bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetics of the reaction of 4,4′‐biphenol with bromoethane and 1‐bromobutane by phase‐transfer catalysis
Authors: Wang Maw‐Ling , Tseng Yao‐Hsuan
Published: February 2003

The reaction of 4,4′‐biphenol and two species of bromoalkanes (e.g., bromoethane and 1‐bromobutane) to synthesize two symmetric products (4,4′‐diethanoxy biphenyl and 4,4′‐dibutanoxy biphenyl) and one asymmetric product (4‐ethanoxy, 4′‐butanoxy biphenyl) was successfully carried out under two‐phase phase‐transfer catalysis conditions. A rational mechanism and kinetic model were built up by considering the reactions both in aqueous phase and in organic phase. The first active catalyst (QO(Ph)2OQ) was also synthesized under two‐phase reaction and was identified by instruments. The experimental data were explained satisfactorily by the pseudo‐steady‐state hypothesis. Two sets of rate constants of organic reactions, i.e. primary (k1 and k2) and secondary (k11, k12, k21, and k22) rate constants participate in the kinetic model. The two primary rate constants were obtained individually via experimental data for synthesizing the symmetric products. The ratios of the other four secondary rate constants were obtained from the reaction of synthesizing asymmetric products and determined from the initial yield rates of symmetric products. The effects of the ratio of bromoethane and 1‐bromobutane, temperature, organic solvents, amount of catalyst, and amount of sodium hydroxide on the reaction rate and the selectivity of products were investigated in detail. The results were explained satisfactorily by the interaction between the reactants and the environmental species. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 139–153, 2003
Conditional stimulatzion of the dorsal penile/clitoral nerve may increase cystometric capacity in patients with spinal cord injury
Authors: Dalmose A.L. , Rijkhoff N.J.M. , Kirkeby H.J. , Nohr M. , Sinkjaer T. , Djurhuus J.C.
Published: February 2003

Aims

To investigate the feasibility of conditional short duration electrical stimulation of the penile/clitoral nerve as treatment for detrusor hyperreflexia, the present study was initiated.

Methods

Ten patients with spinal cord injury, 4 women and 6 men, with lesions at different levels above the sacral micturition center had a standard cystometry performed. During a subsequent cystometry, conditional short duration electrical stimulation of the penile/clitoral nerve was performed as treatment for one or more detrusor hyperreflexic contractions.

Resuts

In all patients, at least one contraction (mean, 7.8; range, 1–16 contractions) was inhibited by the stimulations. The mean cystometric capacity was increased significantly by conditional electrical stimulation, from 210 mL in the control cystometries to 349 mL in the stimulation cystometries (P=0.016). The maximal detrusor pressure during the first contraction in the control cystometries was mean 51 cm H2O, whereas the maximal pressure of the first contraction in the stimulation cystometries was reduced to mean 33 cm H2O (P=0.045).

Conclusions

The authors conclude that repeated conditional short duration electrical stimulation significantly increased cystometric capacity in patients with spinal cord injury. The increase was caused mainly by an inhibition of detrusor contractions. The need for a reliable technique for chronic bladder activity monitoring is emphasized, as it is a prerequisite for clinical application of this treatment modality. Neurourol. Urodynam. 22:130–137, 2003. © 2003 Wiley‐Liss, Inc.
An improved algorithm for the minmax regret median problem on a tree
Authors: Averbakh Igor , Berman Oded
Published: February 2003

We consider the 1‐median problem with uncertain weights for nodes. Specifically, for each node, only an interval estimate of its weight is known. It is required to find a “minmax regret” location, that is, to minimize the worst‐case loss in the objective function that may occur because the decision is made without knowing which state of nature will take place. For this problem on a tree, the best published algorithm has complexity O(n2). We present an algorithm with complexity O(n log2 n). © 2003 Wiley Periodicals, Inc.
Markers for the development of early prostate cancer
Authors: Slater Michael D , Lauer Christopher , Gidley‐Baird Angus , Barden Julian A
Published: February 2003

Biochemical and genetic changes precede histologically identifiable changes accompanying cell transformation often by months or years. De‐expression of the extracellular matrix adhesive glycoprotein tenascin and the cell‐to‐cell adherent protein E‐cadherin have been suggested as markers of early neoplastic change in prostate epithelial cells. Previous studies have been inconclusive, probably due to epitope masking. This study examined 2378 biopsy cores from 289 prostates using a heat antigen retrieval protocol at low pH to improve the accuracy of detection. Tenascin and E‐cadherin de‐expression was correlated with purinergic receptor and telomerase‐associated protein labelling, as well as prostate‐specific antigen (PSA) levels and Gleason scores. E‐cadherin was a poor marker, as it was expressed in all lesions except carcinomas of the highest Gleason score. Tenascin was maximally expressed in the extracellular matrix and acinar basement membrane in normal and prostatic intraepithelial neoplasia tissue. In prostate cancer tissue, tenascin expression did not correlate with Gleason score but was significantly de‐expressed as purinergic receptor and telomerase‐associated protein expression increased. Marked changes in tenascin, telomerase‐associated protein, and purinergic receptor expression were apparent before any histological abnormalities were visible by haematoxylin and eosin (H&E) stain, making these potential markers for early and developing prostate cancer. Moreover, the potential increased accuracy of diagnosis of underlying prostate cancer using purinergic receptor translocation (PRT) assessment suggests that PSA levels may be more accurate than has generally been supposed when apparent false negatives arising from H&E‐based diagnoses are correctly categorized. Copyright © 2003 John Wiley & Sons, Ltd.
Concomitant expression of p16INK4a and p14ARF in primary breast cancer and analysis of inactivation mechanisms
Authors: Silva Javier , Silva José M , Domínguez Gemma , García José M , Cantos Blanca , Rodríguez Rufo , Larrondo Francisco J , Provencio Mariano , España Pilar , Bonilla Félix
Published: February 2003

The INK4a/ARF locus encodes two tumour suppressor proteins, p16INK4a and p14ARF, which act in the two main cell‐cycle control pathways, p16–Rb and p14–p53 respectively. The present study examined the mRNA expression of these genes by reverse transcription‐polymerase chain reaction (RT‐PCR), and the inactivation mechanisms that alter these levels, in 100 primary breast carcinomas. Furthermore, the interdependence of these mechanisms was examined, since it has been reported that p14ARF is altered in most tumours in concordance with p16INK4a. The results show that promoter hypermethylation, tested by methylation‐specific PCR (MSP), was the major mechanism of inactivation of these genes and was present in 31 (31%) and 50 (50%) of the tumours that showed decreased p16INK4a and p14ARF expression, respectively. Hemizygous deletion was the second cause of down‐regulation. Homozygous deletion was rare and mutation was absent. In most tumours overexpressing p16INK4a or p14ARF, no detectable inactivation mechanisms were observed. Finally, the results indicate that these proteins are often co‐altered in primary breast tumours and that p16INK4a and p14ARF had non‐independent behaviour, since they were silenced or overexpressed concomitantly with a significant correlation (p < 0.05). Copyright © 2003 John Wiley & Sons, Ltd.
Reinventing warranty at HP: an engineering approach to warranty
Authors: Kakouros Steve , Cargille Brian , Esterman Marcos
Published: February 2003

The mechanisms used to understand and reduce warranty costs often focus exclusively on the analysis of product failures. However, warranty costs can also be incurred by events such as support calls that do not involve a product failure. We describe a method used by a major electronics manufacturer to understand warranty costs by modeling warranty events. Furthermore, event modeling that uses a time‐dependent warranty event rate instead of the more standard average rate of failure allows the improved prediction of warranty costs and better accruals. As a result of the modeling, warranty engineers can help product managers more accurately predict the costs associated with removing certain warranty events, changing warranty policies and offering extended warranties for their electronic products. Copyright © 2003 John Wiley & Sons, Ltd.
Planting Seeds for the Revolution: The Rise of Russian Agricultural Science, 1860–1920
Authors: Elina Olga
Published: February 2003

Argument

State patronage and the modernizing role of the government have been considered crucial for the development of science in Russia during both Imperial and Soviet periods. This paper argues, on the contrary, that the start of Russian agricultural science had predominantly local and non-governmental sources of support. Amateur experiments by nobles aspiring to become “cultured” landlords, university professors applying their scientific knowledge to their own estates, and the efforts by local community administrations, zemstvo, to compete for grain markets all contributed, by 1900, to the establishment of various stations for agricultural research. The Imperial government became involved in this process rather belatedly, with an effort to further stimulate and coordinate the institutional network of agricultural science. By 1917, this network included more than 300 breeding and experimental stations. Despite revolutionary violence and the loss of former patrons, most of these stations managed to maintain their functions throughout the Civil War and formed the basis of Soviet agricultural science.
Clinical Pharmacology & Therapeutics—An update
Authors: Stein C. Michael
Published: February 2003

Clinical Pharmacology & Therapeutics (2003) 73, 1–3; doi: 10.1067/mcp.2003.31
Hormones and Calcium: Mechanisms Controlling Uterine Smooth Muscle Contractile Activity
Authors: Sanborn Barbara M.
Published: February 2003

The regulation of myometrial contraction is of paramount importance for the maintenance of pregnancy and for parturition. Understanding this regulation involves delineating the pathways that control myometrial contraction and relaxation and defining the regulation of these pathways. The pathways can be broken down further into those signalling cascades controlling the concentration of intracellular free calcium (Ca2+i) and those controlling the contractile apparatus itself. This discussion focuses primarily on the former and their regulation during pregnancy. In particular, cross‐talk between the contractant and relaxant signalling pathways mediated through cyclic AMP is markedly changed at the end of pregnancy.
Adrenomedullin and Proadrenomudullin N‐Terminal 20 Peptide (PAMP) are Present in Human Colonic Epithelia and Exert an Antimicrobial Effect
Authors: Marutsuka K. , Nawa Y. , Asada Y. , Hara S. , Kitamura K. , Eto T. , Sumiyoshi A.
Published: February 2003

The hypotensive and vasorelaxing peptides adrenomedullin (AM) and its gene‐related peptide, proadrenomedullin N‐terminal 20 peptide (PAMP), were found to be distributed on the surface of the colonic mucosa. AM and PAMP showed dose‐dependent antimicrobial activity against E. coli. The results suggest that the novel vasoactive peptides AM and PAMP play an important role in mucosal defence.
Arterial Myogenic Properties of the Spontaneously Hypertensive Rat
Authors: Hughes Jennifer M. , Bund Stuart J.
Published: February 2003

When subject to a transmural pressure gradient resistance arteries develop a spontaneous, intrinsically initiated contraction which varies according to the pressure stimulus and occurs in the absence of vasoconstrictor agonists. Such pressure‐dependent active changes in vascular tone are indicative of the vascular myogenic response and contribute to autoregulation and the setting of total peripheral resistance and hence blood pressure regulation. The myogenic behaviour of blood vessels provides the background tone upon which other vasomotor influences act. Hypertension is associated with a raised vascular resistance and in this article the evidence for increased myogenic activity contributing to the raised vascular resistance is reviewed. Although there are some cases that provide evidence for exaggerated myogenic responsiveness in resistance arteries taken from hypertensive animals it is not possible to conclude that enhanced myogenic contractile responses within normal pressure ranges contribute to the raised total peripheral resistance. However, the myogenic tone of the resistance arteries of the various vascular beds is subject to differing modulatory influences in hypertensive animals and their normotensive controls which may contribute to the aetiology of hypertension.
Bgs3p, a Putative 1,3-β-Glucan Synthase Subunit, Is Required for Cell Wall Assembly in
Schizosaccharomyces pombe
Authors: Martín Victoria , García Blanca , Carnero Elena , Durán Angel , Sánchez Yolanda
Published: February 2003

β-Glucans are the main components of the fungal cell wall. Fission yeast possesses a family of β-glucan synthase-related genes. We describe here the cloning and characterization of
bgs3
+
, a new member of this family.
bgs3
+
was cloned as a suppressor of a mutant hypersensitive to Echinocandin and Calcofluor White, drugs that interfere with cell wall biosynthesis. Disruption of the gene is lethal, and a decrease in Bgs3p levels leads to rounded cells with thicker walls, slightly reduces the amount of the β-glucan, and raises the amount of α-glucan polymer. These cells finally died.
bgs3
+
is expressed in vegetative cells grown in different conditions and during mating and germination and is not enhanced by stress situations. Consistent with the observed expression pattern, Bgs3-green fluorescence protein (GFP-Bgs3p) was found at the growing tips during interphase and at the septum prior to cytokinesis, always localized to growth areas. We also found GFP-Bgs3p in mating projections, during the early stages of zygote formation, and at the growing pole during ascospore germination. We conclude that Bgs3p localization is restricted to growth areas and that Bgs3p is a glucan synthase homologue required for cell wall biosynthesis and cell elongation in the fission yeast life cycle.
Cell Biology of Mating inCandida albicans
Authors: Lockhart Shawn R. , Daniels Karla J. , Zhao Rui , Wessels Deborah , Soll David R.
Published: February 2003

It was recently demonstrated that strains homozygous for either of the mating type-like lociMTLaandMTLα ofCandida albicansundergo white-opaque switching and that expression of the opaque-phase phenotype greatly enhances mating between strains. Exploiting the latter property to obtain high-frequency mating, we have characterized the cell biology of the mating process ofC. albicans. Employing continuous videomicroscopy, computer-assisted three-dimensional reconstruction of living cells, and fluorescence microscopy, we have monitored the mating-associated processes of conjugation, tube formation, fusion, budding, septum formation, and daughter cell development and the spatial and temporal dynamics of nuclear migration and division. From these observations, a model for the stages inC. albicansmating is formulated. The stages include shmooing, chemotropism of conjugation tubes, fusion of tubes and nuclear association, vacuole expansion and nuclear separation in the conjugation bridge, asynchronous nuclear division in the zygote, bud growth, nuclear migration into the daughter cell, septation, and daughter cell budding. Since there was no cytological indication of karyogamy, genetic experiments were performed to assess marker segregation. Recombination was not observed, suggesting that mating takes place in the absence of karyogamy between naturally occurring, homozygousaand α strains. This study provides the first description of the cell biology of the mating process ofC. albicans.
Constitutively Active Protein Kinase A Disrupts Motility and Chemotaxis inDictyostelium discoideum
Authors: Zhang Hui , Heid Paul J. , Wessels Deborah , Daniels Karla J. , Pham Tien , Loomis William F. , Soll David R.
Published: February 2003

The deletion of the gene for the regulatory subunit of protein kinase A (PKA) results in constitutively active PKA in thepkaRmutant. To investigate the role of PKA in the basic motile behavior and chemotaxis ofDictyostelium discoideum,pkaRmutant cells were subjected to computer-assisted two- and three-dimensional motion analysis.pkaRmutant cells crawled at only half the speed of wild-type cells in buffer, chemotaxed in spatial gradients of cyclic AMP (cAMP) but with reduced efficiency, were incapable of suppressing lateral pseudopods in the front of temporal waves of cAMP, a requirement for natural chemotaxis, did not exhibit the normal velocity surge in response to the front of a wave, and were incapable of chemotaxing toward an aggregation center in natural waves generated by wild-type cells that made up the majority of cells in mixed cultures. Many of the behavioral defects appeared to be the result of the constitutively ovoid shape of thepkaRmutant cells, which forced the dominant pseudopod off the substratum and to the top of the cell body. The behavioral abnormalities thatpkaRmutant cells shared withregAmutant cells are discussed by considering the pathway ERK2 —| RegA —| [cAMP] → PKA, which emanates from the front of a wave. The results demonstrate that cells must suppress PKA activity in order to elongate along a substratum, suppress lateral-pseudopod formation, and crawl and chemotax efficiently. The results also implicate PKA activation in dismantling cell polarity at the peak and in the back of a natural cAMP wave.
Glycosylphosphatidylinositol-Dependent Protein Trafficking in Bloodstream Stage
Trypanosoma brucei
Authors: Triggs Veronica P. , Bangs James D.
Published: February 2003

We have previously demonstrated that glycosylphosphatidylinositol (GPI) anchors strongly influence protein trafficking in the procyclic insect stage of
Trypanosoma brucei
(M. A. McDowell, D. A. Ransom, and J. D. Bangs, Biochem. J. 335:681-689, 1998), where GPI-minus variant surface glycoprotein (VSG) reporters have greatly reduced rates of endoplasmic reticulum (ER) exit but are ultimately secreted. We now demonstrate that GPI-dependent trafficking also occurs in pathogenic bloodstream trypanosomes. However, unlike in procyclic trypanosomes, truncated VSGs lacking C-terminal GPI-addition signals are not secreted but are mistargeted to the lysosome and degraded. Failure to export these reporters is not due to a deficiency in secretion of these cells since the N-terminal ATPase domain of the endogenous ER protein BiP is efficiently secreted from transgenic cell lines. Velocity sedimentation experiments indicate that GPI-minus VSG dimerizes similarly to wild-type VSG, suggesting that degradation is not due to ER quality control mechanisms. However, GPI-minus VSGs are fully protected from degradation by the cysteine protease inhibitor FMK024, a potent inhibitor of the major lysosomal protease trypanopain. Immunofluorescence of cells incubated with FMK024 demonstrates that GPI-minus VSG colocalizes with p67, a lysosomal marker. These data suggest that in the absence of a GPI anchor, VSG is mistargeted to the lysosome and subsequently degraded. Our findings indicate that GPI-dependent transport is a general feature of secretory trafficking in both stages of the life cycle. A working model is proposed in which GPI valence regulates progression in the secretory pathway of bloodstream stage trypanosomes.
K+ transport in Malpighian tubules of Tenebrio molitor L.: is a KATP channel involved?
Authors: Wiehart U. I. M. , Klein G. , Steels P. , Nicolson S. W. , Van Kerkhove E.
Published: February 2003

The presence of ATP-regulated K+ (KATP) channels in Tenebrio molitor Malpighian tubules was investigated by examining the effect of glibenclamide on both fluid secretion and basolateral membrane potentials (Vbl). Glibenclamide, a KATP channel blocker, slowed fluid secretion of Tenebrio tubules. In low bath K+ concentration (5 mmol l-1), glibenclamide either hyperpolarized or depolarized Vbl, resembling the effect seen with Ba2+. Subsequent addition of 6 mmol l-1Ba2+ caused a further hyper- or depolarization of Vbl. In control Ringer (50 mmol l-1 KCl, 90 mmol l-1 NaCl), glibenclamide had no visible effect on Vbl. The effect of ouabain was investigated in low bath[K+] in the presence of Ba2+. Vblresponded by a small but significant hyperpolarization from -51±4 mV to-56±4 mV (n=16, P<0.001) in response to 1 mmol l-1 ouabain. Repeating the experiments in the presence of both glibenclamide and Ba2+ resulted in a depolarization of Vbl when ouabain was added. In low bath [K+](high Na+), the Na+/K+-ATPase is expected to function at a high rate. In the presence of Ba2+, replacing Na+ by K+ rapidly depolarized Vbl,but this was followed by a repolarization. Repeating the experiments in the presence of glibenclamide markedly reduced the depolarizing effect and abolished the repolarization, with a gradual decrease in the sensitivity of Vbl to the surrounding [K+]. These results suggest the presence of KATP channels in the basolateral membrane. Glibenclamide had no visible effect on Vbl in high K+ or in the absence of Ba2+, indicating that other highly conductive K+ channels may mask the effect on KATP channels. This is the first demonstration of the presence of KATP channels in an insect epithelium.
ATP‐induced calcium oscillations and change of P2Y subtypes with culture conditions in HeLa cells
Authors: Okuda Akico , Furuya Kishio , Kiyohara Toshikazu
Published: February 2003

ATP, UTP, ADP and UDP induced intracellular Ca2+ responses and oscillations in HeLa cells that sometimes lasted over 1 h. The response is due to the activation of P2Ys, G‐protein coupled ATP receptors, because the oscillations persisted for several minutes even in Ca2+‐free solution, and suramin and PPADS, antagonists of ATP receptors, partially inhibited the response. The potency of these nucleotides varied with the culture or cell conditions, i.e. UTP was generally most potent but in some cases UDP was more potent; responses to UDP were variable while those to ATP were constant. In addition, Ca2+ responses to ATP and UDP were additive. These findings suggested the existence of two or more subtypes of P2Ys in HeLa cells. RT‐PCR experiments revealed the existence of P2Y2, P2Y4 and P2Y6. Recovery from starvation (culture in FBS‐free medium overnight and re‐addition of FBS) increased the responses to UTP and UDP but not to ATP, suggesting that the number or activity of P2Y6 and/or P2Y4 receptors may increase with cell proliferation in HeLa cells. Copyright © 2002 John Wiley & Sons, Ltd.
Effects of steroid hormones on five functional parameters of Tetrahymena: evolutionary conclusions
Authors: Kőhidai László , Katona Júlia , Csaba György
Published: February 2003

The unicellular Tetrahymena pyriformis was studied for chemotaxis, chemotactic selection, phagocytosis, growth and body shape changes in the presence of water soluble (β‐cyclodextrin‐coupled) steroid hormones (testosterone, estradiol, progesterone, hydrocortisone and dexamethasone). Testosterone was chemoattractant over a wide range of concentrations, while progesterone and dexamethasone were active only at one concentration (10−5 and 10−6 mg ml−1 respectively) and were either neutral or repellent at other concentrations. Hydrocortisone and estradiol were unambiguously chemorepellent. Chemotactic selection enhanced the effect of testosterone and estradiol, while in the case of hydrocortisone the action was reversed. The other parameters were mildly influenced by the steroid hormones. The results call attention to the fine molecular recognition capacity of Tetrahymena and to the possible rapid effects of steroid hormones at membrane receptors at a very low evolutionary eukaryotic level. Copyright © 2002 John Wiley & Sons, Ltd.
Improvement of the biocompatibility of alginate/poly‐L‐lysine/alginate microcapsules by the use of epimerized alginate as a coating
Authors: King Aileen , Strand Berit , Rokstad Anne‐Mari , Kulseng Bård , Andersson Arne , Skjåk‐Bræk Gudmund , Sandler Stellan
Published: February 2003

Alginate/poly‐L‐lysine(PLL)/alginate capsules are used widely for the microencapsulation of cells. Alginate consists of guluronic acid and mannuronic acid, the ratio and sequence of which affect the properties of the alginate. Using C5‐epimerases, mannuronic acid can be converted to guluronic acid in the alginate polymer. Such an enzyme, AlgE4, was used to convert blocks of mannuronic acid (M‐blocks) to blocks of alternating sequence (MG‐blocks). The aims of this study were 1) to investigate whether the use of epimerized alginate as a coating could improve the biocompatibility of alginate/PLL/alginate capsules and 2) to study the biocompatibility of simple alginate beads prepared with epimerized alginate. Four different capsules, two of which contained epimerized alginate, were investigated after implantation in C57BL/6 mice for 1 week. The biocompatibility of alginate/PLL/alginate capsules, as measured by retrieval rates of the capsules and DNA contents and glucose oxidation rates of the cellular overgrowth, was improved when an epimerized coating alginate was used. There were, however, no statistically significant differences in the biocompatibility of simple alginate beads made from epimerized alginate when compared with non‐epimerized alginate beads. In general, such beads produced without a PLL coating swelled to a higher extent than the conventional alginate/PLL/alginate capsules. In conclusion, the use of an epimerized coating on alginate‐PLL‐alginate can improve the biocompatibility of such capsules but still cannot completely eliminate the detrimental effects of PLL on the biocompatibility of the capsules. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 64A: 533–539, 2003
Controlled release of fibroblast growth factors and heparin from photocrosslinked chitosan hydrogels and subsequent effect on in vivo vascularization
Authors: Ishihara Masayuki , Obara Kiyohaya , Ishizuka Toshiaki , Fujita Masanori , Sato Masato , Masuoka Kazunori , Saito Yoshio , Yura Hirofumi , Matsui Takemi , Hattori Hidemi , Kikuchi Makoto , Kurita Akira
Published: February 2003

Application of ultraviolet (UV) irradiation to a photocrosslinkable chitosan (Az‐CH‐LA) aqueous solution resulted within 10 s in an insoluble, flexible hydrogel. A low molecular weight acidic molecule like trypan blue and various high molecular weight molecules such as bovine serum albumin (BSA), heparin and protamine were all retained within the hydrogel, while a low molecular weight basic molecule like toluidine blue was rapidly released from the hydrogel. In the present work, we examined the retaining capability of the chitosan hydrogel for growth factors and controlled release of growth factors from the chitosan hydrogel in vitro and in vivo. Fibroblast growth factor‐1 (FGF‐1), fibroblast growth factor‐2 (FGF‐2), vascular endothelial growth factor165 (VEGF165), heparin‐binding epidermal growth factor (HB‐EGF) in phosphate buffered saline (PBS) were mixed with Az‐CH‐LA aqueous solution to form growth factor‐incorporated chitosan hydrogels. About 10–25% of the growth factor was released from a growth factor‐incorporated chitosan hydrogel into PBS within the first day, after which no further substantial release took place. The growth factors interacted with Az‐CH‐LA molecules poly‐ion complexation, and probably were unable to be released after the first day under the in vitro nondegradation conditions of the hydrogel. Although the FGF‐1, FGF‐2, and VEGF165‐incorporated chitosan hydrogels on a culture plate significantly stimulated HUVEC growth, the stimulating activity of the growth factor‐incorporated chitosan hydrogel was completely cancelled out by washing the hydrogel with PBS solution for 3 days or more. The stimulating activity on the HUVEC growth were however highly recovered by treating the washed growth factor‐incorporated chitosan hydrogel during 7 days with chitinase and chitosanase to partly degrade the hydrogel, strongly suggesting that the growth factors within the hydrogel retained their biologically active forms. The chitosan hydrogel (100 μl) when implanted into the back of a mouse was biodegraded in about 10–14 days. When FGF‐1‐ and FGF‐2‐incorporated chitosan hydrogels were subcutaneously implanted into the back of a mouse, significant neovascularization was induced near the implanted site of the FGF‐1‐ and FGF‐2‐incorporated chitosan hydrogels. Furthermore, addition of heparin with either FGF‐1 or FGF‐2 into the hydrogel resulted in a significantly enhanced and prolonged vascularization effect. These results indicate that the controlled release of biologically active FGF‐1 and FGF‐2 with heparin is caused by biodegradation of the chitosan hydrogel, and subsequent induction of vascularization. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 64A: 551–559, 2003
Supraspinal N‐methyl‐D‐aspartate receptor inhibition influences the micturition reflex and function of the upper urinary tract of anesthetized and conscious rats
Authors: Tillig Bernd , Constantinou Christos E.
Published: February 2003

Aims

To examine the effects of N‐methyl‐D‐aspartate (NMDA) receptor antagonists on the frequency/volume (F/V) characteristics of micturition of conscious and anesthetized rats in relation to the mechanisms of renal urine output and pyelo‐ureteral transport function of the upper urinary tract.

Methods

Micturition F/V characteristics of 24 conscious female Sprague‐Dawley rats, each weighting 160–180 g, were evaluated in a metabolic chamber. Control values of (F/V) were first obtained after administration of a 5‐mL loading dose of saline solution and compared with intraperitoneal (i.p.) injection of 0.3–6.0 mg/kg of LY274614 (LY) and 0.3–40 mg/kg of dextromethorphan (DEX). Upper urinary tract studies were performed on two groups of urethane anesthetized rats (1.2 g/kg, s.c.). A group of 17 rats was used for intravenous (i.v.) injection of 1–30 mg/kg of LY and 1–10 mg/kg of DEX. In a second group of 12 rats, 0.2 mg/kg of LY and DEX were administered intracerebroventricularly (i.c.v.), by placing a catheter into the third ventricle. In anesthetized rats, continuous cystometrograms (CMG) were done while perfusing the renal pelvis with indigo carmine, and measuring pelvic and arterial pressure and as well as visualizing the transport of urine within the upper urinary tract by using videomicroscopic imaging.

Results

In conscious rats, the i.p. injection of LY and DEX produced a significant and dose‐dependent increase in functional bladder capacity and a considerable increase in diuresis. In anesthetized rats, i.v. and i.c.v. administration of LY and DEX affected the micturition reflex, reflected as a significant increase in bladder capacity and preleakage pressure. Videomicroscopic imaging shows dilation of the ureter and a dilution of the dyed urine after the i.v. and i.c.v. injection of LY and DEX. The frequency of ureteral peristalsis and renal pelvic contractions were significantly decreased after i.v. and i.c.v. injection of LY as well as DEX.

Conclusions

The present study shows that the NMDA receptor antagonists LY and DEX given systemically (i.v. and i.p.) or intracerebroventricularly influence the micturition reflex and modulate pyelo‐ureteral motility as well as the rate of urine production. From the present study, it is suggested that NMDA receptors are directly involved in regulating pyelo‐ureteral peristalsis as well as in the coordination of urine transport between upper and lower urinary tract. Neurourol. Urodynam. 22:164–175, 2003. © 2003 Wiley‐Liss, Inc.
Leydig cell micronodules are a common finding in testicular biopsies from men with impaired spermatogenesis and are associated with decreased testosterone/LH ratio
Authors: Holm Mette , Rajpert‐De Meyts Ewa , Andersson Anna‐Maria , Skakkebæk Niels E
Published: February 2003

To assess the biological significance of Leydig cell ‘hyperplasia’ in man, Leydig cell distribution, volume, and function were studied in patients with infertility or testicular cancer and in suddenly deceased controls. A total of 156 biopsies from 95 patients and 18 necropsies from 13 controls were examined using a semi‐quantitative stereological method. In patients, serum concentrations of testosterone, sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol and inhibin‐B were correlated with the findings on histological examination. Leydig cell clusters of more than 15 cells in a cross‐section, for which we proposed the name ‘micronodules’, were frequently seen in testicles exhibiting Sertoli‐cell‐only syndrome (SCO), a mixed pattern of impaired spermatogenesis, or complete spermatogenesis in combination with elevated FSH. Median numbers of micronodules per 1.77 mm2 (four fields of vision) in these three histological patterns were 6, 4, and 3.5, respectively. In contrast, micronodules were only occasionally observed in testicular biopsies from patients with complete spermatogenesis and normal gonadotrophin levels (median 1), and were rare in testes from controls (median = 0, p = 0.02). The proportion of testicular tissue occupied by Leydig cells increased with decreasing spermatogenic capacity. In contrast, the total volume of Leydig cells per testis was roughly comparable irrespective of the histological pattern, with the exception of testes with bilateral micronodules, which had significantly increased Leydig cell volume compared to those without micronodules. The number of micronodules correlated positively to LH (r = 0.577, p < 0.01) and FSH (r = 0.595, p < 0.01) and the presence of micronodules was most pronounced in the hyperstimulated testes, as reflected by an increased LH/testosterone ratio. In conclusion, Leydig cell micronodules were more frequent in biopsies with impaired spermatogenesis and associated with decreased ratios of testicular hormones to gonadotrophins. The presence of micronodules thus seems to be a histological marker of testicular failure in man. Copyright © 2003 John Wiley & Sons, Ltd.
Integrating artificial intelligence into on‐line statistical process control
Authors: Guh Ruey‐Shiang
Published: February 2003

Statistical process control (SPC) is one of the most effective tools of total quality management, the main function of which is to monitor and minimize process variations. Typically, SPC applications involve three major tasks in sequence: (1) monitoring the process, (2) diagnosing the deviated process and (3) taking corrective action. With the movement towards a computer integrated manufacturing environment, computer based applications need to be developed to implement the various SPC tasks automatically. However, the pertinent literature shows that nearly all the researches in this field have only focussed on the automation of monitoring the process. The remaining two tasks still need to be carried out by quality practitioners.

This project aims to apply a hybrid artificial intelligence technique in building a real time SPC system, in which an artificial neural network based control chart monitoring sub‐system and an expert system based control chart alarm interpretation sub‐system are integrated for automatically implementing the SPC tasks comprehensively. This system was designed to provide the quality practitioner with three kinds of information related to the current status of the process: (1) status of the process (in‐control or out‐of‐control). If out‐of‐control, an alarm will be signaled, (2) plausible causes for the out‐of‐control situation and (3) effective actions against the out‐of‐control situation. An example is provided to demonstrate that hybrid intelligence can be usefully applied for solving the problems in a real time SPC system. Copyright © 2003 John Wiley & Sons, Ltd.
Hepatocellular carcinoma: Gardening strategies and bridges to transplantation
Authors: Gores Gregory J.
Published: February 2003

Abstract

Background:

Survival after liver transplantation for early hepatocellular carcinoma (HCC) is worsened by the increasing dropout rate while waiting for a donor.

Aims:

To assess the cost effectiveness of adjuvant therapy while waiting for liver transplantation in HCC patients.

Method:

Using a Markov model, a hypothetical cohort of cirrhotic patients with early HCC was considered for: (1) adjuvant treatment-resection was limited to Child-Pugh’s A patients with single tumours, and percutaneous treatment was considered for Child-Pugh’s A and B patients with single tumours unsuitable for resection or with up to three nodules < 3 cm; and (2) standard management. Length of waiting time ranged from six to 24 months.

Results:

Surgical resection increased the transplantation rate (>10%) and provided gains in life expectancy of 4.8-6.1 months with an acceptable cost ($40,000/ year of life gained) for waiting lists > or = 1 year whereas it was not cost effective ($74,000/life of year gained) for shorter waiting times or high dropout rate scenarios. Percutaneous treatment increased life expectancy by 5.2-6.7 months with a marginal cost of approximately $20,000/year of life gained in all cases, remaining cost effective for all waiting times.

Conclusions:

Adjuvant therapies for HCC while waiting for liver transplantation provide moderate gains in life expectancy and are cost effective for waiting lists of one year or more. For shorter waiting times, only percutaneous treatment confers a relevant survival advantage.
Effects of tacrolimus on ischemia-reperfusion injury
Authors: St. Peter Shawn D. , Moss Adyr A. , Mulligan David C.
Published: February 2003

In addition to efficacious immunosuppression for the benefit of organ transplantation, tacrolimus has diverse actions that result in amelioration of ischemia-reperfusion injury. Knowledge is accumulating rapidly on the mechanisms through which tacrolimus exerts these cytoprotective effects, including alterations in microcirculation, free radical metabolism, calcium-activated pathways, inflammatory cascades, mitochondrial stability, apoptosis, stress-response proteins, and tissue recovery. Within the nucleus, actions mediating the effects of tacrolimus appear to be dominantly influenced by interactions with the transcription factor, nuclear factor-κB. Because tacrolimus is a cornerstone agent in immunosuppression regimens throughout the world and knowledge of its cellular mechanisms is evolving, it is important to update the clinical literature with this information. We reviewed the published literature with intent to portray the interactions of tacrolimus in the intricate cellular mechanisms initiated by ischemia and reperfusion.
Teriparatide has no effect on the calcium‐mediated pharmacodynamics of digoxin
Authors: Benson Charles T. , Voelker James R.
Published: February 2003

Background

Teriparatide (recombinant human parathyroid hormone [1‐34]) stimulates bone formation and causes small transient increases in serum calcium concentration. We assessed whether teriparatide causes a change in digoxin pharmacodynamic effects by measuring systolic time intervals and heart rate.

Methods

Measurements were made by echocardiographic Doppler that examined 3 systolic time intervals, as follows: QS2 (time from Q wave on electrocardiogram to the closure of the aortic valve), left ventricular ejection time, and pre‐ejection period, all corrected for changes in heart rate. Fifteen healthy subjects (2 men and 13 women) were administered a single subcutaneous teriparatide dose (20 μg) on day 1 and then equilibrated on a daily oral dose of digoxin for 15 days. Subcutaneous placebo and teriparatide, 20 μg, were given in a randomized crossover design with the 14th (day 15) and 15th (day 16) digoxin doses. Serial systolic time interval and heart rate measurements were obtained on days 1, 15, and 16.

Results

After subjects were dosed to steady state with digoxin, there were statistically significant reductions in QS2 corrected for heart rate (QS2c) of 23 to 25 ms and heart rate of 4 to 6 beats/min. However, there was no difference between treatment with digoxin plus placebo versus digoxin plus teriparatide. The study was powered to find a difference in QS2c as small as 6 ms (α = .05, β = .2).

Conclusion: Teriparatide, 20 μg subcutaneously, does not alter the cardiac effect of digoxin.

Clinical Pharmacology & Therapeutics (2003) 73, 87–94; doi: 10.1067/mcp.2003.7
Effects of Reactive Oxygen Species on Aspects of Excitation‐Contraction Coupling in Chemically Skinned Rabbit Diaphragm Muscle Fibres
Authors: Darnley G. M. , Duke A. M. , Steele D. S. , MacFarlane N. G.
Published: February 2003

Oxidants have been suggested to enhance contractile function in unfatigued muscle. In this study we aimed to determine the effect of oxidants on ‘chemically skinned’ diaphragm muscle fibre bundles. The sarcoplasmic reticulum and contractile proteins were exposed to superoxide anions (O2−) and hydrogen peroxide (H2O2) under controlled conditions. Application of O2− initially increased maximum Ca2+‐activated force but subsequently reduced maximum Ca2+‐activated force without altering myofilament Ca2+ sensitivity. Unlike myocardium, caffeine‐induced Ca2+ release from the sarcoplasmic reticulum was also inhibited by O2− exposure in diaphragm fibre bundles. Application of H2O2 also increased maximum Ca2+‐activated force but had additional effects on resting tension (which increased to 25% of the control maximum Ca2+‐activated force). H2O2 was without effect on myofilament Ca2+ sensitivity or caffeine‐induced Ca2+ release from the sarcoplasmic reticulum. These data demonstrate that oxidants can potentiate contractile force in the diaphragm through a direct action on the contractile proteins. The potentiation of force is not sustained, however, and under these conditions the detrimental effects of O2− on Ca2+ release from the sarcoplasmic reticulum combined with the effects of oxidants on the contractile proteins will ultimately compromise excitation‐contraction coupling in the diaphragm.
Overview of Current Research in Parturition
Authors: Bernal A. López
Published: February 2003

The mechanism of human parturition is not understood and further research into this important physiological process is needed. Preterm labour remains a major cause of perinatal mortality and morbidity and there is controversy about the effectiveness of current tocolytic agents. In some species, notably the sheep, parturition is preceded by an activation of the fetal hypothalamic‐pituitary‐adrenal axis. However, in primates this axis has a supportive, rather than essential, role. A fall in maternal progesterone levels is a prerequisite for parturition in most mammals and this takes place either through increased conversion of progesterone to oestrogens in the placenta, or through the demise of the corpus luteum of pregnancy, depending on the species. In primates and guinea‐pigs parturition occurs without an apparent fall in maternal progesterone levels. Gene targeting experiments in mice have demonstrated the critical role of prostaglandin FP receptors, necessary to mediate the luteolytic effect of PGF2α before parturition. Prostaglandin synthesis is required for the onset and progress of labour as demonstrated by experiments with cPLA2‐ and PGHS‐1‐deficient mice. The importance of local tissue conversion of progesterone to reduced androgens in the regulation of cervical ripening has been demonstrated in 5α‐reductase‐deficient mice. The chronic and ubiquitous gene inactivation obtained with conventional methods has disadvantages, in that it may allow the activation of compensating pathways, making the interpretation of results difficult. This problem may be overcome by using pulsed and tissue‐selective gene knockout strategies. The study of human parturition is complicated by the lack of access to direct experimentation, whereas the endocrine differences between species make it difficult to extrapolate animal data to humans. However, the development of genomic/proteomic technologies that allow the simultaneous screening of thousands of genes and gene products in small samples of tissue, and new methods to study the biochemistry of receptors and proteins involved in smooth muscle physiology promise new insights into the control of human labour. Nevertheless, the integration of rapidly expanding knowledge into a complete understanding of the roles of the mother and the fetus in the initiation of parturition, and the development of selective medication for the effective management of preterm labour remain an arduous challenge for the next decade.
Inescapable and Escapable Pain is Represented in Distinct Hypothalamic‐Midbrain Circuits: Specific Roles for aδ‐ and C‐Nociceptors
Authors: Lumb Bridget M.
Published: February 2003

The affective responses to pain arising from deep somatic and visceral tissues differ markedly from those evoked by brief cutaneous insults. Deep pain evokes passive emotional coping that includes quiescence and vasodepression. In contrast, cutaneous pain evokes an active emotional coping: the fight or flight response. There is now considerable evidence to support the notion that nociceptive inputs arising from different peripheral domains drive the different functional columns of the periaqueductal grey (PAG) that co‐ordinate either active or passive coping strategies. Nociceptive inputs from deep structures drive neurones in the ventrolateral columns that co‐ordinate passive emotional coping whereas brief cutaneous insults activate the dorsolateral/lateral columns that co‐ordinate active coping strategies. An emerging concept, as presented in the preceding article by Keay & Bandler, is that it is the behavioural significance of the nociceptive input, rather than its organ of origin per se, that determines the characteristics of the affective response. These authors provide evidence that brief, escapable stimuli activate neurones in the dorsolateral/lateral columns of the PAG and that inescapable, persistent pain, irrespective of its organ of origin, activates the ventrolateral column. This review will present recent evidence that differential representation of escapable and inescapable pain in the PAG extends to distinct representations of ‘first’ and ‘second’ pain, as indicated by the columnar distribution of neurones activated by inputs from Aδ‐ and C‐nociceptors. Furthermore, the functional organisation of projections from circumscribed regions of the hypothalamus to the different columns of the PAG indicates that the behavioural significance of the pain signal is represented in brain regions other than the PAG.