bluuebunny/crossref_metadata_2025 huggingface dataset:
Computed tomography perfusion imaging in acute stroke
Authors: Keith CJ , Griffiths M , Petersen B , Anderson RJ , Miles KA
Published: March 2003

The development of thrombolytic and neuroprotective agents for the treatment of acute stroke has created an imperative for improved imaging techniques in the assessment of acute stroke. Five cases are presented to illustrate the value of perfusion CT in the evaluation of suspected acute stroke. To obtain the perfusion data, a rapid series of images was acquired without table movement following a bolus of contrast medium. Cerebral blood flow, cerebral blood volume and mean transit time were determined by mathematically modelling the temporal changes in contrast enhancement in the brain and vascular system. Pixel‐by‐pixel analysis allowed generation of perfusion maps. In two cases, CT‐perfusion imaging usefully excluded acute stroke, including one patient in whom a low‐density area on conventional CT was subsequently proven to be tumour. Cerebral ischaemia was confirmed in three cases, one with an old and a new infarction, one with a large conventional CT abnormality but only a small perfusion defect, and one demonstrating infarct and penumbra. Perfusion CT offers the ability to positively identify patients with non‐haemorrhagic stroke in the presence of a normal conventional CT, to select those cases where thrombolysis is appropriate, and to provide an indication for prognosis.
Concomitant diminishing magnetization‐transfer effect and increasing choline level in radiation‐induced temporal‐lobe changes
Authors: Rumpel Helmut , Ho Gaik L , Chan Ling L , Lim Winston EH , Chong Vincent FH
Published: March 2003

This article reports on the use of both magnetization–transfer (MT) imaging and 1H‐MR spectroscopy in two cases of bilateral temporal‐lobe changes after radiation therapy for nasopharyngeal carcinoma. In the first case, the following patterns were noted: (i) although the temporal lobes appeared relatively normal on T2‐weighted MR imaging, corresponding MT imaging clearly showed signal abnormalities (decreased MT effect) consistent with alterations in macromolecular structure; and (ii) concomitant strongly elevated choline on 1H‐MR spectroscopy was observed, and this is associated with metabolic changes in cell membranes. The second case presented similar characteristics. In addition, there was an increased lactate signal and T2 signal changes in keeping with established oedema. Both MT and proton‐spectroscopic findings were consistent with postulated pathophysiological features of radiation injury, but their specificity for this condition remains unclear. Magnetization‐transfer imaging, and possibly 1H‐MR spectroscopy, might be sensitive techniques for the early detection of late radiation injury.
Geographic delivery models for radiotherapy services
Authors: Roberts Gisele H , Dunscombe Peter B , Samant Rajiv S
Published: March 2003

The study described here was undertaken to quantify the societal cost of radiotherapy in idealized urban and rural populations and, hence, to generate a measure of impediment to access. The costs of centralized, distributed comprehensive and satellite radiotherapy delivery formats were examined by decomposing them into institutional, productivity and geographical components. Our results indicate that centralized radiotherapy imposes the greatest financial burden on the patient population in both urban and rural scenarios. The financial burden faced by patients who must travel for radiotherapy can be interpreted as one component of the overall impediment to access. With advances in remote‐monitoring systems, it is possible to maintain technical quality while enhancing patient access. However, the maintenance of professional competence will remain a challenge with a distributed service‐delivery format.
ATM induction insufficiency in a radiosensitive breast‐cancer patient
Authors: Clarke RA , Fang ZH , Marr PJ , Lee CS , Kearsley JH , Papadatos G
Published: March 2003

The ataxia telangiectasia (A–T) gene (ATM) is a dominant breast cancer gene with tumour suppressor activity. ATM also regulates cellular sensitivity to ionising radiation (IR) presumably through its role as a facilitator of DNA repair. In normal cells and tissues the ATM protein is rapidly induced by IR to threshold/maximum levels. The kinase function of the ATM protein is also rapidly activated in response to IR. The fact that women carriers of ATM mutations can have an increased risk of developing breast cancer and that many sporadic breast tumours have reduced levels of the ATM protein broadens the scope of ATM's tumour suppressor within the breast. This report describes the downregulation of ATM protein levels in a radiosensitive breast cancer patient. Postinduction ATM levels were up to tenfold lower in the patient's fresh tissues compared to normal controls. These results might indicate a much broader role for ATM anomalies in breast cancer aetiology.
Part‐time consultants in radiation oncology
Authors: Vinod Shalini K , Jalaludin Bin B , Rodger Alan , Turner Sandra , Kelly Lyndell , Thornton Deborah , Clark Catherine
Published: March 2003

The aim of this study was to evaluate the attitudes and experiences of staff towards radiation oncologists who work part‐time. A questionnaire was sent to all radiation oncologists, radiation oncology registrars and radiation therapists, and a nursing and clerical representative working in all radiation oncology departments throughout Australia and New Zealand. Of 1242 questionnaires, 446 (35.9%) were returned. Of these, 323 out of 435 respondents (74.2%) supported the concept of a radiation oncologist working part‐time. The main barriers to part‐time work were inadequate provision of cover, the inability to be contacted when not rostered on, and perceived reduced quality of patient care. The majority of respondents supported part‐time employment in radiation oncology. However, the conclusions made from this survey are limited by the poor response rate. For a successful part‐time career in radiation oncology, the following points need to be ensured: (i) an equitable pro‐rata workload that encompasses both clinical and non‐clinical duties; (ii) a clear and well‐publicised timetable that is strictly adhered to with special emphasis on completing work prior to non‐rostered days; (iii) clear mechanisms in place to deal with patient or other queries on non‐rostered days; (iv) a mechanism for being contacted for urgent problems; and (v) good communication between the part‐time radiation oncologist, other staff and patients.
MR imaging of a ruptured intraspinal dermoid tumour with fat droplets in the central spinal canal
Authors: Karadag Demet , Karagülle Ayşe Tuba , Erden Ayşe , Erden Ilhan
Published: March 2003

We report a patient with intramedullary ruptured spinal dermoid tumour. The MR imaging revealed an intra­medullary lumbar mass heterogenous in intensity in all sequences. Fat droplets were observed in the subarachnoid space as well as in the dilated central spinal canal. Fat droplets in the subarachnoid space are frequently seen in the rupture of intraspinal dermoid tumours; however, fat droplets within the central canal is quite rare and was unexpected. Magnetic resonance imaging is a useful tool in the determination of spinal pathologies before they become large enough to cause severe symptoms and/or morbidity.
RAT RENOMEDULLARY INTERSTITIAL CELLS POSSESS BRADYKININ B2 RECEPTORS IN VIVO AND IN VITRO
Authors: Dean Rachael , Maric Christine , Aldred G Peter , Casley David , Zhuo Jialong , Harris Peter , Alcorn Daine , Mendelsohn Frederick Ao
Published: March 2003

1. Renomedullary interstitial cells (RMIC), abundant throughout the medulla of the kidney, have been demonstrated to have binding sites for many vasoactive peptides, including atrial natriuretic peptide, endothelin, angiotensin II and bradykinin (BK). These observations would support the hypothesis that interactions between RMIC and vasoactive peptides are important in the regulation of renal function.

2. We aimed to localize the BK B2 receptor binding site to RMIC in vivo and to also demonstrate that these receptors are biologically active in vitro.

3. The present study demonstrates BK B2 binding sites on RMIC of the inner stripe of the outer medulla and the inner medulla of the rat kidney in vivo.

4. We further demonstrate that the BK B2 radioligand [125I]‐HPP‐Hoe140 specifically bound to rat RMIC in vitro. In addition, reverse transcription–polymerase chain reaction detected the mRNA for the BK B2 receptor subtype in cell extracts.

5. For RMIC in vitro, cAMP levels were increased at 1 min and cGMP levels were increased at 2 min after treatment with 10–10 and 10–7 mol/L BK, respectively. Inositol 1,4,5‐trisphosphate was increased at 10 s treatment with both 10–6 and 10–7 mol/L BK.

6. For RMIC in vitro, BK induced an increase in cell proliferation ([3H]‐thymidine incorporation) and an increase in extracellular matrix synthesis (ECM; trans‐[35S] incorporation), both effects mediated by BK B2 receptors.

7. We conclude that BK B2 receptors are present on RMIC both in vivo and in vitro. These receptors are coupled to intracellular second messenger systems and, in vitro, their stimulation results in cellular proliferation and synthesis of ECM.
UPPER AIRWAY FUNCTION AND DYSFUNCTION IN RESPIRATION
Authors: Pierce RJ , Worsnop CJ
Published: March 2003

1. The upper airway not only provides a passage for air to be breathed in and out of the lungs, but it also heats, humidifies and filters the air and is involved in cough, swallowing and speech.

2. The complex muscle structure of the upper airway that produces speech and swallowing in humans also modulates respiratory airflow throughout the respiratory cycle, but is vulnerable to functional problems that may compromise respiration.

3. Even in normals, there is some collapse of the upper airway and increased upper airway resistance during sleep.

4. A substantial proportion of people suffer from obstructive sleep apnoea, in which the collapse of the upper airway is so great that respiration is compromised to the extent that arousal from sleep is required to restore adequate ventilation; the resulting disturbed sleep and hypoxia produce daytime sleepiness and neuropsychological and cardiorespiratory morbidity.

5. Functional abnormalities of the larynx can also occur, including prolonged inspiratory laryngeal dysfunction, brief upper airway dysfunction and expiratory laryngeal dysfunction or factitious asthma.
ENDOTHELIAL CELL RESPONSES TO HYPOXIC STRESS
Authors: Faller Douglas V
Published: March 2003

1. Changes in the environmental oxygen tension to which cells are exposed in vivo result in physiological and sometimes pathological consequences that are associated with differential expression of specific genes.

2. Low oxygen tension (hypoxia) affects endothelial cellular physiology in vivo and in vitro in a number of ways, including the transcriptionally regulated expression of vasoactive substances and matrix proteins involved in modulating vascular tone or remodelling the vasculature and surrounding tissue.

3. Hypoxia results in the transcriptional induction of genes encoding vasoconstrictors and smooth muscle mitogens (PDGF‐B, endothelin‐1, VEGF, thrombospondin‐1) and genes encoding matrix or remodelling molecules (collagenase IV (MMP‐9), thrombospondin‐1) and reciprocal transcriptional inhibition of vasodilatory or anti‐mitogenic effectors (eNOS).

4. Oxygen appears to signal through a novel haem‐containing sensor and signals initiated by this sensor alter the levels and DNA‐binding activity of transcription factors such as activating protein (AP)‐1, nuclear factor‐κB and hypoxia‐inducible transcription factor‐1.

5. The genes encoding vasoactive factors regulated by oxygen tension are themselves also regulated by the vasoactive agent nitric oxide (NO).

6. Nitric oxide and oxygen transduce similar signals (i.e. their absence results in identical patterns of gene expression in endothelial cells and other cell types).

7. Thus, NO can feedback on and modulate signals induced by hypoxia and vice versa. For example, NO, which can act directly on smooth muscle cells as a vasodilator, can also facilitate vasodilation indirectly by reversing the production of vasoconstrictors induced by hypoxia.

8. Short‐term exposure of endothelial cells to low oxygen tension results in the elaboration of predominantly vasoconstricting effectors, while longer‐term and more severe hypoxic exposure generates factors that can induce smooth muscle proliferation and remodelling.

9. Thus, the endothelial cell response to hypoxic stress can result in two different consequences in the surrounding tissues, depending on the duration of the exposure: short‐term exposure causes physiological and reversible modulation of vascular tone and blood flow; chronic hypoxic stress results in irreversible remodelling of the vasculature and surrounding tissues, with smooth muscle proliferation and fibrosis.

10. This dichotomy of responses to hypoxia may explain, in part, both the acute and chronic pathophysiological sequelae of diseases characterized by regional hypoxia, including atherosclerosis, pulmonary hypertension, sickle cell disease and systemic sclerosis (scleroderma).
VASCULAR BIOLOGY OF ENDOTHELIN SIGNAL TRANSDUCTION
Authors: Neylon Craig B
Published: March 2003

1. Endothelins regulate cell function by interacting with two classes of cell surface receptors, ETA and ETB receptors. Both receptor types are members of the heptahelical transmembrane‐spanning receptor superfamily and couple via G‐proteins to multiple intracellular effectors.

2. Many of the cellular responses induced by endothelins are mediated by changes in cytoplasmic Ca2+ concentration. Stimulation of inositol 1,4,5‐trisphosphate (IP3) formation promotes release of Ca2+ from intracellular stores via IP3‐sensitive Ca2+ channels. This mechanism accounts for the initial transient peak of the Ca2+ elevation. The entry of Ca2+ across the plasma membrane through multiple types of Ca2+ channels is responsible for the sustained phase of Ca2+ elevation and, together, both mechanisms regulate cell function.

3. Endothelin‐mediated Ca2+ signals vary markedly in duration, spatial organization and temporal pattern. The elevations in Ca2+ are sustained, transient or oscillatory and occur either globally or are localized to discrete spatial domains. These different Ca2+ signals, which are dependent on the availability of specific ion channels, control distinct cellular functions. Ryanodine‐sensitive Ca2+ release channels may be important in determining the organization of the Ca2+ signal.

4. Endothelin‐induced Ca2+ elevations near the plasma membrane stimulate the opening of Ca2+‐dependent K+ and Cl− channels. These channels are key regulators of membrane potential and, consequently, regulate the activity of voltage‐ dependent Ca2+ influx pathways.

5. Endothelin regulates the growth and differentiation of cells. It markedly potentiates the mitogenic response of other growth factors, an effect that involves activation of the mitogen‐activated protein kinase cascade and induction of early response genes.

6. Finally, the vascular actions of endothelin are influenced by the relative expression of specific ion channels, the spatial and temporal pattern of the Ca2+ signal and the cellular composition of the vascular wall.
CYTOKINES AND THE PROGRESSION OF LIVER DAMAGE IN EXPERIMENTAL BILE DUCT LIGATION
Authors: Plebani Mario , Panozzo Maria Piera , Basso Daniela , Paoli Massimo De , Biasin Raffaella , Infantolino Domenico
Published: March 2003

1. Cytokines are soluble factors whose action has been documented in physiological and pathological conditions. Some may be involved in the pathogenesis of cholestasis, whether of acute or chronic origin.

2. The aim of the present study was to evaluate the influence of epidermal growth factor (EGF), transforming growth factor (TGF)‐β1, interleukin (IL)‐6 and tumour necrosis factor (TNF) on cholestasis. Findings from Sprague‐Dawley rats submitted to bile duct ligation for 1–28 days were compared with those from controls, which underwent laparotomy but not bile duct ligation.

3. Biochemical and morphological findings confirmed that the experimental procedure was successful. At the end of each follow‐up period, the hepatic levels of the cytokines were determined and compared with liver histology findings.

4. The four cytokines studied showed different patterns of activation: hepatic levels of EGF, higher in the experimental than the control group, were comparable with the proliferative picture. The TGF‐β1 pattern was correlated with data of periportal, perivenular and perineoductular fibrosis, confirming that this cytokine has a role in mediating the synthesis of matrix proteins. A fluctuating, phasic pattern was found for TNF in the experimental group, with high values on day 0, a decrease on the first and second postoperative days and then two peaks on days 8 and 14. Finally, immediately after surgical manipulation, high levels of IL‐6 were found in the experimental group, followed by a decrease in levels until zero values were obtained.

5. This suggests that the obstructive condition produces several cytokine responses, each of which contributes to determine the cholestatic condition.
AGE‐RELATED CHANGES IN PLATELET MICROVISCOSITY AND AGGREGATION IN RATS
Authors: Hossain Shahdat , Hashimoto Michio , Masumura Sumio
Published: March 2003

1. To study possible changes in platelet microviscosity in aged animals, 1,6‐diphenyl‐1,3,5‐hexatriene (DPH) was used as a non‐polar probe embedded in thrice‐washed platelets from young, adult and aged rats. With the known values of maximum limiting anisotropy and the structural parameter of DPH and by estimating the steady state of fluorescence anisotropy and the average fluorescence of lifetime, we applied the Perrin equation to calculate the microviscosity.

2. We measured platelet aggregation, platelet lipids and platelet polyunsaturated fatty acids to determine any causal relationship between these parameters. Platelet aggregation, the platelet molar ratio of cholesterol to phospholipid ([C]/[PL]) and platelet microviscosity increased with age (P < 0.05) and were correlated with one another (P < 0.05).

3. Age‐dependent increases in the steady state of fluorescence anisotropy, order parameters and the short component of fluorescence lifetime of the fluorophore were expressed as functions of variables, such as microviscosity or the [C]/[PL] ratio.

4. Platelet concentrations of arachidonic and eicosapentaenoic acids increased with age, but were not associated with aggregation. Age‐related changes in microviscosity and the [C]/[PL] ratio seemed to be determinants affecting biophysical properties of platelet aggregation.
INHIBITION OF HUMAN CARDIAC FIBROBLAST MITOGENESIS BY BLOCKADE OF MITOGEN‐ACTIVATED PROTEIN KINASE AND PHOSPHATIDYLINOSITOL 3‐KINASE
Authors: Hafizi Sassan , Chester Adrian H , Yacoub Magdi H
Published: March 2003

1. Interstitial fibroblast proliferation is an elemental feature in the development of cardiac fibrosis. The effects of inhibitors of the intracellular signalling proteins, MEK, a kinase involved in the mitogen‐activated protein kinase (MAPK) pathway and phosphatidylinositol 3‐kinase (PI3‐K), were tested on growth of cultured human cardiac fibroblasts.

2. Cardiac fibroblasts were isolated from transplant recipient myocardium and made quiescent by serum deprivation for 48 h. Cells were incubated for 24 h with the inhibitors PD 098059 (0.3–30 μmol/L) and LY294002 (1–25 μmol/L) in the presence and absence of platelet‐derived growth factor‐AB (PDGF‐AB, 10 ng/mL). DNA synthesis was measured by [3H]‐thymidine incorporation assay (20–24 h).

3. Both compounds markedly inhibited both basal and PDGF‐stimulated increases in DNA synthesis in a concentration‐dependent manner. Cardiac fibroblast DNA synthesis was reduced to near control levels by PD 098059, while it was inhibited completely by LY294002.

4. These results implicate the importance of MAPK and PI3‐K activation in the signal transduction pathways necessary for cardiac fibroblast replication.
NITRIC OXIDE‐DEPENDENT ENDOTHELIAL FUNCTION IS UNAFFECTED BY ALLOPURINOL IN HYPERCHOLESTEROLAEMIC SUBJECTS
Authors: O’Driscoll JG , Green DJ , Rankin JM , Taylor RR
Published: March 2003

1. Hypercholesterolaemia is associated with abnormal endothelium‐related vasodilator function, possibly due to increased destruction •NO by superoxide anions (•O2–). Oxypurinol, a xanthine oxidase (XO) inhibitor with anti‐oxidant properties and the active metabolite of the commonly used drug allopurinol, reduces •NO quenching in vitro and has been reported to acutely improve endothelial function in hypercholesterolaemic subjects.

2. The purpose of the present study was to determine whether oral allopurinol improves •NO dilator function in hypercholesterolaemic subjects.

3. A randomized double‐blind, placebo‐controlled cross‐over design evaluated the effect of allopurinol (300 mg daily for 4 weeks) on forearm blood flow (FBF) responses to intrabrachial infusion of acetylcholine (ACh), sodium nitroprusside (SNP) and NG‐monomethyl‐
L‐arginine (
L‐NMMA) in nine hypercholesterolaemic subjects.

4. Endothelium‐dependent vascular responses to ACh and L‐NMMA were not significantly altered by allopurinol. The endothelium‐independent vasodilator response to SNP was similarly unchanged.

5. These results indicate that allopurinol does not influence basal or stimulated activity of the •NO dilator system in hypercholesterolaemic subjects. If intracellular •O2– inactivation •NO is responsible for endothelial dysfunction in hypercholesterolaemia, the source may be other than XO dependent. However, generation of •O2– during the conversion of allopurinol to oxypurinol could offer an alternative, and probably more likely, explanation for the ineffectiveness of allopurinol in vivo.
EFFECT OF HOMOCYSTEINE ON THE PRODUCTION OF NITRIC OXIDE IN ENDOTHELIAL CELLS
Authors: Chow KIT , Cheung FILLY , Lao TERENCE TH , O KARMIN
Published: March 2003

1. Homocysteine decreased the release of nitric oxide in cultured human umbilical vein endothelial cells.

2. Homocysteine did not affect constitutive and inducible nitric oxide synthase activity.
ELECTRICALLY INDUCED INTRACELLULAR Ca2+ TRANSIENT IN SINGLE VENTRICULAR MYOCYTES: A USEFUL PARAMETER FOR THE STUDY OF CARDIAC DRUGS
Authors: Wang H‐X , Kwan CY , Wong TM
Published: March 2003

1. Fluorescent Ca2+ indicators, such as fura‐2/AM and calcium green‐1, have become one of the most popular tools for measuring intracellular calcium ([Ca2+]i).

2. Electrical stimulation triggers a cascade of events in the cardiac muscle, which results in a [Ca2+]i transient and, eventually, contraction. The events that occur in electrically induced cardiac myocytes mimic the normal physiological events in vivo.

3. The electrically induced [Ca2+]i transient represents influx of Ca2+ from outside and mobilization of Ca2+ from the intracellular store and is directly related to contraction. Thus, it is more important to determine the electrically induced [Ca2+]i transient than [Ca2+]i. The [Ca2+]i transient can be easily measured with the spectrofluorescence method using fura 2/AM as the Ca2+ indicator in a single ventricular myocyte preparation.

4. We made use of the results of studies on carbachol, tetrandrine and cardiotoxin to illustrate the usefulness of the electrically induced [Ca2+]i transient in the study of actions of cardiac drugs.
ROLE OF COMPLEMENT IN XENOTRANSPLANTATION
Authors: Saadi Soheyla , Platt Jeffrey L
Published: March 2003

1. Xenotransplantation, or transplantation across species, leads to rejection, which destroys the xenograft within hours to days of transplantation.

2. Complement is a major barrier to xenotransplantation of vascularized organs and is believed to play an important role in the rejection process.

3. The present paper reviews three aspects of complement in xenotransplantation. These include the mechanisms and regulation of complement activation as well as tissue injury mediated by complement activation.
POTENTIAL USE OF GENETICALLY MODIFIED PIGS AS ORGAN DONORS FOR TRANSPLANTATION INTO HUMANS
Authors: Logan John S , Sharma Ajay
Published: March 2003

1. Transplantation is currently viewed as a successful treatment for end‐stage organ failure. Its more widespread use is severely limited by a shortage of human organ donors. This has stimulated the scientific and medical communities to look at the potential use of animals to solve this problem. For a number of reasons, the pig appears to be the preferred species.

2. The initial immunological problem encountered in pig‐to‐primate transplantation is a process of hyperacute rejection, which is mediated by the binding of antibodies to the graft endothelium followed by the activation of the complement cascade. We have sought to overcome these initial immunological challenges by focusing our attention not only on the recipient of the graft but also on the donor. Therefore, we have generated transgenic animals with specific genetic modifications designed to inhibit the activation of the complement cascade. Upon transplantation to baboons of organs derived from these transgenic pigs, we have been able to demonstrate that hyperacute rejection can be prevented. We will discuss the generation of these and other transgenic animals and their potential role in clinical xenotransplantation.
Effects Of Intra‐Uterine Growth Restriction On The Control Of Breathing And Lung Development After Birth
Authors: Harding R , Tester Ml , Moss Tj , Davey Mg , Louey S , Joyce B , Hooper Sb , Maritz G
Published: March 2003

1. Low birthweight is now recognized as an important risk factor for early postnatal respiratory illness and it is becoming evident that low birthweight can increase the risk for airway dysfunction in children and adults. Our studies have been aimed at determining how low birthweight, resulting from intra‐uterine growth restriction (IUGR), affects the control of breathing and the structural and functional development of the lung.

2. We have measured ventilatory responsiveness to progressive hypoxia and progressive hypercapnia during the first weeks after birth in postnatal lambs in which IUGR was induced by chronic placental insufficiency. It was found that the postnatal increase in ventilatory sensitivity to hypoxia observed in control lambs was diminished in low birthweight lambs; in contrast, the sensitivity to hypercapnia was not affected. In other studies, we found that IUGR caused by maternal anaemia led to elevated CO2 levels during sleep and wakefulness.

3. Our findings suggest that the prenatal development of the brain‐stem or respiratory chemoreceptors may be affected by intra‐uterine factors associated with IUGR, such as foetal hypoxaemia or hypoglycaemia. It is also possible that the structure of respiratory muscles and, hence, their ability to maintain a high level of ventilation may be affected by IUGR.

4. Recently, we studied the influence of IUGR on foetal lung development, in particular its effects on foetal lung liquid, a major determinant of lung growth, as well as alveolar structure and pulmonary surfactant. Lung liquid secretion and volume, in relation to bodyweight, were unaffected; however, there was evidence of structural and functional immaturity in the lungs. In foetuses exposed to IUGR, the air–blood barrier was thicker and, after birth, the diffusing capacity of the lungs for carbon monoxide was lower. In contrast, surfactant protein gene expression was enhanced, particularly in foetuses with high levels of circulating cortisol.

5. Further studies are needed to characterize the effects of specific types of prenatal compromise on postnatal control of ventilation and lung function, to determine mechanisms underlying these effects and to determine the capacity for postnatal recovery.
Inhibition Of Transcription Factors By Anti‐Inflammatory And Anti‐Rheumatic Drugs: Can Variability In Response Be Overcome?
Authors: Handel Malcolm L , Nguyen Ly Qq , Lehmann Thomas P
Published: March 2003

1. The drugs used in the treatment of rheumatoid arthritis (RA) form a diverse group with unpredictable adverse effects, mostly weak efficacy and variable responses. Despite their differences, a common feature of many anti‐inflammatory and disease‐modifying anti‐rheumatic drugs (DMARD) is inhibition of pro‐inflammatory transcription factors, particularly nuclear factor (NF)‐κB and activator protein (AP)‐1.

2. The present brief review identifies those drugs capable of inhibiting transcription factors, particularly steroids, gold salts, D‐penicillamine, cyclosporine A and possibly salicylates.

3. The newer biological inhibitors of tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β are capable of indirect inhibition of NF‐κB activation, although even with these potent agents the problem of variability in response has not disappeared.

4. The development of selective inhibitors of the transcription factor NF‐κB should have the benefit of the anti‐inflammatory drugs and DMARD, both new and old.

5. It is hypothesized that this strategy will overcome much of the variability in the therapeutic response and adverse effects that limit the usefulness of the exisiting drugs in the treatment of RA.
Importance Of Histamine, Glutathione And Oxyradicals In Modulating Gastric Haemorrhagic Ulcer In Septic Rats
Authors: Hung Chen‐Road
Published: March 2003

1. The ulcerogenesis of gastric haemorrhagic damage during sepsis is unclear. The present study first proposes that gastric haemorrhagic ulcer is modulated by mucosal glutathione, histamine and oxyradicals in lipopolysaccharide (LPS)‐induced sepsis in rats. The protective effects of several drugs on the ulcerogenic parameters also were evaluated.

2. Male specific pyrogen‐free Wistar rats were deprived of food for 24 h. For the induction of sepsis, intravenous LPS (0, 1, 3 or 10 mg/kg in 1 mL sterilized normal saline) was challenged to rats 12 h after withdrawal of food. Rat stomachs were vagotomized, followed by irrigation for 3 h with normal saline or a physiological acid solution containing 100 mmol/L HCl and 54 mmol/L NaCl.

3. The aggravation of gastric ulcerogenic parameters, such as gastric acid back‐diffusion, luminal haemoglobin content, mucosal lipid peroxide production, histamine concentration, as well as lowered concentrations of defensive substances, including mucosal glutathione, were dependent on the doses of LPS used for challenge. A high correlation was observed between mucosal histamine release and lipid peroxide production in LPS rats.

4. The ulcerogenic parameters obtained in LPS (3 mg/kg, i.v.) rats were potently attenuated by diamine oxidase, ketotifen and zinc sulphate.

5. Several oxyradical scavengers, including glutathione, dimethylsulphoxide and allopurinol, also were effective in inhibiting haemorrhagic ulcer.

6. In conclusion, gastric mucosal histamine release and oxyradical generation play pivotal roles in the formation of haemorrhagic ulcers in septic rats.
Effects Of The Na+/H+ Exchange Inhibitor Cariporide (HOE 642) On Cardiac Function And Cardiomyocyte Cell Death In Rat Ischaemic–Reperfused Heart
Authors: Otani Hajime , Uchiyama Takamichi , Yamamura Tadashi , Nakao Yoshihisa , Hattori Reiji , Ninomiya Hideki , Kido Masakuni , Kawaguchi Hideki , Osako Motohiko , Imamura Hiroji
Published: March 2003

1. Na+/H+ exchange has been implicated in the mechanism of reperfusion injury. We examined the effects of the cardiac‐specific Na+/H+ exchange inhibitor cariporide (HOE 642) on postischaemic recovery of cardiac function and cardiomyocyte cell death (i.e. necrosis and apoptosis).

2. Rat isolated and buffer‐perfused hearts were subjected to 25 min normothermic global ischaemia followed by 120 min reperfusion. Cariporide (10 μmol/L) or its vehicle (0.01% dimethylsulphoxide) was administered for 15 min before ischaemia and for the first 30 min after reperfusion.

3. Cariporide significantly improved the recovery of isovolumic left ventricular function (heart rate, left ventricular developed pressure and left ventricular end‐diastolic pressure) and coronary flow throughout reperfusion. Creatine kinase release during reperfusion was significantly less in the cariporide‐treated heart. In situ terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling (TUNEL)‐ positive cardiomyocytes were also significantly less in the cariporide‐treated heart after 120 min reperfusion. Electron microscopy showed necrotic changes without typical apoptotic features in cardiomyocytes after reperfusion. Such necrotic changes were mitigated by cariporide. Simultaneous detection of necrotic and apoptotic cardiomyocytes using propidium iodide (PI) and Annexin V revealed that cardiomyocytes in the infarct area were stained with only PI or both PI and Annexin V. Cariporide did not alter the pattern of cardiomyocyte staining with PI and Annexin V, although the number of cardiomyocytes stained with PI or PI plus Annexin V was less than that in vehicle‐treated hearts.

4. These results suggest that apoptosis is not a major manifestation of cardiomyocyte cell death in the ischaemic– reperfused myocardium and a cariporide‐sensitive mechanism of reperfusion injury promotes both necrotic and apoptotic processes of cell death.
Growth Hormone Secretagogue Actions On The Pituitary Gland: Multiple Receptors For Multiple Ligands?
Authors: Chen Chen
Published: March 2003

1. Growth hormone (GH) secretion is thought to occur under the reciprocal regulation of two hypothalamic hormones, namely GH‐releasing hormone (GHRH) and somatostatin (SRIF), through their engagement with specific cell‐surface receptors on the anterior pituitary somatotropes.

2. In addition to GHRH and SRIF, synthetic GH‐releasing peptides (GHRP) or GH secretagogue(s) (GHS) regulate GH release through the activation of a novel receptor, the GHS receptor (GHS‐R).

3. The cloning of the GHS‐R from human, swine and rat identifies a novel G‐protein‐coupled receptor involved in the control of GH secretion and supports the existence of an undiscovered hormone that may activate this receptor.

4. Varieties of intracellular signalling systems are suggested to mediate the action of GHS, which include changes in intracellular free Ca2+ ([Ca2+]i), cAMP, protein kinases A and C, phospholipase C etc.

5. With regard to the use of signalling systems by GHS, especially a new form of GHRP or GHRP‐2, a clear species difference has been demonstrated, supporting the possibility of more than one type of GHS‐R.
Effect Of Cold On Fetal Heart Rate And Its Variability
Authors: Yu Ze‐Yan , Lumbers Eugenie R
Published: March 2003

1. The effects of cold saline (25 mL) injected over the fetal skin on fetal heart rate (HR) and HR variability (HRV), measured as the coefficient of variation (CV) in pulse interval (PI) and by power spectral analysis (PSA), were measured in 10 chronically catheterized fetal sheep aged 140–144 days. To determine the extent to which effects on HR and HRV were mediated by the sympathoadrenal neuroendocrine axis and the cardiac vagus, experiments were performed before and after β‐adrenoreceptor blockade with propranolol (n = 12 fetuses) or before and after cardiac vagal blockade with atropine (n = 4 fetuses).

2. Injection of ice‐cold saline over the skin caused an immediate rise in mean arterial pressure (MAP) from 46±1 to 55±1 mmHg (P < 0.001) and HR from 156±2 to 182±2 b.p.m. (P < 0.001). Heart rate variability, measured as CV of PI, rose from 3.5±0.2 to 8.0±0.2% (P < 0.001) and total power spectral density (PSD) increased from 78±6 to 278±16 units (P < 0.001) as measured by PSA. Within 100 s, MAP, HR and HRV had returned to baseline.

3. β‐Adrenoreceptor blockade abolished all these changes in HR, HRV and PSD, but had no effect on changes in MAP. Atropine had no demonstrable effect on the responses to cold.

4. Therefore, the increase in fetal MAP, HR and HRV that occurred with stimulation of peripheral thermoreceptors was the result of increased activity of the sympathetic nervous system. Alterations in efferent cardiac vagal tone were not involved in the cardiac response to cold.
Effects Of Dipyridamole And Adenosine On Vasoactive Peptides Calcitonin Gene‐Related Peptide And Atrial Natriuretic Peptide In Humans: Role Of Sympathetic Activation
Authors: Guideri Francesca , Capecchi Pier Leopoldo , Lazzerini Pietro Enea , Pasini Franco Laghi
Published: March 2003

1. It has been observed that dipyridamole (DIP) administration produces equivalent cardiovascular effects at lower systemic adenosine (ADO) plasma concentrations than those obtained with exogenous ADO infusion. This observation led to the identification of DIP for additional ‘ischaemia‐inducing’ mechanisms, possibly based on sympathetic activation.

2. In turn, exogenous ADO administration has proven to elicit a complex neurohumoral response, including an increase in the plasma concentration of catecholamines, associated with augmented levels of the vasoactive peptides calcitonin gene‐related peptide (CGRP) and atrial natriuretic peptide (ANP). More particularly, increases in CGRP seem to be dependent on sympathetic activation, while changes in ANP do not.

3. In order to clarify some aspects of the activity of DIP on neurohumoral systems, the effects of administration of DIP and ADO on plasma levels of noradrenaline (NA), CGRP and ANP were studied in healthy volunteers. Haemodynamic parameters were also monitored.

4. Infusion of exogenous ADO produced plasma levels of ADO as high as 1893±386 nmol/L, together with a significant increase in plasma levels of CGRP, ANP and NA. Similarly, the infusion of DIP produced augmented plasma concentrations of the examined parameters, with a peak plasma ADO concentration of 470±49 nmol/L.

5. At a given ADO plasma concentration of 450±10 nmol/L, the increase in CGRP and NA levels with DIP infusion was significantly higher than that observed following the infusion of ADO, whereas the increase in the plasma concentration of ANP following DIP infusion was very similar to that seen following ADO infusion.

6. The physiological background of these findings is based on evidence that DIP displays a greater sympathoexcitatory activity than does exogenous ADO and only the increase in plasma CGRP seems to be mediated, although indirectly, by β‐adrenoceptor stimulation. The exact mechanism of DIP‐dependent sympathetic activation remains to be elucidated.
High Plasma Concentrations Of Prorenin In A Transgenic Animal Model Of Nephropathy With Overexpression Of Transforming Growth Factor‐β1 In The Kidneys
Authors: Krag Søren , Nielsen Arne Høj , Wogensen Lise
Published: March 2003

1. Plasma concentrations of prorenin were determined in a transgenic animal model of nephropathy induced by overexpression of transforming growth factor (TGF)‐β1 in the juxtaglomerular apparatus.

2. In both female and male mice, plasma concentrations of prorenin were higher in transgenic than in non‐transgenic animals. In sexually mature mice, plasma prorenin concentrations were higher in males than in females in both transgenic and non‐transgenic animals in accordance with a sexual dimorphism of the plasma concentration of prorenin.

3. The results indicate that TGF‐β1‐like androgens increase prorenin secretion in the kidneys and may explain the increased plasma prorenin concentrations in patients with diabetic nephropathy.
Renal And Cardiovascular Actions Of 20‐Hydroxyeicosatetraenoic Acid And Epoxyeicosatrienoic Acids
Authors: Roman Richard J , Maier Kristopher G , Sun Cheng‐Wen , Harder David R , Alonso‐Galicia Magdalena
Published: March 2003

1. Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP)‐dependent pathways to epoxyeicosatrienoic acids (EET) and 20‐hydroxyeicosatetraenoic acid (20‐HETE) in the kidney and the peripheral vasculature.

2. The present short review summarizes the renal and cardiovascular actions of these important mediators.

3. Epoxyeicosatrienoic acids are vasodilators produced by the endothelium that hyperpolarize vascular smooth muscle (VSM) cells by opening Ca2+‐activated K+ (KCa) channels. 20‐Hydroxyeicosatetraenoic acid is a vasoconstrictor that inhibits the opening of KCa channels in VSM cells. Cytochrome P450 4A inhibitors block the myogenic response of small arterioles to elevations in transmural pressure and autoregulation of renal and cerebral blood flow in vivo. Cytochrome P450 4A blockers also attenuate the vasoconstrictor response to elevations in tissue PO2, suggesting that this system may serve as a vascular oxygen sensor. Nitric oxide and carbon monoxide inhibit the formation of 20‐HETE and a fall in 20‐HETE levels contributes to the activation of KCa channels in VSM cells and the vasodilator response to these gaseous mediators. 20‐Hydroxyeicosatetraenoic acid also mediates the inhibitory actions of peptide hormones on sodium transport in the kidney and the mitogenic effects of growth factors in VSM and mesangial cells. A deficiency in the renal production of 20‐HETE is associated with the development of hypertension in Dahl salt‐sensitive rats.

4. In summary, the available evidence indicates that CYP metabolites of AA play a central role in the regulation of renal, pulmonary and vascular function and that abnormalities in this system may contribute to the pathogenesis of cardiovascular diseases.
Quantitative Trait Loci For Lipid Metabolism In The Study Of Oletf × (Oletf × Fischer 344) Backcross Rats
Authors: Yamasaki Yuki , Watanabe Takeshi K , Okuno Shiro , Ono Toshihide , Oga Keiko , Mizoguchi‐Miyakita Ayako , Goto Yoshihiro , Shinomiya Hiroichi , Momota Hiroshi , Miyao Hideo , Hayashi Isamu , Asai Toshihiro , Suzuki Mikio , Harada Yosuke , Hishigaki Haretsugu , Wakitani Shigeyuki , Takagi Toshihisa , Nakamura Yusuke , Tanigami Akira
Published: March 2003

1. The Otsuka Long‐Evans Tokushima Fatty (OLETF) rat is a model of type II diabetes with accompanying dyslipidaemia and obesity.

2. To define chromosomal intervals associated with obesity (abdominal fat weight and plasma leptin levels), dyslipidaemia (plasma triglyceride, cholesterol and free fatty acids) and hyperglycaemia (plasma glucose levels), we have performed genome‐wide quantitative traits loci (QTL) analyses of 115 male OLETF × (OLETF × Fischer 344) backcross animals at 16 weeks of age.

3. The Diabetes Mellitus OLETF type I (Dmo1) locus on rat chromosome 1 showed statistically significant involvement in elevations of plasma levels of triglycerides (P = 4.87 × 10–6 at D1Rat90) and total cholesterol (P = 1.16 × 10–5 at D1Rat306).

4. No other loci produced significant linkage to these observed phenotypes.

5. These analyses have confirmed the importance of Dmo1 in lipid homeostasis at younger ages as well as during overt diabetes, which appears later. Thus, alterations at the Dmo1 locus are a major risk factor for pathogenesis in the strain, a finding that agrees with physiological studies that indicate a role for dyslipidaemia in the type II diabetic syndrome of OLETF rats.
Role Of Nitric Oxide In Adrenocorticotrophin‐Induced Hypertension: L‐Arginine Effects Reversed By N‐Nitro‐	L‐Arginine
Authors: Wen Cheng , Li Ming , Whitworth Judith A
Published: March 2003

1. L‐Arginine prevents adrenocorticotrophin (ACTH)‐induced hypertension in the rat. To confirm that this effect is mediated through the nitric oxide (NO) system, we examined whether N‐nitro‐
L‐arginine (NOLA) could reverse the
L‐arginine‐induced blockade of ACTH‐induced hypertension.

2. Blood pressure and metabolic parameters were examined in sham‐, ACTH‐, L‐arginine + sham‐, NOLA + sham‐, ACTH +
L‐arginine‐ and ACTH +
L‐arginine + NOLA‐treated Sprague‐Dawley rats (n = 40).

3. Adrenocorticotrophin treatment increased systolic blood pressure (SBP), water intake and urine output and decreased bodyweight. N‐Nitro‐
L‐arginine alone increased SBP without affecting metabolic variables.
L‐Arginine alone did not affect blood pressure. The SBP was lower in
L‐arginine + ACTH‐ than ACTH‐treated rats (P < 0.001), but was higher following ACTH +
L‐arginine + NOLA than ACTH +
L‐arginine (P < 0.05).

4. N‐Nitro‐
L‐arginine reversed the blood pressure‐lowering effect of
L‐arginine in ACTH‐induced hypertension in the rat, supporting the notion that NO plays a role in the hypertension.
Characterization And Regulation Of Tachykinin Receptors In The Nucleus Tractus Solitarius
Authors: Mazzone Stuart B , Geraghty Dominic P
Published: March 2003

1. The characteristics, localization and regulation of tachykinin receptors in the rat nucleus tractus solitarius (NTS) involved in respiratory control were investigated using a combination of in vivo microinjection and in vitro autoradiographic techniques.

2. Microinjection of receptor‐selective tachykinin agonists and antagonists into the NTS of urethane‐anaesthetized rats suggests that stimulation of NK1 and NK3 receptors increases tidal volume, whereas NK2 and NK3 receptor activation produces a bradypnoea.

3. Depletion of NK1 receptors in the NTS due to either ageing or acute hypoxia correlates with a markedly reduced respiratory response to substance P. In contrast, chemical ablation of sensory neurons by neonatal capsaicin administration dramatically increases the respiratory response to a variety of NK1, NK2 and NK3 agonists.

4. These studies suggest that all three tachykinin receptors are present in the rat NTS and that these receptors are subject to both acute and chronic regulation.
What Drives The Tonic Activity Of Presympathetic Neurons In The Rostral Ventrolateral Medulla?
Authors: Dampney RAL , Tagawa T , Horiuchi J , Fontes M , Polson JW
Published: March 2003

1. The present review discusses the mechanisms that maintain the tonic activity of presympathetic cardiovascular neurons in the rostral part of the ventrolateral medulla.

2. Experimental evidence is reviewed that indicates that these neurons receive both tonic excitatory and tonic inhibitory synaptic inputs. The former appear to be mediated, at least in part, by glutamate receptors and the latter appear to be mediated by GABA receptors.

3. There is also evidence that these neurons have the capacity to generate action potentials in the absence of synaptic inputs. However, at present, there is not clear evidence that such an intrinsic pacemaker‐like mechanism contributes to the tonic activity of these neurons under normal resting conditions.

4. These neurons are also chemosensitive and this may contribute to their tonic activation under conditions of hypoxia or hypercapnia.