bluuebunny/crossref_metadata_2025 huggingface dataset:
Testing for urinary tract colonization before high‐dose corticosteroid treatment in acute multiple sclerosis relapses: prospective algorithm validation
Authors: Rakusa M. , Murphy O. , McIntyre L. , Porter B. , Panicker J. , Fowler C. , Scott G. , Chataway J.
Published: July 2012

Background and purpose

To evaluate a dipstick algorithm for urinary tract colonization, prior to high‐dose corticosteroid treatment in acute relapses of multiple sclerosis (MS).

Methods

Prospective cohort study of 267 consecutive patients with MS relapses requiring corticosteroid treatment in a hospital‐based, ambulatory, acute MS relapse clinic. A total of 18 participants met the exclusion criteria, leaving 249 for analysis. Main outcome measures were urinary dipstick sensitivity, specificity, positive predictive value, negative predictive value and safety of antibiotic co‐treatment with high‐dose corticosteroids.

Results

Significant bacteriuria (≥105 colonies ml) rate in this population was 11% (95% CI, 7.1–14.9). Specificity and sensitivity of positive leucocyte esterase or nitrite were 78% and 65%. Negative predictive value of urine dipstick was 96%. No clinical adverse events occurred in the 3% (95% CI, 0.9–5.1) of patients with a false‐negative dipstick. Eighteen per cent of patients were unnecessarily treated with antibiotics for 48 h.

Conclusion

Urinary dipstick testing allows for rapid and safe management of patients suffering from an acute MS relapse. The algorithm is conservative, and future work is needed to reduce the false‐positive rate.
Supratentorial and pontine MRI abnormalities characterize recessive spastic ataxia of Charlevoix‐Saguenay. A comprehensive study of an Italian series
Authors: Prodi E. , Grisoli M. , Panzeri M. , Minati L. , Fattori F. , Erbetta A. , Uziel G. , D'Arrigo S. , Tessa A. , Ciano C. , Santorelli F. M. , Savoiardo M. , Mariotti C.
Published: July 2012

Background and purpose

The autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) is an early‐onset neurodegenerative disorder caused by mutations in the SACS gene. The disease, first described in Canadian families from Québec, is characterized by cerebellar ataxia, pyramidal tract involvement and peripheral neuropathy.

Methods

Analysis of SACS gene allowed the identification of 14 patients with ARSACS from 13 unrelated Italian families. Clinical phenotype, gene mutations and magnetic resonance imaging (MRI) findings were analysed.

Results

We found 16 novel SACS gene mutations, including a large in‐frame deletion. The age at onset was in infancy, but one patient presented the first symptoms at age 32. Progression of the disease was variable, and increased muscle tone was mostly recognized in later stages. Structural MRI showed atrophy of the superior cerebellar vermis, a bulky pons exhibiting T2‐hypointense stripes, identified as the corticospinal tract (CST), thinning of the corpus callosum and a rim of T2‐hyperintensity around the thalami in 100% of cases. The presence of iron or other paramagnetic substances was excluded. Diffusion tensor imaging (DTI) revealed grossly over‐represented transverse pontine fibres (TPF), which prevented reconstruction of the CST at this level (100% of cases). In all patients, significant microstructural alterations were found in the supratentorial white matter of forceps, cingulum and superior longitudinal fasciculus.

Conclusions

Our findings further enlarge the genetic spectrum of SACS mutations and widen the study of clinical phenotype. MRI characteristics indicate that pontine changes and supratentorial abnormalities are diagnostic. The over‐representation of TPF on DTI suggests a developmental component in the pathogenesis of the disease.
Frequencies of falls and associated features at different stages of Parkinson's disease
Authors: Hiorth Y. H. , Lode K. , Larsen J. P.
Published: July 2012

Background and purpose

To examine the frequencies and clinical characteristics of fallers and non‐fallers at different stages of Parkinson's disease (PD).

Methods

The sample consisted of 232 patients in an unselected cross‐sectional cohort of patients with PD, 207 newly diagnosed and drug naive patients and 175 controls. The examinations included the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr, Schwab and England, and Mini‐Mental State Examination. According to item 13 of the UPDRS, the participants were classified as fallers, rare‐fallers and non‐fallers.

Results

In the cross‐sectional study cohort, 19% of the patients were classified as fallers and 25% as rare‐fallers. Higher scores on activity of daily living (UPDRS ADL score) and motor complications (UPDRS complication of therapy score) were significantly and independently associated with falling. In the cohort of newly diagnosed patients with PD 2% were classified as fallers and 15% as rare‐fallers. In the age‐ and sex‐matched control group, none were fallers, and only 2% were rare‐fallers. Patients with tremor‐dominated PD subtype in both study populations did not fall.

Conclusions

Falls are a markedly increasing problem in patients with PD as the disease progresses. Healthcare workers should ask patients about falling, and specially focus on patients with motor complications or postural instability and gait disability‐dominated subtype of parkinsonism.
Using robots to understand social behaviour
Authors: Mitri Sara , Wischmann Steffen , Floreano Dario , Keller Laurent
Published: July 2012

A major challenge in studying social behaviour stems from the need to disentangle the behaviour of each individual from the resulting collective. One way to overcome this problem is to construct a model of the behaviour of an individual, and observe whether combining many such individuals leads to the predicted outcome. This can be achieved by using robots. In this review we discuss the strengths and weaknesses of such an approach for studies of social behaviour. We find that robots—whether studied in groups of simulated or physical robots, or used to infiltrate and manipulate groups of living organisms—have important advantages over conventional individual‐based models and have contributed greatly to the study of social behaviour. In particular, robots have increased our understanding of self‐organization and the evolution of cooperative behaviour and communication. However, the resulting findings have not had the desired impact on the biological community. We suggest reasons for why this may be the case, and how the benefits of using robots can be maximized in future research on social behaviour.
Transmembrane semaphorin5B is proteolytically processed into a repulsive neural guidance cue
Authors: Browne Kristen , Wang Wenyan , Liu Rachel Q. , Piva Matthew , O’Connor Timothy P.
Published: July 2012

Developing neuronal growth cones respond to a number of post‐transcriptionally modified guidance cues to establish functional neural networks. The Semaphorin family has well‐established roles as both secreted and transmembrane guidance cues. Here, we describe the first evidence that a transmembrane Semaphorin, Semaphorin 5B (Sema5B), is proteolytically processed from its transmembrane form and can function as a soluble growth cone collapsing guidance cue. Over‐expression of A Disintegrin and Metalloprotease (ADAM)‐17, results in an enhanced release of the Sema5B ectodomain, while removal of a predicted ADAM‐17 cleavage site prevents its release. In contrast, knockdown of ADAM‐17 does not significantly reduce Sema5B release, indicating there are additional unknown compensating proteases. This modulation of the transmembrane Sema5B to a diffusible cue represents a sophisticated method to regulate neuronal guidance in vivo.
Positive feedback regulation of Akt‐FMRP pathway protects neurons from cell death
Authors: Jeon Se Jin , Han Seol‐Heui , Yang Sung‐Il , Choi Ji woong , Kwon Kyoung Ja , Park Seung Hwa , Kim Hahn Young , Cheong Jae Hoon , Ryu Jong Hoon , Ko Kwang Ho , Wells David G , Shin Chan Young
Published: July 2012

J. Neurochem. (2012) 123, 226–238.

Fragile X syndrome (FXS), the most common single genetic cause of mental retardation and autistic spectrum disease, occurs when FMR1 gene is mutated. FMR1 encodes fragile X mental retardation protein (FMRP) which regulates translation of mRNAs playing important roles in the development of neurons as well as formation and maintenance of synapses. To examine whether FMRP regulates cell viability, we induced apoptosis in rat primary cortical neurons with glutamate in vitro and with middle cerebral artery occlusion (MCAO) in striatal neurons in vivo. Both conditions elicited a rapid, but transient FMRP expression in neurons. This up‐regulated FMRP expression was abolished by pre‐treatment with PI3K and Protein Kinase B (Akt) inhibitors: LY294002, Akt inhibitor IV, and VIII. Reduced FMRP expression in vitro or in vivo using small hairpin Fmr1 virus exacerbated cell death by glutamate or MCAO, presumably via hypophosphorylation of Akt and reduced expression of B‐cell lymphoma‐extra large (Bcl‐xL). However, over‐expression of FMRP using enhanced green fluorescent protein (eGFP)‐FMRP constructs alleviated cell death, increased Akt activity, and enhanced Bcl‐xL production. The pro‐survival role of Akt‐dependent up‐regulation of FMRP in glutamate‐stimulated cultured neuron as well as in ischemic brain may have a clinical importance in FXS as well as in neurodegenerative disorders and traumatic brain injury.
Inhibition of G1 cell cycle arrest in human gingival fibroblasts exposed to phenytoin
Authors: Takeuchi Reiri , Matsumoto Hiroko , Akimoto Yoshiaki , Fujii Akira
Published: July 2012

Gingival overgrowth is caused in response to the antiepileptic drug phenytoin (PHT). PHT‐induced gingival overgrowth is characterized by the proliferation of fibroblasts and increased collagen formation in gingiva. Fibroblast proliferation is regulated through the cell cycle. Thus, in the present study, we examined the effects of PHT on the cell cycle, the expression of cell cycle control proteins and the proliferation in human gingival fibroblasts (hGFs). Cells were stimulated in serum‐free DMEM with or without 0.25 μm PHT. Subsequently, the cell cycle phase distribution and the protein expression after 24 h and the cell proliferation after 24, 48 and 72 h were evaluated. PHT significantly inhibited synchronization at the G0/G1 phase of the cell cycle in hGFs through serum starvation. Stimulation with PHT for 48 and 72 h significantly induced a proliferative response in hGFs. PHT decreased the expression of the Cdk‐inhibitory proteins p21 and p27 and increased the levels of the S phase‐promoting proteins phospho‐Thr160‐Cdk2 and phospho‐Ser807/811‐Rb in serum‐free DMEM. The inhibition of G1 cell cycle arrest in hGFs may result from an increase in phosphorylated Cdk2 and Rb proteins and decreased levels of p21 and p27 proteins by PHT. The gingival overgrowth may be caused by the failure of the G1 cell cycle arrest in GFs exposed to PHT.
Effect of DHA+EPA on oxidative stress and apoptosis induced by ischemia‐reperfusion in rat kidneys
Authors: Ajami Marjan , Davoodi Sayed Hossein , Habibey Rouhollah , Namazi Nasim , Soleimani Mansoureh , Pazoki‐Toroudi Hamidreza
Published: July 2012

Apoptosis, as well as necrosis, has an important role in post‐ischemic renal pathology. The effect of pretreatment with Docosahexaenoic acid+Eicosapentaenoic acid (DHA+EPA) on renal injury and apoptotic protein expression was evaluated. Right nephrectomy was completed on male Wistar rats (255–300 g). The rats received DHA+EPA (200 mg/kg/day) of distilled water orally for 14 days before ischemia reperfusion (IR) or sham operation. A total of 81 rats were divided into three main groups with 6, 24 and 48 h of post‐operation or reperfusion period. Serum creatinine (SCr), BUN, creatinine clearance (CCr) and fractional excretion of sodium (FENa) were measured. Tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) activities, Bax and Bcl‐2 protein expressions and renal histological injury were determined. SCr, BUN and FENa increased 6–48 h of reperfusion (P < 0.01). Tissue MDA content and Bax expression increased (P < 0.01) and CAT and SOD activities decreased (P < 0.05) in the IR group. DHA+EPA decreased SCr and BUN, FENa, tissue MDA levels (P < 0.05 vs. IR) and increased CAT and SOD activities and Bcl‐2 expression (P < 0.05 vs. IR) for 6–48 h after ischemia. IR induced mild (6 h, P < 0.05) and severe (24–48 h, P < 0.01) tissue damage. Mild‐to‐moderate tissue damage was observed in DHA+EPA groups from 6 to 48 h of reperfusion period (P < 0.05 vs. IR, 24–48 h). In conclusion, the results suggest that pre‐ischemic exposure to DHA+EPA could improve the outcome of early graft function by inhibition of IR‐induced oxidative stress and apoptosis.
Outcomes for Whites and Blacks at Hospitals That Disproportionately Care for Black Medicare Beneficiaries
Authors: López Lenny , Jha Ashish K.
Published: July 2012

Objective

Hospital care for blacks is concentrated among a small number of hospitals and whether they have worse outcomes across common medical conditions is unknown.

Data Source

We used the 2007 100% Medicare file to calculate 30‐ and 90‐day mortality rates for white and black patients admitted for acute myocardial infarction (AMI), congestive heart failure (CHF), or pneumonia.

Study Design

We ranked all hospitals in the country by their proportion of discharged black patients and identified the top 10 percent of these hospitals as black serving. We examined race‐specific adjusted mortality rates and adjusted for differences in hospital characteristics.

Principal Findings

At 30 days, black‐serving hospitals had, compared with nonblack‐serving hospitals, similar mortality for AMI, lower mortality for CHF, and higher mortality for pneumonia. At 90 days, mortality was higher at black‐serving hospitals for both AMI and pneumonia and comparable for CHF compared with nonblack‐serving hospitals. White patients had worse outcomes at black‐serving hospitals for two conditions at 30 days and all three conditions at 90 days. Blacks also had worse outcomes at black‐serving hospitals.

Conclusions

Hospitals with a high proportion of black patients had worse outcomes than other hospitals for both their white and black elderly patients.
Accidental and experimentally induced 5‐fluorouracil toxicity in dogs
Authors: Sayre Rebecca S. , Barr James W. , Bailey E. Murl
Published: July 2012

Objective

To summarize the literature involving 5‐fluorouracil (5‐FU) toxicosis in dogs.

Etiology

5‐Fluorouracil's mechanism of action revolves around the metabolism of 5‐FU into fluorouridine triphosphate which then interferes with RNA synthesis and function as well as the inhibition of thymidylate synthase which ultimately impairs DNA stability. Toxicity of 5‐FU is the most pronounced on rapidly dividing cells. Toxicity manifests itself mainly in the neurologic, gastrointestinal, respiratory, or hematopoietic systems.

Diagnosis

History of accidental exposure to 5‐FU‐containing products.

Therapy

Therapy for 5‐FU toxicosis involves typical decontamination procedures and symptomatic therapy for the subsequent toxicity. Seizure control and treatment of the severe gastrointestinal signs that follow are the primary goals in the acute setting. As the disease progresses, management of the sequelae to bone marrow suppression and pulmonary complications are essential.

Prognosis

The prognosis for dogs with ingestion of 5‐FU is dependent on the amount consumed, with severe intoxication carrying a poor prognosis. Toxic doses can be as little as 5 mg/kg, and doses ≥40 mg/kg are reported to be uniformly fatal.
Effects of amiloride on active sodium transport by the isolated frog skin: evidence concerning site of action
Authors: SALAKO L. A. , SMITH A. J.
Published: July 2012

Amiloride reduces short‐circuit current and potential difference across the isolated frog skin.

Isotopically measured sodium influx and efflux are diminished.

Total electrical conductance and partial sodium conductance are diminished, the reduction in total conductance being entirely accounted for by the reduction in partial sodium conductance.

The effect of antidiuretic hormone (ADH), cyclic 3′5′‐adenosine monophosphate (cyclic AMP) and theophylline can be antagonized by pretreatment with amiloride but the antagonism can be abolished by increasing the concentration of these compounds.

Amiloride has no effect on oxygen consumption in concentrations which inhibit sodium transport. However, it prevents the stimulatory effect of ADH on oxygen consumption.

The results are consistent with an action of amiloride at the passive outside membrane of the transporting cells of isolated frog skin.
Changes in the molecular composition of circulating hydroxyethyl starch
Authors: FARROW S. P. , HALL M. , RICKETTS C. R.
Published: July 2012

Hydroxyethyl starch (HES) of molecular weight 450,000 has been extensively investigated as a plasma volume expander and HES of molecular weight 60,000 has been proposed for use as a cryoprotective agent in the freezing for preservation of red blood cells. In these applications considerable amounts of HES may be injected intravenously and it is therefore desirable to understand its behaviour in vivo.

After intravenous injection into rabbits, plasma levels of HES and clinical dextrans were determined using anthrone. HES persisted longer in the circulation than did the dextrans.

HES was recovered from the bloodstream of rabbits and shown by gel filtration to be of a narrower molecular size distribution than the injected material. Smaller molecules were removed, presumably by filtration at the glomerulus. Larger molecules may have been removed by cells of the reticuloendothelial system or possibly through the action of amylase.

The amylase in saliva was shown to break down HES into molecules of intermediate size with very little production of maltose units.
Regional circulatory effects of pancreatic glucagon
Authors: ROSS G.
Published: July 2012

The effects of close intra‐arterial injections and infusions of glucagon on blood flow in the femoral, hepatic and superior mesenteric arteries of anaesthetized cats were studied using non‐cannulating electromagnetic flow probes.

Glucagon dilated the mesenteric vasculature. The threshold dose for rapid injections was less than 1 μg and maximal changes were produced by 10–20 μg. The dilatation began within a few seconds of injection and was unaffected by prior denervation or by pre‐treatment with propranolol or atropine.

Close intra‐arterial glucagon increased the resistance of the hepatic arterial bed but had no effect on femoral vascular resistance. Intravenous glucagon failed to alter renal blood flow.

Glucagon is therefore a potent vasoactive substance with its effect wholly or predominantly confined to the splanchnic area.

It has been suggested that the cardiac effects of glucagon and isoprenaline resemble each other because both compounds act on the β‐adrenoceptor mechanism. The different regional vascular effects of glucagon and isoprenaline suggest that glucagon vasodilatation may not be mediated via β‐adrenoceptors.
The effects of cholinomimetic drugs on responses to sympathetic nerve stimulation and noradrenaline in the rabbit ear artery
Authors: RAND M. J. , VARMA B.
Published: July 2012

The effects of infusions of the cholinomimetic drugs acetylcholine, methacholine, muscarine, carbachol, arecoline and pilocarpine were examined on vasoconstrictor responses of the perfused rabbit ear artery to sympathetic nerve stimulation and to injections of noradrenaline.

The first effect of very low concentrations of acetylcholine or muscarine was a slight enhancement of responses to sympathetic nerve stimulation, but when higher concentrations of acetylcholine, methacholine, muscarine, carbachol and arecoline were infused, these vasoconstrictor responses were decreased. With still higher concentrations the responses tended to increase in size during the infusion. After stopping an infusion, the depressed vasoconstrictor responses rapidly recovered and became enhanced.

Infusions of pilocarpine in a wide range of concentrations generally caused enhancement of responses.

The depressant effects of cholinomimetic drugs on the responses to sympathetic nerve stimulation were antagonized by atropine. Larger concentrations of the drugs overcame the blockade by atropine.

The effects of acetylcholine, methacholine and muscarine on the responses to sympathetic nerve stimulation were more pronounced at low than at high frequencies of stimulation.

Vasoconstrictor responses to injected noradrenaline were enhanced by acetylcholine or methacholine, whereas responses to sympathetic nerve stimulation were decreased by the same concentrations of these choline esters.

It is suggested that cholinomimetic drugs may act on receptor sites associated with the adrenergic terminal axon and that they may facilitate or impair the release of noradrenaline and impair noradrenaline uptake.
Mechanism of the antagonism of the hypotensive action of guanethidine by propranolol
Authors: GREWAL R. S. , KAUL C. L.
Published: July 2012

Propranolol antagonizes the hypotensive effect of guanethidine in renal hypertensive but not in adrenal demedullated renal hypertensive rats.

Guanethidine does not interfere with the release of catecholamines from the adrenal gland which follows splanchnic nerve stimulation in cats anaesthetized with pentobarbitone.

Guanethidine does not release or interfere with the release of catecholamines after the intravenous injection of physostigmine in the rat.

Propranolol antagonizes the antihypertensive effect of guanethidine by potentiating the vasopressor effects of catecholamines released from the adrenal glands during the induction stage of ether anaesthesia.
Uptake and metabolism of catecholamines in the perfused hearts of different species
Authors: JARROTT B.
Published: July 2012

The uptake of (±)‐3H‐noradrenaline was studied in isolated perfused hearts of rat, mouse, guinea‐pig, pigeon and toad (Bufo marinus), and the IC50 (concentration causing 50% inhibition) values for inhibition of uptake of (±)‐3H‐noradrenaline by (–)‐noradrenaline were calculated. IC50 values ranging from 0·28 μm (rat heart) to 2·34 μm (toad heart) were found.

In all species except the toad, (–)‐noradrenaline showed a higher affinity than (–)‐adrenaline for the uptake process, but the reverse was found for the toad heart.

Mouse and pigeon hearts contained increasing amounts of metabolites of noradrenaline with increasing perfusion concentrations of noradrenaline, but the guinea‐pig and toad hearts did not. The in vitro activities of noradrenaline catabolizing enzymes in heart homogenates were measured but did not explain the differences in the pattern of catabolism of noradrenaline found in the intact hearts of the different species.

In all hearts except the toad, cocaine was an effective blocking agent for the uptake of (±)‐3H‐noradrenaline and led to an increase in 3H‐normetanephrine in these hearts. In the pigeon heart, cocaine plus phenoxybenzamine in the perfusate resulted in an inhibition of both 3H‐noradrenaline uptake and 3H‐normetanephrine formation.

In guinea‐pig and pigeon perfused hearts, the uptake of 3H‐noradrenaline into atria and ventricles reflected the relative concentrations of endogenous catecholamines in these regions, but this was not found for rat, mouse and toad hearts.

It was concluded that species differences exist for both the accumulation and metabolism of catecholamines in isolated perfused hearts.
Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoceptors
Authors: CHARLIER R.
Published: July 2012

The cardiac actions of amiodarone, a benzofuran derivative used in the treatment of angina pectoris, have been compared with those of (±)‐propranolol in anaesthetized dogs.

After three successive intravenous injections of propranolol, 0·5 mg/kg, had reduced the heart rate by 25%, a fourth dose had no further negative chronotropic action, but amiodarone, 10 mg/kg intravenously, at this point reduced the heart rate by 23%.

Amiodarone, 10 mg/kg intravenously, reduced, but did not abolish, cardiac responses to isoprenaline, 2 μg/kg intravenously. Subsequent successive injections of 10 mg/kg of amiodarone did not further block the responses to isoprenaline, but propranolol, 1 mg/kg intravenously, abolished them.

Amiodarone reduced cardiac chronotropic and inotropic responses to glucagon, which were not affected by propranolol.

Cardiac output was increased 5 min after amiodarone, 10 mg/kg intravenously, but at 10 min and thereafter it did not differ from control values. Propranolol, 1 mg/kg intravenously, reduced cardiac output by 17% at 5 min, and by 30% after 30 min.

From this and other evidence which is discussed, it is concluded that the cardiac actions of amiodarone are not produced by competitive blockade of β‐adrenoceptors.
Role of the vagus nerves in anaphylaxis and histamine‐induced bronchoconstrictions in guinea‐pigs
Authors: MILLS JANET E. , WIDDICOMBE J. G.
Published: July 2012

The effects of vagotomy on the respiratory responses of guinea‐pigs to anaphylactic reactions and to intravenous injections of histamine acid phosphate are described.

In spontaneously breathing guinea‐pigs, vagotomy reduced by 50% or more the decreases in total lung conductance (bronchoconstriction) and the decreases in lung compliance, and almost abolished the rapid shallow breathing due to histamine.

In paralysed, artificially ventilated guinea‐pigs, vagotomy reduced by more than 33% the decreases in total lung conductance, but had little effect on the changes in lung compliance due to histamine.

In paralysed, artificially ventilated guinea‐pigs, vagotomy reduced by 75% the decrease in total lung conductance and halved the decrease in lung compliance due to anaphylaxis.

We conclude that a vagal reflex is mainly responsible for the rapid shallow breathing due to histamine, and partly responsible for the bronchoconstrictions due to histamine and to anaphylaxis in guinea‐pigs. We suggest that “lung irritant receptors” in the bronchial epithelium are the afferent end‐organs involved.
Acetylcholine content in the brain of rats treated with paraoxon and obidoxime
Authors: MILOŠEVIĆ M. P.
Published: July 2012

The effect of obidoxime on the rise in brain acetylcholine caused by the anticholinesterase paraoxon was studied in the rat.

In animals poisoned with a sublethal dose of paraoxon and thereafter treated with obidoxime the levels of both “free” and total brain acetylcholine were practically the same as those in rats injected with paraoxon only.

After poisoning with doses of paraoxon which are lethal unless an oxime is also given, the total acetylcholine in the brain of obidoxime‐protected rats continued to accumulate, reaching a peak 2 h after injection of paraoxon. At this time no signs of central effects such as convulsions or tremor were seen.

Atropine, given 30 min before paraoxon, markedly reduced the rise in total brain acetylcholine seen when the anticholinesterase is given alone.

In rats pretreated with atropine and obidoxime excessive doses of paraoxon which are lethal in the absence of the antidotes produced a rise in total brain acetylcholine which was directly proportional to the dose of paraoxon administered.
Effects of some drugs on the responses of the rat isolated, innervated urinary bladder to indirect electrical stimulation
Authors: DHATTIWALA A. S. , JINDAL M. N. , KELKAR V. V.
Published: July 2012

The effects of some drugs known to inhibit transmission in the superior cervical ganglion and at the neuromuscular junction were investigated on the cholinergic nerve‐smooth muscle junction, using the rat isolated innervated urinary bladder preparation.

HC‐3 and Win 4981 inhibited the indirectly evoked contractions; the block was typically slow in onset, depended on the rate of stimulation and was partially reversed by choline. The moderate coincident inhibition of acetylcholine‐responses disappeared after washing the tissue, while the block of the neuronally evoked contractions persisted.

Morphine, methylpentynol carbamate, chloral hydrate and strychnine inhibited indirectly evoked contractions without inhibiting the responses to acetylcholine. Paraldehyde inhibited both types of response.

Hexamethonium, mecamylamine and tubocurarine had no effect on either type of response. Tetraethylammonium augmented both types of response; the augmentation due to lower concentration was followed by a moderate block of the neuronally evoked contractions.

Small concentrations of procaine markedly inhibited responses to acetylcholine and produced a partial block of the neuronally evoked contractions.

None of the drugs affected conduction in the isolated phrenic nerve.

All the drugs other than paraldehyde and procaine appeared to act at the nerve terminals. The results are generally consistent with the view that HC‐3 and Win 4981 act by limiting transport of choline across nerve membrane and that the other drugs act by inhibiting the release of acetylcholine. A reduction in sensitivity of the effector cell membrane may account, wholly or in part, for the action of paraldehyde and procaine.
A comparison of the sensitivities of innervated and denervated rat vasa deferentia to agonist drugs
Authors: BIRMINGHAM A. T. , PATERSON G. , WÓJCICKI J.
Published: July 2012

One vas deferens of a rat was denervated by stripping away the serous coat; the other vas was left intact as a control. One week later the sensitivity in vitro of both vasa deferentia to noradrenaline, adrenaline, dopamine, oxymetazoline or acetylcholine was measured.

Log concentration response curves for the mean responses of both vasa from a group of four rats for each drug were plotted. Denervated vasa were more sensitive than control vasa to noradrenaline (16‐fold), to adrenaline (8‐fold), to dopamine (2‐fold) and to oxymetazoline (2‐fold). Denervated vasa were more sensitive to acetylcholine over the lower half of the concentration range only.

It is concluded that these results support the theory that at least part of the increased sensitivity of denervated smooth muscle to catecholamines is due to an abolition or reduction of the neuronal uptake process. There is also a small non‐specific increase in sensitivity.
Accumulation of dopamine by blood platelets from normal subjects and parkinsonian patients under treatment with l‐DOPA
Authors: BOULLIN D. J. , O'BRIEN R. A.
Published: July 2012

Human blood platelets have been shown to take up dopamine by an energy‐dependent, saturable process that is inhibited by 5‐hydroxytryptamine (5‐HT), desipramine and other drugs.

Platelets from parkinsonian subjects receiving oral l‐DOPA also took up dopamine.

When the responses of normal and parkinsonian platelets were compared, the parkinsonian cells showed the following differences: increased affinity for the dopamine transport process; decreased equilibrium concentrations of dopamine after incubation for 90 min, and greater efflux of dopamine from loaded platelets during a 10 min incubation.

There were no differences in the uptake of 5‐HT by parkinsonian platelets, but endogenous 5‐HT was significantly reduced; ATP was normal.

In two out of three samples of platelets from parkinsonian subjects, traces of a dopamine‐like substance were detected, but this finding requires confirmation.

If the platelet is a valid model for dopaminergic brain neurones, then the results described would suggest that dopamine uptake and storage may be abnormal in brain neurones in Parkinson's disease.
Hyposensitivity to drugs induced by morphine and some related substances in the cat
Authors: CONTRERAS E. , HUIDOBRO F.
Published: July 2012

Hyposensitivity to noradrenaline occurred concomitantly with morphine tachyphylaxis in the absence of any obvious depressant effect on the heart or peripheral circulation.

The actions of adrenaline, noradrenaline and angiotensin and, occasionally, other drugs were tested before and after repeated injections of morphine or one of ten related substances in various preparations of the spinal cat.

Tachyphylaxis in response to morphine could be related to a simultaneous decrease in the tissue responses to adrenaline, noradrenaline and angiotensin but such a parallelism has not been shown for the substances related to morphine.

The authors wish to express their gratitude to Professor C. Eyzaguirre for his invaluable suggestions and criticism and to Dr. N. F. Grundy for his assistance in the preparation of the paper for publication. This work was partially aided by a grant from the Gildmeister Foundation, Santiago, Chile.
Changes in the composition of hind limb lymph after chemical injury
Authors: BOYLES SUSAN , LEWIS G. P. , WESTCOTT BARBARA
Published: July 2012

Lymph was collected directly from the hind limbs of rabbits and cats anaesthetized with pentobarbitone.

Injury to the hind limb was caused by injection of one of two chemicals; either dimethylsulphoxide (DMSO) which produced a mild injury, or croton oil which produced severe injury.

After subcutaneous injection (6 × 0·2 ml) into the right hind limb there was a good correlation between the changes in concentration of intracellular enzyme systems in the lymph draining the limb and the histological appearance of the injured tissue. DMSO caused an increase in cytoplasmic enzymes only, while after croton oil, which caused cell necrosis, there was an increase in the concentration of all intracellular enzymes examined.

There was an increased lymph flow accompanied by a fall in protein concentration after DMSO, while croton oil caused an increase in protein concentration and a variable effect on lymph flow.
Effects of (±)‐propranolol, (±)‐, (+)‐, and (–)‐alprenolol on unanaesthetized dogs with ventricular arrhythmias resulting from coronary artery ligation
Authors: DUCE B. R. , GARBERG L. , SMITH E. R.
Published: July 2012

The effects of (±)‐propranolol, (±)‐, (+)‐ and (–)‐alprenolol were studied in unanaesthetized dogs with ventricular arrhythmias produced by ligation of the left coronary artery. The responses were compared with those of similar control dogs which were given only isotonic saline.

The ventricular arrhythmias were abolished by cumulative doses of 3·5 mg/kg of (±)‐alprenolol, 7·5 mg/kg of (–)‐alprenolol and (±)‐propranolol and by 15·5 mg/kg of (+)‐alprenolol.

At the time of maximum antiarrhythmic activity none of the drugs produced significant alterations in mean arterial pressure or atrial rate.

Cumulative doses of 7·5 mg/kg and 15·5 mg/kg of the four drugs resulted in some instances of lip licking, emesis and/or head tremors while 31·5 mg/kg was invariably lethal.

Since the β‐adrenoceptor blocking activity of (–)‐alprenolol is 100 times greater than that of (+)‐alprenolol, suppression of these ventricular arrhythmias was apparently unrelated to antagonism of sympathetic influences.

Alprenolol and propranolol have myocardial depressant properties apart from their effects on β‐adrenoceptors which could account for the antiarrhythmic activity observed.
Mechanism of the hypotensive action of methyldopa in normal and immunosympathectomized rats
Authors: AYITEY‐SMITH E. , VARMA D. R.
Published: July 2012

The antihypertensive action of methyldopa was investigated in the light of the prevailing false sympathetic neurotransmitter hypothesis of Day & Rand (1963). Immunosympathectomized and normal animals were used for the investigation.

Methyldopa in a single injection significantly decreased the blood pressure in control hypertensive, immunosympathectomized normotensive, and normal rats. Guanethidine did not decrease the blood pressure of immunosympathectomized rats; it decreased the blood pressure of control and control hypertensive rats.

The hypotensive effect of methyldopa was not antagonized by adrenoceptor and ganglion blocking agents or by the inhibition of dopamine β‐oxidase.

High doses of methyldopa produced less hypotension than relatively low doses. This might be due to an antagonism of the hypotensive effect by methylnoradrenaline, which is formed from methyldopa.

The antihypertensive action of methyldopa could not be correlated with any change in aortic sodium or potassium.

It is concluded that methyldopa does not exert its hypotensive effect by producing a weakly active false sympathetic neurotransmitter.
Metabolism of prostaglandin E1 in dog kidneys
Authors: NAKANO J.
Published: July 2012

The biotransformation of prostaglandin E1 (PGE1) was studied in the isolated, perfused dog kidneys.

An average 43% of PGE1 was converted into the less polar metabolite I by a single passage through the kidney. As the re‐circulation of the perfusate continued, PGE1 was converted not only into metabolite I but also the least polar metabolite II. The velocity of the conversion of PGE1 into metabolite I was significantly greater than that into metabolite II. Usually, six passages elapsed before maximum degradation of PGE1 occurred.

Further separation with silicic acid column chromatography and gas‐liquid chromatography showed that metabolite II consists of two individual metabolites, metabolite IIa and metabolite IIb.

The present study indicates that the kidney biotransforms PGE1 rather rapidly into three metabolites which are less polar than PGE1.
Subcellular localization of renin and kininogenase in the rat kidney
Authors: NUSTAD K. , RUBIN I.
Published: July 2012

The distribution of enzymatic activities was determined in subcellular fractions of rat kidney cortex homogenates after various homogenization procedures. The specific activities of kininogenase (KGA), BAEE esterase (pH 8.5), alkaline phosphatase and glucose‐6‐phosphatase were, on average, 3.4 times higher in the microsomal fraction than in the whole homogenate. The total amount of these activities in the microsomal fraction after gentle, ordinary and forced homogenization were about 15, 40 and 65% of total recovered activities, respectively. These results confirmed the localization of KGA in the microsomal fraction.

Renin activity was primarily recovered in the heavy mitochondrial fraction. When the force of the homogenization was increased some renin activity was shifted to the soluble fraction.

When a mixture of renin and purified urinary KGA was given intravenously to an anaesthetized rat, a hypotensive response due to the KGA was followed by a hypertensive renin response. Over a certain range of concentrations KGA and renin could be measured simultaneously. In fractions of kidney homogenates, however, KGA activity was too low to be measured by this method.
The effect of benzodiazepines and atropine on exploratory behaviour and motor activity of mice
Authors: AHTEE LIISA , SHILLITO ELIZABETH
Published: July 2012

Male albino mice were watched in red light on a tunnel board to test exploration and their motor activity was assessed in an open cage, 30 min after intraperitoneal injection of drugs.

Atropine and methylatropine 5 or 10 mg/kg did not alter the motor activity of the mice, while chlordiazepoxide 25 or 50 mg/kg and diazepam 10 or 20 mg/kg increased the activity, especially at the lower of the two doses used.

All the compounds used except methylatropine adversely affected the exploratory behaviour.

When atropine 10 mg/kg was given with the benzodiazepines, the activity of the mice was reduced and exploratory behaviour was further impaired. Methylatropine did not have this effect.
Suppressing inflammation by inhibiting the NF‐κB pathway contributes to the neuroprotective effect of angiotensin‐(1‐7) in rats with permanent cerebral ischaemia
Authors: Jiang Teng , Gao Li , Guo Jun , Lu Jie , Wang Yao , Zhang Yingdong
Published: July 2012

BACKGROUND AND PURPOSE Angiotensin‐(1‐7) [Ang‐(1‐7)] has anti‐inflammatory effects in peripheral organs, but its effects in ischaemic stroke are unclear as yet. We investigated whether its anti‐inflammatory effect contributes to the neuroprotection induced by Ang‐(1‐7) in a rat model of permanent middle cerebral artery occlusion (pMCAO).

EXPERIMENTAL APPROACH We infused Ang‐(1‐7), Mas receptor antagonist A‐779, angiotensin II type 2 receptor antagonist PD123319 or artificial CSF into the right lateral ventricle of male Sprague‐Dawley rats from 48 h before onset of pMCAO until the rats were killed. Twenty‐four hours after pMCAO, the neuroprotective effect of Ang‐(1‐7) was analysed by evaluating infarct volume and neurological deficits. The levels of oxidative stress were detected by spectrophotometric assay. The activation of NF‐κB was assessed by Western blot and immunohistochemistry analysis. The level of COX‐2 was tested by Western blot analysis and concentrations of pro‐inflammatory cytokines were measured by elisa.

KEY RESULTS Infusion of Ang‐(1‐7), i.c.v., significantly reduced infarct volume and improved neurological deficits. It decreased the levels of oxidative stress and suppressed NF‐κB activity, which was accompanied by a reduction of pro‐inflammatory cytokines and COX‐2 in the peri‐infarct regions. These effects of Ang‐(1‐7) were reversed by A‐779 but not by PD123319. Additionally, infusion of A‐779 alone increased oxidative stress levels and enhanced NF‐κB activity, which was accompanied by an up‐regulation of pro‐inflammatory cytokines and COX‐2.

CONCLUSION AND IMPLICATIONS Our findings indicate that suppressing NF‐κB dependent pathway via Mas receptor may represent one mechanism that contributes to the anti‐inflammatory effects of Ang‐(1‐7) in rats with pMCAO.
Rosuvastatin prevents angiotensin II‐induced vascular changes by inhibition of NAD(P)H oxidase and COX‐1
Authors: Colucci Rocchina , Fornai Matteo , Duranti Emiliano , Antonioli Luca , Rugani Ilaria , Aydinoglu Fatma , Ippolito Chiara , Segnani Cristina , Bernardini Nunzia , Taddei Stefano , Blandizzi Corrado , Virdis Agostino
Published: July 2012

Background and Purpose

NAD(P)H oxidase and COX‐1 participate in vascular damage induced by angiotensin II. We investigated the effect of rosuvastatin on endothelial dysfunction, vascular remodelling, changes in extracellular matrix components and mechanical properties of small mesenteric arteries from angiotensin II‐infused rats.

Experimental Approach

Male rats received angiotensin II (120 ng·kg−1·min−1, subcutaneously) for 14 days with or without rosuvastatin (10 mg·kg−1·day−1, oral gavage) or vehicle. Vascular functions and morphological parameters were assessed by pressurized myography.

Key Results

In angiotensin II‐infused rats, ACh‐induced relaxation was attenuated compared with controls, less sensitive to L‐NAME, enhanced by SC‐560 (COX‐1 inhibitor) or SQ‐29548 (prostanoid TP receptor antagonist), and normalized by the antioxidant ascorbic acid or NAD(P)H oxidase inhibitors. After rosuvastatin, relaxations to ACh were normalized, fully sensitive to L‐NAME, and no longer affected by SC‐560, SQ‐29548 or NAD(P)H oxidase inhibitors. Angiotensin II enhanced intravascular superoxide generation, eutrophic remodelling, collagen and fibronectin depositions, and decreased elastin content, resulting in increased vessel stiffness. All these changes were prevented by rosuvastatin. Angiotensin II increased phosphorylation of NAD(P)H oxidase subunit p47phox and its binding to subunit p67phox, effects inhibited by rosuvastatin. Rosuvastatin down‐regulated vascular Nox4/NAD(P)H isoform and COX‐1 expression, attenuated the vascular release of 6‐keto‐PGF1α, and enhanced copper/zinc‐superoxide dismutase expression.

Conclusion and Implications

Rosuvastatin prevents angiotensin II‐induced alterations in resistance arteries in terms of function, structure, mechanics and composition. These effects depend on restoration of NO availability, prevention of NAD(P)H oxidase‐derived oxidant excess, reversal of COX‐1 induction and its prostanoid production, and stimulation of endogenous vascular antioxidant defences.
First and second generation antipsychotics influence hippocampal gamma oscillations by interactions with 5‐HT3 and D3 receptors
Authors: Schulz Steffen B , Heidmann Karin E , Mike Arpad , Klaft Zin‐Juan , Heinemann Uwe , Gerevich Zoltan
Published: July 2012

BACKGROUND AND PURPOSE Disturbed cortical gamma band oscillations (30–80 Hz) have been observed in schizophrenia: positive symptoms of the disease correlate with an increase in gamma oscillation power, whereas negative symptoms are associated with a decrease.

EXPERIMENTAL APPROACH Here we investigated the effects of first and second generation antipsychotics (FGAs and SGAs, respectively) on gamma oscillations. The FGAs haloperidol, flupenthixol, chlorpromazine, chlorprothixene and the SGAs clozapine, risperidone, ziprasidone, amisulpride were applied on gamma oscillations induced by acetylcholine and physostigmine in the CA3 region of rat hippocampal slices.

KEY RESULTS Antipsychotics inhibited the power of gamma oscillations and increased the bandwidth of the gamma band. Haloperidol and clozapine had the highest inhibitory effects. To determine which receptor is responsible for the alterations in gamma oscillations, the effects of the antipsychotics were plotted against their pKi values for 19 receptors and analysed for correlation. Our results indicated that 5‐HT3 receptors have an enhancing effect on gamma oscillations whereas dopamine D3 receptors inhibit them. To test this prediction, m‐chlorophenylbiguanide, PD 128907 and CP 809101, selective agonists at 5‐HT3, D3 and 5‐HT2C receptors were applied and revealed that 5‐HT3 receptors indeed enhanced the gamma power whereas D3 receptors reduced it. As predicted, 5‐HT2C receptors had no effects on gamma oscillations.

CONCLUSION AND IMPLICATIONS Our data suggest that antipsychotics alter hippocampal gamma oscillations by interacting with 5‐HT3 and dopamine D3 receptors. Moreover, a correlation of receptor affinities with the biological effects can be used to predict targets for the pharmacological effects of multi‐target drugs.
Invariant NKT cells increase drug‐induced osteosarcoma cell death
Authors: Fallarini S , Paoletti T , Orsi Battaglini N , Lombardi G
Published: July 2012

BACKGROUND AND PURPOSE In osteosarcoma (OS) patients, only a limited number of drugs are active and the regimens currently in use include a combination of at least two of these drugs: doxorubicin, cisplatin, methotrexate and ifosfamide. Today, 30–40% of patients still die of OS highlighting the urgent need for new treatments. Invariant NKT (iNKT) cells are a lymphocyte lineage with features of both T and NK cells, playing important roles in tumour suppression. Our aim was to test whether the cytoxicity induced by cisplatin, doxorubicin and methotrexate against OS cells can be enhanced by iNKT cell treatment.

EXPERIMENTAL APPROACH iNKT cells were purified from human peripheral blood mononuclear cells by cell sorting (Vα24Vβ11+ cells) and used as effector cells against OS cells (U2‐OS, HOS, MG‐63). Cell death (calcein‐AM method), perforin/granzyme B and Fas/FasL expressions were determined by flow cytometry. CD1d expression was analysed at both the gene and protein level.

KEY RESULTS iNKT cells were cytotoxic against OS cells through a CD1d‐dependent mechanism. This activity was specific for tumour cells, because human CD1d+ mesenchymal stem cells and CD1d‐ osteoblasts were not affected. iNKT cell treatment enhanced drug‐induced OS cell death in a concentration‐dependent manner and this effect was reduced in CD1d‐silenced OS cells.

CONCLUSION AND IMPLICATIONS iNKT cells kill malignant, but not non‐malignant, cells. iNKT cell treatment enhances the cytotoxicity of anti‐neoplastic drugs against OS cells in a CD1d‐dependent manner. The present data encourage further studies on the use of iNKT cells in OS therapy.