bluuebunny/crossref_metadata_2025_split huggingface dataset:
INVOLVEMENT OF CYTOSKELETAL PROTEINS IN THE MECHANISMS OF ORGANOPHOSPHORUS ESTER‐INDUCED DELAYED NEUROTOXICITY
Authors: Abou‐Donia Mohamed B. 
Published: June 2007

SUMMARY1. Organophosphorus ester‐induced delayed neurotoxicity (OPIDN) is a neurodegenerative disorder characterized by the presence of swellings in the distal parts of large axons in the central and peripheral nervous systems with subsequent axonal degeneration and paralysis.2. An early change in OPIDN is enhanced activity and autophosphorylation of Ca2+/calmodulin‐dependent kinase II.3. In OPIDN, there is also a dose‐ and time‐dependent increase in Ca2+/calmodulin‐dependent kinase mediated phosphorylation of the cytoskeletal proteins, α‐ and β‐tubulin, microtubule associated protein‐2, neurofilament triplet proteins and myelin basic protein.4. Anomalous hyperphosphorylation of neurofilaments decreases their transport rate down the axon relative to their rate of entry resulting in their accumulation.5. Consistent with the neurochemical results is the presence of anomalous aggregations of phosphorylated neurofilaments in early stages of OPIDN.6. These findings suggest that aberrant hyperphosphorylation of cytoskeletal proteins is a post‐translational modification involved in the pathogenesis of OPIDN.
USE OF TISSUE CULTURE MODELS TO STUDY ENVIRONMENTAL‐GENETIC INTERACTIONS RELEVANT TO NEURODEGENERATIVE DISEASES
Authors: Durham Heather D. , O'Brien Catherine , Nalbantoglu Josephine , Figlewicz Denise A. 
Published: June 2007

SUMMARY1. Clonal cell lines, primary cultured neurones and transgenic animals expressing mutant genes linked to familial forms of neurodegenerative diseases provide models in which to examine the interaction between expression of a predisposing gene and exposure to neurotoxic chemicals. Methods of establishing these models are reviewed.2. Mutations in the gene encoding Cu/Zn‐superoxide dismutase (SOD‐1) have been identified in cases of familial amyotrophic lateral sclerosis linked to chromosome 21. We report that in clonal lines of PC12 cells, the cytotoxicity of a glutathione‐depleting epoxide, styrene oxide, varied with SOD activity in a manner similar to that previously demonstrated for redox cycling chemicals. These preliminary data suggest that either low or high SOD‐1 activities may be associated with greater toxicity of a variety of neurotoxic chemicals and their metabolites.
INVOLVEMENT OF OXIDATIVE AND L‐ARGININE‐NO PATHWAYS IN THE NEUROTOXICITY OF DRUGS OF ABUSE IN VITRO
Authors: Cerruti C. , Sheng P. , Ladenheim B. , Epstein C. J. , Cadet J‐L. 
Published: June 2007

SUMMARY1. Inhibitors of nitric oxide (NO) formation or ADP‐ribosylation attenuate methamphetamine (METH)‐ and methyl‐enedioxymetamphetamine (MDMA)‐induced neurotoxicity on dopaminergic and serotonergic cells in primary cultures.2. They also prevent METH‐induced reactive gliosis in dopaminergic cultures.3. Overexpression of superoxide dismutase (SOD) in cells obtained from SOD‐transgenic mice also attenuates drug‐induced toxicity.4. These data indicate a role for oxygen‐based and NO free radicals in the mechanisms of cell death associated with drugs of abuse in vitro.
VALIDATION AND IN VITRO NEUROTOXICITY
Authors: Green Sidney 
Published: June 2007

SUMMARY1. Validation of in vitro systems for studying neurotoxicants generally has not been accomplished, although in vitro tests have been used as screens to identify potential neurotoxic hazards and to study mechanisms.2. A number of factors need to be taken into account when a test is validated: (i) a rationale for developing the test; (ii) clear biological or pathophysiological relevance of the endpoint to the effect detected in vivo; (iii) a standardized protocol and evidence of intra‐ and interlaboratory reproducibility; (iv) testing of chemicals representative of the categories of interest, including very toxic, moderately toxic and relatively non‐toxic substances; and (v) a method to statistically evaluate the data.3. Proper validation should lead to methods which can be used by regulatory agencies to make decisions regarding hazard/risk.
MECHANISMS OF INCREASED AIRWAY MICROVASCULAR PERMEABILITY: ROLE IN AIRWAY INFLAMMATION AND OBSTRUCTION
Authors: Goldie Roy G. , Pedersen Karen E. 
Published: June 2007

SUMMARY1. Airway inflammation is a signal feature of human asthma, as is bronchial obstruction and the resultant airflow limitation. An obligatory accompaniment to airway inflammation is increased airway microvascular permeability, which in turn is causally related to bronchial oedema. In this review, we have attempted to describe the mechanisms of increased airway microvascular permeability and its relationship to oedema, bronchial obstruction and the hyperreactivity to spasmogenic stimuli which are such common features of asthma.2. It is now clear that bronchial obstruction in chronic asthma can involve bronchial wall oedema and swelling in addition to reversible, elevated airway smooth muscle tone, mucus hypersecretion and airway plugging and potentially permanent structural changes in airway architecture. Inflammatory mediators released in the airway wall in asthma including histamine, platelet‐activating factor, leukotrienes and bradykinin are potent inducers of increased bronchial microvascular permeability and are thus promoters of bronchial oedema, airway wall swelling and reduction in luminal calibre.3. The primary mechanism believed to underlie acute increases in microvascular permeability is contraction of post‐capillary venular endothelial cells, resulting in the formation of gaps between otherwise tightly associated cells. Extravasated plasma distributes to the interstitial spaces in the airway wall, resulting in oedema and swelling, but may also traverse the epithelium and collect in the airway lumen.4. Luminal plasma may compromise epithelial integrity and cilial function and thus reduce mucus clearance. Plasma proteins may also promote the production of viscous mucus and the formation of luminal mucus plugs. Together, these effects can result in or contribute to airway obstruction and hyper‐responsiveness.5. An understanding of such mechanisms can provide insight concerning novel and effective anti‐asthma therapies.
ANGIOTENSIN‐CONVERTING ENZYME AND ANGIOTENSINOGEN GENES IN PATTERNS OF LEFT VENTRICULAR HYPERTROPHY AND IN DIASTOLIC DYSFUNCTION
Authors: Wong K. K. , Summers K. M. , Burstow D. J. , West M. J. 
Published: June 2007

SUMMARY1. The association of different patterns of left ventricular hypertrophy and diastolic dysfunction with angiotensin converting enzyme (ACE) genotypes or angiotensinogen dinucleotide repeat alleles were studied in human subjects.2. Three abnormal patterns of hypertrophy (remodelled, eccentric and concentric) were associated with a history of hypertension. The presence of remodelled or concentric hypertrophy was associated with diastolic dysfunction.3. There was no difference between the frequencies of the ACE genotypes in normotensive and hypertensive subjects, in subjects with normal ventricles and those with different patterns of left ventricular hypertrophy, nor in subjects with normal and abnormal diastolic function. Similarly, there was no difference between the relative frequencies of AGT alleles in the same clinical subgroups.4. We conclude that in this population of hospital patients, variants of the ACE and AGT genes do not contribute to the presence of different patterns of hypertrophy or to diastolic dysfunction.
EFFECT OF SODIUM VALPROATE ON NALOXONE‐STIMULATED ACTH AND CORTISOL RELEASE IN HUMANS
Authors: Torpy D. J. , Grice J. E. , Hockings G. I. , Crosbie G. V. , Walters M. M. , Jackson R. V. 
Published: June 2007

SUMMARY1. Gamma‐aminobutyric acid (GABA) and endogenous opioids each inhibit hypothalamic CRH secretion. In humans, the opioid antagonist, naloxone, stimulates the release of CRH, and so of ACTH and cortisol, while alprazolam, an indirect GABAA agonist, blocks naloxone‐induced ACTH and cortisol secretion. Sodium valproate (SV) inhibits ACTH release in response to CRH, metyrapone and substance P. We hypothesized that, if this action is GABAA‐mediated, SV should also inhibit naloxone‐stimulated ACTH release.2. We studied five healthy volunteers in randomized, double‐blind, placebo‐controlled afternoon studies with SV 400 mg, given 180 min before i.v. naloxone 125 μg/kg bodyweight. Plasma concentrations of ACTH, cortisol and SV were measured at intervals during the experiments.3. SV had no effect on the mean integrated ACTH and cortisol responses to naloxone; ACTH. 165 ± 21 versus 284 ± 40 pmolmin per L, P= 0.08; cortisol: 10.5 ± 1.9 versus 12.8 ± 1.2 nmolmin per L‐3, P= 0.14, placebo/nal versus SV/nal respectively. Basal ACTH and cortisol levels were also not significantly altered by SV (P>0.30). Mean SV levels were not significantly different between SV/nal and SV/placebo studies (P>0.50).4. In conclusion, SV had no effect on naloxone‐induced ACTH and cortisol release in normal humans at the dose and plasma drug concentrations studied. This contrasts with the potent inhibitory effect of alprazolam, and suggests that the effect of SV on the human hypothalamic‐pituitary‐adrenal axis may not be through a GABAA‐mediated mechanism. Alternatively, higher plasma SV levels or more sustained exposure to SV may be necessary to inhibit hypothalamic secretion of CRH.
POWER SPECTRAL ANALYSIS OF HEART RATE VARIABILITY DURING GRADED HEAD‐UP TILTING IN PATIENTS WITH VASODEPRESSOR SYNCOPE
Authors: Prinz‐Zaiss M. , Yeap A. N. , Moguilevski V. , Trigg L. , McGrath B. P. 
Published: June 2007

SUMMARY1. Two groups of age‐ and sex‐matched subjects, eight healthy controls and 10 patients, suffering from recurrent vasodepressor syncope, participated in a study to examine autonomic function and sequential changes in power distribution of heart rate (HR) variability during graded head‐up tilt.2. The following autonomic function tests were performed valsalva ratio, HR responses to deep breathing and posture, BP responses to sustained handgrip and postural change. Each subject was tilted at 15°, 30°, 45°, 60° and 80° head‐up, each for 15 min, or until symptoms occurred. The eight control subjects completed the tilt study without any symptoms, while all 10 patients developed presyncope and/or syncope at various tilt angles.3. Resting blood pressure (BP) was lower in the patient group, while resting HR, autonomic function tests and resting HR variability components were similar in the two groups.4. The control group showed a progressive increase in low frequency power component (LF) from supine to end tilt (ΔLF 20.06 ± 14.50%) and a progressive fall in high frequency (HF) component (ΔHF—24.62 ± 10.64%). In contrast, in the patient group, LF fell during tilt in the presyncope period (ΔLF ‐10.57 ± 12.93%, P < 0.01 vs control group). HF and HF: LF ratio responses did not differ significantly in the two groups.5. At end tilt, the increase in plasma noradrenaline was significantly greater in the control group than in the patient group (ΔNA 0.83 ± 0.27 vs 0.28 ± 0.14 pmol/mL, P < 0.01). Plasma adrenaline: noradrenaline ratio at end tilt did not change in the control group, but increased significantly in the patient group (supine 0.07 ± 0.03, end tilt 0.16 ± 0.09, P < 0.05).6. It was concluded that sympathetic withdrawal plays a major role in the mechanism of vasodepressor syncope.
LAPAROSCOPIC ADRENALECTOMY FOR ADRENAL TUMOURS CAUSING HYPERTENSION AND FOR ‘INCIDENTALOMAS’ OF THE ADRENAL ON COMPUTERIZED TOMOGRAPHY SCANNING
Authors: Rutherford John C. , Gordon Richard D. , Stowasser Michael , Tunny Terry J. , Klemm Shelley A. 
Published: June 2007

SUMMARY1. In a 19 month period from June 1993 to December 1994, 60 patients (mean age 54.8 ±.5 years s.e.m.; 32 males, 28 females) underwent unilateral laparoscopic adrenalectomy by one of us (JCR) for the treatment of hypertension due to primary aldosteronism (n = 48), phaeochromocytoma (n = 3) and cortisol‐producing adenoma (n = 1) or to remove adrenal masses incidentally discovered on abdominal computerized tomography scanning (‘incidentaloma’) performed for other reasons (seven adenomas without biochemical evidence of excessive steroid hormone or catecholamine secretion and one carcinoma autonomously producing cortisol).2. Compared with conventional open procedures, laparoscopic adrenalectomy was associated with reduced recovery time and a low complication rate (one pulmonary embolus and one port site incisional hernia).3. Operation time with experience approximates that of open procedures (60 min), but is significantly longer in obese than in non‐obese patients, and in males than in females.4. Patients with adrenal causes of hypertension were cured or significantly improved by laparoscopic unilateral adrenalectomy.5. Because of our concern regarding malignant potential of incidentalomas and high patient acceptance of laparoscopic techniques, we have reduced our size criteria for removal of incidentalomas.
CROSS‐SECTIONAL STUDY OF A MICROSATELLITE MARKER IN THE LOW DENSITY LIPOPROTEIN RECEPTOR GENE IN OBESE NORMOTENSIVES
Authors: Griffiths Lyn R. , Nyholt Dale R. , Curtain Robert P. , Gaffney Philip T. , Morris Brian J. 
Published: June 2007

SUMMARY1. The low density lipoprotein receptor is an important regulator of serum cholesterol which may have implications for the development of both hypertension and obesity. In this study, genotypes for a low density lipoprotein receptor gene (LDLR) dinucleotide polymorphism were determined in both lean and obese normotensive populations.2. In previous cross‐sectional association studies an Apa LI and a Hinc II polymorphism for LDLR were shown to be associated with obesity in essential hypertensives. However, these polymorphisms did not show an association with obesity in normotensives.3. In contrast, this study reports that preliminary results for an LDLR microsatellite marker, located more towards the 3’ end of the gene, show a significant association with obesity in the normotensive population studied. These results indicate that LDLR could play an important role in the development of obesity, which might be independent of hypertension.
AUGMENTED ENDOGENOUS NITRIC OXIDE PRODUCTION IN PARTIAL PORTAL VEIN‐LIGATED RATS
Authors: Hori Naoki , Takahashi Hakuo , Okanoue Takeshi , Sawa Yoshihiko , Mori Takashi , Takami Shiro , Yoshimura Manabu , Kashima Kei 
Published: June 2007

SUMMARY1. Endothelium‐derived nitric oxide (NO) is a potent vasodilator. Because the body oxidizes it to nitrate ions, NO3‐, measurement of the serum concentration and the urinary excretion of NO3‐ may be an index for endogenous NO. We investigated the role of NO on hyperdynamic circulation in cirrhotic and partial portal vein‐ligated rats by measuring NO3.2. Liver cirrhosis was induced by administration of thioacetamide. Systemic and splanchnic haemodynamics and splenic‐systemic shunting were determined by tracer microspheres. The concentration of NO3‐ was measured by using high‐performance liquid chromatography with an anion‐column.3. We found that systemic and splanchnic hyperdynamic circulation existed to almost the same extent in cirrhotic and in portal vein‐ligated rats as compared to the controls and sham‐operated rats, respectively. Splenic‐systemic shunting was markedly greater in portal vein‐ligated rats than in cirrhotic rats.4. Serum NO3‐ levels and urinary excretion of NO3‐ in cirrhotic rats tended to increase as compared to the controls. On the other hand, the levels in portal vein‐ligated rats were significantly increased as compared to those of the sham‐operated rats, and were significantly and negatively correlated to the splanchnic arterial resistance and total vascular resistance. The amount of urinary excretion of NO3‐ significantly correlated to splenic‐systemic shunting (r = 0.61, P<0.05) only in portal vein‐ligated rats.5. We suggest that these high levels of NO3‐ in portal vein‐ligated rats relate to the extensive formation of porto‐collateral vasculature or acute changes in systemic and splanchnic haemodynamics due to portal vein‐ligation.
EFFECT OF RENAL NERVE DENERVATION ON TISSUE CATECHOLAMINE CONTENT IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Yoshida Makoto , Yoshida Emiko , Satoh Susumu 
Published: June 2007

SUMMARY1. To clarify the possible role of tissue catecholamines in the development of hypertension, we investigated the effect of bilateral renal denervation on the catecholamine contents of central and peripheral tissues in spontaneously hypertensive rats (SHR).2. Norepinephrine (NE) content in renal cortex, renal medulla, and adrenal gland was higher in 7 week old SHR than age‐matched Wistar‐Kyoto rats (WKY). Dopamine (DA) content in the brainstem and hypothalamus was also higher in SHR, but NE and epinephrine (EPI) content in these areas were not different between strains. Similar differences in catecholamines were observed in 9 week old rats in which a sham operation of bilateral renal denervation was performed 2 weeks previously.3. Bilateral renal denervation produced an almost complete reduction of NE content in the kidney in both strains and prevented the development of hypertension. DA content in the brainstem was also decreased by renal denervation in SHR but not in WKY. NE and EPI content in central tissues were not affected by renal denervation.4. These results suggest that DA content in brainstem area, as well as NE content in the kidney, have a relationship in the development of hypertension in SHR.
REPAIR AND RECOVERY FOLLOWING SPINAL CORD INJURY IN A NEONATAL MARSUPIAL (MONODELPHIS DOMESTICA)
Authors: Saunders N. R. , Deal A. , Knott G. W. , Varga Z. M. , Nicholls J. G. 
Published: June 2007

SUMMARY1. Repair and recovery following spinal cord injury (complete spinal cord crush) has been studied in vitro in neonatal opossum (Monodelphis domestica), fetal rat and in vivo in neonatal opossum.2. Crush injury of the cultured spinal cord of isolated entire central nervous system (CNS) of neonatal opossum (P4–10) or fetal rats (E15–E16) was followed by profuse growth of fibres and recovery of conduction of impulses through the crush. Previous studies of injured immature mammalian spinal cord have described fibre growth occurring only around the lesion, unless implanted with fetal CNS.3. The period during which successful growth occurred in response to a crush is developmentally regulated. No such growth was obtained after P12 in spinal cords crushed in vitro at the level of C7–8.4. In vivo, in the neonatal (P4–8) marsupial opossum, growth of fibres through, and restoration of, impulse conduction across the crush was apparent 1–2 weeks after injury. With longer periods of time after crushing a considerable degree of normal locomotor function developed.5. By the time the operated animals reached adulthood, the morphological structure of the spinal cord, both in the region of the crush and on either side of the site of the lesion, appeared grossly normal.6. The results are discussed in relation to the eventual longterm possibility of devising effective treatments for patients with spinal cord injuries.
EFFECTS OF A CONTINUOUS INFUSION OF DOPAMINE ON THE VENTILATORY AND CAROTID BODY RESPONSES TO HYPOXIA IN CATS
Authors: Ide Tohru , Shirahata Machiko , Chou Chung‐Long , Fitzgerald Robert S. 
Published: June 2007

SUMMARY1. We investigated how a continuous infusion of dopamine (DA; 5μg/kg per min), which is often used clinically, would affect the ventilation and carotid chemoreceptor neural activity in anaesthetized cats.2. In anaesthetized, spontaneously breathing cats, tidal volume (Vt) and respiratory frequency (f) were continuously monitored at five levels of inspired oxygen (P102= 110,130, 150, 170, 760mmHg) during Da or saline infusion. Vt and f were sampled for 1 min after 3 min exposure to each level of P102. Time control study was also performed.3. DA infusion significantly lowered VT under both normoxia and hypoxia in seven of eight cats. Respiratory frequency was not affected by DA infusion. Depression of ventilation during post‐hypoxic hyperoxia was augmented by DA infusion. Chemodenervntion abolished the ventilatory response to hypoxia and DA did not further affect the ventilatory response to hypoxia.4. In a second group of artificially ventilated cats, carotid chemoreceptor neural activity was recorded at five levels of arterial oxygen tension. DA infusion significantly depressed carotid chemoreceptor neural activity during normoxia and hypoxia in six of seven cats.5. These findings suggest that changes in ventilation during low dosage of DA infusion closely correlate with carotid body neural output. A predominant effect of this dosage of DA (5 μg/kg per min) was depression in the ventilatory response to hypoxia due to an inhibition of carotid body neural output.
α1‐ADRENOCEPTORS ON RABBIT AORTIC SMOOTH MUSCLE CELLS IN CULTURE AND IN EXPERIMENTAL INTIMAL THICKENING
Authors: Manderson John A. , Hayward Ian P. , Pak Elena , Horrigan Sophie , Hanley Glenys E. , Stephenson Jennifer A. , Brown Lindsay , Campbell Julie H. , Campbell Gordon R. 
Published: June 2007

SUMMARY1. This study has defined α1‐adrenoceptors and their reactivity in rabbit aorta, following removal of the endothelium and formation of a myointimal thickening, and also in smooth muscle cells (SMC) in cell culture which had undergone serial passaging and changes in phenotype.2. [3H]‐prazosin binding to SMC from control aorta, vessels 2 weeks after endothelial denudation and sub‐cultured SMC (passage 3–6) was specific (displaceable with 10 μmol/L phentolamine), and of high affinity to a single class of sites (Kd range: 71–114 pmol/L). The maximum binding density (Bmax) of α1‐adrenoceptors on SMC from the neointima (11105 ± 771 sites/cell) was not significantly different to that of control medial SMC (14014 ± 2472 sites/cell). However, SMC cultured to passage 6, showed a 2‐fold increase in Bmax (30227 ± 4349 sites/cell).3. The production of inositol phosphates (IP1, IP2 and IP3) by SMC following 10μmol/L phenylephrine was assayed. Both freshly‐dispersed aortic SMC and sub‐cultured SMC were stimulated to produce increased inositol phosphates by the addition of phenylephrine which was completely inhibited by pre‐incubation with 10 μmol/L phentolamine, suggesting that the stimulation was via α1‐adrenoceptors.4. Maximal contractile responses of isolated thoracic and abdominal aortic rings to KCl (100 mmol/L), 5‐HT and phenylephrine were unchanged two weeks after endothelial denudation. However, phenylephrine was significantly less potent (2.7‐fold) in both areas of the aorta, while the potency of 5‐HT was significantly enhanced (2.7‐fold) after endothelial denudation only in the abdominal aorta.5. The decreased sensitivity of the rabbit aorta to α1‐adrenoceptor agonists following endothelial denudation and the formation of a myointimal thickening is not due to changes in affinity or density of α1‐adrenoceptors. However multiple passaging of SMC in culture leads to an increase in α1‐adrenoceptor density. This change can be related to the altered cytodifferentiation of irreversible synthetic state SMC which are similar to those in atherosclerotic lesions.