien Ching‐Ling , Harrison Michael R. , Tuan Tai‐Lan , Starnes Vaughn A.
Published: July 2012

Cardiovascular disease is the leading cause of death in the US and worldwide. Failure to properly repair or regenerate damaged cardiac tissues after myocardial infarction is a major cause of heart failure. In contrast to humans and other mammals, zebrafish hearts regenerate after substantial injury or tissue damage. Here, we review recent progress in studying zebrafish heart regeneration, addressing the molecular and cellular responses in the three tissue layers of the heart: myocardium, epicardium, and endocardium. We also compare different injury models utilized to study zebrafish heart regeneration and discuss the differences in responses to injury between mammalian and zebrafish hearts. By learning how zebrafish hearts regenerate naturally, we can better design therapeutic strategies for repairing human hearts after myocardial infarction.
OVERLOOKED HETEROPOLARITY IN SURIRELLA CF. FASTUOSA (BACILLARIOPHYTA) AND RELATIONSHIPS BETWEEN VALVE MORPHOGENESIS AND AUXOSPORE DEVELOPMENT
Authors: Watanabe Tsuyoshi , Mayama Shigeki , Idei Masahiko
Published: July 2012

Surirella cf. fastuosa is an apparently isopolar elliptic marine raphid diatom. We observed cells before and after sexual reproduction in monoclonal cultures using light and scanning electron microscopy (LM and SEM). After sexual reproduction cells were approximately twice as large as before, in valve length and width. The stria and infundibula densities were stable during the life cycle. Subtle morphological differences were detectable between the two poles of the frustule. One pole (pole A) was characterized by endings of the external raphe fissure that turned toward the valve face, continuity of the domed wall of the raphe canal externally, an elliptic chamber visible internally, a shallow nick in the interior of the valvocopula. The other pole (pole B) was with the following: straight endings of the external raphe fissures, a dent in the domed wall of the raphe canal externally, a double chamber internally, presence of the open ends of the valvocopula nearby, a deep nick in the valvocopula. Furthermore, at pole A virgae developed at an early stage in morphogenesis, whereas at pole B they were not formed. In the auxospores, pole A was situated beneath the primary transverse perizonial band. Pole A is suggested to be homologous with the head pole in heteropolar Surirella and is the “protopole” likely equivalent to the central nodule in naviculoid taxa. Pole B is homologous with the foot pole in heteropolar Surirella and is the “synaptic pole” formed by fusion of components equivalent to both poles of naviculoid taxa.
Voluntary Intravenous Self‐Administration of Alcohol Detects an Interaction Between GABAergic Manipulation and GABRG1 Polymorphism Genotype: A Pilot Study
Authors: Plawecki Martin H. , Wetherill Leah , Vitvitskiy Victor , Kosobud Ann , Zimmermann Ulrich S. , Edenberg Howard J. , O'Connor Sean
Published: July 2012

Background

Operant responding paradigms quantify a subject's motivation for reward, but such studies employing ingested alcohol cannot assure the same incremental increase in brain exposure to alcohol across subjects because of substantial variability in absorption kinetics. We developed a human progressive ratio (PR) paradigm using the computer‐assisted self‐infusion of ethanol (CASE) system that overcomes such variability and conducted a pilot study to assess its utility for detecting an interaction of subjects' GABRA2 or GABRG1 genotype and pretreatment with 1 mg of lorazepam (LZ) vs. placebo on their willingness to work for alcohol rewards.

Methods

Twenty healthy, nondependent drinkers, aged 21 to 27, were balanced on rs279871 and rs2350439 single nucleotide polymorphisms in the GABRA2 and GABRG1 genes, respectively. Subjects worked for alcohol, with water as an alternative reinforcer (AR), using a progressive schedule of a task that required constant attention and adapted to both fatigue and drug effects. Testing began 1 hour after pretreatment with 1 mg LZ or placebo in a crossover design.

Results

The CASE system performed well, and the constant attention task was perceived as work by all subjects. GABRA2 homozygosity did not significantly predict either breakpoint or cumulative work, whereas a significant GABRG1 genotype by LZ pretreatment interaction for cumulative work was detected (p = 0.04). Breakpoint revealed a weak trend toward pretreatment drug effects (p = 0.11), and a somewhat stronger interaction of LZ pretreatment with GABRG1 genotype (p = 0.06). GABRG1 status revealed a more complex relationship with respect to motivation for alcohol with and without LZ pretreatment; AG and GG individuals worked more for alcohol under both pretreatment conditions, while AA individuals worked more for the AR.

Conclusions

The CASE PR paradigm shows promise as a laboratory method for use in drug development and phenotyping studies.
The Effect of Foreclosures on Crime in Indianapolis, 2003–2008*
Authors: Stucky Thomas D. , Ottensmann John R. , Payton Seth B.
Published: July 2012

Objective

Until recently, few studies have examined the relationship between home foreclosures and crime. Foreclosures are one major source of neighborhood instability and can be expected to affect crime from several theoretical perspectives. Some recent research has found conflicting results on whether foreclosures cause crime.

Method

This study examines whether foreclosures are a robust predictor of crime and whether the effect of foreclosures on crime varies across neighborhood contexts. We estimate fixed‐effects negative binomial models using geocoded Indianapolis foreclosure and crime data for 2003–2008 to predict crime counts in 1,000 feet × 1,000 feet square grid cells.

Result

Foreclosures exhibit consistent positive effects on indices of overall, property, and violent UCR‐reported (where UCR is Uniform Crime Report) offenses in a cell and rape, aggravated assault, and burglary counts. In addition, foreclosures had greater effects on reported UCR crimes in stable neighborhoods, especially those with more owner‐occupied homes.

Conclusion

Foreclosures were a robust predictor of crime in the current study.
Home Foreclosures and Community Crime: Causal or Spurious Association?*
Authors: Kirk David S. , Hyra Derek S.
Published: July 2012

Objective

Aggregate crime rates continue to decline in the United States despite the depth and breadth of the current foreclosure crisis. This trend calls into question conventional wisdom and prior research that suggest a causal, positive relationship between foreclosures and crime. The objective of this article is to consider an alternative argument, that foreclosures and crime are part‐and‐parcel of the same community‐level dynamics, and thus are not causally related.

Methods

We use random effects models to analyze community crime and foreclosure data from Chicago between 2004 and 2009.

Results

Findings reveal that crime and foreclosures are spuriously related; controlling for confounding factors such as concentrated disadvantage and the political hierarchy of communities renders the foreclosure‐crime association nonsignificant.

Conclusion

Foreclosures and crime are each explained by antecedent community characteristics. To understand why social problems are unevenly distributed across geographic space, it is necessary to investigate why power and political influence are unevenly distributed.
Aquaporin‐4 Positron Emission Tomography Imaging of the Human Brain: First Report
Authors: Suzuki Yuji , Nakamura Yukihiro , Yamada Kenichi , Huber Vincent J. , Tsujita Mika , Nakada Tsutomu
Published: July 2012

BACKGROUND AND PURPOSE

Aquaporin 4 (AQP‐4) is the most abundant aquaporin isoform in the brain. Alterations in its expression and distribution have been correlated with the progression of several clinical disorders; however, the specific roles of AQP‐4 in those disorders are not well understood. Visualizing AQP‐4 in vivo is expected to provide fresh insights into its roles in disease pathology, as well as aiding the clinical assessment of those disorders.

METHODS

We developed a 11C‐labeled analogue of the AQP‐4 ligand TGN‐020 (2‐nicotinamido‐1,3,4‐thiadiazole) suitable for in vivo positron emission tomography (PET) imaging.

RESULTS

In the present study, we report the first PET images of AQP‐4 in the human brain. The results unequivocally demonstrated a specific distribution pattern for AQP‐4 within the brain, namely, the subpial and perivascular endfeet of astrocytes. The choroid plexus, where both AQP‐4 and AQP‐1 are expressed, also showed substantial uptake of the ligand.

CONCLUSIONS

Based on these initial results, we believe [11C]TGN‐020 PET will be valuable in determining the role of AQP‐4 in disease progression, and for the clinical assessment of water homeostasis under various settings.
Cerebral Embolus Following Chiropractic Manipulation in a Patient with a Calcified Carotid Artery
Authors: Dandamudi Venkata S. , Thaler David E. , Malek Adel M.
Published: July 2012

BACKGROUND AND PURPOSE

Dissection of the cervicocranial vessels is the principal cause of ischemic brain injury following cervical spinal manipulation. Cervical spinal manipulation leading to cerebral embolus in the absence of dissection is not described in the literature. Current case documents cerebral embolism originating from extensively calcified internal carotid artery immediately following cervical spinal manipulation in the absence of dissection.

METHODS

We describe a case and imaging findings of a 63‐year‐old male who underwent cervical spinal manipulation and developed sudden onset of left‐arm numbness and weakness.

RESULTS

Computed tomography angiography demonstrated extensively calcified right internal carotid artery at the site of redone carotid endarterectomy as well as calcified embolus in the right inferior middle cerebral artery.

CONCLUSIONS

Calcified carotid artery may be at risk for embolization following cervical spinal manipulation. Our recommendation is that, patients with extensively calcified carotid arteries should refrain from aggressive neck maneuvers and cervical spine manipulation therapy to avoid liberation of cerebral embolus.
The expression and significance of WWOX and β‐catenin in hepatocellular carcinoma
Authors: Li Yu‐Pu , Wu Chun‐Chieh , Chen Wan‐Tzu , Huang Ya‐Chun , Chai Chee‐Yin
Published: July 2012

WW domain‐containing oxidoreductase (WWOX) is a novel tumor suppressor gene, and its expression is reduced in various cancers, including hepatocellular carcinoma (HCC). WWOX has been reported to be downregulated in HCC cell lines as well as in primary HCC tissues. It has been suggested that WWOX is implicated in Wnt/β‐catenin pathway, which is frequently affected in HCC. The aim of this study was to evaluate the expression of WWOX, β‐catenin and T‐cell factor 4 (TCF4) in HCC. Our result showed that downregulation of WWOX in HCC was correlated with cytoplasmic accumulation of β‐catenin. In addition, strong nuclear TCF4 expression was associated with tumor grade and stage in HCC. In conclusion, our result implied that downregulation of WWOX might lead to accumulation of cytoplasmic β‐catenin and the subsequent activation of Wnt/β‐catenin signaling pathway in HCC.
The PtdIns3P‐Binding Protein Phafin 2 Mediates Epidermal Growth Factor Receptor Degradation by Promoting Endosome Fusion
Authors: Pedersen Nina Marie , Raiborg Camilla , Brech Andreas , Skarpen Ellen , Roxrud Ingrid , Platta Harald W. , Liestøl Knut , Stenmark Harald
Published: July 2012

Phosphatidylinositol 3‐phosphate (PtdIns3P) orchestrates endosomal cargo transport, fusion and motility by recruiting FYVE or PX domain‐containing effector proteins to endosomal membranes. In an attempt to discover novel PtdIns3P effectors involved in the termination of growth factor receptor signalling, we performed an siRNA screen for epidermal growth factor (EGF) degradation, targeting FYVE and PX domain proteins in the human proteome. This screen identified several potential regulators of EGF degradation, including HRS (used as positive control), PX kinase, MTMR4 and Phafin2/PLEKHF2. As Phafin2 has not previously been shown to be required for EGF receptor (EGFR) degradation, we performed further functional studies on this protein. Loss of Phafin2 was found to decrease early endosome size, whereas overexpression of Phafin2 resulted in enlarged endosomes. Moreover, both the EGFR and the fluid‐phase marker dextran were retained in abnormally small endosomes in Phafin2‐depleted cells. In yeast two‐hybrid analysis we identified Phafin2 as a novel interactor of the endosomal‐tethering protein EEA1, and Phafin2 colocalized strongly with EEA1 in microdomains of the endosome membrane. Our results suggest that Phafin2 controls receptor trafficking and fluid‐phase transport through early endosomes by facilitating endosome fusion in concert with EEA1.
Dentin Bond Strengths of Four Adhesion Strategies after Thermal Fatigue and 6‐Month Water Storage
Authors: SEZINANDO ANA , PERDIGÃO JORGE , REGALHEIRO RITA
Published: July 2012

Statement of Problem:  The stability of current dental adhesives after artificial aging may depend on the adhesion strategy.

Purpose:  To evaluate the effect of thermal fatigue and water storage on the dentin microtensile bond strengths (µTBS) of four adhesion strategies.

Materials and Methods:  Forty‐eight human molars were assigned to four dentin adhesives: FL—OptiBond FL (Kerr Corporation, Orange, CA, USA); SOLO—OptiBond SOLO Plus (Kerr Corporation); XTR—OptiBond XTR (Kerr Corporation); and AIO—OptiBond All‐in‐One (Kerr Corporation). Teeth were restored with a hybrid composite, and sectioned to obtained bonded beams. For each adhesive, one‐third of the central and peripheral beams were assigned to one of three aging conditions: (1) kept in distilled water for 24 hours (24h); (2) thermocycled (TC) for 20,000 cycles; and (3) stored in distilled water for 6 months (6M). Beams were tested in tension mode. Statistical analysis (p < 0.05) was computed using Analysis of Variance and Fisher's Least Significant Difference post hoc test.

Results:  The highest mean µTBS for 24h, TC, and 6M were obtained with XTR, but only the 6M mean µTBS were significantly higher than those of the other three adhesives. For FL, mean µTBS decreased significantly from 24h to TC. For SOLO, mean µTBS remained stable over the three aging conditions. Mean µTBS for AIO decreased significantly from 24h to 6M.

Conclusion:  The self‐etch adhesives XTR and AIO performed similarly or better than the etch‐and‐rinse adhesives FL and SOLO for all three testing conditions. Their aging stability seems to be material‐dependent.

CLINICAL SIGNIFICANCE

The dentin bonding ability of the newest self‐etch adhesives has improved compared with other similar materials, including etch‐and‐rinse adhesives. Adhesives that contain a hydrophobic resin (FL and XTR) tend to be more stable in water storage.

(J Esthet Restor Dent ••:••–••, 2012)
Small molecule tools for functional interrogation of protein tyrosine phosphatases
Authors: He Rongjun , Zeng Li‐Fan , He Yantao , Zhang Sheng , Zhang Zhong‐Yin
Published: July 2012

The importance of protein tyrosine phosphatases (PTPs) in the regulation of cellular signalling is well established. Malfunction of PTP activity is also known to be associated with cancer, metabolic syndromes and autoimmune disorders, as well as neurodegenerative and infectious diseases. However, a detailed understanding of the roles played by the PTPs in normal physiology and in pathogenic conditions has been hampered by the absence of PTP‐specific small molecule agents. In addition, the therapeutic benefits of modulating this target class are underexplored as a result of a lack of suitable chemical probes. Potent and specific PTP inhibitors could significantly facilitate functional analysis of the PTPs in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. We highlight the current challenges to and opportunities for developing PTP‐specific small molecule agents. We also review available selective small molecule inhibitors developed for a number of PTPs, including PTP1B, TC‐PTP, SHP2, lymphoid‐specific tyrosine phosphatase, haematopoietic protein tyrosine phosphatase, CD45, PTPβ, PTPγ, PTPRO, Vaccinia H1‐related phosphatase, mitogen‐activated protein kinase phosphatase‐1, mitogen‐activated protein kinase phosphatase‐3, Cdc25, YopH, mPTPA and mPTPB.
The Role of Cultural Factors in the Development of Latino Preschoolers' Self‐Regulation
Authors: Li‐Grining Christine Pajunar
Published: July 2012

This review summarizes the literature on factors that contribute to individual differences in Latino preschool‐aged children's self‐regulation, which is defined here as the ability to manage one's behavior, emotions, and attention, voluntarily and adaptively. Because Latino children are more likely to live in low‐income families, existing studies have embedded developmental models of Latino preschoolers' self‐regulation in socioeconomic contexts. However, scholars also highlight the importance of situating ethnic minority children's self‐regulation in sociocultural contexts. Existing studies have investigated both mean differences in children's self‐regulation by race and ethnicity and the moderating role of race and ethnic group. Also, extant research has begun examining mean differences in children's socioemotional adjustment by immigrant status. Still, the literature has not extensively studied the moderating roles of acculturation or cultural values such as familism in the socialization of Latino preschool‐aged children's self‐regulation. This article takes a first step toward identifying different types of interaction effects involving familism and acculturation, and concludes with recommendations for future research.
Inactivation of Vaccinia Virus by Natural Sunlight and by Artificial UVB Radiation
Authors: Sagripanti Jose‐Luis , Voss Luzie , Marschall Hans‐Juergen , David Lytle Carl
Published: July 2012

This study determined the sensitivity of vaccinia virus, an orthopox virus commonly used as a surrogate for variola virus (etiological agent of smallpox), exposed to UVB radiation emitted by a solar simulator, or to direct natural sunlight. The data obtained indicate that: (1) the virucidal effect of natural sunlight can be mimicked adequately by an artificial light source with similar spectral characteristics in the UVB, (2) viral sensitivity to UVB or to solar radiation can be correlated with experimental data previously obtained with UVC, (3) the correlation factor between virus inactivation by solar radiation (measured at 300 ± 5 nm) and by UVC (254 nm) is between 33 and 60, and (4) the sensitivity of viruses either dry on glass surfaces or in liquid suspension is similar when in the presence of similar amounts of cellular debris and growth media. The findings reported in this study should assist in estimating the threat posed by the persistence of virus during epidemics or after an accidental or intentional release.