bluuebunny/crossref_metadata_2025 huggingface dataset:
Motor evoked potentials from the striated urethral sphincter: A comparison of concentric needle and surface electrodes
Authors: Brostrom Soren , Jennum Poul , Lose Gunnar
Published: February 2003

Aims

The aim of this study is to compare two different surface electrodes (intravaginal and intraurethral) with the concentric needle as a criterion standard and concomitant testing of the levator ani as a potential contaminator.

Methods

Thirty healthy women with a mean age of 52 years. Bland‐Altman plots were used to compare recorded latencies from the various electrodes and muscles.

Results

There was no significant difference between the latencies recorded with the various electrodes from either muscle, but the limits of agreement were wide. However, the concentric needle electrodes proved more reliable with a higher rate of reproducible responses.

Conclusions

We did not encounter major difficulties in using the concentric needle electrode for recordings in the external urethral sphincter, and this electrode was also more reliable than either surface electrode. Therefore, we advocate the use of concentric needle electrodes in future studies. Neurourol. Urodynam. 22:123–129, 2003. © 2003 Wiley‐Liss, Inc.
Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer
Authors: Tadrous Paul J , Siegel Jan , French Paul MW , Shousha Sami , Lalani El‐Nasir , Stamp Gordon WH
Published: February 2003

Fluorescence lifetime imaging (FLIM) depends on the fluorescence decay differences between tissues to generate image contrast. In the present study FLIM has been applied to fixed (but unstained) breast cancer tissues to demonstrate the feasibility of this approach for histopathological assessment. As the FLIM method relies on natural autofluorescence, it may be possible to circumvent tissue processing altogether and so FLIM has the potential to be a powerful new method of in vivo tissue imaging via an endoscopic or per‐operative approach in a variety of organs, as well as a research tool for in vivo animal models of disease. Unstained, alcohol‐fixed tissue samples from 13 patients were stimulated by laser pulses at 415 nm. The temporal decay of the autofluorescence was imaged over a period of 2 ns after cessation of the pulse. The decay rate at each image pixel was calculated as the ‘lifetime’ factor τ. A tissue classification scheme was used to define regions in each image. The average lifetimes of different tissue regions were compared. A total of 167 tissue regions were measured. Within individual fields, stroma had a larger τ (slower decay) than epithelium (p < 0.001). Within individual patients (taking the mean τ of a given tissue type across all fields from each patient), there was a statistically significant difference between benign and malignancy‐associated stroma (p < 0.05). Also, benign collagen had a longer τ than benign epithelium (p < 0.05). Multivariate analysis showed a significant difference between benign stroma, malignancy‐associated stroma, blood vessels, and malignant epithelium (p < 0.05). Statistically significant differences between benign and malignancy‐associated stroma were obtained even with small patient numbers, indicating that lifetime‐based instruments can be developed for real‐time diagnostic imaging with microscopic resolution. Copyright © 2003 John Wiley & Sons, Ltd.
Increased expression of IgE‐dependent histamine‐releasing factor in endometriotic implants
Authors: Oikawa Kosuke , Kosugi Yoshinori , Ohbayashi Tetsuya , Kameta Akemi , Isaka Keiichi , Takayama Masaomi , Kuroda Masahiko , Mukai Kiyoshi
Published: February 2003

A complex network of cytokines mediates the immunoregulatory responses leading to endometriosis. Recent intensive studies suggest that monocyte and T cell chemoattractants contribute to the inflammatory environment of endometriotic implants. The relationship between the inflammation present during endometriosis and the development of endometriotic implants in the peritoneal cavity remains unclear. On the other hand, the association between endometriosis and 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD; dioxin) exposure has been discussed in recent years, and our previous results revealed that IgE‐dependent histamine‐releasing factor (HRF) is inducible by TCDD. The present study aimed to clarify the expression, localization, and function of HRF in endometriosis. Northern blot analysis demonstrated that HRF is overexpressed in endometriotic implants. RT‐PCR with Southern blot analysis, however, showed that HRF overexpression was not always accompanied by CYP1A1 induction in endometriotic implants, suggesting that HRF is inducible in endometriosis without exposure to TCDD. HRF is also inducible by macrophage colony‐stimulating factor (M‐CSF). Immunohistochemistry showed CD68‐positive macrophages in the stroma of endometriotic implants, adjacent to regions with prominent HRF accumulation. HRF‐overexpressing cells exhibited high implantation efficiency in comparison to control cells when the cells were injected into the peritoneal cavities of nude mice. These results suggest that the accumulation of macrophages in endometriotic implants induces HRF; the overexpression of HRF accelerates the growth of endometriotic implants. Copyright © 2003 John Wiley & Sons, Ltd.
Dynamic Ventilatory Response to Acute Isocapnic Hypoxia in Septuagenarians
Authors: Smith W. D. F. , Poulin M. J. , Paterson D. H. , Cunningham D. A.
Published: February 2003

This study compared the ventilatory response to 20 min of acute isocapnic hypoxia (end‐tidal PO2, 50 mmHg) using the technique of dynamic end‐tidal forcing in young (Y) and old (O) men. Two groups of non‐smoking male subjects (mean ± s.d. age: Y, 29.8 ± 6.9 years; O, 73.4 ± 2.8 years) with similar body size, normal age‐predicted spirometry, and normal moderate levels of physical activity were studied. Compared with baseline ventilation in euoxia (10.79 ± 1.99 and 11.88 ± 0.91 l min−1) both groups responded to the abrupt onset of isocapnic hypoxia with peak ventilatory responses of 22.58 ± 2.60 and 24.56 ± 2.54 l min−1 for Y and O, respectively (not significant, n.s.). Both groups demonstrated a significant increment in neuromuscular drive (i.e. tidal volume (VT)/inspiratory time (TI); 0.46 ± 0.06 to 0.91 ± 0.15 and 0.48 ± 0.06 to 0.91 ± 0.12 l s−1 for Y and O, respectively) with a small (but also significant) change in central timing (TI/total ventilation time (Ttot); 0.38 ± 0.02 to 0.41 ± 0.02 and 0.42 ± 0.02 to 0.45 ± 0.02 for Y and O, respectively). Oxygen sensitivity was assessed using Weil's equation, and gave a hyperbolic factor (A) of 282 ± 75 and 317 ± 72, and using the linear equation: change in expiratory minute volume (ΔVE)/change in arterial O2 saturation (ΔSa,O2) which gave ‐1.17 ± 0.57 and ‐1.17 ± 0.42 l min−1%−1 (n.s.) for Y and O, respectively. After 20 min of sustained isocapnic hypoxia, ventilation declined to 14.29 ± 1.92 and 16.85 ± 2.34 l min−1 for Y and O, respectively (n.s.). The acute response to hypoxia was characterised by similar time constants (16.0 ± 5.4 and 18.5 ± 6.7 s) and time delays (4.8 ± 2.1 and 4.6 ± 1.9 s) for Y and O, respectively. Thus, the dynamic ventilatory response to acute isocapnic hypoxia is maintained into the eighth decade in a group of habitually active elderly men.
Role of Endothelin ETA Receptor Antagonism in the Post‐Transplant Renal Response to Angiotensin II in the Rat
Authors: Hammad F. T. , Wheatley A. M. , Davis G.
Published: February 2003

The role of endothelins in the renal damage associated with ischaemic‐reperfusion (I‐R) injury during organ transplantation was determined by selective blockade of the ETA receptors with the receptor antagonist ABT‐627. The integrity of kidney function was determined 2 and 8 weeks after transplantation by investigation of the renal response to angiotensin II. Under pentobarbitone anaesthesia (70 mg kg−1, I.P.), rats underwent a right nephrectomy. Transplantation of the left kidney was performed after 2 h cold ischaemia without or with ABT‐627 treatment. Control animals underwent left renal denervation. The renal response to angiotensin II was measured 2 weeks later following blockade of endogenous production of angiotensin II with captopril. A further transplant group was allowed to recover for 8 weeks before the terminal study. In the control group, angiotensin II reduced renal blood flow (RBF), glomerular filtration rate (GFR), urine flow rate (UV), and fractional sodium excretion (FENa) by 29 ± 5%, 19 ± 4%, 25 ± 4% and 32 ± 7%, respectively. Conversely, in the transplant group, angiotensin II left RBF unchanged and increased GFR (59 ± 12%) and UV (93 ± 8%). FENa decreased by 24 ± 9%. In both the transplant group treated with ABT‐627 and the long‐term recovery group, the renal response to angiotensin II was normalised. In conclusion, renal transplantation following 2 h cold I‐R injury resulted in a temporary abnormal renal response to angiotensin II, which was reversed by ETA receptor antagonism at the time of transplantation.
Reflex Nature of the Cardiorespiratory Response to Primary Thoracic Blast Injury in the Anaesthetised Rat
Authors: Ohnishi M. , Kirkman E. , Guy R. J. , Watkins P. E.
Published: February 2003

Blast injuries represent a problem for civilian and military populations. Primary thoracic blast injury causes a triad of bradycardia, hypotension and apnoea. The objective of this study was to investigate the reflex nature of this response and its modulation by vagotomy or administration of atropine. The study was conducted on terminally anaesthetised (alphadolone/alphaxalone, 18‐24 mg kg h−1, I.V.) male Wistar rats randomly allocated to the groups indicated below. Blast injuries were produced with compressed air while sham blast involved the sound of a blast only. Primary blast injury to the thorax resulted in a bradycardia (measured as an increase in the interval between beats, or heart period (HP) to 489 ± 37 ms from 133 ± 3 ms with a latency of onset of 4.3 ± 0.3 s, mean ± S.E.M.), hypotension (fall in mean arterial blood pressure (MBP) from 128.1 ± 3.7 mmHg to 34.8 ± 4.1 mmHg, latency of onset 2.0 ± 0.1 s) and apnoea lasting 28.3 ± 2.3 s. Sham blast had no effect. The bradycardia and apnoea following thoracic blast were abolished by cervical vagotomy while the hypotension was attenuated. Atropine (0.3 mg kg−1, I.V.) caused a significant reduction in the bradycardia (HP increasing from 124 ± 3 ms to 142 ± 4 ms) but did not modulate either the hypotension or apnoea. It is concluded that a reflex involving the vagus nerve mediates the bradycardia, apnoea and a component of the hypotension associated with thoracic blast. The pattern of this response is similar to effects that follow stimulation of the pulmonary afferent C‐fibres.
Expression of Sarco(endo)Plasmic Reticulum Ca2+‐Atpase Slow (SERCA2) Isoform in Regenerating Rat Soleus Skeletal Muscle Depends on Nerve Impulses
Authors: Germinario E. , Esposito A. , Midrio M. , Betto R. , Danieli‐Betto D.
Published: February 2003

We have examined the influence of innervation on the expression of different isoforms of sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA) in regenerating rat slow twitch muscle. The process of degeneration/ regeneration was induced by injection of bupivacaine into rat soleus muscle under four different conditions: (1) in the presence of intact motor nerves, (2) after surgical denervation, (3) with nerve impulse conduction blocked by the Na+‐channel blocker tetrodotoxin (TTX), and (4) with the axoplasmic flow blocked by vinblastine. Expression of SERCA isoforms was visualized by immunohistochemical and Western blot analysis. In regenerating innervated muscle, SERCA1, the isoform normally expressed in fast twitch fibres, was present after 5 days and was then progressively replaced by SERCA2, the isoform typical of slow twitch fibres. The maximum Ca2+ uptake, measured in single skinned fibres regenerating for 10‐21 days, was similar to that of slow adult fibres and significantly lower than that of fast adult fibres. Denervation or TTX treatment prevented the expression of the SERCA2 isoform. Conversely, vinblastine did not affect the expression of SERCA isoforms. These data indicate that nerve impulses play a determinant role in the expression of the SERCA2 isoform.
Live Now ‐ Pay by Ageing: High Performance Mitochondrial Activity in Youth and its Age‐Related Side Effects
Authors: Hofhaus G. , Berneburg M. , Wulfert M. , Gattermann N.
Published: February 2003

Radical oxygen species are a byproduct of normal energy metabolism in mitochondria. The short‐lived radicals cause damage to their immediate surrounding, i.e. the mitochondria. While most of this damage will be removed by normal mitochondrial turnover, damage to mitochondrial DNA (mtDNA) can persist and may accumulate with age. Recent evidence indicates that mutant mtDNA molecules can accumulate within individual cells, potentially hampering mitochondrial function.
Targeting the Variable Surface of African Trypanosomes with Variant Surface Glycoprotein-Specific, Serum-Stable RNA Aptamers
Authors: Lorger Mihaela , Engstler Markus , Homann Matthias , Göringer H. Ulrich
Published: February 2003

African trypanosomes cause sleeping sickness in humans and Nagana in cattle. The parasites multiply in the blood and escape the immune response of the infected host by antigenic variation. Antigenic variation is characterized by a periodic change of the parasite protein surface, which consists of a variant glycoprotein known as variant surface glycoprotein (VSG). Using a SELEX (systematic evolution of ligands by exponential enrichment) approach, we report the selection of small, serum-stable RNAs, so-called aptamers, that bind to VSGs with subnanomolar affinity. The RNAs are able to recognize different VSG variants and bind to the surface of live trypanosomes. Aptamers tethered to an antigenic side group are capable of directing antibodies to the surface of the parasite in vitro. In this manner, the RNAs might provide a new strategy for a therapeutic intervention to fight sleeping sickness.
Echoes of bat-pollinated bell-shaped flowers: conspicuous for nectar-feeding bats?
Authors: Helversen Dagmar v. , Holderied Marc W. , Helversen Otto v.
Published: February 2003

Nectar-feeding glossophagine bats searching for flowers are guided by their echolocation system as well as olfactory cues in detecting and recognizing nectar sources. Therefore, chiropterophilous plants, which depend on these bats as pollinators, may be expected to have evolved acoustically conspicuous flowers that facilitate detection. As it is poorly understood how bats manage to find and recognize flowers acoustically, we investigated the echoes of some of the flowers pollinated by bats.

Echoes of bell-shaped bat-pollinated flowers have characteristic features with respect to the echoes they reflect to a calling bat and differ from the echoes of leaves or other objects in their surroundings: the echoes are comparatively long and of complex spectral composition. Owing to the specific shape of the flowers, characteristic `spectral directional patterns' result when the spectra of the echoes are plotted against the angle of sound incidence.

We suggest that bats are able to recognize such flowers — and probably other objects as well — not only by a characteristic spectral composition of the echo but also by comparing sequential echoes, at the same time taking into account their exact calling position relative to the object.
Leg morphology and locomotion in birds: requirements for force and speed during ankle flexion
Authors: Zeffer A. , Norberg U. M. Lindhe
Published: February 2003

Muscle force production and speed of movement of a bone are not only highly dependent on muscle properties but also on the biomechanical arrangements of the musculoskeletal systems. The aim of this study was to investigate whether the leverages of a leg flexion system alone could be used to trace adaptations to different locomotion patterns by different groups of birds. We focused on ankle flexion, and measured the length (tmt) of the tarsometatarsus,representing the out-force lever arm, and the distance (d) between the ankle joint and the tendon insertion of the flexor muscle of the tarsometatarsus, representing the in-force lever arm. By the use of residuals from regressions, tmt and d were made independent of body mass, and d independent of tmt, forming indices of the lever arms, dindex and tmtindex.

The investigation included 67 bird species divided into six groups according to differences in their hind limb movements and requirements of force and speed. These were birds that walk/run/hop (WH), climb (C) or hang(H), birds of prey (BOP), fast swimmers (FS) and slow swimmers (SS). Predictions for each group correlating their requirements for force and speed are made, based on biomechanical and ecological factors, and the lengths of the moment arms are calculated. The results show that the means for the groups could largely be separated from the norm (i.e. zero), and in many cases the predictions are fulfilled. d is significantly larger than average in species affected by strong forces, for example, gravity (BOP and C), but shorter in species affected only by drag (WH, FS and SS). No differences associated with drag due to differences in medium density were seen. Furthermore, the tarsometatarsus is longer than average only in the BOP species, and shorter in the SS species. Discriminant analysis reveals that using our predictions there is a 53.7% chance of placing a species in the correct group, compared with the 17% chance expected if the species are randomly placed in a group.
Cell‐based bonding of articular cartilage: An extended study
Authors: Peretti Giuseppe M. , Zaporojan Victor , Spangenberg Kimberly M. , Randolph Mark A. , Fellers Jonathan , Bonassar Lawrence J.
Published: February 2003

This study evaluated the biomechanical characteristics of newly formed cartilaginous tissue synthesized from isolated chondrocytes and seeded onto devitalized cartilage in an extended study in vivo. Cartilage from porcine articular joints was cut into regular discs and devitalized by multiple freeze‐thaw cycles. Articular chondrocytes were enzymatically isolated and incubated in suspension culture in the presence of devitalized cartilage discs for 21 days. This procedure allowed the isolated chondrocytes to adhere to the devitalized matrix surfaces. Chondrocyte‐matrix constructs were assembled with fibrin glue and implanted in dorsal subcutaneous pockets in nude mice for up to 8 months. Histological evaluation and biomechanical testing were performed to quantify the integration of cartilage pieces and the mechanical properties of the constructs over time. Histological analysis indicated that chondrocytes grown on devitalized cartilage discs produced new matrix that bonded and integrated individual cartilage elements with mechanically functional tissue. Biomechanical testing demonstrated a time dependent increase in tensile strength, failure strain, failure energy, and tensile modulus to values 5–30% of normal articular cartilage by 8 months in vivo. The values recorded at 4 months were not statistically different from those collected at the latest time point, indicating that the limits of the biomechanical property values were reached after four months from implantation. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 64A: 517–524, 2003
The pancreatitis‐associated protein induces lung inflammation in the rat through activation of TNFα expression in hepatocytes
Authors: Folch‐Puy Emma , García‐Movtero Andrés , Iovanna Juan L , Dagorn Jean Charles , Prats Neus , Vaccaro Maria Inés , Closa Daniel
Published: February 2003

The pancreatitis‐associated protein (PAP) is a pancreatic stress protein overexpressed during acute pancreatitis, a disease often accompanied by lung inflammation. We investigated whether PAP was involved in the occurrence of this remote complication of pancreatitis and whether the liver might be implicated in the process. PAP was injected into the vena cava of rats (40 or 400 µg/kg body weight). For comparison, pancreatitis was induced in rats by intraductal administration of sodium taurocholate. Three hours later, parameters of inflammation and mRNA concentrations of TNFα, P‐selectin, heat shock protein (HSP)‐70, and extracellular superoxide dismutase (EC‐SOD) were monitored in lung and liver. Significant increases in P‐selectin expression, neutrophil infiltration, and oxidative stress revealed that PAP treatment induced lung inflammation in rats and exacerbated inflammation in animals with pancreatitis. Plasma TNFα level was increased and TNFα mRNA was strongly overexpressed in liver, with concomitant activation of NF‐κB; in situ hybridization revealed that TNFα overexpression was mainly located to hepatocytes. Lung inflammation induced by PAP could be prevented by injection of anti‐TNFα antibodies. It was concluded that, during pancreatitis, PAP released by the pancreas could mediate lung inflammation through induction of hepatic TNFα expression and subsequent increase in circulating TNFα. Copyright © 2003 John Wiley & Sons, Ltd.
A continuous sampling plan using sums of conforming run‐lengths
Authors: Bourke Patrick D.
Published: February 2003

A continuous sampling plan, CSP‐SUM, is proposed based on the use of sums of run‐lengths of conforming items for deciding when to switch between the phases of sampling inspection and 100% inspection. The conventional measures of performance of CSPs such as the average outgoing quality, average fraction inspected, and the proportion passed under sampling inspection are evaluated for CSP‐SUM. Using these and other measures, comparisons with some standard CSPs are provided and indicate better performance for CSP‐SUM. Comparisons are also made with a recently‐proposed CSP utilizing CUSUMs, termed CSP‐CUSUM, and indicate that the performance of CSP‐SUM can be close to that of CSP‐CUSUM. A table is provided to aid the choice of parameters for the operation of CSP‐SUM. It is recommended that a conforming run‐length control chart be maintained in parallel with CSP‐SUM to detect significant upward shifts in the fraction defective of the process. Copyright © 2003 John Wiley & Sons, Ltd.
Potassium Channels in the Human Myometrium
Authors: Khan Raheela N. , Matharoo‐Ball Balwir , Arulkumaran Sabaratnam , Ashford Michael L. J.
Published: February 2003

The contractility of the human uterus is under the fine control of a variety of interacting bioactive agents. During labour, the excitability of the uterus is drastically transformed in comparison with the non‐labour state and is manifest at the membrane level via the acivity of uterine ion channels. This article reviews the contribution of potassium (K+) channels to human uterine excitability.
The Structure and Regulation of the Oxytocin Receptor
Authors: Ivell Richard , Kimura Tadashi , Müller Dieter , Augustin Kai , Abend Nicole , Bathgate Ross , Telgmann Ralph , Balvers Marga , Tillmann Gina , Fuchs Anna‐Riitta
Published: February 2003

The oxytocin receptor (OTR) is part of an ancient hormone system expressed in diverse phyla in relation to acute reproductive smooth muscle responses, such as egg‐laying, birth, or milk letdown. The regulation of the OTR gene, while correlating with steroid levels in vivo, remains elusive. There appear to be both inhibitory and stimulatory influences acting upon a constitutive pattern of basal expression. We have found no evidence, however, for an effect of the sex steroids either directly on gene transcription, or on the receptor itself at the protein level. In the prostatic carcinoma cell line Du145, we have shown that up‐regulation of the OTR gene transcription can be effected by cAMP. In an attempt to characterize the expression of the OTR protein in vivo, we have shown, using ligand‐blotting, that the OTR can be expressed at different sizes in transfected cells and in myometrium. Also, in the myometrium at term, immunohistochemistry suggests that there is both an increase in OTR protein per cell, as well as in the number of smooth muscle cells expressing OTR, emphasizing that perinatal changes are the results of both individual gene activation events and gross cellular differentiation. The OTR is a valuable model system reflecting molecular changes in the perinatal period. When we understand how this important molecule is regulated, we will also be a long way towards understanding the mechanisms controlling myometrial contractility at birth.
Early Myocardial Fibrosis is Associated with Depletion of Vasoactive Intestinal Peptide in Rat Heart
Authors: Ye Victor Z. C. , Hodge George , Yong James L. C. , Duggan Karen A.
Published: February 2003

In this study we sought to determine whether early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide (VIP) in the heart, thereby suggesting a possible pathogenetic role for depletion of myocardial VIP levels in the development of fibrosis in the heart. Spontaneously hypertensive rats (SHRs) and normotensive control Wistar‐Kyoto rats (WKYs) were assigned randomly to low, intermediate or high sodium diets and their blood pressure was recorded twice weekly for 4 weeks. At the end of this period the rats were anaesthetised, blood was sampled for plasma VIP concentration and the hearts were harvested for histology and determination of the concentration of VIP in the heart. The degree of myocardial fibrosis increased with increasing dietary sodium intake in both the WKYs (P < 0.001) and the SHRs (P < 0.01). Myocardial VIP concentration decreased with increasing dietary sodium intake in the WKYs (P < 0.01) and in the SHRs (P < 0.01). There was a negative correlation between myocardial VIP concentration and the degree of myocardial fibrosis in both the WKYs (P < 0.0005) and the SHRs (P < 0.005). Dietary sodium intake induces myocardial fibrosis in a dose‐dependent manner. Further, in early myocardial fibrosis resulting from increasing dietary sodium intake in both normotensive and hypertensive rats the concentration of VIP in the heart was negatively correlated with the degree of fibrosis. This suggests a possible role for depletion of VIP in the myocardium in the pathogenesis of myocardial fibrosis.
Autonomous Activity in the Isolated Guinea Pig Bladder
Authors: Drake M. J. , Harvey I. J. , Gillespie J. I.
Published: February 2003

Phasic changes in pressure have been reported to occur in the bladder which are not associated with micturition. Spontaneous intravesical pressure changes can be recorded from bladders in vitro or bladders in vivo isolated from the central nervous system suggesting that the bladder itself is capable of autonomous activity. Experiments using isolated cells and muscle strips indicate that the smooth muscle can generate spontaneous activity. Whether this is the origin of phasic changes in the intact organ remains unknown. The present study set out to establish the presence and characteristics of autonomous activity in the isolated guinea pig bladder. Multiple‐point motion analysis and concurrent intravesical pressure recording were used to identify and quantify spontaneous and evoked activity. Highly complex autonomous activity was observed in unstimulated bladders. This activity comprised localised micro‐contractions in single or multiple discrete regions, waves of activity and micro‐stretches. Low‐amplitude phasic ‘micro‐transients’ were seen in the intravesical pressure trace in association with micro‐contractions. Incremental increases in the intravesical volume recruited additional areas of activity. Atropine and tetrodotoxin had no effect on the micro‐transients or micro‐contractions. Exposure to the muscarinic agonist arecaidine (10‐300 nM) initially increased the incidence of micro‐contractions which subsequently became co‐ordinated into phasic pressure rises and contraction waves, interspersed with periods of total quiescence. The findings describe the generation and co‐ordination of autonomous activity in the bladder wall and also demonstrate complex phasic activity. This approach has shown the importance of assessing the integrative properties of the entire organ in studies of the physiology and patho‐physiology of the bladder.
Plasticity of Skeletal Muscle Mitochondria in Response to Contractile Activity
Authors: Adhihetty Peter J. , Irrcher Isabella , Joseph Anna‐Maria , Ljubicic Vladimir , Hood David A.
Published: February 2003

Regularly performed exercise in the form of endurance training produces a well‐established adaptation in skeletal muscle termed mitochondrial biogenesis. The physiological benefit of this is an enhanced performance of muscle when subject to endurance exercise. This is not only of great advantage for athletic endeavours, but it also clearly improves the quality of life of previously sedentary individuals and those involved in injury rehabilitation. Here we review the molecular basis for mitochondrial biogenesis in muscle, from the initial signals arising in contracting muscle, to the transcription factors involved in mitochondrial and nuclear DNA transcription, as well as the post‐translational import mechanisms required for the synthesis of the organelle. We discuss specific protein components associated with reactive oxygen species production, and suggest some questions which remain unanswered with respect to the role of exercise‐induced mitochondrial biogenesis in ageing, apoptosis and disease.
Molecular structures and interactions of repetitive peptides based on wheat glutenin subunits depend on chain length
Authors: Feeney K. A. , Wellner N. , Gilbert S. M. , Halford N. G. , Tatham A. S. , Shewry P. R. , Belton P. S.
Published: February 2003

Synthetic and recombinant peptide models of the central repetitive domain of the high molecular weight subunits of wheat glutenin with different numbers of the consensus repeat motifs PGQGQQ + GYYPTSLQQ (21, 45, 110, and 203 residues long) and a recombinant 58,000‐Da relative molecular mass (Mr 58,000) repetitive peptide from a single subunit (1Dx5) are studied using Fourier transform IR spectroscopy. The spectra of the dry peptides are very similar; at low water contents (<76% relative humidity) there is an increase in β‐sheet structures in all peptides. However, on further hydration the content of β sheets decrease and more β turns are observed. The changes during the second step of hydration are very marked in the 21 and 45 residue peptides, but they are less apparent in the longer perfect repeat peptides. In the 110 and 203 residue peptides hydration results in increased contents of intermolecular β‐sheets and less β‐turn formation. In contrast, the β‐turn content of the Mr 58,000 peptide increases during the second hydration step. The decreased extent of structure changes with increasing chain length indicates that cumulative intermolecular interactions, in particular hydrogen bonds, are an important factor in determining the structures in the solid state. The regularity of the perfect repeat sequences in the 21, 45, 110, and 203 residue peptides may favor the formation of larger stretches of intermolecular β sheets. In contrast, the Mr 58,000 peptide contains imperfect repeats (in common with native glutenin subunits), which may limit its ability to form intermolecular β sheets. © 2003 Wiley Periodicals, Inc. Biopolymers (Biospectroscopy) 72: 123–131, 2003
The promise of the Internet for disability: a study of on‐line services and web site accessibility at Centers for Independent Living
Authors: Ritchie Heather , Blanck Peter
Published: February 2003

The Internet provides individuals with disabilities numerous tools to live independently. In the convenience of the home, a person can access an abundance of information, an electronic community, updates on the latest disability advocacy news, education through distance‐learning classes, and on‐line shopping for books, clothes, assistive technology, and a host of other consumer goods. Centers for Independent Living (CILs) are consumer‐run, non‐profit grassroots disability service organizations at the forefront of the disability rights movement. Providing services to individuals across the range of disabilities, CILs have begun to use the Internet as a complement to their traditional service delivery methods. This article examines the emerging trend of independent living services on the web. The investigation examines 200 CIL Internet sites across the United States during the period of April to August 2001. Information is collected and analyzed about how CILs are using the Internet to provide their services and programs. In addition, the article examines the technological accessibility of their web sites. Implications of the findings for CILs, consumers with disabilities, and disability policy are examined. Copyright © 2003 John Wiley & Sons, Ltd.
Pathophysiological role of nitric oxide and adrenomedullin in autism
Authors: Zoroğlu Süleyman Salih , Yürekli Muhittin , Meram İclal , Söğüt Sadik , Tutkun Hamdi , Yetki̇n Özer , Si̇vasli Ercan , Savaş Haluk Asuman , Yanik Medaim , Herken Hasan , Akyol Ömer
Published: February 2003

Several studies indicate that nitric oxide (NO) is involved in the aetiopathogenesis of many neuropsychiatric disorders such as schizophrenia, bipolar disorder, depression, Alzheimer's disease, Hungtington disease and stroke. Although it has not been investigated yet, several recent studies proposed that NO may have a pathophysiological role in autism. Adrenomedullin (AM), a recently discovered 52‐amino acide peptide hormone, induces vasorelaxation by activating adenylate cyclase and also by stimulating NO release. AM immune reactivity is present in the brain consistent with a role as a neurotransmitter. It has been stated that NO and AM do function in the regulation of many neurodevelopmental processes. We hypothesized that NO and AM activities have been affected in autistic patients and aimed to examine these molecules. Twenty‐six autistic patients and 22 healthy control subjects were included in this study. AM and total nitrite (a metabolite of NO) levels have been measured in plasma. The mean values of plasma total nitrite and AM levels in the autistic group were significantly higher than control values, respectively (p < 0.001, p = 0.028). There is no correlation between total nitrite and AM levels (r = 0.11, p = 0.31). Certainly, this subject needs much further research investigating autistic patients in earlier periods of life and with subtypes of the disorder. Copyright © 2002 John Wiley & Sons, Ltd.
Three‐dimensional, bioactive, biodegradable, polymer–bioactive glass composite scaffolds with improved mechanical properties support collagen synthesis and mineralization of human osteoblast‐like cells in vitro
Authors: Lu Helen H. , El‐Amin Saadiq F. , Scott Kimberli D. , Laurencin Cato T.
Published: February 2003

In the past decade, tissue engineering‐based bone grafting has emerged as a viable alternative to biological and synthetic grafts. The biomaterial component is a critical determinant of the ultimate success of the tissue‐engineered graft. Because no single existing material possesses all the necessary properties required in an ideal bone graft, our approach has been to develop a three dimensional (3‐D), porous composite of polylactide‐co‐glycolide (PLAGA) and 45S5 bioactive glass (BG) that is biodegradable, bioactive, and suitable as a scaffold for bone tissue engineering (PLAGA‐BG composite). The objectives of this study were to examine the mechanical properties of a PLAGA‐BG matrix, to evaluate the response of human osteoblast‐like cells to the PLAGA‐BG composite, and to evaluate the ability of the composite to form a surface calcium phosphate layer in vitro. Structural and mechanical properties of PLAGA‐BG were measured, and the formation of a surface calcium phosphate layer was evaluated by surface analysis methods. The growth and differentiation of human osteoblast‐like cells on PLAGA‐BG were also examined. A hypothesis was that the combination of PLAGA with BG would result in a biocompatible and bioactive composite, capable of supporting osteoblast adhesion, growth and differentiation, with mechanical properties superior to PLAGA alone. The addition of bioactive glass granules to the PLAGA matrix resulted in a structure with higher compressive modulus than PLAGA alone. Moreover, the PLAGA‐BA composite was found to be a bioactive material, as it formed surface calcium phosphate deposits in a simulated body fluid (SBF), and in the presence of cells and serum proteins. The composite supported osteoblast‐like morphology, stained positively for alkaline phosphatase, and supported higher levels of Type I collagen synthesis than tissue culture polystyrene controls. We have successfully developed a degradable, porous, polymer bioactive glass composite possessing improved mechanical properties and osteointegrative potential compared to degradable polymers of poly(lactic acid‐glycolic acid) alone. Future work will focus on the optimization of the composite scaffold for bone tissue‐engineering applications and the evaluation of the 3‐D composite in an in vivo model. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 64A: 465–474, 2003
CF3CH(ONO)CF3: Synthesis, IR spectrum, and use as OH radical source for kinetic and mechanistic studies
Authors: Andersen M. P. Sulbaek , Hurley M. D. , Ball J. C. , Schneider W. F. , Wallington T. J. , Nielsen O. J.
Published: February 2003

The synthesis, IR spectrum, and first‐principles characterization of CF3CH(ONO)CF3as well as its use as an OH radical source in kinetic and mechanistic studies are reported. CF3CH(ONO)CF3exists in two conformers corresponding to rotation about the RCONO bond. The more prevalent trans conformer accounts for the prominent IR absorption features at frequencies (cm−1) of 1766 (NO stretch), 1302, 1210, and 1119 (CF stretches), and 761 (ONO bend); the cis conformer contributes a number of distinct weaker features. CF3CH(ONO)CF3was readily photolyzed using fluorescent blacklamps to generate CF3C(O)CF3and, by implication, OH radicals in 100% yield. CF3CH(ONO)CF3photolysis is a convenient source of OH radicals in the studies of the yields of CO, CO2, HCHO, and HC(O)OH products which can be difficult to measure using more conventional OH radical sources (e.g., CH3ONO photolysis). CF3CH(ONO)CF3photolysis was used to measurek(OH + C2H4)/k(OH + C3H6) = 0.29 ± 0.01 and to establish upper limits of 16 and 6% for the molar yields of CO and HC(O)OH from the reaction of OH radicals with benzene in 700 Torr of air at 296 K. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 159–165, 2003
A GRASP with path‐relinking for private virtual circuit routing
Authors: Resende Mauricio G. C. , Ribeiro Celso C.
Published: February 2003

A frame relay service offers virtual private networks to customers by provisioning a set of long‐term private virtual circuits (PVCs) between customer endpoints on a large backbone network. During the provisioning of a PVC, routing decisions are made without any knowledge of future requests. Over time, these decisions can cause inefficiencies in the network and occasional offline rerouting of the PVCs is needed. In this paper, the offline PVC routing problem is formulated as an integer multicommodity flow problem with additional constraints and with an objective function that minimizes propagation delays and/or network congestion. We propose variants of a GRASP with path‐relinking heuristic for this problem. Experimental results for realistic‐size problems are reported, showing that the proposed heuristics are able to improve the solutions found with standard routing techniques. Moreover, the structure of our objective function provides a useful strategy for setting the appropriate value of its weight parameter, to achieve some quality of service (QoS) level defined by a desired balance between propagation delay and delay due to network congestion. © 2003 Wiley Periodicals, Inc.
Apoptosis and melanoma: molecular mechanisms
Authors: Hussein Mahmoud R , Haemel Anna K , Wood Gary S
Published: February 2003

Melanoma cells can undergo self‐destruction via programmed cell death, i.e. apoptosis. In these tumours, the molecular components of apoptosis include positive (apoptotic) and negative (anti‐apoptotic) regulators. The former include p53, Bid, Noxa, PUMA, Bax, TNF, TRAIL, Fas/FasL, PITSLRE, interferons, and c‐KIT/SCF. The latter include Bcl‐2, Bcl‐XL, Mcl‐1, NF‐KB, survivin, livin, and ML‐IAP. Alternatively, some molecules such as TRAF‐2, c‐Myc, endothelins, and integrins may have either pro‐ or anti‐apoptotic effects. Some of these molecules are of potential therapeutic use, such as: (1) p53, which influences resistance to chemotherapy; (2) Mcl‐1 and Bcl‐XL, which can override apoptosis; (3) TRAIL, which has selective fatal effects on tumour cells; (4) NF‐KB, which when downregulated sensitizes cells to TRAIL and TNF; (5) the PITSLRE kinases, whose alteration appears to result in Fas resistance; (6) interferons, which sensitize cells to other factors; and (7) survivin and other IAPs that inhibit apoptosis. This review summarizes the state of current knowledge about the key molecular components and mechanisms of apoptosis in melanoma, discusses potential therapeutic ramifications, and provides directions for future research. Copyright © 2003 John Wiley & Sons, Ltd.
Songwriting and Digital Video Production Interventions for Pediatric Patients Undergoing Bone Marrow Transplantation, Part I: An Analysis of Depression and Anxiety Levels According to Phase of Treatment
Authors: Robb Sheri L. , Ebberts Allison G.
Published: February 2003

Purposes of this exploratory case study were: (1) to examine how anxiety and depression levels vary with phase of bone marrow transplantation (BMT) and (2) to examine the effect of the proposed music therapy treatment protocol on anxiety and depression levels. Six pediatric BMT patients participated in the study. Three participants experienced the music condition and three participants experienced the no-music contact condition. Both conditions consisted of six, one-hour sessions that occurred over a three week period. The Children's Depression Inventory (CDI) was administered at the conclusion of each session to examine changes in depression levels across each phase of treatment. The State Trait Anxiety Inven tory for Children (STAIC) served as a pre-/post-session measure of state anxiety. Graphic analysis of scores from the CDI and STAIC indicated a consistent trend in depression and anxiety levels according to phase of treatment for all participants. Four participants (3 music; 1 no-music) experienced decreased anxiety following a majority of sessions.
Effects of nelfinavir and its M8 metabolite on lymphocyte P‐glycoprotein activity during antiretroviral therapy
Authors: Donahue John P. , Dowdy David , Ratnam Krishna K. , Hulgan Todd , Price James , Unutmaz Derya , Nicotera Janet , Raffanti Steven , Becker Mark , Haas David W.
Published: February 2003

The efflux pump P‐glycoprotein decreases drug penetration into cells and tissues. To determine whether nelfinavir or its metabolites inhibit P‐glycoprotein in lymphocytes from a healthy volunteer, whole blood cells from human immunodeficiency virus‐negative donors were incubated either in human plasma to which nelfinavir or its M8 metabolite were added ex vivo or in plasma from human immunodeficiency virus‐positive patients receiving nelfinavir. The 50% P‐glycoprotein inhibitory concentrations of purified nelfinavir and M8 were 10.9 μmol/L and 29.5 μmol/L, respectively, for CD4+ T cells and 19.3 μmol/L and >48 μmol/L, respectively, for CD8+ T cells. Significant inhibitory activity was present in plasma from 27 of 46 patients (59%) receiving nelfinavir. Plasma nelfinavir concentrations correlated with percent inhibition on CD4+ (ρ = 0.85, P < .0001) and CD8+ (ρ = 0.83, P < .0001) T cells. The M8 concentrations correlated weakly with both inhibition and nelfinavir concentrations. On the basis of our findings in lymphocytes from a healthy volunteer exposed to plasma from human immunodeficiency virus‐positive patients, we believe it is likely that CD4+ and CD8+ lymphocytes in patients receiving nelfinavir as therapy for human immunodeficiency virus may have P‐glycoprotein inhibited by plasma concentrations of nelfinavir.

Clinical Pharmacology & Therapeutics (2003) 73, 78–86; doi: 10.1067/mcp.2003.11
Analgesic effects of morphine and morphine‐6‐glucuronide in a transcutaneous electrical pain model in healthy volunteers
Authors: Skarke Carsten , Darimont Jutta , Schmidt Helmut , Geisslinger Gerd , Lötsch Jörn
Published: February 2003

Objective

Our objective was to quantify the extent and time course of the effects of morphine‐6‐glucuronide and morphine on pain threshold, pain tolerance, pupil diameter, and side effects.

Methods

In a double‐blind, placebo‐controlled, randomized, 3‐way crossover study, 12 healthy volunteers (6 men and 6 women) received 63 to 112 mg of morphine‐6‐glucuronide or 26 to 66 mg of morphine as an intravenous bolus, followed by an infusion of the same medication for 1.8 to 6.4 hours. Analgesia was assessed every 30 minutes for up to 16 hours by means of transcutaneous electrical stimulation (sine wave, 5 Hz; intensity, 0–9.99 mA). Pupil diameter and side effects were recorded concomitantly.

Results

At the administered doses, morphine‐6‐glucuronide and morphine had comparable effects on pain tolerance, pupil diameter, and side effects. The delay between the time course of the plasma concentrations and the time course of the effects was longer for morphine‐6‐glucuronide than for morphine (transfer half‐life, 8.2 hours versus 2.6 hours for pain tolerance and 7.7 hours versus 2.8 hours for pupil diameter). The slope of the linear concentration versus effect relationship for pain tolerance was flatter for morphine‐6‐glucuronide than for morphine (0.05% versus 0.6% increase in pain tolerance per nanomole per liter of morphine‐6‐glucuronide and morphine at effect site, respectively). Morphine‐6‐glucuronide was less potent than morphine in producing pupil constriction (mean concentration at half‐maximum effect, 745 nmol/L versus 26.4 nmol/L for morphine‐6‐glucuronide and morphine, respectively). In carriers of the mutated G118 allele of the μ‐opioid receptor, the potency of the pupil‐constricting effects of morphine‐6‐glucuronide and morphine was significantly smaller, and carriers of the G118 allele reported less nausea and vomited less often after administration of morphine‐6‐glucuronide.

Conclusions

Morphine‐6‐glucuronide clearly produced analgesic effects in healthy volunteers. However, the high amounts of systemic morphine‐6‐glucuronide needed to produce the same effects as morphine suggest that morphine‐6‐glucuronide barely contributes to the central nervous opioid effects after administration of analgesic doses of morphine.

Clinical Pharmacology & Therapeutics (2003) 73, 107–121; doi: 10.1067/mcp.2003.5