bluuebunny/crossref_metadata_2025 huggingface dataset:
Waiting for radiation therapy: Does it matter?
Authors: Seel Matthew , Foroudi Farshad
Published: March 2003

The aim of this study was to determine the direct and indirect effects of prolonged waiting times for radiation therapy. We used the Medline, CancerNet and EMBASE databases to search the international research using the keywords radiotherapy, waiting times and delay. The negative effects of prolonged waiting times for radiation therapy can be broken down into direct and indirect effects. Direct effects include tumour control factors and patient factors. Indirect effects include changes in referral patterns and change in management of tumours. The precise effects of prolonged waiting times for radiation therapy are difficult to define. Evidence exists for some tumour sites, such as postoperative head and neck, small‐cell lung cancer and high‐grade cerebral gliomas, that tumour control might be adversely affected. The effect on other tumour sites is less established. Patient factors are likely to be consistent across all tumour types and indirect effects are hard to quantify.
Toxic leucoencephalopathy after heroin inhalation
Authors: Au‐Yeung Kai , Lai Chi
Published: March 2003

The neurological symptoms after inhalation of contaminated heroin vapour could be the result of toxic leucoencephalopathy. We describe a case of a 53‐year‐old man who has typical symptoms and MR features of toxic leucoencephalopathy.
MR findings of primary Ewing's sarcoma of greater wing of sphenoid
Authors: Singh Paramjeet , Jain Manoj , Singh DP , Kalra Naveen , Khandelwal N , Suri S
Published: March 2003

Primary Ewing's sarcoma of the skull is a very rare entity. We report MRI findings in a case of Ewing's sarcoma of the greater wing of sphenoid in a 4‐year‐old patient. Magnetic resonance imaging showed markedly heterogenous signal intensity with areas of haemorrhage and necrosis. It also demonstrated the exact extent of tumour due to its multiplanar capabilities and was, therefore, helpful in planning surgery.
Bilateral common carotid occlusion without neurological deficit
Authors: Karaköse Serdar , Karabacakoglu Aydin , Solak Hasan
Published: March 2003

A 40‐year‐old man presented with pain and numbness in his right arm. On his clinical examination, no neurological deficit was found. Bilateral common carotid artery duplex sonography scan demonstrated no flow in either lumen. No abnormality was recognized on brain CT. On cerebral digital substraction angiogram, total occlusion of the brachiocephalic trunk and left carotid artery were shown. There was a modest stenosis in the left vertebral artery. Collateral circulation feeding the intracranial carotid system mainly originated from the left vertebrobasilar system. Previous cases of bilateral carotid occlusion are reviewed and discussed.
Radiosurgery for brain metastases at the Royal Adelaide Hospital: Are we treating the right patients?
Authors: Roos Daniel E , Brophy Brian P , Zavgorodni Sergei F , Katsilis Evangelos S
Published: March 2003

Although non‐randomized data strongly suggest improved outcome from radiosurgery (RS) for brain metastases relative to whole brain radiotherapy (WBRT) alone, selection factors account for much of the observed differences. This retrospective review of the 16 brain metastases patients treated so far with RS at the Royal Adelaide Hospital confirms a median survival of 10.1 months, consistent with recent multi‐institutional pooled results and significantly longer than the median survival of 3−6 months typically reported for WBRT alone. The emerging randomized trials comparing surgery, RS and WBRT for brain metastases are reviewed in the context of the Radiation Therapy Oncology Group Recursive Partitioning Analysis prognostic Class concept in order to assess whether we are using this resource intensive technique to treat the ‘right’ patients. We conclude that it is reasonable to continue our current policy of considering RS primarily for patients of good performance status with solitary brain metastases. We have a flexible approach to adjuvant WBRT which appears to decrease brain relapse, but not improve survival.
Hydatid disease of bone: A mimic of other skeletal pathologies
Authors: Morris Burzin S , Madiwale Chitra V , Garg Ashwin , Chavhan Govind B
Published: March 2003

Skeletal hydatidosis results from the deposition of the larval form of the Echinococcus, a genus of tapeworm. The incidence of bone disease is extremely low as most larvae are trapped by the liver and lung upon release of the embryo into the portal blood stream. The interpretation of imaging studies can prove very confusing because bone changes evolve with time, and the non‐specificity of these findings often leads to a mistaken diagnosis. We present the case of a 35‐year‐old woman with long‐standing pain in the left hip joint in which the findings on CT were thought of as being either tuberculous or neoplastic in nature. The result of a CT‐guided biopsy and another done following surgery concurred on an unexpected diagnosis of a hydatid cyst. This case illustrates that in the absence of a high index of suspicion for echinococcal infection, the semblance of imaging findings of hydatid disease in bone to those of other skeletal pathologies can lead to misinterpretation.
Pancreatic cancer: Preliminary experience with sodium iodide fluorodeoxyglucose positron emission tomography in Australia
Authors: Keith CJ , Miles KA , Wong D
Published: March 2003

Previous studies of fluorodeoxyglucose positron emission tomography (FDG‐PET) in pancreatic cancer have used Bismuth Germinate detector systems. This preliminary Australian study aims to confirm the accuracy of FDG‐PET in pancreatic cancer using a dedicated sodium iodide (NaI) PET system. Fifteen consecutive patients underwent FDG‐PET using a GE QUEST dedicated NaI PET scanner. The indications were the characterization of a pancreatic mass seen on CT or ultrasonographic imaging (nine cases), diagnosis or exclusion of recurrent disease following surgery and adjuvant therapy (four cases) and presurgical staging of primary pancreatic cancer (two cases). The final diagnosis was determined from histology or, when no histology was available, by radiological and clinical follow up. The FDG‐PET accurately characterized eight out of nine pancreatic masses (seven were true negative, one was true positive and one was false positive). Of the four cases performed to determine recurrent disease, three were accurately diagnosed (two true negatives and one true positive). In the fourth case, PET accurately detected a liver metastasis but did not detect the local recurrence. Results in the two cases where PET was performed for preoperative staging comprised one true positive and one false negative. Sodium iodide FDG‐PET is useful in the diagnosis of pancreatic cancer, particularly in the presence of a previously detected mass.
Imaging of primary leiomyosarcoma of the seminal vesicle
Authors: Upreti Lalendra , Bhargava Satish K , Kumar Atin
Published: March 2003

Leiomyosarcoma of the seminal vesicle is exceedingly rare. The ultrasound and CT findings in a recent case are described. These consist of a mass causing enlargement of the right seminal vesicle with involvement of the urinary bladder and prostate. The prostate gland was displaced inferiorly and to the left. Surgical resection and subsequent histology confirmed the diagnosis. The role of imaging in retrovesical masses is also discussed.
MRI in greater trochanter pain syndrome
Authors: Walsh Geraldine , Archibald Colin G
Published: March 2003

The greater trochanter pain syndrome refers to pain on the lateral aspect of the hip joint. This is frequently attributed to trochanteric bursitis and distension of the subgluteal bursae. Associated tears of the tendons of gluteus medius and minimus have been described and may result from repetitive frictional trauma to these tendons and their associated bursae secondary to impingement beneath the tensor fascia lata. Occasionally tendinous damage may result from acute local direct trauma or a hyperadductive strain injury. We describe MRI in two patients with chronic lateral hip pain.
ENDOTHELIUM‐DERIVED HYPERPOLARIZING FACTOR(S): SPECIES AND TISSUE HETEROGENEITY
Authors: Triggle CR , Waldron H Dong, Gj , Cole WC
Published: March 2003

1. Endothelium‐derived relaxing factor is almost universally considered to be synonymous with nitric oxide (NO); however, it is now well established that at least two other chemically distinct species (prostacyclin (PGI2) and a hyperpolarizing factor) may also contribute to endothelium‐dependent relaxation.

2. Only relatively few studies have provided definitive evidence that an endothelium‐derived hyperpolarizing factor (EDHF), which is neither NO nor PGI2, exists as a chemical mediator.

3. There is a lack of agreement as to the likely chemical identity of this putative factor. Some evidence suggests that EDHF may be a cytochrome P450‐derived arachidonic acid product, possibly an epoxyeicosatrienoic acid (EET); conflicting evidence supports an endogenous cannabinoid as the mediator and still other studies infer an unknown mediator that is neither a cytochrome P450 nor a cannabinoid.

4. Data from our laboratory with a rabbit carotid artery ‘sandwich’ preparation have provided evidence that a mediator that meets the pharmacological expectations of a cytochrome P450 product is an EDHF.

5. Data from guinea‐pig mesenteric arterioles suggest that EDHF is not a cytochrome P450 product, whereas in guinea‐pig middle cerebral arteries, relaxation mediated by the NO/PGI2‐independent mediator(s) is sensitive to cytochrome P450 inhibitors. In addition, in the rabbit middle cerebral artery, it is likely that endothelium‐dependent hyperpolarization is mediated by both NO and PGI2.

6. In conclusion, these data indicate that EDHF is unlikely to be a single factor and that considerable tissue and species differences exist for the nature and cellular targets of the hyperpolarizing factors.
RELATIONSHIPS BETWEEN THE ENDOTHELIN AND NITRIC OXIDE PATHWAYS
Authors: Warner Timothy D
Published: March 2003

1. In the normal blood vessel, the vascular endothelium regulates the tone of the underlying smooth muscle and the reactivity of blood elements, such as platelets and neutrophils, by the release of mediators, in particular nitric oxide (NO) and endothelin‐1 (ET‐1).

2. Nitric oxide is a potent vasodilator that also inhibits platelet and neutrophil aggregation and adhesion; ET‐1 is the most potent mammalian vasoconstrictor peptide yet found. Recently, much research effort has focused on examining the interactions between these two important mediators. At a simple level, ET‐1 acts on specific receptors on the endothelium to increase the release of NO, while NO depresses the production and/or release of ET‐1 from endothelial cells.

3. While ET‐1 appears to have a relatively small influence on the basal regulation of blood pressure, NO appears central. For example, inhibition of NO production in normotensive animals produces a marked elevation in blood pressure.

4. Conversely, numerous vascular disease states have been associated with elevations in the production and/or release of ET‐1 and it has been implicated in the deleterious changes associated with ischaemia–reperfusion injury, subarachnoid haemorrhage and hypertension. In these conditions, NO production may also be increased by the induction of NO synthetic pathways within the vascular smooth muscle. Endothelin‐1 may also be produced by the vascular smooth muscle under similar circumstances.

5. Therefore, in pathological states, a new balance between NO and ET‐1 production may be central to changes in blood vessel reactivity, smooth muscle proliferation and blood coagulability.
ACUTE INTERACTIONS BETWEEN ENDOTHELIN AND NITRIC OXIDE IN THE CONTROL OF RENAL HAEMODYNAMICS
Authors: Baylis Chris
Published: March 2003

1. Endogenous endothelin (ET) does contribute to control of renal vascular tone via nitric oxide (NO)‐dependent vasodilation in the rat.

2. Endothelin mediates some of the renal vascular responses to acute nitric oxide synthase (NOS) inhibition, being particularly important when a rise in renal perfusion pressure occurs.

3. Tonically produced NO blunts the renal vasoconstrictor responses to acutely administered ET.

4. The similarity between the renal vascular responses to ET administration and NOS inhibition is not fortuitous but, in part, reflects important interactions between these vasoactive agents.
KINETIC ASPECTS OF DRUG DISPOSITION IN THE LUNGS
Authors: Upton Rn , Doolette Dj
Published: March 2003

1. The pharmacokinetic role of the lungs has been extensively studied usingin vitropreparations, but this information has not been well integrated into many systemic pharmacokinetic models.

2. The lung is characterized by short diffusion distances, extremely high relative perfusion and heterogeneous cell types. Anionic and neutral lipophilic drugs have relatively small distribution volumes in the lungs due to their low lipid content. Cationic lipophilic drugs can accumulate in the lungs, probably due to trapping in mitochondria and lysosomes, forming very slowly eluting pools.

3. Drug metabolism in the lungs is possible, but not universal. The lung, generally, has a low activity for many of the metabolic enzymes found in the liver, although this activity is relatively more inducible. The resultant drug extraction would be ‘enzyme limited’, variable and flow dependent.

4. Double indicator studies of first‐pass lung kinetics can characterize short‐term distribution in the lungs, but not longer‐term distribution or metabolism; the converse applies for studies of drug concentration gradients across the lungs. No single study or model has adequately defined the short‐ and long‐term kinetics of drugs in the lungs.

5. Drug clearance in the lungs can contribute to an apparent total body clearance in excess of hepatic blood flow and cardiac output. The lung is a first pass filter for any drug administered on the venous side of the circulation and can act as a ‘capacitor’ that damps the first‐pass concentration peak in the blood after intravenous bolus injection.
OPIOID RECEPTOR SIGNALLING MECHANISMS
Authors: Connor Mark , Christie MacDonald J
Published: March 2003

1. Three pharmacological types of opioid receptors, μ, δ and κ, and their corresponding genes have been identified. Although other types of opioid receptors have been suggested, their existence has not been established unequivocally. A fourth opioid receptor, ORL1, which is genetically closely related to the others, has also been isolated. ORL1 responds to the endogenous agonist nociceptin (orphanin FQ) and displays a pharmacological profile that differs greatly from μ, δ and κ receptors.

2. All opioid receptors mediate many of their cellular effects via activation of heterotrimeric G‐proteins. The μ, δ and κ receptors are all capable of interacting with the pertussis toxin‐sensitive G‐protein α‐subunits Gi1, Gi2, Gi3, Go1, Go2 and the pertussis toxin‐insensitive Gz and G16. None of the opioid receptors interacts substantially with Gs and μ receptors do not activate Gq, G11, G12, G13 or G14.

3. Differential coupling of different opioid receptors to most types of G‐proteins is marginal. The μ, δ and κ receptors appear to preferentially activate Go and Gi2 over other pertussis toxin‐sensitive G‐proteins, although there is evidence that μ receptors show some preference for Gi3. δ Receptors couple more efficiently to G16 than do μ or κ receptors.

4. There is some evidence that opioid receptors, particularly μ and ORL1 receptors, can also couple to cellular effectors in a G‐protein‐independent manner.

5. In general, the consequences of activation of any of the opioid receptors in a given cell type depend more on the profile (stoichiometry) of the G‐proteins and effectors expressed than on the type of opioid receptor present in the cell. Notions that different types of opioid receptors intrinsically couple preferentially to one type of effector rather than another should, therefore, be discarded.
HYPERTENSION MECHANISMS CAUSING STROKE
Authors: Johansson Barbro B
Published: March 2003

1. Although it is well established that hypertension is the main risk factor for stroke, the complexity of cerebrovascular problems related to hypertension is not generally appreciated.

2. Hypertension can cause stroke through many mechanisms. A high intraluminal pressure will lead to extensive alteration in endothelium and smooth muscle function in intracerebral arteries. The increased stress on the endothelium can increase permeability over the blood–brain barrier and local or multifocal brain oedema. Endothelial damage and altered blood cell–endothelium interaction can lead to local thrombi formation and ischaemic lesions. Fibrinoid necrosis can cause lacunar infarcts through focal stenosis and occlusions. Degenerative changes in smooth muscle cells and endothelium predisposes for intracerebral haemorrhages. Furthermore, hypertension accelerates the arteriosclerotic process, thus increasing the likelihood for cerebral lesions related to stenosis and embolism originating from large extracranial vessels, the aortic arch and from the heart.

3. Adaptive structural changes in the resistance vessels, while having the positive effect of reducing the vessel wall tension, have the negative consequence of increased peripheral vascular resistance that may compromise the collateral circulation and enhance the risk for ischaemic events in connection with episodes of hypotension or distal to a stenosis.

4. Hypertension is clearly a risk factor for vascular dementia. All the mechanisms referred to above may be important.
Olanzapine Transfer By Human Placenta
Authors: Schenker S , Yang Y , Mattiuz E , Tatum D , Lee M
Published: March 2003

1. The present study assessed the human transplacental transport of olanzapine, a new antipsychotic drug effective in the treatment of schizophrenia.

2. Using the normal‐term placenta perfused single cotyledon system, we show that: (i) 5–14% of labelled olanzapine crosses from the maternal to foetal compartments in 4 h; (ii) transport depends significantly on binding characteristics, especially of albumin; (iii) no oxidative metabolites of olanzapine appear in the placental perfusate over 4 h; and (iv) approximately 17% of olanzapine, on average, is converted to the glucuronide, which is transferred by the placenta at a rate slightly slower than the parent drug.
EVIDENCE FOR A COMMON DEFECT ASSOCIATED WITH PRESSURE IN THE AORTA OF TWO HYPERTENSIVE RAT STRAINS
Authors: Chamiot‐Clerc Ph , Colle  , Legrand  , Sassard  , Safar  , Renaud
Published: March 2003

1. Thoracic aortas of normotensive (Wistar‐Kyoto (WKY) and Lyon normotensive (LN)) and hypertensive (spontaneously hypertensive rats (SHR) and Lyon hypertensive (LH)) rats from two groups (Japanese (WKY rats and SHR) and Lyon (LN and LH rats)) were compared using organ chambers. Changes in endothelium and smooth muscle reactivity to noradrenaline (NA), carbamylcholine and Nω‐nitro‐
L‐arginine (
L‐NNA) were analysed to distinguish between changes in reactivity that are associated with the presence of hypertension and those that are dependent on group (Japanese vs Lyon).

2. Aortas of hypertensive rats had lower pD2 values for NA than aortas from normotensive rats. These differences were associated with hypertension (P < 0.005 and P < 0.01) and group (P < 0.005 and P < 0.005) in presence or absence of endothelium, respectively, whereas no difference was seen in the maximal developed tension in response to NA.

3. Aortas also differed by a reduced ability to relax in response to carbamylcholine in hypertensive rats; this effect is hypertension (P < 0.05) and group (P < 0.005) dependent, without any change in carbamylcholine pD2 values.

4. Changes in maximum developed tension in the presence of L‐NNA were found to be endothelium dependent and pressure and group independent. Furthermore, the change in tension induced by
L‐NNA appears significantly more pronounced in SHR than in LH rats (P < 0.05).

5. These results indicate that the common defect associated with hypertension appears to be linked to the endothelium through α‐adrenoceptors and muscarinic receptors in both the Japanese and Lyon groups. However, SHR differs markedly from LH rats by having a higher developed tension in response to NA, this increased tension being counterbalanced by the release of nitric oxide, as observed in the presence of L‐NNA.
ROLE OF INDUCIBLE NITRIC OXIDE SYNTHASE IN TRANSPLANT ARTERIOSCLEROSIS
Authors: Lee Paul C , Shears Larry L Shears , Billiar Timothy R
Published: March 2003

1. Transplant arteriosclerosis is a major obstacle to long‐term allograft survival. Nitric oxide (NO) has been implicated as a mediator in the development of this disease.

2. We and others have shown that inducible nitric oxide synthase (iNOS) is up‐regulated in allografts with transplant arteriosclerosis. Despite the acute cytotoxic effects produced by high levels of NO, a chronic increase in NO availability is protective against neointimal hyperplasia, mainly by suppressing the inflammatory cell recruitment and neointimal smooth muscle cell accumulation.

3. Currently, we have the technology to directly transfer the iNOS gene to allografts. We have demonstrated that this exciting strategy is feasible and therapeutic and may improve the long‐term survival and function of allografts. Future challenges include optimizing the methods and the vectors of gene delivery.
Myoendothelial Electrical Coupling In Arteries And Arterioles And Its Implications For Endothelium‐Derived Hyperpolarizing Factor
Authors: Coleman Harold A , Tare Marianne , Parkington Helena C
Published: March 2003

1. Considerable progress has been made over the past decade in evaluating the presence of electrical coupling between the endothelial and smooth muscle layers of blood vessels, prompted, in part, by ultrastructural evidence for the presence of myoendothelial junctions.

2. In a variety of vessels ranging in size from conduit arteries down to small arterioles, action potentials have been recorded from endothelial cells that were associated with constriction of the vessels and/or occurred in synchrony with and were indistinguishable from action potentials recorded from the smooth muscle. From these results, it is now firmly established that myoendothelial electrical coupling occurs in at least some blood vessels.

3. Spread of hyperpolarizing current from the endothelium to the smooth muscle is the most likely explanation of the smooth muscle hyperpolarization attributed to endothelium‐derived hyperpolarizing factor. Because this hyperpolarization can evoke considerable relaxation of the smooth muscle, myoendothelial electrical coupling has important implications for endothelial regulation of the contractile activity of blood vessels.
Alzheimer’s Disease And Inflammation: A Review Of Cellular And Therapeutic Mechanisms
Authors: Halliday Glenda , Robinson Stephen R , Shepherd Claire , Kril Jillian
Published: March 2003

1. Of the neurodegenerative diseases that cause dementia, Alzheimer’s disease (AD) is the most common. Three major pathologies characterize the disease: senile plaques, neurofibrillary tangles and inflammation. We review the literature on events contributing to the inflammation and the treatments thought to target this pathology.

2. The senile plaques of AD consist primarily of complexes of the β‐amyloid protein. This protein is central to the pathogenesis of the disease.

3. Inflammatory microglia are consistently associated with senile plaques in AD, although the classic inflammatory response (immunoglobulin and leucocyte infiltration) is absent. β‐Amyloid fragments appear to mediate such inflammatory mechanisms by activating the complement pathway in a similar fashion to immunoglobulin.

4. Epidemiological studies have identified a reduced risk of AD in patients with arthritis and in leprosy patients treated with anti‐inflammatory drugs. Longitudinal studies have shown that the consumption of anti‐inflammatory medications reduces the risk of AD only in younger patients (< 75 years).

5. There is a considerable body of in vitro evidence indicating that the inflammatory response of microglial cells is reduced by non‐steroidal anti‐inflammatory drugs (NSAID). However, no published data are available concerning the effects of these medications on brain pathology in AD.

6. Cyclo‐oxygenase 2 enzyme is constitutively expressed in neurons and is up‐regulated in degenerative brain regions in AD. Non‐steroidal anti‐inflammatory drugs may reduce this expression.

7. Platelets are a source of β‐amyloid and increased platelet activation and increased circulating β‐amyloid have been identified in AD. Anti‐platelet medication (including NSAID) would prevent such activation and its potentially harmful consequences.

8. Increased levels of luminal β‐amyloid permeabilizes the blood–brain barrier (BBB) and increases vasoconstriction of arterial vessels, paralleling the alterations observed with infection and inflammation. Cerebral amyloidosis is highly prevalent in AD, compromising the BBB and vasoactivity. Anti‐inflammatory medications may alleviate these problems.
Carbonic Anhydrase I Inhibition By Nitric Oxide: Implications For Mediation Of The Hypercapnia‐Induced Vasodilator Response
Authors: Puscas Ioan , Coltau Marcela , Domuta Gabriela , Baican Michael , Puscas Carmen , Pasca Radu
Published: March 2003

1. At present, CO2 is considered to be the most important factor in regulating cerebral blood flow by modification of the interstitial fluid and extracellular pH, but the mechanism by which hypercapnia produces vasodilation is still controversial. In the present paper we investigated the effect of hypercapnia on carbonic anhydrase (CA) activity. We also studied the combined effects of CO2 with either indomethacin or an L‐arginine analogue on CA activity.

2. Nine groups of 12 rabbits each were established. Groups 1–4 were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 20, 60, 120 and 180 min. Group 5 rabbits received 15 mg/kg bodyweight, i.v., indomethacin and, after 1 h, were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 2 h. Group 6 animals were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 2 h and then received indomethacin. Group 7 rabbits received 100 mg/kg bodyweight, i.v., NG‐monomethyl‐L‐arginine (L‐NMMA) and, after 1 h, were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 2 h. Group 8 rabbits were ventilated for 2 h with a mixture of 10% CO2, 21% O2 and 69% N2 and were then administered L‐NMMA. Group 9 rabbits received L‐NMMA treatment concomitant with ventilation for 2 h with a mixture of 10% CO2, 21% O2 and 69% N2. In all groups, the erythrocyte CA activity was measured, as well as PaCO2 before and after ventilation or treatment.

3. The present study shows that CO2 reduces CA I activity down to complete inhibition and antagonizes the activating effects of indomethacin and L‐NMMA on this isozyme. Our data prove that nitric oxide‐ and prostaglandin‐induced CA I inhibition is involved in the vasodilation produced by hypercapnia. These results suggest that, due to subsequent pH changes, CA I is directly implicated in the modulation of vascular processes in the organism.
Chemistry And Biological Effects Of Dietary Phenolic Compounds: Relevance To Cardiovascular Disease
Authors: Morton Lincoln W , Caccetta Rima Abu‐Amsha , Puddey Ian B , Croft Kevin D
Published: March 2003

1. There has been considerable recent interest in the possibility that increased intake of dietary anti‐oxidants may protect against cardiovascular disease. This is partly due to the knowledge that oxidative events in vivo may play a role in the pathogenesis of atherosclerosis.

2. While dietary anti‐oxidants, such as vitamins E and C, have received considerable attention in this regard, relatively little is known about a similar anti‐oxidant role for plant‐derived polyphenolic compounds, such as the flavonoids and phenolic acids. A review of the distribution, bioavailability and biological activity of these compounds suggests that they may have a physiological role as anti‐oxidants.

3. Human trials on the anti‐oxidant effects of beverages rich in polyphenolics, such as red wine, fruit juice or tea, have been limited and results are, at present, inconclusive. This is due, in part, to poor methodologies available to measure oxidative damage in vivo.

4. There is a sound rationale for considering polyphenolics as important contributors to the dietary anti‐oxidant intake derived from fruits and vegetables. However, continuing research is needed using appropriate biomarkers of oxidant damage in vivo before these compounds can be conclusively considered as dietary anti‐oxidants with nutritional benefit.
Role Of Brain Angiotensin Ii In The Somatosensory Induced Antinatriuresis In The Anaesthetized Rat
Authors: Huang Chunlong , Johns Edward J
Published: March 2003

1. The present study set out to explore the importance of angiotensin (Ang)II in the brain in allowing the somatosensory system to cause a reflex renal nerve‐mediated reduction in renal sodium and water excretion.

2. In chloralose–urethane‐anaesthetized rats receiving saline i.c.v. (2 μL + 1 μL/h), the administration of capsaicin (0.5 mg, s.c.) increased blood pressure by 14% (P < 0.001) and, while renal perfusion pressure was regulated at an unchanged level, neither renal blood flow (RBF) nor glomerular filtration rate was changed. However, urine flow and absolute and fractional sodium excretion was reduced between 29 and 38% (P < 0.05–0.01). All variables had returned to control levels 30 min later.

3. The administration of captopril (40 μg + 20 μg/h i.c.v.) decreased blood pressure and sodium excretion by 6 and 17%, respectively (both P < 0.05). Under these conditions, capsaicin s.c. increased blood pressure by 9% (P < 0.05); however, with renal perfusion pressure regulated at a constant level, neither renal haemodynamics nor water nor sodium excretion were changed.

4. A final group of animals received AngII (100 ng + 50 ng/h) concomitantly with captopril i.c.v., which increased blood pressure, RBF and urine flow, absolute and fractional sodium excretions by 8 (P < 0.05), 22 (P < 0.001) and 52–149% (P < 0.05–0.01), respectively. Capsaicin given s.c. under these conditions increased blood pressure by 6% (P < 0.05) and, while renal perfusion pressure was maintained at an unchanged value and renal haemodynamics remained constant, urine flow and absolute and fractional sodium excretion were reduced by 35–38% (all P < 0.05).

5. These data show that for the somatosensory system to induce a reflex increase in renal sympathetic nerve activity sufficient to cause an antinatriuresis and antidiuresis, the presence of AngII is necessary in the brain. How AngII exerts this facilitatory action within the central nervous system remains to be investigated.
Chronotropic And Vasodilatory Responses To Adenosine And Isoproterenol In Mouse Heart: Effects Of Adenosine A1 Receptor Overexpression
Authors: Headrick John P , Gauthier Naomi S , Morrison R Ray , Matherne G Paul
Published: March 2003

1. Chronotropic and vasodilatory effects of adenosine receptor activation with 2‐chloroadenosine (2‐ClAdo) and β‐adrenoceptor activation with isoproterenol were studied in wild‐type murine hearts and transgenic hearts overexpressing the A1 adenosine receptor.

2. Treatment of wild‐type hearts with 2‐ClAdo induced bradycardia (pEC50 6.4±0.2) and vasodilatation (pEC50 7.9±0.1; minimal resistance 2.2±0.2 mmHg/mL per min per g). The A1 receptor‐mediated bradycardia was 20‐fold more sensitive in transgenic hearts (pEC50 7.7±0.2), whereas coronary vasoactivity of 2‐ClAdo was unaltered (pEC50 7.6±0.1).

3. β‐Adrenoceptor stimulation with isoproterenol increased heart rate (pEC50 8.5±0.2; maximal rate 594±23 b.p.m.) and produced vasodilation (pEC50 8.7±0.1; minimal resistance 1.7±0.2 mmHg/mL per min per g) in wild‐type hearts. Treatment with 10 IU/mL adenosine deaminase increased the magnitude of the tachycardia (maximal rate 653±27 b.p.m.) without altering potency (pEC50 8.5±0.1). Antagonism of A1 receptors with 10 nmol/L 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) produced a comparable increase in the magnitude of the chronotropic response (maximal rate 695±26 b.p.m.) without altering potency (pEC50 8.3±0.1).

4. Isoproterenol‐mediated vasodilatation was unaltered by transgenic A1 receptor overexpression. Overexpression of A1 receptors significantly reduced the maximal heart rate during β‐adrenoceptor stimulation by 35% (to 381±28 b.p.m.) without altering potency (pEC50 8.4±0.2). At 10 nmol/L, DPCPX increased the magnitude of the chronotropic response to isoproterenol in transgenic hearts (maximal heart rate 484±36 b.p.m.) without altering potency (pEC50 8.3±0.2).

5. The data show that transgenic A1 receptor overexpression selectively sensitizes the cardiovascular A1 receptor response and that A1 receptor activation by endogenous adenosine depresses the magnitude, but not potency, of the β‐adrenoceptor‐mediated chronotropic response in mouse heart. The A1 receptor‐mediated depression of β‐adrenoceptor responsiveness is non‐competitive (reduced response magnitude with no change in sensitivity). This indicates that A1 receptor activation non‐competitively inhibits effector mechanisms activated by β‐adrenoceptors (e.g. adenylate cyclase) and/or A1 receptors activate unrelated but opposing mechanisms. This inhibitory response may have physiological importance during periods of sympathetic stimulation of cardiac work.
Nitric Oxide As A Metabolic Regulator During Exercise: Effects Of Training In Health And Disease
Authors: Kingwell Bronwyn A
Published: March 2003

1. Accumulating animal and human data suggest that nitric oxide (NO) is important for both coronary and peripheral haemodynamic control and metabolic regulation during performance of exercise.

2. While still controversial, NO of endothelial origin is thought to potentiate exercise‐induced hyperaemia, both in the peripheral and coronary circulations. The mechanism of release may include both acetylcholine derived from the neuromuscular junction and vascular shear stress.

3. A splice variant of neuronal nitric oxide synthase (NOS), nNOSμ, incorporating an extra 34 amino acids, is expressed in human skeletal muscle. In addition to being a potential modulator of blood flow, skeletal muscle‐derived NO is an important regulator of muscle contraction and metabolism. In particular, recent human data indicate that NO modulates muscle glucose uptake during exercise, independently of blood flow.

4. Exercise training in healthy individuals promotes adaptations in the various NO systems, which can increase NO bioavailability through a variety of mechanisms, including increased NOS enzyme expression and activity. Such adaptations likely contribute to increased exercise capacity and protection from cardiovascular events.

5. Cardiovascular risk factors, including hypercholesterolaemia, hypertension, diabetes and smoking, as well as established disease, are associated with impairment of the various NO systems. Given that NO is an important signalling mechanism during exercise, such impairment may contribute to limitations in exercise capacity through inadequate coronary or peripheral blood delivery and via metabolic effects.

6. Exercise training in individuals with elevated cardiovascular risk or established disease can increase NO bioavailability and may represent an important mechanism by which exercise training provides benefit in the setting of secondary prevention.
Antihypertensive Effect Of Cattle Bone Collagen‐Derived Peptides In Ovariectomized Stroke‐Prone Spontaneously Hypertensive Rats
Authors: Mizutani K , Ikeda K , Ishikado A , Kawai Y , Yamori Y
Published: March 2003

1. The effect of food collagen, cattle bone collagen‐derived (CBC) peptides, on ovariectomy induced increases in blood pressure was examined in stroke‐prone spontaneously hypertensive rats (SHRSP).

2. Long‐term administration of CBC peptides to ovariectomized SHRSP suppressed the hypertension compared with ovariectomized SHRSP fed standard chow.

3. The CBC peptides showed an inhibitory activity (IC50 = 40 μg/mL) for angiotensin I‐converting enzyme (ACE) in vitro. Furthermore, pre‐incubation of CBC peptides with gastrointestinal proteases did not change this inhibitory activity of CBC for ACE.

4. These results indicate that CBC peptides may prevent increases in blood pressure in ovariectomized SHRSP by a possible mechanism of an inhibitory action against ACE.
Effects Of Prostaglandins On Baroreflex During Reperfusion Of The Ischaemic Myocardium
Authors: Wang You‐Ping , Xu Hui , Mizoguchi Kazuhiro , Tsuruhara Yoshikazu , Oe Masahiro , Maeta Hajime
Published: March 2003

1. The present study was planned to: (i) determine whether the baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) was attenuated during reperfusion of short‐term ischaemic myocardium; and (ii) study whether blockade of prostaglandin synthesis with indomethacin reversed the inhibitory baroreflex.

2. Arterial pressure was lowered with intravenous sodium nitroprusside before coronary occlusion and 3 min after release of a 5 min occlusion of the left circumflex coronary artery in anaesthetized rabbits. The protocol was repeated 20 min after indomethacin (5 mg/kg, i.v.) or indomethacin vehicle (50 mmol/L tris(hydroxymethyl)aminomethane buffer, pH 8.4) treatment. In addition, this study was performed in a group of vagotomized rabbits.

3. Before indomethacin treatment, the slope of the mean arterial pressure (MAP)–RSNA relationship decreased from –3.3±0.77 to –2.01±0.69% change in RSNA/mmHg (P < 0.05) during reperfusion of ischaemic myocardium in intact rabbits. The decrease in the slope was reversed by administration of indomethacin. However, the decrease in the slope was not reversed by indomethacin vehicle. Furthermore, the reduction in the slope of the MAP–RSNA relationship during reperfusion of ischaemic myocardium was abolished in vagotomized rabbits. However, there was no inhibition of the slope of the MAP–HR relationship during reperfusion of ischaemic myocardium in either intact or vagotomized rabbits.

4. In conclusion, our data suggest that prostaglandins released by ischaemic myocardium can attenuate the baroreflex‐mediated response of RSNA to lowered arterial pressure via vagal afferents during reperfusion of short‐term ischaemic myocardium.
Islet Amyloid Polypeptide (Amylin) Modulates Chylomicron Metabolism In Rats
Authors: Smith D , Mamo Jcl
Published: March 2003

1. Amylin is a pancreatic peptide that has been shown to be able to induce a state of peripheral insulin resistance. Hyperamylinaemia, which occurs in type 2 diabetes, may be central to a number of metabolic abnormalities present in the diabetic state. Because lipoprotein metabolism is often disturbed in diabetes, we investigated whether amylin was a regulating factor of lipoprotein metabolism in rats; specifically, whether exogenous amylin influences production and clearance of triglyceride (TG)‐rich lipoproteins.

2. When amylin was given acutely to rats or by way of infusion, total plasma TG was significantly elevated. Acute doses of amylin decreased fractional clearance rates of TG‐rich lipoproteins by 45%. Hydrolysis of lipoproteins by endothelial lipases was not decreased; rather, amylin appeared to reduce hepatic uptake of TG‐rich lipoproteins, following conversion to the remnant form. Consistent with the kinetic data in vivo, cell culture studies found that amylin reduced the high‐affinity uptake of remnant lipoproteins, probably by inhibiting low‐density lipoprotein receptor expression.

3. We have found that amylin can influence the kinetics of TG‐rich lipoproteins in vivo and in vitro. Amylin can reduce chylomicron uptake, most probably by regulating lipoprotein receptors either directly, or via modulation of insulin activity. Increased levels of amylin in type 2 diabetes may contribute to the raised concentration of TG‐rich remnant lipoproteins present in this disease.
Pain Control by Immune‐Derived Opioids
Authors: Machelska H , Stein C
Published: March 2003

1. The nervous and immune systems communicate with each other by use of cytokines and neuropeptides.

2. Interactions between immune cell‐derived opioid peptides and opioid receptors located in peripheral inflamed tissue lead to endogenous analgesia.

3. In addition to their immunological functions, immunocytes are involved in intrinsic pain inhibition. This provides new insights into pain associated with a compromised immune system, as in AIDS or in cancer.

4. The activation of opioid production and release from immune cells may be a novel approach to the development of peripherally acting analgesics. Because such drugs would be targeted towards events in peripheral injured tissue, these analgesics should lack unwanted central side effects typically associated with opioids.
Biopharmaceutical Considerations In Topical Ocular Drug Delivery
Authors: Davies Nigel M
Published: March 2003

1. Despite the accessibility of the front of the eye, efficient delivery of drug to treat various ocular disorders is a challenge to the formulation scientist. The majority of ophthalmic medications are formulated as eye drops. Due to anatomical constraints, the volume that can be administered is limited to approximately 30 μL. This, together with the efficient clearance system that exists in the front of the eye, makes it difficult to maintain an effective pre‐ocular drug concentration for a desired length of time. Various formulation strategies have been used to increase pre‐ocular retention of eye drops. The most successful of these has been the inclusion of viscosity enhancing polymers, particularly those able to interact with the mucous layer on the eye surface or those that can undergo a transition from a solution to a gel under the conditions of the pre‐ocular area.

2. When the target site is intra‐ocular, drug must be absorbed from the pre‐ocular region into the eye. The main route for absorption is across the cornea. However, absorption of drug across the cornea is inefficient due to its impermeable nature and small surface area. Thus, the intra‐ocular bioavailability of topically administered medications is typically less than 10%.

3. Corneal permeability favours moderately lipophilic compounds. These compounds often have a low aqueous solubility. Problems in ocular drug delivery and formulation are compounded for poorly soluble drugs that must be formulated as suspensions.

4. Reformulation of ophthalmic suspensions as solutions has many advantages. This may be achieved by complexation using cyclodextrins. Solubilization using cyclodextrins can overcome many of the formulation problems. However, it is unclear as to their potential for improving ocular bioavailability, which is seemingly drug dependent and may be influenced by both the physicochemical properties of the drug and the complex formed.
Role Of Neurotrophin Receptor p75NTR In Mediating Neuronal Cell Death Following Injury
Authors: Coulson Ej , Reid K , Murray Ss , Cheema Ss , Bartlett Pf
Published: March 2003

1. The neurotrophin receptor p75NTR has been shown to mediate neuronal cell death after nerve injury.

2. Down‐regulation of p75NTR by antisense oligonucleotides is able to inhibit both sensory and motor neuron death and this treatment is more effective than treatment with growth factors.

3. p75NTR induces cell death by a unique death signalling pathway involving transcription factors (nuclear factor κB and c‐jun), Bcl‐2 family members and caspases.
Spinal Repair In Immature Animals: A Novel Approach Using The South American Opossum Monodelphis Domestica
Authors: Fry Ej , Saunders Nr
Published: March 2003

1. The adult mammalian central nervous system (CNS) is unable to regenerate following injury and repair has only been seen when implants of peripheral nervous tissue, fetal tissue or Schwann cells are used, or antibodies or trophic molecules applied. However, the immature mammalian CNS has revealed a capacity to repair without extrinsic influence.

2. The marsupial mammal provides a unique opportunity to access the immature CNS without invasive in utero surgery. In particular, the South American opossum Monodelphis domestica is an ideal animal for spinal cord injury studies examining the ability of the immature CNS to repair after injury.

3. The Monodelphis spinal cord may be examined for its response to injury either as an in vitro or in vivo system and, therefore, is a flexible model, allowing many different questions to be addressed by the most suitable approach.

4. The immature Monodelphis CNS was able to support fibre growth that reappeared 4 days after a crush at P3‐P8 in vitro. Conduction was also restored at this time, accompanied by synaptic connections.

5. A cut lesion performed in vivo on Monodelphis spinal cords at P7 took longer to repair, with fibres reappearing across the injury site 2 weeks after the lesion; greater disruption to structure was noted both during early stages of repair and in adulthood.

6. Neural pathway tracing with dextran amine from the lumbar cord to the brain in adult Monodelphis, which received spinal lesions at P7, revealed a similar distribution of labelled cells in brainstem and mid‐brain nuclei to that of control animals.

7. Studies of the locomotor behaviour of adult Monodelphis that had received either a cut or crush lesion at P7‐P8 showed remarkably similar abilities to control animals when performing complex tasks.

8. The results of spinal cord injury studies with the immature Monodelphis CNS may help in the development of treatments for spinal injury patients.
Type‐C Natriuretic Peptide Prevents Development Of Experimental Atherosclerosis In Rabbits
Authors: Gaspari Tracey A , Barber Melissa N , Woods Robyn L , Dusting Gregory J
Published: March 2003

1. We investigated the effect of local administration of type‐C natriuretic peptide (CNP) on the endothelial dysfunction and development of an atheroma‐like neointima induced by a peri‐arterial collar in rabbits.

2. Peri‐arterial collars were placed on both common carotid arteries allowing local treatment of the collared region with either CNP (10 μmol/L) or saline. After 7 days, uncollared (control) and collared sections were taken from both arteries for pharmacological and morphological analysis.

3. Application of the collar markedly attenuated (P < 0.05) endothelium‐dependent vasorelaxation induced by acetylcholine (ACh); inhibition of 5‐hydroxytryptamine contraction was 80±5% in control sections compared with 44±4% in collared sections from the same arteries. Local infusion of CNP (10 μmol/L) into the collar restored ACh‐induced vasorelaxation (74±3% from collared arteries + CNP vs 77±2% from control sections from the same arteries).

4. Type‐C natriuretic peptide treatment also reduced (P < 0.05) intimal thickening compared with contralateral collared arteries (intima/media ratio 0.06±0.01 vs 0.16±0.01).

5. These results provide evidence that locally administered CNP is effective in preventing the endothelial dysfunction and development of a neointima in this model.
Assessment Of Gastric Emptying In The Mouse Using The [13C]‐Octanoic Acid Breath Test
Authors: Symonds Erin L , Butler Ross N , Omari Taher I
Published: March 2003

1. Gastric emptying studies in small laboratory animals are hampered by the deficiency of a technique that is non‐invasive and repeatable. The aim of the present study was to adapt the non‐invasive [13C]‐octanoic acid breath test, which has been validated in humans, to assess both liquid and solid gastric emptying in the mouse.

2. Gastric emptying rates were investigated for a liquid meal (Intralipid®; Kabi Pharmacia AB, Stockholm, Sweden; n = 7) and two solid meals (egg yolk and mouse chow; n = 7) incorporating [13C]‐octanoic acid. All meals were analysed for natural enrichment of [13C]. Mathematical analysis of the 13CO2 excretion rate allowed the determination of gastric emptying parameters.

3. Gastric emptying of Intralipid® was more rapid than egg yolk (P < 0.0001). Gastric emptying of mouse chow could not be assessed due to intragastric separation of [13C]‐octanoic acid and natural [13C] enrichment of the pellet.

4. The [13C]‐octanoic acid breath test can reproducibly assess both liquid and solid gastric emptying non‐invasively in the mouse. This method can now be used to assess gastric emptying in drug studies and disease studies for which there are established mouse models.