bluuebunny/crossref_metadata_2025 huggingface dataset:
Normocalcaemic, vitamin D‐sufficient hyperparathyroidism – high prevalence and low morbidity in the general population: A long‐term follow‐up study, the WHO MONICA project, Gothenburg, Sweden
Authors: Kontogeorgos Georgios , Trimpou Penelope , Laine Christine M. , Oleröd Göran , Lindahl Anders , Landin‐Wilhelmsen Kerstin
Published: May 2015

Objective

There is limited knowledge about the natural history of normocalcaemic, vitamin D‐sufficient hyperparathyroidism (nHPT). The aim was to study the prevalence of nHPT and its relation to morbidity.

Design

Cross‐sectional and retrospective study at the Sahlgrenska University Hospital, Gothenburg, Sweden.

Subjects

A random population of 608 men and women, age 25–64 years, was studied in 1995 as part of the WHO MONICA study and reinvestigated in 2008 (n = 410, of whom 277 were vitamin D sufficient).

Measurements

A serum intact parathyroid hormone (S‐PTH) ≥60 ng/l was considered as HPT, S‐calcium 2·15–2·49 mmol/l as normocalcaemia and S‐25(OH)D ≥ 50 nmol/l as vitamin D sufficiency. Data on fractures, stroke and myocardial infarction were retrieved until 2013, that is a 17‐year follow‐up.

Results

The prevalence of nHPT was 2·0% in 1995 (age 25–64) and 11·0% in 2008 (age 38–79). S‐PTH was positively correlated with age and BMI. After adjustment for these variables, a high S‐PTH level (≥60 ng/l) at follow‐up was associated with previously low S‐25(OH)D, high osteocalcin, S‐PTH and both past and presently treated hypertension. No relation was seen with creatinine, cystatin C, malabsorption markers, thyroid function, glucose, insulin, lipids, calcaneal quantitative ultrasound, fractures, myocardial infarction, stroke or death at follow‐up.

Conclusions

This small random population study showed that nHPT was common, 11% at follow‐up. Only one individual developed mild hypercalcaemia in 13 years. Previous S‐PTH was predictive of nHPT and hypertension was prevalent, but no increase in hard end‐points was seen over a 17‐year period.
State restrictions on the interstate practice of dermatopathology are unconstitutional: the tissue is the issue
Authors: Marsch Amanda F. , Feinberg James S.
Published: May 2015

The regulation of the interstate practice of dermatopathology, teledermatopathology and teledermatology is the subject of discussion in many recent articles. Laws and regulations in many states complicate such interstate practice, requiring the dermatopathologist to be licensed in the state where the biopsy is taken if the dermatopathologist practices in and is licensed in a different state. To date, this discussion has been from the viewpoint of the dermatopathologist or dermatologist. But, when seen from the patient's viewpoint, its apparent that most such state regulation may be void as an unconstitutional infringement of a patient's fundamental right of unrestricted interstate travel under the Constitution of the United States of America.
Keep Your Friends Close? Supply Chain Design and Disruption Risk
Authors: Habermann Marco , Blackhurst Jennifer , Metcalf Ashley Y.
Published: May 2015

In this article, we evaluate the relationship between supply chain design decisions and supply chain disruption risk. We explore two supply chain design strategies: (i) the dispersion of supply chain partners to reduce supply chain disruption risk versus (ii) the co‐location of supply chain partners to reduce supply chain disruption risk. In addition, we assess supply chain disruption risk from three perspectives: the inbound material flow from the supplier (supply side), the internal production processes (internal), and the outbound material flow to the customer (customer side) as a disruption can occur at any of these locations. We measure disruption risk in terms of stoppages in flows, reductions in flow, close calls (disruptions that were prevented at the last minute), disruption duration (time until normal operation flow was restored), and the spread of disruptions all the way through the supply chain. We use seemingly unrelated regression (SUR) to analyze our data, finding that lead times, especially supply side lead times, are significantly associated with higher levels of supply chain disruption risk. We find co‐location with suppliers appears to have beneficial effects to the reduction of disruption duration, and, overall supply side factors have a higher impact when it comes to supply chain disruption risk than comparable customer side factors.
Farmers' Preference for Farming: Evidence From a Nationally Representative Farm Survey in India
Authors: Birthal Pratap S. , Roy Devesh , Khan Md. Tajuddin , Negi Digvijay Singh
Published: May 2015

Using data from a nationally representative farm survey in India, we have analyzed Indian farmers' stated preference for farming as a profession. Findings show that more than 40% of farmers dislike farming as a profession because of low profits, high risk, and lack of social status, yet they continue with it owing to a lack of opportunities outside agriculture. Farmers who express a preference for moving out of agriculture are mostly those with small landholdings, poor irrigation facilities, fewer productive assets including livestock, and follow a cereal‐centric cropping pattern. They also have relatively lower access to credit, insurance, and information, and are weakly integrated with social networks such as self‐help groups and farmers' organizations. Importantly, the disinclination for farming, conditional on other covariates, is not significantly differentiated by caste, an important indicator of social status in rural India. Yet, within a caste group, the dislike for farming moderates with larger landholdings.
Disease hazard identification and assessment associated with wildlife population declines
Authors: Pacioni Carlo , Eden Paul , Reiss Andrea , Ellis Trevor , Knowles Graeme , Wayne Adrian F.
Published: May 2015

Disease is increasingly being recognised as a risk factor in declining wildlife populations around the globe. However, there are limited protocols to assess disease risks in declining wildlife. Using epidemiological principles, we define a step‐by‐step framework to complete this complex and critical task. As an example, we assessed the potential role of diseases in relation to the decline of the woylie or brush‐tailed bettong (Bettongia penicillata ogilbyi)inWesternAustralia. Between 1999 and 2006, woylie populations declined by 90%. The wildlife disease risk assessment began with a list of all known or suspected diseases to which the woylie, a species of macropod, is susceptible. This list was assessed against the spatial, temporal and demographic characteristics of the decline. Diseases causing widespread and high mortalities or debilitation leading to predation received high scores. Based on this assessment, priority diseases or pathogens for investigation identified were haemoparasites, gastrointestinal helminths,Neospora caninum,Toxoplasmosis (Toxoplasma gondii),Encephalomyocarditis virus,MacropodOrbiviruses (Wallal virusandWarrego virus),MacropodHerpesviruses (Macropodid herpesvirus 1and2) andSalmonellaspp.
Where has all the fire gone? Quantifying the spatial and temporal extent of fire exclusion in Byron Shire, Australia
Authors: Baker Andrew G. , Catterall Claudia
Published: May 2015

Fire is a major determinant of vegetation structure worldwide, and structural vegetation change following fire exclusion is well documented throughout Australia. Such changes include the displacement of treeless ecosystems by forest and the transition of open forest to rainforest. These changes displace essential habitat for myriad plant and animal species and are likely drivers of localised species extinctions. Despite these potential consequences, research identifying the spatial extent of fire‐excluded ecosystems is largely absent from the ecological literature. This study identifies the spatial and temporal extent of fire exclusion in Byron Shire in north‐east New South Wales. GIS analysis compared modern fire history with recommended fire intervals for the maintenance of fire‐dependent vegetation types. Fire exclusion (low‐frequency fire) vastly exceeded high‐frequency fire, comprising 99.1% of areas affected by inappropriate fire frequency. Most fire‐dependent vegetation was fire‐excluded, with less than 10% within recommended fire interval thresholds. Most affected areas were fire‐excluded for multiple recommended fire‐return cycles, increasing the likelihood of vegetation change and localised extinctions. These findings demonstrate the operation of a major threatening process affecting Byron Shire's biodiversity that has previously been little recognised. A growing body of ecological literature suggests that irreversible change to fire‐excluded vegetation is likely wherever plant growth resources are sufficient to enable transition. Irreversible vegetation change and rapid species declines have been reported for several communities in Byron Shire, and there is compelling evidence that further change may be widespread. With increasing time since fire, efforts to restore these sites may be complicated by encroaching trees resistant to removal by fire alone and the difficulties of reintroducing low‐intensity understorey fires where the flammable understorey has been lost through shading. Further research into the impacts of fire exclusion is urgently required, as is the reinstatement of fire to fire‐excluded vegetation to prevent ongoing displacement of fire‐dependent biodiversity values.
Primordial Moral Awareness: Levinas, Conscience, and the Unavoidable Call to Responsibility
Authors: Fleming Daniel J.
Published: May 2015

The phenomenon of conscience as articulated in Roman Catholic moral theology has at least three dimensions: a fundamental and universal call to moral goodness; the search for moral truth; and a commitment to act in a particular way. Recent moral theology has tended to focus on the latter two dimensions, but there has been a strong call from Thomas Ryan for attention to the first dimension of conscience, especially its constitution in ‘horizontal relationality’. In this article I respond to Ryan's call, and demonstrate that the philosophy of Emmanuel Levinas can show how the experience of conscience is constituted in horizontal relationality, as well as that it supports an understanding of conscience as a universal call to responsibility. Correlatively, and perhaps more significantly, the introduction of Levinas’ philosophy into the discussion of conscience sheds light on a significant aspect of this call to moral responsibility. This highlights that the Roman Catholic understanding of conscience has ethical consequences for theology more broadly considered (as well as the other academic disciplines) in terms of understanding why it is impossible to set aside considerations of responsibility in the search for truth.
Engaging in research: challenges and opportunities for health library and information professionals
Authors: Murphy Jeannette
Published: May 2015

This year's virtual issue (the 6th in the series) has been published to coincide with the European Association for Health Information and Libraries’ (EAHIL) 2015 workshop (10–12 June, Edinburgh): Research‐Minded: Understanding, Supporting, Conducting Research. This event is being run in collaboration with the International Conference of Animal Health Information Specialists and the International Clinical Librarian Conference. Although research has always been a central part of any librarian's role, until recently health librarians and library users and funding bodies assumed that librarians were ‘midwives’ – there to assist students, clinicians, academics and managers set up and carry out their research. The notion of the librarian as a professional with a research agenda, who understands research methods, submits research grants, and publishes, is a relatively new perspective. If librarians are to take an evidence‐based approach to their profession they need to acquire research skills. This is the rationale for the 2015 EAHIL workshop. To support the workshop, this virtual issue contains six original articles published in Health Information and Libraries Journal over the last 2 years that demonstrate the range of research activities carried out by health librarians, as well as a review article and articles from each of the three feature columns. All articles included in this virtual issue are available free online.
Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long‐acting formulation in healthy volunteers
Authors: Verloes R , Deleu S , Niemeijer N , Crauwels H , Meyvisch P , Williams P
Published: May 2015

Objectives

This phase I healthy volunteer study (NCT01031589) was carried out to investigate the safety/tolerability and pharmacokinetics of a rilpivirine (RPV; TMC278) long‐acting (LA) formulation after single and multiple intramuscular (IM) injections.

Methods

In the first part of the study, which had an open‐label design, a single RPV LA IM injection (300 mg/mL) of 300 (n = 6) or 600 (n = 5) mg was given to the volunteers. In the second part of the study, which had a double‐blind, randomized, placebo‐controlled design, three RPV LA IM injections (one every 4 weeks) at 1200/600/600 mg (n = 6) or placebo (n = 2) were given. Safety and local tolerability were monitored. RPV plasma concentrations were analysed up to 28 days after injection or until they were < 20 ng/mL.

Results

Grade 1/2 RPV‐related adverse events in the 300, 600 and 1200/600/600 mg groups were: rash (zero, one and one subject, respectively, the last of whom discontinued participation in the study); musculoskeletal stiffness (three, zero and zero subjects, respectively); injection site reactions (one, two and two subjects, respectively). After one injection of 300, 600 or 1200 mg RPV LA, the mean (standard deviation) maximum plasma concentration was 39 (25), 48 (13) and 140 (16) ng/mL, and the mean (standard deviation) area under the concentration–time curve (28 days) was 17 090 (8907), 25 240 (8184) and 55 350 (13 550) ng h/mL, respectively. RPV pharmacokinetics were largely comparable after the 1200 mg loading dose and both 600 mg injections of RPV LA. The mean (standard deviation) RPV plasma concentration across the 28‐day dosing interval after the last injection in the 1200/600/600 mg group was 79 (19) ng/mL.

Conclusions

Single and multiple IM injections of RPV LA demonstrated favourable local/systemic tolerability in healthy volunteers. RPV pharmacokinetics suggested that clinically relevant plasma concentrations can be achieved with this LA formulation.
Preparation and characterisation of films from xylose‐glycosylated peanut protein isolate powder
Authors: Lin Wei‐Jing , Liu Hong‐Zhi , Shi Ai‐Min , Liu Li , Adhikari Benu , Wang Qiang
Published: May 2015

This work aimed at producing and characterising xylose‐glycosylated peanut protein isolate (PPI‐X) films by dissolving PPI‐X powder in water at ambient temperature and further plasticising with glycerol. The effect of powder dissolution temperature (20–100 °C) and glycerol concentration (15.0–45.0%, w/w) on mechanical properties and integrity of these films was quantified. The results showed that the powder dissolution temperature had no significant effect on the mechanical and water resistance properties of PPI‐X films within the temperature range tested. With increasing concentration of glycerol, the tensile strength and water resistance of PPI‐X films decreased and elongation increased. The films produced by dissolving the PPI‐X powder at 20 °C and plasticising with 25.0% glycerol had comparable mechanical properties and better water resistance compared to some other plant protein films plasticising with glycerol. The results suggested that PPI‐X films could potentially be used as biodegradable packaging materials.
Relationship of carrot sensory crispness with acoustic signal characteristics
Authors: Liu Yang , Huang Bi‐Zhu , Sun Yong‐Hai , Chen Fang‐Yuan , Yang Liu , Mao Qian , Liu Jing‐Sheng , Zheng Ming‐Zhu
Published: May 2015

The purpose of this study was to investigate the relationships of carrot sensory crispness with acoustic signal characteristics and microstructure after storage under common shelf conditions. The results showed that carrot sensory crispness declined significantly after the 14th day of storage, and the sensory score reduction was nearly up to 42% after the 28th day of storage. The carrot sensory crispness was positively related to both the waveform index (r = 0.785, P < 0.01) and sound intensity (r = 0.732, P < 0.01) of the acoustic signals in the time domain. Hilbert–Huang transform is a useful method for the observation of frequency changes in the time domain. The overall frequency bands were distributed around 200–2000 Hz through the Hilbert spectra. Rupture did not occur until the 14th day (crispness declined significantly) of storage through the scanning electron microscopy images of microstructure, and the crispness declined gradually with the increase of rupture.
Hemoglobin H identification by high‐performance liquid chromatography in confirmed hemoglobin H disease
Authors: Turley E. , McFarlane A. , Halchuk L. , Verhovsek M.
Published: May 2015

Introduction

Among hemoglobin (Hb) H disease cases diagnosed by DNA testing in our hemoglobinopathy laboratory, we have noted instances of unreported Hb H from high‐performance liquid chromatography (HPLC) results of referring laboratories.

Methods

To characterize these issues, we identified all cases of genotypic Hb H disease diagnosed in our laboratory. HPLC chromatograms were reviewed to determine the presence and retention time of the Hb H peak.

Results

Hemoglobin H was not reported in 24.2% of patients (23 of 95) with genotypic Hb H disease. The characteristic prerun peak of Hb H was present on review of all eight Variant or Variant II β‐thalassemia short‐program chromatograms. Elevated Hb F (≥3%) was reported in 14 cases. The Hb H peak was found in the Hb F window in 11 dual program cases. The incorrect identification of Hb H as elevated Hb F resulted in two testing referrals for ‘δβ‐thalassemia’.

Conclusions

Hemoglobin H may go unreported due to failure to examine for or recognize its peak on Variant or Variant II β‐thalassemia short‐program chromatograms. Elution of Hb H in the Hb F window resulted in misidentification of Hb H for Hb F and may indicate a Variant II HbA2/HbA1C program software error. Our findings highlight the need for careful chromatogram inspection and clinical correlation in the diagnosis of Hb H disease.
Sustainability‐oriented Innovation: A Systematic Review
Authors: Adams Richard , Jeanrenaud Sally , Bessant John , Denyer David , Overy Patrick
Published: May 2015

This paper is intended as a contribution to the ongoing conceptual development of sustainability‐oriented innovation (SOI) and provides initial guidance on becoming and being sustainable. The authors organize and integrate the diverse body of empirical literature relating to SOI and, in doing so, develop a synthesized conceptual framework onto which SOI practices and processes can be mapped. Sustainability‐oriented innovation involves making intentional changes to an organization's philosophy and values, as well as to its products, processes or practices to serve the specific purpose of creating and realizing social and environmental value in addition to economic returns. A critical reading of previous literature relating to environmental management and sustainability reveals how little attention has been paid to SOI, and what exists is only partial. In a review of 100 scholarly articles and 27 grey sources drawn from the period of the three Earth Summits (1992, 2002 and 2012), the authors address four specific deficiencies that have given rise to these limitations: the meaning of SOI; how it has been conceptualized; its treatment as a dichotomous phenomenon; and a general failure to reflect more contemporary practices. The authors adopt a framework synthesis approach involving first constructing an initial architecture of the landscape grounded in previous studies, which is subsequently iteratively tested, shaped, refined and reinforced into a model of SOI with data drawn from included studies: so advancing theoretical development in the field of SOI.
Comparison of the beta2‐adrenoceptor selectivity of rimiterol, salbutamol and isoprenaline by the intravenous route in man.
Authors: Marlin GE , Turner P
Published: May 2015

1 The bronchodilating efficacy and the degree of beta2‐adrenoceptor selectivity of rimiterol, salbutamol and isoprenaline were determined in seven subjects who exhibited histamine‐induced bronchoconstriction. 2 Rimiterol, 0.5 (high dose) and 0.05 (low dose) mug kg‐1 min‐1, salbutamol, 0.3 and 0.03 mug kg‐1 min‐1, isoprenaline, 0.05 and 0.005 mug kg‐1 min‐1 and placebo were administered by a single intravenous injection over 6 min, and the protection against histamine‐induced bronchoconstriction, changes in heart rate, pulse pressure and skeletal muscle tremor were measured. 3 Rimiterol (98%), salbutamol (96%) and isoprenaline (69%) protected against histamine‐induced bronchoconstriction. For these ventilatory responses, there was a heart rate increase of 31.9, 24.7 and 44.3 beats/min for rimiterol, salbutamol and isoprenaline respectively. The three drugs produced similar increases in pulse pressure and tremor. 4 Significant dose‐ responses were obtained for all the parameters with each drug. 5 Isoprenaline was approximately 7 and 5 times as potent as rimiterol and salbutamol respectively in bronchodilator action when equimolar doses were compared. Similarly, isoprenaline was approximately 14 and 10 times as potent in increasing the heart rate as rimiterol and salbutamol respectively. 6 Rimiterol, a new beta‐adrenoceptor stimulating drug, is an effective bronchodilator and has similar beta2‐ adrenoceptor selectivity to salbutamol when administered intravenously. The relative potencies and degrees of beta2‐adrenoceptor selectivity of these drugs depend partly on their route of administration.
The effect of metoclopramide on the absorption of effervescent aspirin in migraine.
Authors: Volans GN
Published: May 2015

1 The absorption of effervescent aspirin was studied in two groups of patients during attacks of migraine. The first group received effervescent aspirin alone whilst the second group received intramuscular metoclopramide before effervescent aspirin. 2 After effervescent aspirin alone there was significant impairment in the rate of aspirin absorption during migraine attacks compared with the rate of aspirin absorption in normal volunteers and in the same patients when headache‐free. 3 When metoclopramide was given before effervescent aspirin the rate of aspirin absorption during migraine attacks was not significantly different from that obtained in normal volunteers given effervescent aspirin alone or from that obtained in the patients themselves when given both metoclopramide and effervescent aspirin when headache‐free. 4 It is concluded that the impairment of absorption of effervescent aspirin during migraine attacks is related to impaired gastro‐intestinal motility with delayed gastric emptying and that this impaired motility can be overcome by parenteral metoclopramide.
The formation and release of metaraminol during exposure to warm or cold environments
Authors: JOHNSON G. E. , PUGSLEY T. A.
Published: May 2015

Rats were injected intraperitoneally with alpha‐methyl‐m‐tyrosine (400 mg/kg) and placed at either 27° C or 4° C. The levels of alpha‐methyl‐m‐tyramine, metaraminol and noradrenaline were determined in heart tissue after 1, 4 and 12 hr of treatment. The excretion of metaraminol, alpha‐methyl‐m‐tyramine, noradrenaline, adrenaline and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) was also estimated in both treated and control rats.

Cold exposure increased both the formation and excretion of metaraminol. Hearts removed from the cold‐stressed rats 4 hr after injection contained significantly more metaraminol than hearts taken from animals maintained in the warm environment. Twelve hours after treatment, no metaraminol remained in the hearts of cold‐exposed rats, whereas significant quantities of the amine still remained in the hearts of rats kept at 27° C. These results support the false transmitter concept advanced for metaraminol as they demonstrate that in vivo sympathetic stimulation can increase both the formation and release of metaraminol.

Alpha‐methyl‐m‐tyrosine produced a greater fall in cardiac noradrenaline in the rats kept at 27° C. Whereas an approximate mole‐for‐mole replacement of metaraminol for noradrenaline existed at 27° C, no such relationships existed at 4° C. Twelve hours after treatment the hearts of cold‐stressed rats contained no metaraminol and only 40% of control noradrenaline levels. These results do not support the necessity for a mole‐for‐mole replacement of noradrenaline with metaraminol to produce a catecholamine loss.

Alpha‐methyl‐m‐tyrosine depressed the noradrenaline excretion for at least 24 hr in the cold‐stressed rats. Excretion of 3‐methoxy‐4‐hydroxyphenylglycol was also lower in the treated rats between 0 and 12 hr in the cold but rose abruptly between 12 and 24 hr to exceed the quantity excreted by the control animals. This increase suggests an increase in noradrenaline synthesis, which may be related to the depletion of metaraminol from the body.

The results of this paper support the postulate that metaraminol may function as a false transmitter. They do not agree with the concept that the loss of noradrenaline from tissue sites is dependent upon a mole‐for‐mole replacement with metaraminol.
The actions of caerulein on the smooth muscle of the gastrointestinal tract and the gall bladder
Authors: BERTACCINI G. , DE CARO G. , ENDEAN R. , ERSPAMER V. , IMPICCIATORE M.
Published: May 2015

In the intact conscious dog, caerulein causes emesis and evacuation of the bowel. The mean effective dose by the intravenous route is 0.4–0.5 μg/kg, and by the subcutaneous route 3–4 μg/kg.

The gall bladder in situ or as an isolated preparation is highly sensitive to caerulein. A few ng/kg injected intravenously are sufficient to stimulate the gall bladder in situ and less than 1 ng/kg per min is effective when infused intravenously. The isolated gall bladder is contracted by caerulein in concentrations as low as 0.03–2 ng/ml. Krebs solution. There is no tachyphylaxis but, generally, a good dose‐response relationship. Hence the gall bladder, especially that of the guinea‐pig, appears to be very suitable for the bioassay of caerulein and related peptides.

In situ, the musculature of the gastrointestinal tract is also highly sensitive to caerulein. Doses as low as 1–5 ng/kg, administered intravenously, have a spasmogenic action on jejunal loops of the dog, and slightly larger doses contract the small intestine of the cat. The stomach and the large intestine seem to be somewhat less sensitive to the polypeptide. Caerulein has a considerable spasmogenic action on the rat pylorus but relaxes the sphincter of Oddi of the guinea‐pig.

Isolated preparations of the gastrointestinal tract are relatively insensitive to caerulein and tachyphylaxis occurs readily.

Blockade with atropine produces different effects in different intestinal segments and in different animal species. The spasmogenic action of caerulein on the gall bladder is atropine‐resistant.

The effects of caerulein are similar to those of cholecystokinin‐pancreozymin in the organs tested in situ or as isolated preparations. Caerulein, however, is always more potent than cholecystokinin‐pancreozymin, even on a molar basis. Compared with caerulein, human gastrin I has negligible activity.

The possible use of caerulein in cholecystography is discussed.
The analgesic action of morphine‐N‐oxide
Authors: FENNESSY M. R.
Published: May 2015

The analgesic activity of morphine‐N‐oxide in mice and rats has been investigated and compared with that of morphine.

Both morphine and morphine‐N‐oxide were more active when given subcutaneously than when given intraperitoneally.

Given subcutaneously, morphine was 11–22 times more potent than morphine‐N‐oxide and when given intraperitoneally it was 39–89 times more potent. The potencies depended on the test situation and the species of animal used.

In animals pretreated with amiphenazole or tacrine, the analgesic activities of morphine and morphine‐N‐oxide were increased. The potencies of these analgesic drugs given intraperitoneally were increased to a greater extent than were the potencies obtained by subcutaneous administration.

A possible explanation for the increase in analgesic potency of morphine‐N‐oxide produced by pretreatment with amiphenazole or tacrine may be that morphine‐N‐oxide is rapidly inactivated in the liver and this inactivation is impaired by amiphenazole and tacrine.
The ganglion‐stimulating effects of some amino‐acid esters
Authors: BRIMBLECOMBE R. W. , SUTTON JOAN V.
Published: May 2015

The effects of some amino‐acid esters possessing both muscarinic and nicotinic activity have been investigated on the cat superior cervical ganglion. The compounds were applied to the ganglion in vivo by close intra‐arterial injection and responses were measured by contraction of the nictitating membrane or by recording post ganglionic compound action potentials.

The esters, like carbachol, produced effects which were blocked by hexamethonium and reduced by atropine. Pretreatment with an anticholinesterase agent had no effect on the response and the chronically denervated ganglion was, if anything, slightly more sensitive to the drugs.

Effects of standard muscarinic and nicotinic drugs were also studied and the results support the view that both muscarinic and nicotinic receptors are present in the ganglion.

From the results of this investigation it appears that the amino‐acid esters and carbachol produce their effects by interacting with post synaptic receptors in the ganglion. This is in contrast to other results in the literature which suggest that the receptors might be presynaptic. Further studies are required to resolve this difference.
The effect of antidepressants and “tranquillizers” on the response of mice to ethanol
Authors: MILNER G.
Published: May 2015

The techniques and apparatus used for investigation of the interaction of various psychotropic drugs with ethanol in mice are described. The parameters measured were (a) length of loss of righting reflexes; (b) continuous coma; (c) subjects remaining in coma 12 hr after dosing; (d) changes in toxicity.

The following drugs were tested: amitriptyline, trimipramine, imipramine, nortriptyline, desipramine, thioridazine, phenelzine, methylphenidate, chlorpromazine, trifluoperazine, phenobarbitone, and diazepam. The total number of mice used was 3,140.

Imipramine caused no significant changes in the effects of ethanol. Methylphenidate and desipramine protected the mice against ethanol induced coma. All other drugs induced statistically significant potentiation of the depressant and toxic effects of ethanol in mice.

Late (delayed) deaths after a tricyclic antidepressant have been noted in animals and man.

It is suggested that the potentiation of alcohol by some psychotropic drugs may add to the hazards of drug overdosage and contribute to traffic accidents. Hence it is necessary to test all psychotropic drugs for interaction with alcohol.
The excretion and metabolism of oral 14C‐pyridostigmine in the rat
Authors: HUSAIN M. A. , ROBERTS J. B. , THOMAS B. H. , WILSON A.
Published: May 2015

Pyridostigmine labelled with carbon‐14 in the methyl group of the quaternary nitrogen has been used to investigate the excretion and metabolism of the drug after administration of single doses (500 μg) to the rat by stomach tube.

Pyridostigmine is slowly excreted in the urine; the maximum excretion occurs between 1–3 hr after administration. In 24 hr 42% of the dose is excreted in urine and 38.4% is present in faeces and intestinal contents.

The peak concentration of radioactivity in liver and blood occurs about 2 hr after administration.

About 75% of the radioactivity in urine is present as unchanged pyridostigmine, the remainder as metabolite.

The results are compared with those previously obtained after oral administration of neostigmine.

It is concluded that after oral administration the absorption of pyridostigmine is greater and the metabolism substantially less than that of neostigmine.
Interaction in the cerebral metabolism of the biogenic amines. Effects of phenelzine on the cerebral metabolism of the 5‐hydroxyindoles in dog brain
Authors: MOIR A. T. B.
Published: May 2015

Chronic administration of phenelzine to dogs caused 5‐hydroxyindol‐3‐ylacetic acid (5‐HIAA) concentrations in c.s.f. from the lateral ventricle to be maintained at 50% of their normal values, but did not alter the concentrations of 5‐HIAA in c.s.f. from the cisterna magna.

Following 10 days treatment with phenelzine, the active transport of 5‐HIAA from c.s.f. which normally occurs in the region of the fourth ventricle, was inhibited. This transport system was also inhibited by the addition of phenylacetic acid, the acid metabolite of phenelzine, to the fluid perfusing the cerebral ventricles.

After 10–12 days treatment with phenelzine all regions of brain showed concentration increases to approximately 300% for 5‐HT and 150% for 5‐HIAA, but no alteration in the tryptophan concentration.

Intravenous administration of tryptophan to dogs pretreated with phenelzine caused large increases in the concentration of tryptophan in brain and body fluids but did not alter either the concentrations of 5‐hydroxytryptamine and 5‐HIAA in brain or of 5‐HIAA in c.s.f.

A model of the cerebral metabolism of 5‐hydroxytryptamine is proposed and the results are interpreted to mean that phenelzine has inhibitory actions, either directly or in some instances indirectly, on intracerebral tryptophan 5‐hydroxylase, monoamine oxidase and the transport of 5‐HIAA from both brain and c.s.f.
Intracellular pH in rat isolated superior cervical ganglia in relation to nicotine‐depolarization and nicotine‐uptake
Authors: BROWN D. A. , HALLIWELL J. V.
Published: May 2015

The intracellular pH (pHi) of rat isolated superior cervical ganglia incubated in normal Krebs solution (pHo = 7·37) was estimated to be 7·33 from the uptake of a weak acid, 14C‐5,5‐dimethyloxazolidine‐2,4‐dione (DMO). Addition of 30 μm nicotine for 30 min reduced the DMO‐estimated pHi by 015 units to 7·18. This effect was prevented by hexamethonium (2·5 mm) or by depolarizing the ganglion with K+ (124 mm).

3H‐Nicotine (30 μm) was concentrated within the ganglia to an intracellular/extracellular concentration ratio (Ci/Co) of 5·54 in normal Krebs solution and 4·61 in 2·5 mm hexamethonium. This would suggest an intracellular pH of 6·54 and 6·63 respectively. In ganglia previously depolarized by K+ the corresponding values for Ci/Co were 402 (minus hexamethonium, estimated pHi 6·95) and 4·17 (plus hexamethonium, estimated pHi 6·94).

A multicompartment cell interior comprising an acid cytoplasm (pH˜6·6) and more alkaline nucleus and mitochondria is proposed to explain the difference between the values of pHi estimated from the uptake of DMO and nicotine. It is suggested that the fall in pHi during nicotine‐depolarization results from metabolic stimulation following Na+ entry.
ADRENOCEPTORS IN INTRACEREBRAL RESISTANCE VESSELS
Authors: MITCHELL G. , SCRIVEN D.R.L. , ROSENDORFF C.
Published: May 2015

The effects of tyramine and isoprenaline on hypothalamic blood flow (HBF) were measured in conscious rabbits.

Injections of small doses of tyramine caused an increase in HBF while larger doses caused a decrease in HBF.

Isoprenaline injections also produced an increase in HBF.

The vasodilatation induced by isoprenaline and the small dose of tyramine was blocked by propranolol.

The vasoconstriction induced by the larger doses of tyramine was abolished by phenoxybenzamine.

Chemical sympathectomy of the hypothalamus with 6‐hydroxydopamine and depletion of biogenic amines by reserpine also abolished tyramine‐induced vasoconstriction.

These results suggest the presence of α‐ and β‐adrenoceptors in cerebral resistance vessels, and that these receptors may be activated by released (endogenous) noradrenaline.
MODULATION BY ACETYLCHOLINE OF ADRENERGIC TRANSMISSION IN THE RABBIT EAR ARTERY
Authors: ALLEN G.S. , GLOVER A.B. , McCULLOCH M.W. , RAND M.J. , STORY D.F.
Published: May 2015

Low concentrations of acetylcholine (4 × 10−11 and 1 × 10−10 M) increase the vasoconstrictor response of the isolated ear artery of the rabbit to stimulation of the periarterial sympathetic nerves. Higher concentrations (4 × 10−8 M and greater) decrease the response.

Low concentrations of acetylcholine (1 × 10−11 and 1 × 10−10 M) increase the stimulation‐induced efflux of radioactivity from artery segments previously incubated with [3H]‐noradrenaline. Higher concentrations (3 × 10−8 M and greater) decrease the efflux.

Neither atropine nor hexamethonium affects the facilitatory action of low concentrations of acetylcholine on adrenergic transmission in the rabbit ear artery.

Atropine antagonizes the inhibitory effect of higher concentrations of acetylcholine on adrenergic transmission.
INTERACTION OF COMPETITIVE ANTAGONISTS: THE ANTI‐CURARE ACTION OF HEXAMETHONIUM AND OTHER ANTAGONISTS AT THE SKELETAL NEUROMUSCULAR JUNCTION
Authors: BLACKMAN J.G. , GAULDIE R.W. , MILNE R.J.
Published: May 2015

In the rat isolated diaphragm preparation hexamethonium and other low potency competitive antagonists of acetylcholine (ACh), including gallamine and hyoscine butylbromide, reverse block by the potent antagonists tubocurarine, pancuronium and alcuronium.

In the presence of tubocurarine, hexamethonium increases the amplitude of the end‐plate potential without increasing the quantal content. It enhances the response to ACh applied iontophoretically to the end‐plate but does not enhance the response to ACh applied in the bath.

The anti‐curare effect of hexamethonium is abolished in the diaphragm of the rat, guinea‐pig and mouse by inhibitors of acetylcholinesterase. The effect is not observed in the indirectly stimulated toad sartorius muscle.

The effect is explained if tubocurarine does not dissociate appreciably in the time taken for ACh to achieve high occupancy of receptors, so that a fraction of receptors is completely excluded from occupation by ACh. Equilibration with hexamethonium reduces the fraction excluded by tubocurarine and the transmitter now competes with hexamethonium for more receptors and produces a larger response.

On the basis of this explanation the half‐time for dissociation of tubocurarine must be about 1 millisecond. It follows that tubocurarine does not act competitively with ACh at synapses when transmitter action is sufficiently brief, and that its binding to the receptor is probably diffusion‐limited.
THE ACTIONS OF DIHYDROXYPHENYLALANINE AND DIHYDROXYPHENYLSERINE ON THE SLEEP‐WAKEFULNESS CYCLE OF THE RAT AFTER PERIPHERAL DECARBOXYLASE INHIBITION
Authors: ALTIER H. , MOLDES M. , MONTI J.M.
Published: May 2015

The actions of dihydroxyphenylalanine (DOPA) and dihydroxyphenylserine (DOPS) were assessed on the sleep‐wakefulness cycle of male Wistar rats.

In comparative studies the extracerebral decarboxylase was inhibited with serinetrihydroxybenzylhydrazide (RO 4‐4602) before injection of DOPA or DOPS.

DOPA (80‐160 mg/kg, i.p.) with or without previous inhibition of the peripheral decarboxylase gave rise to an initial significant increase of slow wave activity, which may be related to a release of 5‐hydroxytryptamine.

During the subsequent 8 h sessions, DOPA significantly decreased slow wave sleep and rapid eye movement sleep (REM) and increased wakefulness.

DOPS (80‐160 mg/kg, i.p.) did not significantly modify the sleep‐wakefulness cycle apart from a decrease of the latency for the first REM episode after 160 mg/kg in the RO 4‐4602 pretreated animals.
THE SIZE OF HYDROXYL GROUPS IN SOLUTION AND THE CHANGES IN SIZE ASSOCIATED WITH THE IONIZATION OF PHENOLIC, CARBOXYLIC AND AMINO GROUPS IN PHENOLIC QUATERNARY AMMONIUM SALTS, NICOTINE AND SOME AMINO ACIDS: POSSIBLE IMPLICATIONS FOR DRUG‐WATER AND DRUG‐RECEPTOR INTERACTIONS
Authors: BARLOW R.B.
Published: May 2015

Size in solution can be expressed either as the apparent molal volume at infinite dilution (φv0) and the concentration parameter (j) or as the partial molal volume of the solute at infinite dilution () and the concentration parameter for the solute or solvent (qs or qw). Although calculated differently, these are derived from the same results and are equivalent.

From measurements with phenolic quaternary ammonium salts, including compounds with high nicotine‐like activity, the apparent size of the hydroxyl group in water is small and variable. Phenolic groups are slightly larger than alcoholic groups, which should be better hydrogen donors.

By measuring the volume change associated with ionisation it is possible to measure the size of charged groups such as phenate and carboxylate; these are much smaller than phenolic and carboxyl. Ammonium groups, however, are only slightly smaller than the corresponding amines.

The zwitterion forms of amino acids are associated with a minimum in volume but the volume changes increase with chain length from glycine to γ‐aminobutyric acid. Groups separated by less than this distance interact in their effects on water.

Decreases in volume or unexpectedly small increments in apparent molal volume represent decreases in entropy which must be taken into account in drug‐water‐receptor interactions. Although they may be offset by enthalpy changes, they should favour binding because there is more scope for an increase in entropy. This might explain the association of the small apparent size in water of the hydroxyl group in many compounds with its effects on their affinity for receptors.
STIMULATION OF THE ANTIGEN‐INDUCED CONTRACTION OF GUINEA‐PIG TRACHEA AND IMMUNOLOGICAL RELEASE OF HISTAMINE AND SRS‐A FROM SENSITIZED GUINEA‐PIG LUNG BY (2‐ISOPROPYL‐3‐INDOLYL)‐3 PYRIDYL KETONE (L8027) AND INDOMETHACIN
Authors: HITCHCOCK MARGARET
Published: May 2015

(2‐Isopropyl‐3‐indolyl)‐3 pyridyl ketone (L8027) and indomethacin reduced basal tension and enhanced the antigen‐ and histamine‐induced contractions of tracheal spirals obtained from actively sensitized guinea‐pigs. The stimulating effect of L8027 required the presence of the drug, while that of indomethacin persisted after its removal from the organ bath.

L8027 and indomethacin stimulated the immunological release of histamine and slow reacting substance of anaphylaxis (SRS‐A) and inhibited the de novo synthesis and release of malondialdehyde from actively sensitized guinea‐pig lung fragments.

L8027 was 2,800 times more potent than indomethacin in both in vitro models of anaphylaxis.

A selective antagonist of SRS‐A (FPL 55712) inhibited contractions produced by antigen, but had no effect on contractions produced by histamine.

Prostaglandins E and F2α were continuously released into the organ bath fluid by the resting trachea. Contractions induced by antigen or histamine increased the rate of prostaglandin efflux.

L8027 had no effect on the efflux of prostaglandins E and F2α at rest and during contraction. Indomethacin inhibited prostaglandin efflux at rest and during contraction while present in the organ bath. Prostaglandin efflux was restored to 80% of control after removal of indomethacin.

The results suggest that prostaglandins E and F2α have no role in the stimulation by L8027 and indomethacin of the contractile responses of guinea‐pig trachea. The possible mechanism for the effects of these drugs is discussed.
THE EFFECT OF γ‐AMINOBUTYRIC ACID ON THE INPUT CONDUCTANCE AND MEMBRANE POTENTIAL OF ASCARIS MUSCLE
Authors: MARTIN R.J.
Published: May 2015

Twin intracellular recordings were made from the bag region of Ascaris muscle in order to make conductance measurements. The preparation was bathed in a cool (22°C) Ringer solution to abolish the large spontaneous depolarizing potentials and to improve stability for recording.

The resting membrane potential was − 31 ± 1 mV, mean ± s.e. mean (n = 17). The current‐voltage plots were linear in the hyperpolarizing direction but showed evidence of delayed rectification during the application of depolarizing currents. The input conductance of the bag was measured from the slope of these plots during the application of hyperpolarizing current. The resting conductance of the bags was 2.4 ± 0.2 μS, mean ± s.e. mean (n = 12).

When the preparation was perfused with γ‐aminobutyric acid (GABA) in concentrations greater than 3 μm, a dose‐dependent increase in conductance associated with a hyperpolarizing potential was recorded. The log dose‐response relationship obtained from 6 preparations was sigmoidal and had an ED50 of 3 μm.

When Cl− in the Ringer was replaced by SO2‐4, the GABA‐induced conductance changes decreased and were associated with depolarizing potentials.

Voltage responses were recorded in the bag region during the iontophoretic application of GABA to different regions of the muscle cell. The largest responses were recorded when GABA was applied to the bag region. Smaller responses were recorded when GABA was applied to the arms and syncytial regions. The responses of the bags were dose‐dependent and were antagonized by bath‐applied picrotoxin.

An extrapolation method using 10−5 m GABA suggested that the GABA reversal potential was about 30 mV more negative than the resting membrane potential. This was confirmed by means of a two microelectrode voltage clamp technique. The reversal potential was thus estimated as − 61.2 + 2.2 mV mean ± s.e. mean (n = 27).
EFFECTS OF METOCLOPRAMIDE AND ISOPRENALINE IN THE RAT VAS DEFERENS; INTERACTIONS WITH α‐ADRENOCEPTORS
Authors: SPEDDING M.
Published: May 2015

Metoclopramide (2.8 to 280 μm) augmented contractions of rat vas deferens preparations induced by field stimulation (6 Hz for Is). This effect was antagonized by phentolamine (0.1 μm). Metoclopramide (2.8 to 280 μm) did not affect phenylephrine‐induced contractions.

Metoclopramide (2.8 to 280 μm) antagonized the inhibitory effects of clonidine on the contractions induced by field stimulation, but not the inhibitory effects of purine nucleosides.

From these results it is concluded that metoclopramide (2.8 to 280 μm) is a presynaptic α‐adrenoceptor antagonist in the rat vas deferens.

Following β‐adrenoceptor blockade with (±)‐propranolol (3.3 μm), (‐)‐isoprenaline (0.47 to 14 μm) inhibited responses to field stimulation but not to phenylephrine. These propranolol‐resistant effects of isoprenaline were antagonized by metoclopramide (2.8 to 280 μm) and by phentolamine (0.1 to 10 μm), indicating that isoprenaline may stimulate presynaptic α‐adrenoceptors in this preparation.