bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelin as a causative factor of blunted volume reflex in diabetic rats
Authors: Wongmekiat Orawan , Johns Edward J
Published: April 2003

The study investigated whether endothelin (ET) contributed to the diabetes‐associated alterations in volume reflex and characterised the receptor subtype that might be involved. The influence of renal sympathetic nerves on these aspects of ET was also examined.

Groups of nondiabetic and streptozotocin‐induced diabetic rats were subjected to an acute isotonic saline volume expansion (VE), 10% body wt in the presence and absence of ET antagonists.

Cumulative urine sodium excretion (CuUNaV) after VE in diabetic rats reached values of 116±10 in the denervated and 74±6 μmol min−1 g kidney wt−1 in the innervated kidneys, which were both less (both P<0.001) than those achieved in the nondiabetic rats, at 267±9 in the denervated and 183±10 μmol min−1 g kidney wt−1 in the innervated kidney, respectively.

Diabetic rats pretreated with a nonselective ETA/ETB antagonist had an enhanced CuUNaV in the denervated kidneys by 37% (P<0.01) compared to that of untreated diabetic rats. At both doses of SB209670 these increments were less than the values obtained previously in nondiabetic rats (both P<0.01). The ETA/ETB antagonist had no meaningful effect on CuUNaV in the innervated kidneys of the diabetic rats, whereas previous studies in nondiabetic rats showed the response to be depressed. The CuUNaV responses to VE in diabetic rats given the selective ETA antagonist were not different from those observed in untreated diabetic rats, irrespective of whether or not the renal nerves were present. In nondiabetic rats, the ETA antagonist had an action similar to the mixed antagonist.

These findings demonstrate that activation of ETB receptors contributes to the depressed ability to excrete a saline load in diabetes mellitus, but its impact is obscured by the influence of the renal nerves.

British Journal of Pharmacology (2003) 138, 1403–1410. doi:10.1038/sj.bjp.0705133
Ezetimibe potently inhibits cholesterol absorption but does not affect acute hepatic or intestinal cholesterol synthesis in rats
Authors: Van Heek Margaret , Farley Constance , Compton Douglas S , Hoos Lizbeth M , Smith‐Torhan April , Davis Harry R
Published: April 2003

Ezetimibe (1‐(4‐fluorophenyl)‐(3R)‐[3‐(4‐fluorophenyl)‐(3S)‐hydroxypropyl]‐(4S)‐(4‐hydroxyphenyl)‐2‐azetidinone) and its analog SCH48461 are potent and selective cholesterol absorption inhibitors that inhibit the transport of cholesterol across the intestinal wall, thereby lowering plasma cholesterol.

After a dose response for ezetimibe in rats was established, experiments were conducted to determine whether acute administration could alter hepatic or intestinal cholesterol synthesis. To determine whether this class of intestinal cholesterol absorption inhibitors could discriminate between newly synthesized cholesterol in the intestine versus exogenously administered cholesterol, rats were intraduodenally dosed with 14C‐cholesterol and 3H‐mevalonate, and mesenteric lymph was analyzed for radiolabeled cholesterol and cholesteryl ester content.

Ezetimibe attenuated diet‐induced hypercholesterolemia 60–94% at doses of 0.1–3 mg kg−1 in rats. A single administration of ezetimibe did not have a direct effect on intestinal or hepatic cholesterol synthesis, while ketoconazole significantly inhibited cholesterol synthesis after a single dose. The ezetimibe analog, SCH48461, inhibited the movement of exogenously administered cholesterol into lymph, but did not affect the appearance of newly synthesized cholesterol into lymph.

These data suggest that this class of cholesterol absorption inhibitors does discriminate by blocking the movement of exogenous cholesterol in the enterocyte before it reaches the intracellular cholesterol pool to be incorporated into intestinal lipoproteins, without affecting the incorporation of newly synthesized cholesterol into intestinal lipoproteins.

British Journal of Pharmacology (2003) 138, 1459–1464. doi:10.1038/sj.bjp.0705187
Cacospongionolide B suppresses the expression of inflammatory enzymes and tumour necrosis factor‐α by inhibiting nuclear factor‐κB activation
Authors: Posadas Inmaculada , De Rosa Salvatore , Carmen Terencio M , Payá Miguel , José Alcaraz M
Published: April 2003

The marine product cacospongionolide B, a sesterterpene isolated from the Mediterranean sponge Fasciospongia cavernosa, is an inhibitor of secretory phospholipase A2 with anti‐inflammatory properties. In this work, we have studied the mechanism of action of this compound in the inflammatory response induced by zymosan in primary cells and in the mouse air pouch.

In mouse peritoneal macrophages, cacospongionolide B was able to downregulate the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2), resulting in decreased production of NO and prostaglandin E2 (PGE2). This compound also reduced tumour necrosis factor‐α (TNF‐α) mRNA expression and TNF‐α levels.

Cacospongionolide B inhibited nuclear factor‐κB (NF‐κB)‐DNA binding activity and the nuclear translocation of this transcription factor.

Treatment of cells with cacospongionolide B impaired NF‐κB inhibitory protein (IκB‐α) phosphorylation and enhanced IκB‐α expression.

Inhibition of iNOS, COX‐2 and inflammatory mediators was confirmed in the mouse air pouch.

These results show that cacospongionolide B is able to control NO, PGE2 and TNF‐α production in vitro and in vivo, effects likely dependent on NF‐κB inhibition.

British Journal of Pharmacology (2003) 138, 1571–1579. doi:10.1038/sj.bjp.0705189
Localization of the GSH‐dependent photolabelling site of an agosterol A analog on human MRP1
Authors: Ren Xiao‐Qin , Furukawa Tatsuhiko , Aoki Shunji , Sumizawa Tomoyuki , Haraguchi Misako , Che Xiao‐Fang , Kobayashi Motomasa , Akiyama Shin‐ichi
Published: April 2003

Human multidrug resistance protein 1 (MRP1) is a 190 kDa membrane glycoprotein that confers multidrug resistance (MDR) to tumor cells. We recently demonstrated that glutathione (GSH) is required for the labelling of the C‐terminal half of MRP1 with a photoanalog of agosterol A (azido AG‐A). In this study, we further characterized the GSH‐dependent photolabelling site of azido AG‐A on MRP1.

An epitope‐inserted MRP1, MRP1 1222HA, which has two hemagglutinin A (HA) epitopes in the extracellular loop between transmembrane segment (TM) 16 and TM17 of the transporter, could bind azido AG‐A in a GSH‐dependent manner.

Protease digestion of the photolabelled MRP1 1222HA, followed by immunoprecipitation with an anti‐HA antibody suggested that the GSH‐dependent azido AG‐A photolabelling site on MRP1 resides in the region within TM14‐17 and the cytoplasmic region proximate to the C‐terminus of TM17.

Arg1210 in human MRP2 that corresponds to Arg1202 in human MRP1 has an important role in the transporting activity of MRP2. Therefore, we replaced the Arg residue at position 1202 of MRP1 with Gly. Whereas photolabelling of the mutant MRP1 R1202G was greatly reduced, it retained leukotriene C4 (LTC4) transport activity and conferred Vincristine resistance in LLC‐PK1 cells.

In summary, this study demonstrated that the GSH‐dependent azido AG‐A photolabelling site on MRP1 resides in the region within TM14‐17 and the cytoplasmic region proximate to the C‐terminus of TM17. The charged amino acid Arg1202 proximate to TM helix 16 is of critical importance for the GSH‐dependent photolabelling of MRP1 with azido AG‐A. Arg1202 itself or the region nearby Arg1202 may be involved in azido AG‐A photolabelling.

British Journal of Pharmacology (2003) 138, 1553–1561. doi:10.1038/sj.bjp.0705197
The vasoactive peptide urotensin II stimulates spontaneous release from frog motor nerve terminals
Authors: Brailoiu E , Brailoiu G C , Miyamoto M D , Dun N J
Published: April 2003

The effect of urotensin II (U‐II) on spontaneous transmitter release was examined in the frog to see if the biological activity of this vasoactive peptide extended to neural tissues.

In normal Ringer solution, frog and human U‐II (fU‐II and hU‐II, respectively) caused concentration‐dependent, reversible increases in miniature endplate potential (MEPP) frequency, with hU‐II about 22 times more potent than fU‐II. hU‐II caused a dose‐dependent increase in MEPP amplitude, whereas fU‐II caused an increase, followed by a decrease with higher concentrations.

Increasing extracellular Ca2+ three‐fold had no effect on the MEPP frequency increase to 25 μM hU‐II. Pretreatment with thapsigargin to deplete endoplasmic reticulum Ca2+ caused a 61% reduction in the MEPP frequency increase to 25 μM hU‐II.

Pretreatment with the phospholipase C inhibitor U‐73122 caused a 93% reduction in the MEPP frequency increase to 25 μM hU‐II and a 15% reduction in the increase in MEPP amplitude. Pretreating with antibodies against the inositol 1,4,5‐trisphosphate (IP3) type 1 receptor using liposomal techniques reduced the MEPP frequency increase by 83% but had no effect on MEPP amplitude.

Pretreating with protein kinase C inhibitors (bisindolylmaleimide I and III) had no effect on the response to 25 μM hU‐II, but pretreating with protein kinase A inhibitors (H‐89 and KT5720) reduced the MEPP frequency increase by 88% and completely abolished the increase in MEPP amplitude.

Our results show that hU‐II is a potent stimulator of spontaneous transmitter release in the frog and that the effect is mediated by IP3 and cyclic AMP/protein kinase A.

British Journal of Pharmacology (2003) 138, 1580–1588. doi:10.1038/sj.bjp.0705204
Effects of different beta adrenoceptor ligands in mice with permanent occlusion of the left anterior descending coronary artery
Authors: Callaerts‐Vegh Zsuzsanna , Evans Kenda L J , Shipley Gregory L , Davies Peter J A , Cuba Donald L , Gurji Hunaid A , Giles Heather , Bond Richard A
Published: April 2003

We have studied the effects of three βAR ligands (carvedilol, alprenolol, and ICI‐118,551) with different pharmacological profiles and negative efficacy at the β2AR on cardiac in vivo, in vitro, biochemical and gene expression parameters in mice with permanent occlusion of the left anterior descending coronary artery.

Cardiac in vivo parameters were determined using Doppler studies. Mitral‐wave E peak velocity (EPV) and aortic peak velocity (AoPV) decreased in the first 2 weeks postocclusion. After 3 weeks of drug treatment, EPV was improved in the carvedilol group to preocclusion values; however, a further reduction in EPV in the alprenolol and control permanent occlusion group was measured and there was no change after ICI‐118,551 treatment. AoPV was unchanged between weeks 2 and 5 in all groups.

The left atria were isolated to record isometric tension responses to isoprenaline. Permanent occlusion significantly reduced the maximum isoprenaline response to 30% of control and carvedilol increased the maximum response to isoprenaline significantly to 60%.

The biochemical and gene expression studies revealed different effects of the three βAR ligands. Most notably, carvedilol reduced gene expression of myosin heavy chain β.

These results indicate that chronic treatment with carvedilol is beneficial in a mouse model of myocardial damage resulting from ischaemia. We hypothesise that these beneficial effects of the drug may be because of the negative efficacy at the β2AR, combined with β1AR antagonism.

British Journal of Pharmacology (2003) 138, 1505–1516. doi:10.1038/sj.bjp.0705205
Implication of the bradykinin receptors in antigen‐induced pulmonary inflammation in mice
Authors: Eric Jadranka , Gabra Bichoy H , Sirois Pierre
Published: April 2003

The involvement of bradykinin (BK) receptors in the allergic inflammation associated with airway hyper‐reactivity (AHR) was evaluated by means of the selective bradykinin B1 receptor (BKB1‐R) antagonists R‐715 (Ac‐Lys‐[D‐βNal7, Ile8]desArg9‐BK) and R‐954 (Ac‐Orn[Oic2, α‐MePhe5, D‐βNal7, Ile8]desArg9‐BK) or the selective bradykinin B2 receptor (BKB2‐R) antagonist HOE‐140 (D‐Arg0‐Hyp3‐Thi5‐D‐Tic7‐Oic8‐BK). Cellular migration and AHR were examined 24 h after the second ovalbumin (OA) challenge.

R‐715 (10–500 μg kg−1) and R‐954 (1–100 μg kg−1) injected intravenously (i.v.), 5 min prior to aerosol OA challenges, decreased by approximately 50% the induced lung eosinophilia in OA‐sensitized mice but did not reduce AHR.

HOE‐140 (1 μg kg−1) administered in the same manner, decreased mononuclear cell and eosinophil infiltration in the bronchoalveolar lavage fluid (BALF) of OA‐sensitized mice. Moreover, treatment of OA‐sensitized mice with HOE‐140 (100 μg kg−1) completely abolished the AHR to carbachol.

The BKB1‐R agonist desArg9‐BK (DBK; 10–1000 μg kg−1) administered intratrachealy to normal mice had no effect on the basal cell counts recovered in BALF nor on the plasma extravasation, while the BKB2‐R selective agonist BK (20 μg kg−1) stimulated mononuclear cell migration, neutrophilia and plasma extravasation in normal mouse lungs. Such effects were inhibited by HOE‐140 (10 μg kg−1).

Our results suggest that the airway inflammatory response induced by antigen challenge in mice is mediated by stimulation of both BKB1‐R and BKB2‐R.

British Journal of Pharmacology (2003) 138, 1589–1597. doi:10.1038/sj.bjp.0705207
Gene therapy for cerebral vascular disease: update 2003
Authors: Toyoda Kazunori , Chu Yi , Heistad Donald D
Published: May 2003

Gene therapy is a promising strategy for cerebrovascular diseases. Several genes that encode vasoactive products have been transferred via cerebrospinal fluid for the prevention of vasospasm after subarachnoid hemorrhage. Transfer of neuroprotective genes, including targeting of proinflammatory mediators, is a current strategy of gene therapy for ischemic stroke. Stimulation of growth of collateral vessels, stabilization of atherosclerotic plaques, inhibition of thrombosis, and prevention of restenosis are important objectives of gene therapy for coronary and limb arteries, but application of these approaches to carotid and intracranial arteries has received little attention. Several fundamental advances, including development of safer vectors, are needed before gene therapy achieves an important role in the treatment of cerebrovascular disease and stroke.

British Journal of Pharmacology (2003) 139, 1–9. doi:10.1038/sj.bjp.0705217
Alteration of the purinergic modulation of enteric neurotransmission in the mouse ileum during chronic intestinal inflammation
Authors: De Man Joris G , Seerden Tom C , De Winter Benedicte Y , Van Marck Eric A , Herman Arnold G , Pelckmans Paul A
Published: May 2003

The effect of chronic intestinal inflammation on the purinergic modulation of cholinergic neurotransmission was studied in the mouse ileum. Chronic intestinal inflammation was induced by infection of mice with the parasite Schistosoma mansoni during 16 weeks.

S. mansoni infection induced a chronic inflammatory response in the small intestine, which was characterised by intestinal granuloma formation, increased intestinal wall thickness, blunted mucosal villi and an enhanced activity of myeloperoxidase.

In control ileum and in chronically inflamed ileum, electrical field stimulation (EFS) of longitudinal muscle strips induced frequency‐dependent contractions that were abolished by tetrodotoxin (TTX) and atropine. Carbachol induced dose‐dependent contractions that were not affected by TTX but abolished by atropine.

In control ileum, adenosine and ATP dose‐dependently inhibited the contractions to EFS. Theophylline and 8‐phenyltheophylline, P1 and A1 receptor antagonists respectively, prevented this inhibitory effect of adenosine and ATP. PPADS, DMPX and MRS 1220, antagonists of P2, A2 and A3 receptors, respectively, did not prevent this inhibitory effect of adenosine and ATP. Adenosine and ATP did not affect the contractions to carbachol.

The inhibitory effect of adenosine and ATP on contractions to EFS in control ileum was mimicked by the stable adenosine analogue methyladenosine and by the A1‐receptor agonist N(6)‐cyclohexyladenosine, but not by the A3 receptor agonist 2‐Cl IB‐MECA or by the ATP analogues αβ‐methylene‐ATP and ADPβS. The inhibitory effect of adenosine on contractions to EFS was lost after prolonged (90 min) treatment of control ileum with methyladenosine (100 μM).

In chronically inflamed ileum, adenosine, methyladenosine, N(6)‐cyclohexyladenosine and ATP all failed to inhibit the cholinergic nerve‐mediated contractions to EFS. Also theophylline, 8‐phenyltheophylline, PPADS, DMPX and MRS 1220 had no effect on the contractions to EFS and carbachol. The loss of effect of adenosine and ATP was still evident after 52 weeks of infection.

These results indicate that in physiological conditions neuronal adenosine A1 receptors modulate cholinergic nerve activity in the mouse ileum. However, during chronic intestinal inflammation, this purinergic modulation of cholinergic nerve activity is impaired. This suggests that chronic intestinal inflammation leads to a dysfunction of specific neuronal regulatory mechanisms in the enteric nervous system.

British Journal of Pharmacology (2003) 139, 172–184. doi:10.1038/sj.bjp.0705218
Phoneutria nigriventer spider venom activates 5‐HT4 receptors in rat‐isolated vagus nerve
Authors: Costa Soraia K P , Brain Susan D , Antunes Edson , De Nucci Gilberto , Docherty Reginald J
Published: May 2003

The venom of Phoneutria nigriventer spider (PNV) causes intense pain and inflammation following an attack. We have investigated the involvement of capsaicin‐sensitive nerve fibres by utilizing an in vitro nerve preparation. Extracellular DC potential recordings were made from the rat‐isolated vagus nerve, a preparation that is rich in capsaicin‐sensitive, that is, nociceptive, C‐fibres.

PNV (1–10 μg ml−1), capsaicin (0.03–0.3 μM) or 5‐hydroxytriptamine (5‐HT) (0.3–3 μM) induced dose‐dependent depolarizations of vagus nerve fibres. Depolarizing responses to capsaicin were blocked by ruthenium red (RR, 10 μM), but responses to PNV were not. Depolarizing responses to PNV or veratridine (50 μM) were inhibited by tetrodotoxin (TTX, 10 μM), but those to capsaicin were not. This suggests that capsaicin and PNV depolarize the nerve fibres by distinct mechanisms.

Depolarization in response to 5‐HT (3 μM) was reduced by the 5‐HT3 receptor antagonists Y25130 (0.5 μM) and tropisetron (10 nM) or, to a lesser extent, by the 5‐HT4 receptor antagonist RS39604 (1 or 10 μM). Depolarizing responses to PNV were not affected significantly by Y25130 or tropisetron, but were blocked by RS39604.

These data show that 5‐HT4 receptors play a significant role in the activation of nociceptive sensory nerve fibres by PNV and suggest that this is of importance in the development of the pain and inflammation associated with bites from the P. nigriventer spider.

British Journal of Pharmacology (2003) 139, 59–64. doi:10.1038/sj.bjp.0705240
The potential of antibody‐based immunosuppressive agents for corneal transplantation
Authors: Thiel Michael A , Coster Douglas J , Williams Keryn A
Published: May 2003

Corneal transplantation is a sight‐restorative procedure but its success is limited by irreversible graft rejection, which accounts for up to 50 per cent of failures. The normal eye is an immune‐privileged site. Multiple mechanisms maintain ocular privilege, including the blood–eye barrier, the lack of blood vessels and lymphatics in the normal cornea, the relative paucity of mature antigen‐presenting cells in the central cornea, the presence of immunomodulatory factors in ocular fluids, and the constitutive expressive of CD95L (Fas ligand) within the eye. However, privilege can be eroded by the sequelae of inflammation and neovascularization. Corneal graft rejection in humans is currently suppressed with topical glucocorticosteroids, which are moderately effective. Systemically administered immunosuppressive therapy is of limited efficacy and may be accompanied by unacceptable morbidity. Alternative therapies are needed to improve outcomes. Corneal graft rejection is primarily a cell‐mediated response controlled by the CD4+ T cell, and thus CD4 and costimulatory molecule blockade are appealing targets for new therapeutic interventions. A number of monoclonal antibodies have shown promise as immunosuppressants to prolong corneal graft survival in experimental animal models, and may eventually prove to be useful adjuncts to corticosteroids.
Ovarian hemangioma presenting as pseudo–Meigs’ syndrome with elevated CA125
Authors: Kaneta Yoshibumi , Nishino Ruriko , Asaoka Kentaro , Toyoshima Kiwamu , Ito Kimihiko , Kitai Hirokatsu
Published: May 2003

We report the first case of ovarian hemangioma presenting as pseudo–Meigs’ syndrome with elevated CA125. Abdominopelvic computed tomography (CT) assumed ovarian carcinoma. Chest CT revealed pleural effusion. Intraoperative frozen‐section examination of the right ovary showed benign hemangioma. After operation, chest radiograph and ultrasonography showed no pleural effusion or ascites.
Utero‐vaginal prolapse due to portio vaginal fibroma
Authors: Gurung Geeta , Rana Ashma , Bahadur Rana Magar Dhan
Published: May 2003

Utero‐vaginal prolapse can be caused by traction on to the cervix by heavy myoma. Here we present a unique case of huge, compressed, pedunculated fibromyoma of the cervix, which led to cervical elongation and third‐degree utero‐vaginal prolapse.
The ‘frameless’ intrauterine system for long‐term, reversible contraception: A review of 15 years of clinical experience
Authors: Wildemeersch Dirk , Batár István , Affandi Biran , Andrade Amaury , Shangchun Wu , Jing Hu , Xiaoming Cao
Published: May 2003

Aim:  The development of the ‘frameless’ intrauterine system (IUS) is a response to the growing need to develop high‐performing, long‐acting, reversible, and acceptable contraceptives with a high continuation of use.

Methods:  This is a review of 15 years of clinical experience in randomized controlled and non‐randomized clinical trials.

Results:  The IUS has a similar failure rate as the TCu380A Intrauterine device (IUD), considered the ‘golden standard’ IUD, which is attributed to the optimal target delivery of the copper ions in the upper part of the uterine cavity. Its performance is further optimized by the atraumatic design, which reduces partial and total expulsion and minimizes the side‐effects and discomforts experienced with conventional ‘framed’ IUDs. The mini IUS is likely to further reduce the menstrual blood loss due to the very small size. The safety of the anchoring concept is beyond doubt as was demonstrated in all clinical studies covering 15 000 woman‐years experience.

Conclusions:  Young nulliparous/nulligravid and parous women may significantly benefit from the advantages the ‘frameless’ IUS, which could be strategically important to help in reducing the increasing number of unintended pregnancies and induced abortions worldwide. Furthermore, the ‘frameless’ IUS has been shown to be highly effective for emergency contraception and for immediate postabortal insertion. The long lifespan of the IUS could constitute a cost‐effective reversible alternative to irreversible female sterilization.
The Na+,K+pump and muscle excitability
Authors: CLAUSEN T. , NIELSEN O. B. , HARRISON A. P. , FLATMAN J. A. , OVERGAARD K.
Published: May 2003

In most types of mammalian skeletal muscles the total concentration of Na+,K+pumps is 0.2–0.8 nmol g wet wt−1. At rest, only around 5% of these Na+,K+pumps are active, but during high‐frequency stimulation, virtually all Na+,K+pumps may be called into action within a few seconds. Despite this large capacity for active Na+,K+transport, excitation often induces a net loss of K+, a net gain of Na+, depolarization and ensuing loss of excitability. In muscles exposed to high [K+]oor low [Na+]o, alone or combined, excitability is reduced. Under these conditions, hormonal or excitation‐induced stimulation of the Na+,K+pump leads to considerable force recovery. This recovery can be blocked by ouabain and seems to be the result of Na+,K+pump induced hyperpolarization and restoration of Na+,K+gradients. In muscles where the capacity of the Na+,K+pump is reduced, the decline in the force developing during continuous electrical stimulation (30–90 Hz) is accelerated and the subsequent force recovery considerably delayed. The loss of endurance is significant within a few seconds after the onset of stimulation. Increased concentration of Na+channels or open‐time of Na+channels is also associated with reduced endurance and impairment of force recovery. This indicates that during contractile activity, excitability is acutely dependent on the ratio between Na+entry and Na+,K+pump capacity. Contrary to previous assumptions, the Na+,K+pump, due to rapid activation of its large transport capacity seems to play a dynamic role in the from second to second ongoing restoration and maintenance of excitability in working skeletal muscle.
Training effects on the contractile apparatus
Authors: PETTE D.
Published: May 2003

Skeletal muscle is an extremely heterogeneous tissue, composed of a large variety of fibre types. Its dynamical nature is reflected by the ability to adapt to altered functional demands by qualitative alterations in fibre type composition. The molecular basis of this versatility is that specific myofibrillar and Ca2+‐regulatory protein isoforms are assembled to functionally specialized fibre types. Based on this diversity, adult muscle fibres are capable of changing their molecular composition by altered gene expression. Myosin heavy chain (MHC) isoforms and their unique expression in 'pure' fibres, as well as their coexpression in 'hybrid' 'fibres' represent the best markers of muscle fibre diversity and adaptive changes. Chronic low‐frequency stimulation (CLFS) and endurance training represent highly suitable models for studying the effects of increased neuromuscular activity on myofibrillar protein isoform expression and fibre type composition. Generally, both models induce fast‐to‐slow transitions in myofibrillar protein isoforms and fibre types. However, the responses to endurance training are quantitatively less pronounced than those in muscles exposed to CLFS. Parallel changes in isoforms of specific myofibrillar or Ca2+‐regulatory proteins during the induced fast‐to‐slow transitions point to the existence of fibre type‐specific patterns of gene expression. The fast‐to‐slow transitions do not proceed in abrupt jumps from one extreme to the other, but occur in a gradual and orderly sequential manner. Depending on the basal protein isoform profile, and hence the position within the fast–slow spectrum, the adaptive ranges of different fibre types vary. However, adaptive ranges not only depend on a particular fibre type, but also are influenced by species‐specific properties.
Energy supply and muscle fatigue in humans
Authors: SAHLIN K. , TONKONOGI M. , SÖDERLUND K.
Published: May 2003

Limitations in energy supply is a classical hypothesis of muscle fatigue. The present paper reviews the evidence available from human studies that energy deficiency is an important factor in fatigue. The maximal rate of energy expenditure determined in skinned fibres is close to the rate of adenosine triphosphate (ATP) utilisation observed in vivo and data suggest that performance during short bursts of exercise (<5 s duration) primarily is limited by other factors than energy supply (e.g. Vmax of myosine adenosine triphosphatase (ATPase), motor unit recruitment, engaged muscle mass). Within 10 s of exercise maximal power output decreases considerably and coincides with depletion of phosphocreatine. During recovery, maximal force and power output is restored with a similar time course as the resynthesis of phosphocreatine. Increases in muscle store of phosphocreatine through dietary supplementation with creatine increases performance during high‐intensity exercise. These findings support the hypothesis that energy supply limits performance during high‐intensity exercise. It is well documented that pre‐exercise muscle glycogen content is related to performance during moderate intensity exercise. Recent data indicates that the interfibre variation in phosphocreatine is large after prolonged exercise to fatigue and that some fibres are depleted to the same extent as after high‐intensity exercise. Despite relatively small decreases in ATP, the products of ATP hydrolysis (Pi and free ADP) may increase considerably. FreeADP calculated from the creatine kinase reaction increases 10‐fold both after high‐intensity exercise and after prolonged exercise to fatigue. It is suggested that local increases in ADP may reach inhibitory levels for the contraction process.
Recovery of the immune system after exercise
Authors: PEDERSEN B. K. , ROHDE T. , OSTROWSKI K.
Published: May 2003

In the recovery phase after intense exercise is found suppressed blood concentration of lymphocytes, suppressed natural immunity of blood lymphocytes, decreased concentration of secretory IgA in mucosa, but increased blood concentration of neutrophils and increased levels in the blood of inflammatory cytokines. Thus, after intense long‐term exercise, the immune system is characterized by concomitant inflammation and temporary suppression of the cellular immune system, the most pronounced findings being 2–4 h after the exercise. The underlying mechanisms are multifactorial and include neuroendocrinological and metabolic factors. High levels of cytokines, especially interleukin‐6, are found in the recovery period after eccentric exercise, and it has been demonstrated that a close association exists between muscle damage and increased levels of interleukin‐6.
Alterations in hepatic lipase and lipoprotein subfractions with transdermal testosterone replacement therapy
Authors: Tan K. C. B. , Shiu S. W. M. , Kung A. W. C.
Published: May 2003

OBJECTIVES

The effect of sex hormone replacement therapy on lipoprotein metabolism is thought to be less marked with the transdermal route because of the lack of hepatic first‐pass effect. The aim of this study was to evaluate the effects of testosterone replacement therapy given transdermally via a permeation‐enhanced system on plasma lipolytic enzymes (hepatic and lipoprotein lipase), LDL and HDL subfraction concentrations.

MEASUREMENTS

Ten patients with primary testicular failure were started on transdermal testosterone (Testoderm®). Plasma lipids, lipoproteins and post‐heparin plasma lipolytic enzymes were evaluated before and after 3 months of treatment. LDL and HDL subfractions were measured by density gradient ultracentrifugation and hepatic and lipoprotein lipase activities by radio‐enzymatic method.

RESULTS

Serum testosterone level increased to within the normal range in all subjects whereas serum dihydrotestosterone (DHT) increased to supra‐normal values. Plasma hepatic lipase (HL) activity increased after testosterone replacement (24.7 ± 7.5 vs. 29.2 ± 8.3 μmol free fatty acid released per hour, P < 0.05) and the increase in HL correlated with the increase in DHT (r = 0.64, P < 0.05). Small changes were observed in LDL subfraction pattern with an increase in the concentration of small dense LDL‐III (80.1 ± 30.3 vs. 93.0 ± 27.8 mg/l, P < 0.05). No significant change was seen in the HDL2 subfraction but HDL3 decreased after treatment (0.93 ± 0.17 vs. 0.79 ± 0.14 mmol/l, P < 0.01).

CONCLUSIONS

Testosterone replacement, given via a permeation‐enhanced transdermal system, is associated with changes in hepatic lipase activity and in LDL and HDL subfractions. Whether these changes adversely influence the cardiovascular risk in the longterm remains to be determined.
Polycystic ovaries and associated clinical and biochemical features in young women
Authors: Michelmore K. F. , Balen A. H. , Dunger D. B. , Vessey M. P.
Published: May 2003

OBJECTIVE

To determine the prevalence of polycystic ovaries as identified by ultrasound in a group of young, postmenarcheal women in the normal population, and to investigate how polycystic ovaries are related to the spectrum of clinical and biochemical symptoms associated with the polycystic ovary syndrome (PCOS).

DESIGN

Cross‐sectional observational study.

SUBJECTS AND METHODS

Volunteers were recruited from two universities and two general practice surgeries in Oxford. 230 women aged 18–25 years participated. Information collected and measurements performed included: a menstrual history, anthropometric measurements, clinical observation of acne and hirsutism, transabdominal pelvic ultrasound, and biochemical analysis of a fasting blood sample.

MAIN OUTCOME MEASURES

Prevalence of polycystic ovaries and their association with symptoms of the polycystic ovary syndrome.

RESULTS

Polycystic ovarian morphology was identified in 74 (33%, 95% CI = 27–39%) of the 224 women who attended for an ultrasound scan. In the non‐users of hormonal contraception, irregular menstrual cycles were 20% more common in women with polycystic ovaries than in women with normal ovaries (P = 0.07). There were no significant differences in acne, hirsutism, body mass index or body fat percentage between women with polycystic and normal ovaries. Analysis of biochemical data showed that women with polycystic ovaries had higher total serum testosterone concentrations (P = 0.03). The prevalence of PCOS in this age group was as low as 8% or as high as 26% depending on which criteria were applied to define the syndrome. Sub‐group analyses of women according to ovarian morphology and features of PCOS revealed greater mean BMI in women with PCOS, and also indicated lower fasting insulin concentrations and greater insulin sensitivity in polycystic ovary and PCOS groups when compared to women with normal ovaries.

CONCLUSIONS

Polycystic ovaries are very common in this age group but are not necessarily associated with other symptomatology. The prevalence of polycystic ovary syndrome varies widely according to the definition applied. Sub‐group analysis of women with polycystic ovaries according to the presence or absence of features of polycystic ovary syndrome does not reveal an increasing trend for progression of endocrine abnormalities usually associated with polycystic ovary syndrome.
Cushing's syndrome due to an ectopic ACTH‐secreting pituitary tumour mimicking occult paraneoplastic ectopic ACTH production
Authors: Bethge H. , Arlt W. , Zimmermann U. , Klingelhöffer G. , Wittenberg G. , Saeger W. , Allolio B.
Published: May 2003

A 32‐year‐old man presenting with typical features of Cushing's syndrome showed baseline cortisol and ACTH values indicating ACTH‐dependent disease. Dynamic function tests (dexamethasone, corticotropin releasing hormone (CRH), desmopressin), were suggestive of paraneoplastic ectopic ACTH production. However, inferior petrosal sinus (IPS) ACTH sampling demonstrated a maximum baseline central (363 pmol/l)—peripheral (19 pmol/l) ACTH gradient of 19.1 for the right IPS, conventionally suggestive of Cushing's disease. However, again, IPS ACTH level did not increase after CRH stimulation. Magnetic resonance imaging, while showing no evidence of an intrasellar tumour, revealed an 1.5 × 1.0 cm mass in the left sphenoid sinus which was initially interpreted as most probably being a mucosal polyp. After neurosurgical removal of the tumour, transient secondary adrenal insufficiency was present. The structure and immunostaining characteristics of the tumour demonstrated an ACTH cell adenoma of the pituitary. Ectopic ACTH‐secreting pituitary adenomas may cause significant difficulties in differential diagnosis, localisation and appropriate therapy. Thus, although these tumours are rare, they should be included in the list of possible causes of ACTH‐dependent Cushing's syndrome.
Influence of Antioxidants on the Quality of Stored Blood
Authors: Racek Jaroslav , Herynková Růžena , Holeček Václav , Jeřábek Zdeněk , Sláma Vladislav
Published: May 2003

Background and objectives: Blood is exposed to oxidation stress and therefore has a high antioxidant capacity (AOC). With the many factors increasing the demands on the AOC, there may be damage to erythrocytes by free radicals. This study was to investigate evidence of erythrocyte damage in stored donor blood and to affect this by premedication of blood donors. Materials and methods: Blood samples of 15 healthy donors were collected in CPDA‐1 solution and analyzed immediately, and then again after 10 days of incubation at 4 °C and 1 day of incubation at 37 °C. Prior to incubation, the following parameters were evaluated: Na+, K+, malondialdehyde (MDA), hemoglobin (Hb), AOC in the supernatant, superoxide dismutase (SOD) in erythrocytes, and glutathione peroxidase (GSHPx) in whole blood. Blood donors of group 1 were not given any drugs or vitamins before blood sampling. The same blood donors were then supplemented with the following daily doses of antioxidants for 10 days before the next blood sampling: 36 mg of β‐carotene, 300 mg of vitamin E, 200 mg of vitamin C, and 40 mg of selenium. Results: The blood from donors of group 2 had a significantly smaller increase in MDA, K+, and Hb, and a smaller decrease in Na+ and AOC in the supernatant compared with that of group 1, while the activity of SOD and GSHPx did not change during blood storage. Conclusions: These results suggest that antioxidants given to blood donors can improve red cell storage parameters by reducing cell damage caused by free radicals.
A Monolayer Coagglutination Microplate Technique for Typing Red Blood Cells
Authors: Llopis F. , Carbonell‐Uberos F. , Planelles MD. , Montero M. , Puig N. , Atienza T. , Alba E. , Montoro J.A.
Published: May 2003

Background and objectives: Serologic agglutination tests have the disadvantage of lack of an objective endpoint that can be easily read and quantitated. We have developed a new method for ABO and Rh typing based on producing a red blood cell (RBC) monolayer on microplates and the mixed hemagglutination reaction. Materials and methods: We have employed a new red cell fixation buffer to prepare the RBC monolayer. As the technique for grouping, we used a mixed agglutination reaction between the RBC monolayer and the RBCs to be typed. Results: Compared with an automated hemagglutination system in 34,519 samples, the method is shown to be more sensitive, free of false positive reactions, and cost‐effective. Conclusions: The microplate coagglutination method is accurate and lower in cost than conventional methods.
Uterus‐Innervating Neurones in Porcine Inferior Mesenteric Ganglion: an Immunohistochemical Characteristic
Authors: Wasowicz K.
Published: May 2003

The presence of tyrosine hydroxylase, neuropeptide Y, vasoactive intestinal polypeptide, galanin, Met‐enkephalin‐Arg‐Gly‐Leu, substance P and calcitonin gene‐related peptide was studied with immunohistochemistry in uterus‐innervating neurones found in the inferior mesenteric ganglia after fluorescent tracer (Fast Blue) injection into different regions of the porcine uterus (uterine cervix, paracervical, middle and paraoviductal part of the uterine horn). Virtually all Fast Blue‐positive neurones found in the inferior mesenteric ganglia after tracer injection into all studied parts of the uterus contained tyrosine hydroxylase and ca. 45% of them contained neuropeptide Y. Single galanin‐positive/Fast Blue‐positive cells were found in the ganglia only after tracer injections into uterine cervix. No other studied substances were found in the Fast‐Blue positive neurones of the inferior mesenteric ganglia.
Plasma and whole blood taurine in normal dogs of varying size fed commercially prepared food
Authors: Delaney S. J. , Kass P. H. , Rogers Q. R. , Fascetti A. J.
Published: May 2003

The objective of the present study was to examine the effect of signalment, body size and diet on plasma taurine and whole blood taurine concentrations. A total of 131 normal dogs consuming commercially prepared dog food had blood drawn 3–5 h post‐prandially to be analysed for plasma amino acids and whole blood taurine. Body weight and morphometric measurements of each dog were taken. Plasma and whole blood taurine concentrations were 77 ± 2.1 nmol/ml (mean ± SEM) and 266 ± 5.1 nmol/ml (mean ± SEM), respectively. No effect of age, sex, body weight, body size, or diet was seen on plasma and whole blood taurine concentrations. Mean whole blood taurine concentrations were lower in dogs fed diets containing whole grain rice, rice bran or barley. The lowest whole blood concentrations were seen in dogs fed lamb or lamb meal and rice diets. Plasma methionine and cysteine concentrations were lower in dogs fed diets with animal meals or turkey, and whole grain rice, rice bran or barley. Fifteen of 131 dogs had plasma taurine concentrations lower than, or equal, to the previously reported lowest mean food‐deprived plasma taurine concentration in normal dogs of 49 ± 5 nmol/ml (mean ± SEM) (Elliottet al., 2000). These findings support the theory that taurine deficiency in dogs may be related to the consumption of certain dietary ingredients. Scientific and clinical evidence supports the hypothesis that dilated cardiomyopathy is associated with low blood taurine concentration in dogs; therefore, further work is indicated to determine the mechanism by which diet can affect taurine status in dogs.
A multiaxial fatigue criterion for random loading
Authors: CARPINTERI ANDREA , SPAGNOLI ANDREA , VANTADORI SABRINA
Published: May 2003

ABSTRACTA multiaxial fatigue criterion for random loading is proposed. Firstly, the orientation of the critical plane, where fatigue life estimation is carried out, is determined from the weighted mean position of the principal stress directions. Then, the scalar value of the normal stress vectorN(t) perpendicular to the critical plane is taken as the cycle counting variable since the direction of such a vector is fixed with respect to time (conversely to the time‐varying direction of the shear stress vectorC(t)), and a nonlinear combination of normal and shear stress components acting on the critical plane is used to define an equivalent stress amplitude. Finally, a damage accumulation model is employed to process such an equivalent stress amplitude and to determine fatigue endurance. This criterion is herein applied to some relevant random fatigue tests (proportional bending and torsion).
Mixed‐mode delamination growth of laminar composites by using three‐dimensional finite element modeling
Authors: SILVA A. , MOREIRA DE FREITAS M. J.
Published: May 2003

ABSTRACT Delamination is one of the most frequent failure modes in laminated composites. Its importance is crucial, because a delamination can occur in the interior of a panel without any noticeable damage on the surface, drastically reducing its strength and stiffness. A study has to be made on critical dimensions of delaminations and their shape, through the calculation of the strain energy release rate (SERR), G. This study was performed numerically, for a given geometry, with varying loads and shapes of delamination, in pure and mixed‐mode propagation. All numerical values were obtained with three‐dimensional finite element (FE) analyses from a commercial package. The use of three‐dimensional analyses in simple geometries helps establish the basis for the more complex ones, and the correspondence with the usual analytical or numerical bi‐dimensional plane‐strain analysis. The conclusions were (a) G is not constant along the crack tip, even for mode I propagation and straight crack tip; (b) the mean value of G obtained from a three‐dimensional analysis equals the value obtained in bi‐dimensional plane‐strain analysis; (c) in mixed‐mode propagation, the method exhibits a good correlation with experimental results and (d) the shape and mode partitioning of the SERR depend not only on the loading, but also on the shape of the crack front.
The view of the child health nurse among mothers
Authors: Fägerskiöld Astrid , Timpka Toomas , Ek Anna‐Christina
Published: May 2003

The aim of this exploratory study was to investigate mothers' experiences of their encounters with the child health (CH) nurse. A cross‐sectional design was used for the study, based on data from 140 mothers gathered by the critical incident technique. The analysis was accomplished by a thematic content analysis, using inductive reasoning in three steps. Symbolic interactionism was used as a frame of reference. The results suggest that the central factor in the encounter between mother and nurse is that they are able to share the realm of motherhood, meaning that the nurse is open and willing to share all types of emotions, experiences and attitudes related to being a mother. Given this basis, other important factors are the supply of sound advice and practical interventions, and that the nurse is reassuring and accessible. The majority of the participating mothers had experienced CH nurses who had provided them with valuable support during troublesome incidents. However, there were also several dissatisfied mothers who had expected support but thought they received insulting treatment instead. The mothers and the nurses have varying experiences and background and therefore different perspectives, which may lead to difficulties in understanding each other. Knowledge about the important factors, that affect the mother–nurse encounter, can be used to strengthen the nurses' positive behaviours and facilitate understanding of how disappointed mothers have experienced their health care encounters.
Maternal adaptation during childbearing in Norway, Sweden and the United States
Authors: Kiehl Ermalynn M. , White Marjorie A.
Published: May 2003

The purpose of the study of 147 healthy primiparous women is to investigate the relationship between maternal adaptation during pregnancy and postpartum. This report is part of a larger study of relationships between family dynamics and maternal adaptation during childbearing in Norway, Sweden and the US. Variables included maternal adaptation, age, social status, mother's employment, type of birth, length of hospitalization and mother infant time together in the hospital. Mothers reporting greater adaptation during pregnancy reported greater adaptation postpartum. Mothers who believed themselves adapted indicated that they were better prepared for labour, had more control over their birth experience, a better relationship with their partner, and perceived greater participation in child care from their partner. Few differences were found in maternal adaptation among all mothers, and few relationships were found among selected sociodemographic variables and maternal adaptation. Formation of maternal identity and mother's confidence in her ability to cope with the tasks of motherhood was affected by mothers' prenatal identification with the motherhood role, supporting the notion that knowing what to expect provides a sense of control. Mothers' prenatal identification with the motherhood role directly or indirectly affected her satisfaction with motherhood. Nurses may want to develop practice strategies to support these findings.
Strength of motherhood: nonrecurrent breast cancer as experienced by mothers with dependent children
Authors: Billhult Annika , Segesten Kerstin
Published: May 2003

The experience of breast cancer in mothers of dependent children and the strategies these women use to handle their situation of illness in relation to the children was the focus of this study. Ten women with nonrecurrent breast cancer were interviewed using phenomenology as a theoretical framework. The findings reveal that the women needed to balance themselves from being needed and perhaps not existing, balancing between demands, a will to be strong and allowing herself to be sick, and balancing between telling the truth and protecting the children from the truth. The women had strategies to help them in this struggle. To carry on as usual and continue everyday life became very important to them. To do this they had to combine their own strength with support from others and try to turn things into a positive perspective. The essential meaning of living with breast cancer and having dependent children implied using the strength of motherhood to balance conflicting forces and thereby continuing everyday life. The clinical implications include awareness and support to maintain everyday routines and generate strength.