bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Notch3‐deficient mice: Normal embryonic development and absence of genetic interactions with a Notch1 mutation
Authors: Krebs Luke T. , Xue Yingzi , Norton Christine R. , Sundberg John P. , Beatus Paul , Lendahl Urban , Joutel Anne , Gridley Thomas
Published: October 2003

The Notch signaling pathway is an evolutionarily conserved signaling mechanism and mutations in its components disrupt cell fate specification and embryonic development in many organisms. To analyze the in vivo role of the Notch3 gene in mice, we created a deletion allele by gene targeting. Embryos homozygous for this mutation developed normally and homozygous mutant adults were viable and fertile. We also examined whether we could detect genetic interactions during early embryogenesis between the Notch3 mutation and a targeted mutation of the Notch1 gene. Double homozygous mutant embryos exhibited defects normally observed in Notch1‐deficient embryos, but we detected no obvious synergistic effects in the double mutants. These data demonstrate that the Notch3 gene is not essential for embryonic development or fertility in mice, and does not have a redundant function with the Notch1 gene during early embryogenesis. genesis 37:139–143, 2003. © 2003 Wiley‐Liss, Inc.
Naphthalene exposure: Effects on gene expression and proliferation in human cord blood cells
Authors: Diodovich Cristina , Malerba Ilaria , Bowe Gerard , Acquati Francesco , Bianchi Marco Giorgio , Taramelli Roberto , Parent‐Massin Dominique , Gribaldo Laura
Published: October 2003

In this study, the effect of naphthalene on the induction of apoptosis and gene expression profiles in cord blood cells has been evaluated, as well as its activity on the BCL‐2 related protein expression. After 6, 24, and 48 h of exposure to naphthalene (500 μM), a decrease in cell death was observed: the cells became more resistant to the toxicant and capable of surviving after the treatment. A Western blot analysis revealed an overexpression of BCL‐2, c‐JUN, c‐FOS, and RAF‐1 proteins, which are involved in the antiapoptotic response and in the regulation of cell growth, differentiation, and development. Furthermore, macroarray analysis showed that naphthalene modified cord blood gene expression, inducing IL‐8 precursor and T‐cell transcription factor and decreasing the level of RNA‐binding protein FUS/TLS. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:286–294, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10091
Effect of oxalomalate on lipid metabolism and antioxidant defense system in rats
Authors: Jung Un Ju , Kwon Oh‐Shin , Park Yong Bok , Huh Tae‐Lin , Lee Mi‐Kyung , Choi Myung‐Sook
Published: October 2003

The metabolic functions of NADP+‐specific isocitrate dehydrogenase (ID2), which may participate in the production of NADPH and biosynthesis of fatty acids, are not yet clearly understood. Accordingly, the current study investigated the effect of oxalomalate, known as a competitive inhibitor of ID2 in vitro, on lipid metabolism and the cellular defense system in vivo. Male Sprague Dawley rats (3 weeks old) were divided into two groups, fed a pelletized AIN‐76 semisynthetic diet for 8 weeks, and injected intraperioneally with either saline or oxalomalate (25 mg/kg BW) dissolved in saline every 2 days. Oxalomalate did not lower the body weight and adipose tissue weight significantly; however, it significantly lower the plasma leptin concentration (p < 0.000), plasma and hepatic triglyceride levels (p < 0.01, p < 0.05), and adipocyte lipoprotein lipase activity (p < 0.01) compared to the control group. Meanwhile, hepatic antioxidant enzyme activities, except for superoxide dismutase activity (p < 0.01), glutathione content, and thiobarbituric acid reactive substances levels were not significantly different between the groups. Therefore, the current data suggests that oxalomalate produces a triglyceride‐lowering activity and play a possible inhibitory role in fat accumulation. Furthermore, it was not found to affect the most antioxidative enzyme activities, glutathione content, and thiobarbituric acid reactive substances levels in rats fed normal diet. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:295–302, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10092
Primary linitis plastica carcinoma of the colon accompanied by peritoneal abscess
Authors: Fujii Yasutomo , Taniguchi Nobuyuki , Ono Tomoko , Omoto Kiyoka , Itoh Kouichi , Shitoh Kazuhisa , Okada Masaki , Yasuda Yoshikazu , Nagai Hideo
Published: October 2003

We describe the case of a 75‐year‐old woman with linitis plastica carcinoma of the colon, accompanied by a peritoneal abscess, in which the use of transabdominal sonography enabled prompt detection and diagnosis. Sonographic examinations revealed diffuse wall thickening with blurred layer stratification in the ascending colon. The irregular outer margin of the affected area was surrounded by thickened pericolic fat. A peritoneal abscess covered by the omentum was also found. CT confirmed these findings. We extensively resected the right half of the colon. Histopathologic examination of the excised segment of the colon revealed a poorly differentiated adenocarcinoma with fibrotic infiltration. The patient was discharged 6 weeks postoperatively, and chemotherapy was begun, but she was lost to our follow‐up. Although linitis plastica carcinoma of the colon is rare, it must be considered when patients have extensive colonic wall thickening with blurred layer stratification and an irregular outer margin surrounded by thickened pericolic fat. Transabdominal sonography should be considered the imaging modality of choice for the detection and diagnosis of this disease entity. © 2003 Wiley Periodicals, Inc. J Clin Ultrasound 31:488–492, 2003
Choledochal cysts in children: Evaluation with three‐dimensional sonography
Authors: Haliloglu Mithat , Akata Deniz , Gurel Safiye , Özmen Mustafa N. , Akhan Okan
Published: October 2003

In this report, we describe the application of 3‐dimensional (3D) sonography for diagnosing choledochal cysts in 3 girls who were 18 months, 2 years, and 11 years old. The 3D images that were obtained during the sonographic examination revealed that all 3 patients had a type I choledochal cyst and also demonstrated dilatation of the biliary tracts. The 3 patients then underwent surgical excision of their cysts, cholecystectomy, and hepaticojejunostomy. Besides its other clinical applications, 3D sonography promises to be a valuable adjunct to conventional 2‐dimensional imaging for the evaluation of choledochal cysts in pediatric patients. © 2003 Wiley Periodicals, Inc. J Clin Ultrasound 31:478–480, 2003
The nonisothermal decomposition kinetics of copper(II) complexes with phthalanilic acids and amino acids
Authors: Ren Li‐Ping , Dai Wei‐Lin , Cao Yong , Li He‐Xing , Zheng Xiao‐Hui , Fan Kangnian
Published: October 2003

Fifteen new kinds of mixed ligand complexes Cu(x‐P)A [P = 2‐(COO)C6H4CONH‐C6H4; x = H, 2‐Cl, 2‐CH3, 2‐OCH3, 4‐OCH2CH3; A = dehydronium Met, Leu, Phen] were synthesized. The thermal decomposition behavior of each complex is studied by TG. Coats‐‐Redfern, MacCallum‐‐Tammer, and Zsako methods are adopted to estimate the values of the apparent activation energy Ea, the activation entropy δS≠, the reaction order n, and the frequency factor A. The results showed that the reaction order is 2/3 for each of the complex. Studies on the mechanism of the thermal decomposition reactions suggested that these reactions all fit the kinetic equation 1 − (1 − α)1/3 = © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 623–628, 2003
Kinetic and thermodynamic study of the Na4(UO2)2(OH)4(C2O4)2 complex
Authors: Rodante Fabrizio , Vecchio Stefano , Materazzi Stefano , Vasca Ermanno
Published: October 2003

The synthesis, the characterization, and the thermal decomposition of the dioxouranium(VI) ternary complex of formula Na4(UO2)2(OH)4(C2O4)2, has been studied. The identification of the compound was performed by chemical analysis and by infrared spectrometry. Thermal decomposition of the compound occurs in several steps due to the decomposition of the salt to Na2O and UO3 oxides. The stoichiometry of the steps, hypothesized by means of the thermodynamic and kinetic parameters, is confirmed by the evolved gas analysis studied by FTIR spectrometer coupled to TG/DSC apparatus.

Model‐fitting and model‐free kinetic methods have been used in kinetic analysis. The latter allows determining kinetic scheme. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 661–669, 2003
Differences in vasculature between pilocytic and anaplastic astrocytomas of childhood
Authors: Gesundheit Benjamin , Klement Giannoula , Senger Christof , Kerbel Robert , Kieran Mark , Baruchel Sylvain , Becker Laurence
Published: October 2003

Background

The clinical manifestations of childhood pilocytic astrocytoma (PA) and anaplastic astrocytoma (AA) markedly differ, especially in the time to progression and prognosis. Because of the aggressive course and poor survival rate of AA, one would expect it to be associated with a high angiogenic index. Counterintuitively, we often find higher microvessel density counts in PA than in AA.

Procedure

We examined the differences in type or density of microvasculature between the two neoplasms. To differentiate established, mature vessels from immature growing ones, we used antibodies to Factor VIII (FVIII) to stain endothelial cells (ECs) of blood vessels and α‐smooth muscle actin (α‐SMA) antibodies to stain vessels supported by adventitia.

Results

We found that large, mature, α‐SMA‐positive vessels predominated in PA, and small, immature, α‐SMA‐negative vessels in AA. The vessel maturation index was 54.5% for PA, and 6.1% for AA. Immunostaining with vascular endothelial growth factor (VEGF) and anti‐flt‐1/VEGF receptor‐1 antibodies showed distinct tissue patterns. VEGF immunoreactivity occurred mainly in the processes of the tumor astrocytes in PA; the opposite was observed in AA. flt‐1/VEGFR‐1 was detected in the tumor cells of AA but not in those of PA.

Conclusions

We propose that the predominance of small, α‐SMA‐negative vessels in AA represents immature, unstable vasculature with a potentially greater susceptibility to anti‐angiogenic therapy. The expression of both flt‐1 and VEGF by AA tumor cells also suggests a possible autocrine growth‐promoting function for VEGF in addition to its role as paracrine pro‐angiogenic growth factor for activated ECs, thus making anti‐angiogenesis an attractive therapeutic target in the treatment of AA. Med Pediatr Oncol 2003;41:516–526. © 2003 Wiley‐Liss, Inc.
Urodynamic evaluation of surgical outcome in patients with urinary retention due to central lumbar disc prolapse
Authors: Yamanishi Tomonori , Yasuda Kosaku , Yuki Takao , Sakakibara Ryuji , Uchiyama Tomoyuki , Kamai Takao , Tsujii Toshihiko , Yoshida Ken‐Ichiro
Published: October 2003

Aims

To investigate whether acute urinary retention due to central lumbar disc prolapse is reversible after emergency spinal surgery.

Methods

Eight patients (two males, six females) with a mean age of 31.5 years (range, 18–42 years) with urinary retention due to lumbar disc prolapse were studied. An emergency surgery was performed within 48 hours (mean, 42 hours) after the onset of urinary retention. Urodynamic study was performed before and after the operation.

Results

All patients had acontractile detrusor without bladder sensation and four of seven patients had inactive external sphincter on electromyogram at presentation. Two patients were unable to void up to 1 and 5 months after surgery and were then lost for follow‐up. The remaining six patients could void with straining or changing their voiding postures (bending forward), postoperatively. A follow‐up urodynamic study was performed in all patients from 1 month to 6 years postoperatively. All patients demonstrated acontractile detrusor on cystometrogram. On external sphincter electromyogram, four patients had normal activities. The remaining four patients recovered electromyographic activities, but two of them had denervation motor unit potentials and two had low activities.

Conclusions

Bladder function was irreversible after spinal surgery, whereas urethral function showed a better recovery in patients with acute urinary retention due to central lumbar disc prolapse. However, most of our patients could empty their bladder only by straining or changing their voiding postures postoperatively. Neurourol. Urodynam. 22:670–675, 2003. © 2003 Wiley‐Liss, Inc.
Motor evoked potentials from the pelvic floor
Authors: Brostrøm Søren
Published: October 2003

Aims

Proper function of the lower urinary tract depends on the integrity of the central and peripheral nervous pathways on multiple levels, and the complexity of this system leaves it susceptible to even minor lesions. While dysfunction of the lower urinary tract is prevalent amongst patients with nervous system disease, e.g., multiple sclerosis (MS), most women with lower urinary tract dysfunction (LUTD) have no overt neurological cause. Refined neuro‐diagnostic approaches are needed to reveal neurogenicity in these patients. A potential method is transcranial magnetic stimulation (TMS), which is used routinely to test the motor innervation of limb muscles, but also can be applied to test pelvic floor efferents. To resolve the lack of methodological clarity and the need for normative values for the use of pelvic floor motor evoked potentials (MEPs), 30 healthy women and 16 women with MS were studied.

Methods

The healthy women underwent MEP studies with various stimulus and recording modalities, and, to test reproducibility, 18 of them were retested at a separate session. The women with MS underwent MEP testing as well as urodynamic studies.

Results

From the methodological studies of healthy women, the use of invasive concentric needle electrodes was found to be superior to surface electrodes. When applying magnetic stimuli over the sacral region, various methodological problems were encountered. In the healthy women, a large variability of responses was noted, the long‐term reproducibility of pelvic floor MEP latencies was poor, and in some cases responses could not be obtained. In the study of women with MS, prolonged central conduction times were found, along with many cases of unevokable responses, and a poor correlation of MEPs to urodynamic findings. The problems of obtaining selective recordings from the inaccessible pelvic floor musculature are discussed, and possible sources of variability in MEPs from the pelvic floor are considered. By relating the findings in the present studies to those of others using different modalities, some reflections are presented on the nature of the neural pathways to the pelvic floor activated by magnetic stimulation. As unevokable responses from the pelvic floor were an occasional finding among the healthy women, it is argued that a pelvic floor non‐response in a patient with suspected corticospinal lesion should be interpreted with care, and should not carry the same clinical significance as an absent limb response.

Conclusions

The inherent limitations of pelvic floor MEPs are discussed, and it is concluded that while there seems to be only limited clinical value of pelvic floor MEP testing, there might be some interesting scientific perspectives in studies that aim to control and explain the variability of responses. Neurourol. Urodynam. 22:620–637, 2003. © 2003 Wiley‐Liss, Inc.
Pelvic floor muscle strength and response to pelvic floor muscle training for stress urinary incontinence
Authors: Bø Kari
Published: October 2003

Aims

Several randomized controlled trials have demonstrated that pelvic floor muscle training is effective to treat stress urinary incontinence. The aim of the present study was to compare muscle strength increase and maximal strength in responders and non‐responders to pelvic floor muscle training.

Materials and Methods

Fifty‐two women with urodynamically proven stress incontinence who had participated in a six months randomized controlled trial on pelvic floor muscle training, mean age 45.4 years (range 24–64), participated in the study. The women were classified as responders and non‐responders based on a combination of five effect variables covering urodynamic measurement, pad test with standardized bladder volume, and self‐reports. Pelvic floor muscle strength was measured with a vaginal balloon connected to a fiber optic micro tip transducer (Camtech AS, Sandvika, Norway).

Results

There was a positive correlation between improvement in PFM maximal strength and improvement measured by leakage index (r = 0.34, P < 0.01), and reduction in urinary leakage measured by the pad test (r = 0.23, P = 0.05). The total sample of 52 women comprised 21 responders, 18 unclassifiable, and 13 non‐responders. There was a statistically significant difference in maximal strength after the training period between responders and non‐responders; 24.0 cm H2O (95% CI:18.1–29.9) versus 12.7 cm H2O (95% CI: 6.8–18.6) P < 0.001), and strength increase; 14.8 cm H2O (95% CI: 8.9–20.7) versus 5.0 cm H2O (95% CI: 2.6–12.6), respectively (P = 0.03).

Conclusions

There was a positive relation between both pelvic floor muscle strength increase and maximal strength, and improvement of stress urinary incontinence. Neurourol. Urodynam. 22:654–658, 2003. © 2003 Wiley‐Liss, Inc.
Free vibration analysis of arches using curved beam elements
Authors: Wu Jong‐Shyong , Chiang Lieh‐Kwang
Published: October 2003

The natural frequencies and mode shapes for the radial (in‐plane) bending vibrations of the uniform circular arches were investigated by means of the finite arch (curved beam) elements. Instead of the complicated explicit shape functions of the arch element given by the existing literature, the simple implicit shape functions associated with the tangential, radial (or normal) and rotational displacements of the arch element were derived and presented in matrix form. Based on the relationship between the nodal forces and the nodal displacements of a two‐node six‐degree‐of‐freedom arch element, the elemental stiffness matrix was derived, and based on the equation of kinetic energy and the implicit shape functions of an arch element the elemental consistent mass matrix with rotary inertia effect considered was obtained. Assembly of the foregoing elemental property matrices yields the overall stiffness and mass matrices of the complete curved beam. The standard techniques were used to determine the natural frequencies and mode shapes for the curved beam with various boundary conditions and subtended angles. In addition to the typical circular arches with constant curvatures, a hybrid beam constructed by using an arch segment connected with a straight beam segment at each of its two ends was also studied. For simplicity, a lumped mass model for the arch element was also presented. All numerical results were compared with the existing literature or those obtained from the finite element method based on the conventional straight beam element and good agreements were achieved. Copyright © 2003 John Wiley & Sons, Ltd.
Finite element analysis of time‐dependent semi‐infinite wave‐guides with high‐order boundary treatment
Authors: Givoli Dan , Neta Beny , Patlashenko Igor
Published: October 2003

A new finite element (FE) scheme is proposed for the solution of time‐dependent semi‐infinite wave‐guide problems, in dispersive or non‐dispersive media. The semi‐infinite domain is truncated via an artificial boundary ℬ︁, and a high‐order non‐reflecting boundary condition (NRBC), based on the Higdon non‐reflecting operators, is developed and applied on ℬ︁. The new NRBC does not involve any high derivatives beyond second order, but its order of accuracy is as high as one desires. It involves some parameters which are chosen automatically as a pre‐process. A C0 semi‐discrete FE formulation incorporating this NRBC is constructed for the problem in the finite domain bounded by ℬ︁. Augmented and split versions of this FE formulation are proposed. The semi‐discrete system of equations is solved by the Newmark time‐integration scheme. Numerical examples concerning dispersive waves in a semi‐infinite wave guide are used to demonstrate the performance of the new method. Copyright © 2003 John Wiley & Sons, Ltd.
Photolysis of intracellular caged sphingosine‐1‐phosphate causes Ca2+ mobilization independently of G‐protein‐coupled receptors
Authors: Meyer zu Heringdorf Dagmar , Liliom Karoly , Schaefer Michael , Danneberg Kerstin , Jaggar Jonathan H. , Tigyi Gabor , Jakobs Karl H.
Published: October 2003

Sphingosine‐1‐phosphate (S1P), the product of sphingosine kinase, activates several widely expressed G‐protein‐coupled receptors (GPCR). S1P might also play a role as second messenger, but this hypothesis has been challenged by recent findings. Here we demonstrate that intracellular S1P can mobilize Ca2+ in intact cells independently of S1P‐GPCR. Within seconds, S1P generated by the photolysis of caged S1P raised the intracellular free Ca2+ concentration in HEK‐293, SKNMC and HepG2 cells, in which the response to extracellularly applied S1P was either blocked or absent. Ca2+ transients induced by photolysis of caged S1P were caused by Ca2+ mobilization from thapsigargin‐sensitive stores. These results provide direct evidence for a true intracellular action of S1P.
Arthrodesis of the Wrist for Osteoarthritis: Outcome with a Minimum Follow-up of 4 Years
Authors: DE SMET L. , TRUYEN J.
Published: November 2003

The outcome of total wrist arthrodesis was reviewed in 36 patients with osteoarthritis after a minimum follow-up of 4 years. Pain relief was not complete, and although 20 were pain free at rest, only six were pain-free during manual activity. Grip strength was 63% of the contralateral side and the DASH score remained high. Only 21 of the 34 could be re-employed. The mean time off work was 14 months. Complications were numerous and additional surgery was required in 21 patients.
Molecular pathology of von Hippel–Lindau disease and the VHL tumour suppressor gene
Authors: Richards Frances M.
Published: October 2003

von Hippel–Lindau (VHL) disease is a dominantly inherited cancer syndrome characterised by predisposition to multiple tumours of the eyes and central nervous system (haemangioblastomas), kidneys (renal cell carcinoma; RCC), adrenal chromaffin cells (phaeochromocytoma), and other organs. The VHL gene was isolated in 1993 and mutations or deletions in the VHL gene have been identified in the germline of nearly all tested individuals with VHL disease. Genotype–phenotype correlations have been observed: individuals with missense mutations are more likely to develop phaeochromocytoma than those with deletions or protein-truncating mutations are, and specific missense mutations at certain codons might not predispose to RCC. In accordance with its role as a tumour suppressor gene, the normal allele of the VHL gene is deleted, mutated or silenced by promoter methylation in the tumours from VHL patients, and in a large proportion of sporadic tumours of the same histological types as observed in VHL disease. Thus, the VHL gene is of major importance in the development of RCC in the general population. Recent advances in understanding the structure and function of the VHL protein (pVHL) have revealed insights into the different phenotypes, with indications that some retention of function might be required for predisposition to phaeochromocytoma. pVHL interacts with many cellular proteins, mainly via one of two protein-binding domains (α and β). The best-characterised interaction is that of pVHL with elongin C, which forms a complex with elongin B and Cullin 2 proteins. This complex has E3 ubiquitin ligase activity and promotes ubiquitin-mediated proteasomal degradation of the hypoxia-inducible factor 1α (HIF-1α) transcription factor under normal oxygen (normoxic) conditions. Loss of pVHL function leads to stabilisation of HIF-1 and expression under normoxic conditions of hypoxia-inducible genes including vascular endothelial growth factor (VEGF), which might explain the hypervascular phenotype of VHL tumours. Several other genes implicated in intra- and intercellular signalling and control of tumour growth are overexpressed in the absence of pVHL, but it is not yet clear which features of pVHL function are most significant for tumour suppression in different tissues. Further advances in understanding pVHL function might eventually enable development of specific therapies for prevention or treatment of VHL tumours and RCC.
Cartilage catabolism in arthritis: factors that influence homeostasis
Authors: Rowan Andrew D.
Published: October 2003

Preventing the destruction of articular cartilage has long been a goal in the treatment of arthritic diseases, in which a combination of cytokines and growth factors affect the catabolic state of cells within the joint. Normal tissue turnover can be viewed as a balance between degradation and synthesis of the macromolecules that constitute the extracellular matrix. This process is tightly regulated such that highly degradative proteinases are controlled at several levels, including synthesis and secretion, activation and inhibition. Tissue destruction occurs when proteinase-mediated degradation exceeds synthesis, and this is markedly influenced by cytokines and growth factors that stimulate matrix synthesis as well as the production of proteinases and/or their endogenous inhibitors. This review outlines current knowledge of factors that influence cartilage biology, with particular emphasis on chondrocytes and synovial fibroblasts. Recent findings from the delivery of cytokines to affected tissues are also summarised, and the potential impact these observations might have on new therapies for arthritic diseases is discussed.
Interactions between laminin and epithelial cells in intestinal health and disease
Authors: Teller Inga C. , Beaulieu Jean-François
Published: October 2003

Laminins are a multigene family of extracellular matrix molecules. Quantitatively, they are one of the most abundant glycoproteins present in basement membranes. Functionally, they can modulate several key biological activities, including cell adhesion and migration, gene expression and cell survival. Variability in the spatial and temporal expression of laminins, as well as of their specific receptors of the integrin family, in various tissues and organs, suggests that different laminins perform distinct functions. This article focuses on the human intestinal epithelium as a paradigm to illustrate the potential relationship between laminin–cell interactions and the cell state. This rapidly renewing epithelium consists of spatially separated proliferative and differentiated cell populations located in the crypts and on the villi, respectively. Differential distributions of the various laminins and laminin-binding integrins have been observed along the crypt–villus axis in both the developing and the adult intestine, and important alterations in the pattern of laminin expression have been reported in various intestinal pathologies, such as tufting enteropathy, Crohn's disease and ulcerative colitis, and colorectal cancer. More-direct approaches, including experimentation with in vitro and in vivo models, have provided evidence in support of a role for laminins in intestinal cell functions. Although further work is still needed, laminins emerge more and more as key regulators of specific cell functions important in both intestinal health and intestinal disease.
Atherosclerosis: role of chemokines and macrophages
Authors: Lucas Andrew D. , Greaves David R.
Published: October 2003

Atherosclerosis is a pathological process that takes place in the major arteries and is the underlying cause of heart attacks, stroke and peripheral artery disease. The earliest detectable lesions, called fatty streaks, contain macrophage foam cells that are derived from recruited monocytes. More-advanced atherosclerotic lesions, called fibro-fatty plaques, are the result of continued monocyte recruitment and smooth muscle cell migration and proliferation. Variable numbers of CD4+ T cells are found in atherosclerotic lesions, and cytokines secreted by T helper 1 (Th1)- or Th2-type cells can have a profound influence on macrophage gene expression within atherosclerotic plaques. This review briefly addresses the key features of macrophage biology and discusses the factors that influence the growth and development of atherosclerotic lesions (atherogenesis). It then considers the potential role of chemokines in mediating monocyte recruitment and macrophage differentiation within atherosclerotic lesions.
New DNA-based PCR approaches for rapid real-time detection and prevention of group B streptococcal infections in newborns and pregnant women
Authors: Bergeron Michel G. , Ke Danbing
Published: October 2003

Group B streptococci (GBS) are an important cause of neonatal sepsis and meningitis, and maternal infection. Although the pathogenesis of GBS infection is not well understood, several virulence factors have been identified. Two prevention strategies have been proposed: chemoprophylaxis and immunoprophylaxis. Implementation of selective intrapartum chemoprophylaxis on the basis of either screening or risk assessment has led to a substantial decrease in the morbidity and mortality of GBS disease in both mothers and infants. Penicillin remains the antibiotic of choice with no reported resistant GBS so far, whereas resistance of 10–20% of GBS to erythromycin and clindamycin has been reported in North America. Chemoprophylaxis based on screening requires optimal detection methods for GBS, which involve selective broth culture of combined vaginal and anal samples. Other conventional methods are useful for rapid identification of heavily colonised women, but are unreliable for the detection of light GBS colonisation because of poor sensitivity. GBS-specific polymerase chain reaction (PCR) assays using real-time PCR coupled with fluorescence-labelling technology offer powerful tools for sensitive and specific, yet rapid (less than 1 h), detection of GBS directly from clinical specimens at the time of delivery. The application of these assays to the current prevention strategies will simplify the prevention practice and rationalise the use of antibiotics. Immunoprophylaxis relies on the development of new vaccines against GBS, and active research is being conducted in this area.
Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications
Authors: Tellioglu Tahir , Robertson David
Published: October 2003

The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This article reconsiders the important role of the NET protein in the regulation of the nervous and cardiovascular systems, reviews the literature for its polymorphisms and their suggested clinical manifestations, and finally focuses on the effects of its defect on the pathophysiology of OI, the only confirmed direct association between a genetic mutation of the NET and a clinical syndrome.
Role of Fas–FasL in inflammatory diseases
Authors: O'Connell Joe
Published: October 2003

Fas ligand (FasL) induces programmed cell death, or ‘apoptosis’, in cells expressing its cognate receptor, Fas (CD95/APO-1). There is evidence that FasL precludes inflammatory reactions from sites of ‘immune privilege’ by triggering Fas-mediated apoptosis of infiltrating pro-inflammatory cells. The ability of FasL to impair immune responses is being pursued as a possible means of protecting tissue transplants from immunological rejection, and therapeutic promise has been reported in some experiments. However, FasL is becoming an enigmatic molecule, exhibiting pro-inflammatory activity independently of its ability to mediate immune downregulation. FasL can recruit and activate neutrophils and macrophages in some experimental situations. Triggering of Fas in some cell types has been shown to upregulate expression of certain pro-inflammatory cytokines and chemokines, providing an unexpected link between apoptosis and inflammation. FasL appears to contribute to the destruction of Fas-sensitive end-organ cells during inflammation. This appears to occur in two ways: (1) direct killing by cytotoxic immune effector cells expressing FasL; or (2) autocrine cell suicide of end-organ cells that upregulate their own FasL in the inflammatory context. Depending on the condition, or the site of inflammation, either or both mechanisms may occur. Prevention of Fas-mediated end-organ apoptosis and enhancement of Fas-mediated apoptosis of inflammatory cells are emerging as potential anti-inflammatory therapeutic goals.
Measles virus and immunomodulation: molecular bases and perspectives
Authors: Schneider-Schaulies Sibylle , ter Meulen Volker
Published: October 2003

Measles virus (MV) remains among the most potent global pathogens, killing more than 1 million children annually. The virus induces a profound suppression of immune functions that favours the establishment of, and aggravates the course of, secondary infections. By contrast, MV-specific immune responses are efficiently generated, and these clear the virus from the organism and confer a long-lasting immunity. As sensitisers of pathogen encounter and instructors of the adaptive immune response, professional antigen-presenting cells (APCs) such as dendritic cells play a decisive role in the induction and quality of the MV-specific immune response. However, key features of immune suppression associated with MV are compatible with interference with APC maturation and function, and subsequent qualitative and quantitative alterations of T-cell activation.
Why does inflammation persist: a dominant role for the stromal microenvironment?
Authors: Douglas Michael R. , Morrison Karen E. , Salmon Michael , Buckley Christopher D.
Published: October 2003

Inflammatory responses occur within tissue microenvironments, with functional contributions from both haematopoietic (lymphocytic) cells and stromal cells (including macrophages and fibroblasts). These environments are complex – a compound of many different cell types at different stages of activation and differentiation. Traditional models of inflammatory disease highlight the role of antigen-specific lymphocyte responses and attempt to identify causative agents. However, recent studies have indicated the importance of tissue microenvironments and the innate immune response in perpetuating the inflammatory process. The prominent role of stromal cells in the generation and maintenance of these environments has begun to challenge the primacy of the lymphocyte in regulating chronic inflammatory processes. Sensible enquiries into factors regulating the persistence of inflammatory disease necessitate an understanding of the mechanisms regulating tissue homeostasis and remodelling during inflammation. This article highlights recent insights into the factors regulating dynamic aspects of inflammation, focusing particularly on mononuclear cell infiltrates, their interactions with stromal cells in tissues and the relevance of these interactions to existing and possible future therapies. A key feature of current research has been a growing appreciation that disordered spatial and temporal interactions between infiltrating immune cells and resident stromal cells lie at the heart of disease persistence.
Lipid rafts: structure, function and role in HIV, Alzheimer's and prion diseases
Authors: Fantini Jacques , Garmy Nicolas , Mahfoud Radhia , Yahi Nouara
Published: October 2003

The fluid mosaic model of the plasma membrane has evolved considerably since its original formulation 30 years ago. Membrane lipids do not form a homogeneous phase consisting of glycerophospholipids (GPLs) and cholesterol, but a mosaic of domains with unique biochemical compositions. Among these domains, those containing sphingolipids and cholesterol, referred to as membrane or lipid rafts, have received much attention in the past few years. Lipid rafts have unique physicochemical properties that direct their organisation into liquid-ordered phases floating in a liquid-crystalline ocean of GPLs. These domains are resistant to detergent solubilisation at 4°C and are destabilised by cholesterol- and sphingolipid-depleting agents. Lipid rafts have been morphologically characterised as small membrane patches that are tens of nanometres in diameter. Cellular and/or exogenous proteins that interact with lipid rafts can use them as transport shuttles on the cell surface. Thus, rafts act as molecular sorting machines capable of co-ordinating the spatiotemporal organisation of signal transduction pathways within selected areas (‘signalosomes’) of the plasma membrane. In addition, rafts serve as a portal of entry for various pathogens and toxins, such as human immunodeficiency virus 1 (HIV-1). In the case of HIV-1, raft microdomains mediate the lateral assemblies and the conformational changes required for fusion of HIV-1 with the host cell. Lipid rafts are also preferential sites of formation for pathological forms of the prion protein (PrPSc) and of the β-amyloid peptide associated with Alzheimer's disease. The possibility of modulating raft homeostasis, using statins and synthetic sphingolipid analogues, offers new approaches for therapeutic interventions in raft-associated diseases.
Retinoblastoma: from bench to bedside
Authors: Hurwitz Richard L. , Chévez-Barrios Patricia , Boniuk Milton , Chintagumpala Murali , Hurwitz Mary Y.
Published: October 2003

Retinoblastoma (Rb) is the most common primary ocular malignancy of children and is caused by a mutation in the gene RB1. Approximately 40% of cases are associated with one or more constitutional mutations, and are therefore heritable, whereas the other 60% are sporadic. Rb is exclusively found in young children. In some cases, Rb tumours metastasise to extraocular organs including bone, lung and brain. Although there is no effective treatment for metastatic disease, non-metastatic cases can be cured by removal of the eye (enucleation). Newer treatment strategies emphasise salvaging the affected eye whenever possible. Animal models of Rb have been developed with xenograft and transgenic techniques. Each model has both strengths and weaknesses for exploring the mechanisms of disease development and progression and the efficacy of new treatment strategies.
Antitumour immune responses
Authors: Mitra Roshni , Singh Sarvjeet , Khar Ashok
Published: October 2003

The role of the immune system in combating tumour progression has been studied extensively. The two branches of the immune response – humoral and cell-mediated – act both independently and in concert to combat tumour progression, the success of which depends on the immunogenicity of the tumour cells. The immune system discriminates between transformed cells and normal cells by virtue of the presence of unique antigens on tumour cells. Despite this, the immune system is not always able to detect and kill cancerous cells because neoplasms have also evolved various strategies to escape immune surveillance. Attempts are being made to trigger the immune system into an early and efficient response against malignant cells, and various therapeutic modalities are being developed to enhance the strength of the immune response against tumours. This review aims to elucidate the tumouricidal role of various components of the immune system, including macrophages, lymphocytes, dendritic cells and complement.
Cyclooxygenase isoforms and atherosclerosis
Authors: Belton Orina , Fitzgerald Desmond J.
Published: October 2003

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and pain. However, their long-term use is limited by gastrointestinal (GI) side effects such as gastric ulcers. NSAIDs act by inhibiting an enzyme called cyclooxygenase. Cyclooxygenase (COX) catalyses the generation of prostaglandins from arachidonic acid. Two isoforms of the enzyme exist – COX-1 and COX-2 – both of which are targets for NSAIDs. Although they are associated with GI toxicity, NSAIDs have important antithrombotic and anti-inflammatory effects. The GI injury has been attributed to COX-1 inhibition and the anti-inflammatory effects to COX-2 inhibition. As COX-2 is traditionally viewed as an inducible enzyme, selective inhibition of COX-2 by ‘coxibs’ (selective COX-2 inhibitors) has been employed to achieve anti-inflammatory and analgesic effects without GI side effects. However, recently there have been suggestions that chronic administration of coxibs might increase the risk of cardiovascular events, such as atherosclerosis, compared with traditional NSAIDs. In vascular disease, there is increased expression of both COX-1 and COX-2, resulting in enhanced prostaglandin generation. The specific role of COX-1 and COX-2 in vascular regulation is still unknown but such knowledge is essential for the effective use of coxibs. Although more evidence is pointing to selective COX-1 inhibition as a therapeutic measure in inflammatory atherosclerosis, there are some studies that suggest that inhibition of COX-2 might have a potential benefit on atherosclerosis.
MHC-based vaccination approaches: progress and perspectives
Authors: Mehra Narinder K. , Kaur Gurvinder
Published: October 2003

The major histocompatibility complex (MHC) harbours genes whose primary function in regulating immune responsiveness to infection is to present foreign antigens to cytotoxic T lymphocytes (CTLs) and T helper cells. In the case of infection by human immunodeficiency virus (HIV), defining the optimal HIV epitopes that are recognised by CTLs is important for vaccine design, and this in turn will depend on the characteristics of the predominant infecting virus. Moreover, the particular MHC human leukocyte antigens (HLAs) expressed by a geographical population is important since these are likely to determine which HIV epitopes are immunodominant in the anti-HIV immune response. Consideration of these aspects has lead to the dawn of a new era of MHC-based vaccine design, in which the CTL epitopes are selected on the basis of the frequency of restricting MHC alleles. This article reviews data on the distribution patterns of molecular subtypes of HLA class I and class II extended haplotypes, discussing distribution among Asian Indians but with reference to global distributions. These data provide a genetic basis for the possible predisposition and fast progression of HIV infections in the Indian population. Since there is selective predominance of different HLA alleles and haplotypes in different populations, a dedicated screening effort is required at the global level to develop MHC-based vaccines against infectious diseases. It is hoped that this might lead to the development of multivalent, poly-epitope, subtype-specific HIV vaccines that are specific for the target geographical location.
Genetic factors underlying prostate cancer
Authors: Luo Jian-Hua , Yu Yan Ping
Published: October 2003

Prostate cancer is one of the leading causes of cancer-related death in the USA. In the past decade, tremendous progress has been made in the identification and understanding of the genetic factors related to prostate cancer development. Unlike many other types of cancers, only a small fraction of prostate cancer cases are aggressive and life-threatening. The factors related to prostate cancer development and progression appear complex and diverse. This review summarises some of the important findings in the areas of genome and gene expression abnormalities in prostate cancer, and aims to provide a comprehensive view of new developments in these areas.
A multifaceted role for ATM in genome maintenance
Authors: Pandita Tej K.
Published: October 2003

The pleiotropic nature of the clinical phenotypes of patients with ataxia-telangiectasia (A-T) – which encompass cerebellar degeneration (leading to ataxia), gonadal atrophy, and cancer predisposition – suggests multiple functions of the gene responsible for the disease. The ataxia-telangiectasia mutated gene product (ATM), whose loss of function is responsible for ataxia-telangiectasia, is a protein kinase that interacts with several substrates and is implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control and telomere maintenance. This review focuses on the critical roles that ATM appears to play in cell-cycle checkpoints, DNA repair, telomere metabolism and oxidative stress, indicating how defects in these processes might lead to ataxia-telangiectasia.
Metalloproteinases and their inhibitors in angiogenesis
Authors: Lafleur Marc A. , Handsley Madeleine M. , Edwards Dylan R.
Published: October 2003

Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is an integral part of physiological processes such as embryonic development, the female reproductive cycle and wound healing. Angiogenesis is also central to a variety of pathologies including cancer, where it is recognised as being crucial for the growth of solid tumours. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, most notably MMP-2 and -9 and membrane-type-1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, liberation of angiogenic factors, production of endogenous angiogenic inhibitors, and the unmasking of cryptic biologically relevant sites in ECM components. This review brings together what is currently known about the functions of the MMPs and the closely related adamalysin metalloproteinase (ADAM) family in angiogenesis, and discusses how this information might be useful in manipulation of the angiogenic process, with a view to controlling aberrant neovascularisation.
Molecular mechanisms of learning and memory
Authors: Dunning Jane , During Matthew J.
Published: October 2003

Memory is the process by which organisms are able to record their experiences, and use this information to adapt their responses to the environment. As such, it is vital for survival. In recent years, the development of spatially and temporally selective techniques for the regulation of gene expression has allowed the molecular details of this process to emerge. Here we review the molecular mechanisms thought to underlie memory acquisition and storage, as well as discuss recent evidence regarding the mechanisms of subsequent memory consolidation.