bluuebunny/crossref_metadata_2025 huggingface dataset:
p53 and bcl-2 Overexpression as Associated Risk Factors in Patients 40 Years Old or Less with Transitional Cell Carcinoma of the Bladder
Authors: Asci Ramazan , Yildiz Levent , Sarikaya Saban , Buyukalpelli Recep , Yilmaz Ali Faik , Kandemir Bedri
Published: April 2003

Objectives: Transitional cell carcinoma (TCC) of the bladder in younger patients has historically a favourable prognosis. bcl-2 and p53 genes are implicated in cell cycle regulation with roles on programmed cell death. Presence of nuclear accumulation of p53 and cytoplasmic accumulation of bcl-2 were proposed to confer a growth advantage to tumour cells. In this study, we investigated the roles of p53 and bcl-2 as prognostic factors in TCC of bladder in patients younger than 40 years. Patients and Methods: From 1986 to 1998, 25 patients younger than 40 years were treated for TCC of bladder in our hospital. Of the tumour specimens, 24 were adequate for evaluating p53 and bcl-2 oncoproteins (group I). As a control (group II), we randomly selected 30 patients older than 50 years treated for bladder cancer in this period. Two oncoproteins were detected by immunohistochemical analysis in paired tumour tissue specimens in both groups. Retrospectively obtained clinical follow-up data were available, with a mean follow-up of 44 and 25.5 months in groups I and II, respectively. Relations between tumour recurrences and progression with positivity of bcl-2 and p53 were investigated. Results: Expression of bcl-2 was observed in 13 (54.1%) and 11 (36.7%) and nuclear p53 accumulation in 9 (37.5%) and 17 (56.7%) of groups I and II, respectively. In the presence of p53 expression, tumours showed significantly more progression in group I (55 vs. 6.7%) and group II (41.1 vs. 0%). Recurrence rates were not significantly different in tumours with and without nuclear p53 overexpression in both groups. Also, recurrence and progression rates were not significantly different in tumours with and without cytoplasmic bcl-2 overexpression in both groups. Grade (G) and stage appeared as important prognostic factors in both groups since 60% of GIII tumours showed progression in group I, but none of GI and GII tumours. Similarly, 75% of T3 tumours progressed, while these rates were 25 and 25% for T1–T2 tumours in group I. In group II, 31.2, 25 and 0% of GIII, GII and GI tumours progressed, while 50, 41.6 and 0% of T3, T2 and T1 tumours progressed, respectively. Conclusions: Nuclear p53 expression in TCC appears to be associated with a poorer prognosis in both younger and older patients. Although cytoplasmic bcl-2 overexpression is found in the majority of tumours in the younger group, it is not associated with tumour progression and recurrence.
Synchronous Bladder Augmentation and Living Related Kidney Transplantation
Authors: Jones Jon , Bickeböller Ralf , Binder Jochen , Kramer Wolfgang
Published: April 2003

Ileocystoplasty for enlargement of bladder capacity in conjunction with renal transplantation has been described in several cases. However, the surgical approach has been accomplished as a two-stage procedure. We report the case of a 21-year-old female myelomeningocele patient with end-stage renal insufficiency who was treated with ileocytstoplasty and living related renal transplantation at a single stage. Convalescence remained uneventful. On follow-up 13 months after the operation, the renal parameters remained stable.
Indolent Behaviour of Low-Grade B Cell Lymphoma of Mucosa-Associated Lymphoid Tissue Arising in the Kidney
Authors: Jindal B. , Sharma S.C. , Das A. , Banerjee A.K.
Published: April 2003

We report a case of low-grade MALT lymphoma (mucosa-associated lymphoid tissue) arising in the kidney. It had very indolent behaviour with multiple extranodal relapses (parotid gland, orbit, skin, breast, prostate) over a period of 13 years; presently, the patient is asymptomatic.
Testicular Sarcoid
Authors: Naseem S. , Lindley R. , Mufti G.R.
Published: April 2003

Sarcoidosis occurs rarely in Caucasian males and seldom involves the testis. We report an unusual case of asymptomatic testicular sarcoid in a Caucasian man.
Endocrine Alteration in the Adrenal Gland in Kidney Transplant Patients
Authors: Wunderlich H. , Zermann D.-H. , Reichelt O. , Wilhelm S. , Seidel E. , Schubert J.
Published: April 2003

Introduction: Endocrine alterations associated with chronic renal failure have been reviewed recently. Some of these alterations are of clinical relevance. The aim of this study was to investigate the effect of renal transplantation on the endocrine system of the adrenal gland of the transplant recipients. Methods: The serum angiotensin-converting enzyme (SACE), plasma renin (PR) and plasma aldosterone (PA) were examined in 30 patients before and after renal allotransplantation. Additionally measured parameters were blood pressure, serum creatinine, potassium, sodium, the duration of dialysis and immunosuppressive medication. Results: Six weeks after renal transplantation, serum creatinine decreased from 820.07 ± 172.01 to 138.12 ± 67.54 µmol/l. In the same periode, serum potassium decreased from 5.42 ± 0.89 to 4.17 ± 0.42 mmol/l. PA and PR decreased from 1,150.84 ± 976.06 to 233.52 ± 217.07 µmol/l, and from 121.07 ± 100.12 to 26.16 ± 10.86 µU/ml, respectively. SACE decreased from 0.21 ± 0.21 to 0.13 ± 0.11 µmol/l. No significant correlation was seen with blood pressure, serum sodium, the duration of dialysis and immunosuppressive drugs. Additionally, 2 patients with acute renal graft dysfunction showed significant increases in PR and PA. After successful treatment both levels declined very quickly to prerejection levels. Patients after binephrectomy show no elevation in PR (5–47 µU/ml) or PA (21–416 µmol/l) neither before nor after renal transplantation. Conclusions: We conclude that renal transplantation has profound effects on the recipient’s renin-angiotensin-aldosterone system. Because of the rapid depression after renal transplantation, it does not appear to be involved in the pathogenesis of post transplantation hypertension but may reflect a role for repair processes after renal allotransplantation.
Skin Involvement from Micropapillary Bladder Carcinoma as the First Clinical Manifestation of Metastatic Disease
Authors: Dominici Alberto , Nesi Gabriella , Mondaini Nicola , Amorosi Andrea , Rizzo Michelangelo
Published: April 2003

Cutaneous metastases from transitional cell carcinoma (TCC) of the bladder occur infrequently. We report the case of a 68-year-old man presenting with an isolated skin nodule a few weeks after local excision of a micropapillary bladder carcinoma. This rare variant of TCC, which is strikingly reminiscent of the histological pattern of ovarian papillary serous carcinoma, is associated with poor prognosis and apparently high metastatic potential.
Symptomatic Unilateral Renal Angiomyolipoma in a Child with Tuberous Sclerosis
Authors: Avolio Luigi , Savasta Salvatore , Matteotti Chiara , Fusillo Mario , Bragheri Romano
Published: April 2003

We report a case of unilateral renal angiomyolipoma in a 10-year-old boy with tuberous sclerosis. The case is worthy of attention because the symptoms occurred at an early age and because the lesion was unilateral, the latter confirmed at 11-year follow-up. The presentation and treatment are discussed, and the pertinent literature is reviewed. The case demonstrates that it is of clinical importance to monitor renal involvement in children with tuberous sclerosis.
A Giant Renal Calculus Treated without Nephrectomy
Authors: Bayazıt Yıldırım , Arıdogan İ. Atilla , Zeren Sinan , Payaslı Kerem , Türkyilmaz Ruhi K.
Published: April 2003

The case of a patient with a giant renal calculus weighing 770 g in a solitary functioning kidney is reported. A 57-year-old man presented with right lumbar pain and macroscopic hematuria, and a giant stone was diagnosed in his right kidney. Nine days after a percutaneous nephrostomy placement, the patient underwent selective right renal angiography and transcatheter superselective embolization due to a sudden gross hematuria observed from both the nephrostomy tube and urethra. Embolization was successful. Right anatrophic nephrolithotomy was performed after stabilization of the patient. There were no complications during the recovery period. The case reported here is significant not only because it is the 7th biggest and the heaviest stone in the literature but also because it is the first giant stone reported to be in a solitary functioning kidney and treated without nephrectomy.
Relationship of Comorbidity, Age and Perioperative Complications in Patients Undergoing Radical Prostatectomy
Authors: Froehner Michael , Litz Rainer , Manseck Andreas , Hakenberg Oliver W. , Leike Steffen , Albrecht D.-Michael , Wirth Manfred P.
Published: April 2003

Objectives: To investigate the prevalence and distribution of comorbidity and its association with perioperative complications in patients undergoing radical prostatectomy (RPE). Methods: In 431 unselected RPE patients, the American Society of Anesthesiologists Physical Status classification (ASA-PS), the New York Heart Association classification of cardiac insufficiency (NYHA), the classification of angina pectoris of the Canadian Cardiovascular Society (CCS), height, weight, the body mass index (BMI), and the number of concomitant diseases (NCD) were assessed and related to perioperative cardiovascular complications. Results: In RPE patients less than 70 years old, comorbidity rose nearly continuously with increasing age. However, after reaching an age of 70 years, the proportion of NYHA-0 patients increased (60–64 years, 86%; 65–69 years, 85%; ≧70 years, 87%). Furthermore, the severe comorbidities decreased in patients selected for RPE aged 70 or more years. There was a nonsignificant trend towards higher comorbidity in patients with perioperative cardiovascular complications. Conclusions: These data suggest that documentation of the distribution of ASA-PS, CCS, NYHA and of concomitant diseases might be helpful to characterize the general health status and the degree of selection of prostate cancer treatment populations especially in series with a high portion of patients aged 70 or more years. Concerning perioperative complications, the individual predictive value of comorbidity seems to be poor in the radical prostatectomy setting.
Phase 1/2 Study of Synchronous Methotrexate, Cisplatin, Vincristine (MOPq10) Chemotherapy and Radiation for Patients with Locally Advanced Bladder Cancer
Authors: Goonewardene T.I. , Bozcuk H. , Oliver R.T.D. , Barua J. , Nargund V. , Philip T. , Mair G. , Gibbs S.
Published: April 2003

Purpose: This phase 1/2 study was designed to test toxicity and effectiveness of combination chemotherapy and concurrent radiotherapy in the treatment of invasive bladder cancer. Methods and Materials: 17 patients with localised muscle-invasive bladder cancer, clinical stages T2–3 N0, M0, were treated with a radiotherapy schedule of 55 Gy in 20 fractions over 4 weeks restricted to the bladder and 3 cycles of concurrent dose-intensive combination chemotherapy consisting of cisplatin 60 mg/m2, vincristine 2 mg and methotrexate 60 mg/m2 at 10-day intervals (MOPq10). Results: The complete remission rate following MOPq10 chemotherapy and radiotherapy was 88% as assessed at first cystoscopy with 82% remaining disease-free at 1 year. Risk factor analysis shows those older than 63 years (median) and those with creatinine clearance equal or less than the mean did worse. Actuarial disease-free survival at 2 years was 68% and of the patients treated 4/17 experienced acute G3/4 toxicity. Conclusion: This combination regimen was feasible. Its high initial response rate justifies further exploration in a randomised phase 2/3 trial setting with bladder volume and quality of life assessment.
Hydatid Disease of the Kidney Caused by Echinococcus multilocularis: A Rare Clinical Entity
Authors: Türker Köksal İsmail , Tefekli Ahmet , Kılıçaslan Işın , Erdemir Fikret , Kadıoğlu Teoman , Esen Tarık
Published: April 2003

Hydatid disease of the urinary tract is extremely rare and constitutes approximately 4% of all cases of hydatid disease. The Echinococcus multilocularis is a relatively rare form of echinococcus as the cause of renal hydatid disease. We describe a patient who had renal hydatidosis which is rarely caused by the E. multilocularis.
Development of Axonal Projections in Cocultures of the Hippocampal Formation Visualized with β-Actin-gfp Transgenic Slices
Authors: Glumm Robert , Klöting Anna , Heimrich Bernd
Published: April 2003

Coculture of immature brain tissue is a widely used model to study the formation of connections and neuronal differentiation under experimental conditions. Very often, the labeling of fiber outgrowth is incomplete and accompanied by tissue damage due to the application of the tracer. Here we used organotypic slice cocultures from neonate wild-type mice and β-actin-gfp transgenic mice, which allowed us to prelabel the vital axons and to monitor the complete axonal projection. In cocultures from entorhinal cortex and hippocampus, gfp-labeled entorhinal axons terminate in their correct hippocampal layers. Cocultures between the CA3 region of a gfp transgenic mouse and a CA1 slice from wild-type mouse show green fluorescent Schaffer collaterals in the stratum radiatum of the CA1 target slice. β-Actin-gfp-expressing cells often migrated into the wild-type part of the coculture and developed processes. From our data, we demonstrate that this chimeric coculture approach is appropriate in tracing entire developing projections and may serve as a tool to directly observe the navigation and axonal elongation of living axons.
Adenosine Diphosphate Ribose Dilates Bovine Coronary Small Arteries through Apyrase- and 5′-Nucleotidase-Mediated Metabolism
Authors: Zhang David X. , Zou Ai-Ping , Li Pin-Lan
Published: April 2003

Cyclic adenosine diphosphate ribose and adenosine diphosphate ribose (ADPR) play an important role in the regulation of intracellular Ca2+ release and K+ channel activity in the coronary arterial smooth muscle. The role of these signaling nucleotides in the control of vascular tone has yet to be determined. The present study was designed to determine whether ADPR produces vasodilation in coronary arteries and to explore the mechanism of action of ADPR. ADPR (10–60 µmol/l) was found to produce endothelium-independent relaxation in a concentration-dependent manner in isolated and pressurized small bovine coronary arteries. The ADPR-induced vasodilation was substantially attenuated by adenosine deaminase (0.2 U/ml), and the P1 purinoceptor antagonist 8-(p-sulfophenyl)theophylline (50 µmol/l), with maximal inhibitions of 60 and 80%, respectively. When the coronary arterial homogenates were incubated with ADPR, the production of adenosine and 5′-AMP was detected. The adenosine production was blocked by the 5′-nucleotidase inhibitor, α,β-methylene adenosine 5′-diphosphate (MADP, 1 mmol/l), which was accompanied by a corresponding accumulation of 5′-AMP. This 5′-AMP accumulation was substantially inhibited by the apyrase inhibitor sodium azide (10 mmol/l). Moreover, ADPR was hydrolyzed into 5′-AMP by purified apyrase. In agreement with their inhibitory effect on the adenosine production, MADP and sodium azide significantly attenuated the vasodilator response to ADPR. The metabolism of ADPR to adenosine was only detected in cultured coronary arterial smooth muscle cells but not in endothelial cells. We concluded that ADPR produces vasodilation in small coronary arteries and that the action of ADPR is associated with the adenosine production via an apyrase- and 5′-nucleotidase-mediated metabolism.
Vascular Biology of the Isoprostanes
Authors: Cracowski Jean-Luc , Devillier Philippe , Durand Thierry , Stanke-Labesque Françoise , Bessard Germain
Published: April 2003

Isoprostanes are a family of compounds produced from polyunsaturated fatty acids via a free-radical-catalysed mechanism. F2-isoprostanes are prostaglandin F2α isomers derived from arachidonic acid. These compounds induce potent vasoconstriction, mediated primarily by TP receptor stimulation, and in some vessels by the release of cyclooxygenase products. This vasoconstriction may be modulated by the endothelium through the release of NO. Potent vasoconstriction is also observed with E2-isoprostanes. Experimental and clinical data suggest a role for F2-isoprostanes in atherogenesis. These compounds can be detected in free forms in biological fluids as well as esterified in low-density lipoproteins or cell membranes. Their quantification represents a reliable marker of lipid peroxidation. Elevated levels of F2-isoprostanes in biological fluids in pathological conditions including atherosclerosis, ischaemia-reperfusion injury, and inflammatory vascular diseases, suggest a relationship between lipid peroxidation and such diseases. F2-isoprostanes are currently being investigated as non-invasive quantitative markers to monitor the response to anti-oxidant treatment.
Identification and Characterization of Novel Smoothelin Isoforms in Vascular Smooth Muscle
Authors: Krämer Jochen , Quensel Christina , Meding Joerg , Cardoso M. Cristina , Leonhardt Heinrich
Published: April 2003

Smoothelin is a cytoskeletal protein specifically expressed in differentiated smooth muscle cells and has been shown to colocalize with smooth muscle alpha actin. In addition to the small smoothelin isoform of 59 kD, we recently identified a large smoothelin isoform of 117 kD. The aim of this study was to identify and characterize novel smoothelin isoforms. The genomic structure and sequence of the smoothelin gene were determined by genomic PCR, RT-PCR and DNA sequencing. Comparison of the cDNA and genomic sequences shows that the small smoothelin isoform is generated by transcription initiation 10 kb downstream of the start site of the large isoform. In addition to the known smoothelin cDNA (c1 isoform) we identified two novel cDNA variants (c2 and c3 isoform) that are generated by alternative splicing within a region, which shows similarity to the spectrin family of F-actin cross-linking proteins. Visceral organs express the c1 form, while the c2 form prevails in well-vascularized tissue as analyzed by RT-PCR. We then generated specific antibodies against the major smoothelin isoforms and could show by Western blotting and immunohistochemistry that the large isoform is specifically expressed in vascular smooth muscle cells, while the small isoform is abundant in visceral smooth muscle. These results strongly suggest that the smoothelin gene contains a vascular and a visceral smooth muscle promoter. The cell-type-specific expression of smoothelin isoforms that are associated with actin filaments may play a role in the modulation of the contractile properties of different smooth muscle cell types.
Liposome-Mediated High-Efficiency Transfection of Human Endothelial Cells
Authors: Kaiser Simone , Toborek Michal
Published: April 2003

Liposome-mediated transfection of endothelial cells provides a valuable experimental technique to study cellular gene expression and may also be adapted for gene therapy studies. However, the widely recognized disadvantage of liposome-mediated transfection is low efficiency. Therefore, studies were performed to optimize transfection techniques in human endothelial cells. The majority of the experiments were performed with primary cultures of human umbilical vein endothelial cells (HUVEC). In addition, selected experiments were performed using human brain microvascular endothelial cells and human dermal microvascular endothelial cells. To study transfection rates, HUVEC were transfected with the pGL3 vector, containing the luciferase reporter gene, complexed with several currently available liposomes, such as different Perfect Lipid (pFx) mixtures, DMRIE-C, or lipofectin. The optimal transfection rate was achieved in HUVEC transfected for 1.5 h with 5 µg/ml of DNA plasmid in the presence of 36 µg/ml of pFx-7. In addition, transfection with the VR-3301 vector encoding for human placental alkaline phosphatase revealed that, under the described conditions, transfection efficiency in HUVEC was approximately 32%. Transfections mediated by other liposomes were less efficient. The usefulness of the optimized transfection technique was confirmed in HUVEC transfected with NF-ĸB or AP-1-responsive constructs and stimulated with TNF or LPS. We conclude that among several currently available liposomes, pFx-7 appears to be the most suitable for transfections of cultured human endothelial cells.
Differential Effects of Vascular Endothelial Growth Factor-C and Placental Growth Factor-1 on the Hydraulic Conductivity of Frog Mesenteric Capillaries
Authors: Hillman N.J. , Whittles C.E. , Pocock T.M. , Williams B. , Bates D.O.
Published: April 2003

Vascular endothelial growth factors (VEGFs) are known to increase vascular permeability. VEGF-A acts on two receptor tyrosine kinases, VEGF receptor-1 (VEGF-R1 or flt-1) and VEGF receptor-2 (VEGF-R2, flk-1 or KDR). VEGF-C acts only on VEGF-R2 on vascular endothelial cells, whereas placental growth factor-1 (PlGF-1) acts only on VEGF-R1. The effects of perfusion of these receptor-specific proteins on hydraulic conductivity (Lp) was measured in frog mesenteric capillaries. The effect of PlGF on Lp was not conclusive, and overall fluid flux did not increase during that time. VEGF-C acutely and transiently increased Lp (4.5 ± 0.9-fold), which was more obvious in a subset of vessels, in a similar manner to that reported for VEGF-A. In the subset of vessels in which VEGF-C significantly increased Lp acutely, there was a sustained 12-fold increase in Lp 20 min after perfusion, but this was not seen in those vessels which did not respond acutely to VEGF-C, or in vessels exposed to PlGF-1. Lp was also increased 24 h after perfusion with VEGF-C, but not with PlGF-1. Western blot analysis showed that VEGF-R1 and VEGF-R2 are both present in frog tissue. These data show that the VEGFs that stimulate VEGF-R2 chronically increase Lp, but not those that stimulate VEGF-R1 only. This supports the hypothesis that chronic increases in microvascular permeability induced by VEGF are mediated via activation of VEGF-R2 rather than VEGF-R1.
Epoxygenase Metabolites Contribute to Nitric Oxide-Independent Afferent Arteriolar Vasodilation in Response to Bradykinin
Authors: Imig John D. , Falck John R. , Wei Shouzou , Capdevila Jorge H.
Published: April 2003

In the kidney, epoxyeicosatrienoic acids (EETs) have been suggested to be endothelium-derived hyperpolarizing factors (EDHFs). The aim of the present study was to determine the contribution of EETs to the preglomerular vasodilation elicited by bradykinin. Sprague-Dawley rats were studied utilizing an in vitro perfused juxtamedullary nephron preparation. The afferent arteriolar diameter was determined and the diameter averaged 19 ± 1 µm (n = 26) at a renal perfusion pressure of 100 mm Hg. Addition of 1, 10 and 100 nM bradykinin to the perfusate dose-dependently increased afferent arteriolar diameter by 5 ± 1, 12 ± 2 and 17 ± 2%, respectively. The nitric oxide inhibitor Nω-nitro-L-arginine reduced bradykinin-induced afferent arteriolar vasodilation by 50%, and the diameter increased by 9 ± 2% in response to 100 nM bradykinin. Epoxygenase inhibitors N-methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide or miconazole greatly attenuated the nitric oxide-independent component of the vasodilation elicited by bradykinin. Cyclooxygenase (COX) inhibition attenuated the nitric oxide-independent vasodilation elicited by 1 nM bradykinin but did not significantly affect the vascular response to 100 nM bradykinin. Combined inhibition of nitric oxide, COX and epoxygenase pathways completely abolished bradykinin-mediated afferent arteriolar vasodilation. In additional studies, renal microvessels were isolated and incubated with bradykinin and samples were analyzed by NICI/GC/MS. Under control conditions, renal microvascular EET levels averaged 49 ± 9 pg/mg/20 min (n = 7). In the presence of bradykinin, EET levels were significantly higher and averaged 81 ± 11 pg/mg/20 min (n = 7). These data support the concept that EETs are EDHFs and contribute to the nitric oxide-independent afferent arteriolar vasodilation elicited by bradykinin.
Measurement of the Lymphatic Clearance of the Human Skin Using a Fluorescent Tracer
Authors: Leu Anders J. , Husmann Marc J.W. , Held Torsten , Frisullo Roberto , Hoffmann Ulrich , Franzeck Ulrich K.
Published: April 2003

The lymphatic clearance of the human skin at the instep of the foot was measured in 20 healthy volunteers (mean age ± SD 33.8 ± 10.5 years). Ten microliters of fluorescein isothiocyanate-dextran 150,000 were injected intradermally and the fluorescent light intensity of the deposit was measured 10 min and 24 h after injection by window densitometry. Fluorescent light intensity decreased by 31.2 ± 13.5 arbitrary units (p < 0.0001) or by a factor of 4.1 ± 3.9. Reproducibility was tested 2–6 weeks later in 7 subjects and an intraclass reliability of 0.76 was found. These are the first measurements of the lymphatic clearance of the human skin using a fluorescent tracer. The method is easier and safer than the isotope clearance technique and small areas of the human skin can be investigated. The data found form a basis with which to compare measurements made in patients with different forms of edema.
A Genetically Modified Adenoviral Vector Exhibits Enhanced Gene Transfer of Human Smooth Muscle Cells
Authors: Su Enming J. , Stevenson Susan C. , Rollence Michele , Marshall-Neff Jennifer , Liau Gene
Published: April 2003

Adenoviral vector-based gene therapy is a promising approach for the treatment of restenosis postangioplasty. However, a high concentration of adenoviral vector can cause cellular activation, damage, and an enhanced immune response. One approach to solving this problem is to increase gene transfer efficiency by directing adenoviral vector entry via an alternate receptor system. We have constructed an adenoviral vector, Av9LacZ, that encodes the β-galactosidase gene and contains a chimeric fiber protein that redirects viral vector binding to the Ad3 adenoviral receptor on the host cell. We examined the ability of Av9LacZ to transduce primary human smooth muscle cells (SMC) and found that it showed a 10- to 15-fold higher transduction efficiency when compared to the prototypic adenoviral vector currently used for preclinical and clinical studies. While both vectors were able to transduce rabbit, pig and monkey SMCs, the genetically modified vector transduced human SMC with much higher efficiency. SMC obtained from the aorta, coronary, renal, popliteal and pulmonary arteries were all efficiently transduced by Av9LacZ. Consistent with the data obtained from cultured cells, Av9LacZ also transduced fresh human arterial tissues considerably more efficiently than Av1LacZ. We conclude that the large discrepancy between transduction of animal and human cells by conventional vectors supports a cautious extrapolation of the results of in vivo animal studies to man. Furthermore, the genetically modified AV9 vector may deliver better efficacy and studies in large animal models with this vector could be more predictive of therapeutic efficacy in the treatment of human restenosis.
Smooth Muscle Cells Influence Monocyte Response to LDL as well as Their Adhesion and Transmigration in a Coculture Model of the Arterial Wall
Authors: Kinard Fabienne , Jaworski Kathy , Sergent-Engelen Thérèse , Goldstein Dan , van Veldhoven Paul P. , Holvoet Paul , Trouet André , Schneider Yves-Jacques , Remacle Claude
Published: April 2003

We investigated the possible interference of smooth muscle cells with monocyte response to LDL as well as with their adhesion and transmigration in a coculture of porcine endothelial and smooth muscle cells. Lysophosphatidylcholine (LPC), a component of oxidized LDL (oxLDL), stimulated the adhesion of THP-1 cells to endothelial cells both in mono- and in coculture with smooth muscle cells. When THP-1 cells were incubated with endothelial cells in the presence of copper oxLDL, their adhesion was increased, but only in coculture. The addition of sodium nitroprusside (SNP) together with oxLDL markedly increased the adhesion of THP-1 cells in coculture. Close proximity between endothelial and smooth muscle cells was necessary to observe that effect. Furthermore, this increase in adhesion of THP-1 cells can, at least in part, be attributed to the augmented production of monocyte chemoattractant protein-1 (MCP-1) observed in coculture under the influence of oxLDL and SNP. The passage of THP-1 cells through the coculture was stimulated by MCP-1 and LPC. These results show that physical contacts or close proximity between endothelial and smooth muscle cells play a key role in the adhesion of monocytes and their infiltration into the intima in response to oxLDL.
Determination of Aortic Elastic Modulus by Pulse Wave Velocity and Wall Tracking in a Rat Model of Aortic Stiffness
Authors: Marque Valérie , van Essen Helma , Struijker-Boudier Harry A.J. , Atkinson Jeffrey , Lartaud-Idjouadiene Isabelle
Published: April 2003

Several methods have been used to evaluate the elastic modulus of the aortic wall in the rat, but these have never been compared when used simultaneously. We measured thoracoabdominal pulse wave velocity (PWV) and changes in thoracic aorta diameter during the cardiac cycle (with wall echo-tracking) in pentobarbital-anesthetized adult male Wistar rats; half of the group had previously received vitamin D3 plus nicotine (VDN) in order to increase the stiffness of the aortic wall. The Moens-Korteweg elastic modulus (EMK) was calculated from PWV and the ratio of the internal diameter to the medial thickness determined by histomorphometry following in situ pressurized fixation. The incremental elastic modulus (Einc) was calculated from the distensibility coefficient and end-diastolic diameter measured by wall echo-tracking and the medial thickness determined by histomorphometry. Both values were higher in VDN rats than in controls: Einc 8.9 ± 0.5 and 5.7 ± 0.4·106 dyne/cm2, p < 0.05; EMK 7.6 ± 0.5 and 4.1 ± 0.5·106 dyne/cm2, p < 0.05. Einc was greater than EMK and this was partially due to the fact that the in vivo end-diastolic diameter measured by ultrasound was greater than the mean aortic diameter measured ex vivo by histomorphometry. In conclusion, different methods for the measurement of the elastic properties of the aortic wall gave similar results in controls and in a rat model of aortic stiffness.
Imbalance in the Synthesis of Collagen Type I and Collagen Type III in Smooth Muscle Cells Derived from Human Varicose Veins
Authors: Sansilvestri-Morel Patricia , Rupin Alain , Badier-Commander Cécile , Kern Patrick , Fabiani Jean-Noël , Verbeuren Tony J. , Vanhoutte Paul M.
Published: April 2003

Varicose veins have a thickening wall. Their smooth muscle cells are disorganized as regards proliferation and production of extracellular matrix protein. An imbalance between the synthesis of collagen type I protein (collagen I) and collagen type III protein (collagen III) could explain the lack of elasticity of varicose veins. Therefore, collagen synthesis was compared in the media and in cultured smooth muscle cells derived from human control and varicose saphenous veins. An increase in total collagen synthesis was observed in the media and in smooth muscle cells derived from varicose veins. This augmentation was due to an overproduction of collagen I in cultured cells from varicose veins consistent with an increase in the release of collagen I metabolites in the media. A concomitant decrease in collagen III was observed in cultures of smooth muscle cells from varicose veins. The increase in the synthesis of collagen I in cells from varicose veins was correlated with an overexpression of the gene since mRNAs for collagen I were augmented without change in mRNA-half-life. This augmentation in the synthesis of collagen I was reduced by the addition of exogenous collagen III in cultures from varicose veins. These findings suggest a dysregulation of the synthesis of collagen I and III in smooth muscle cells derived from varicose veins.
Influence of Type II Diabetes on Arterial Tone and Endothelial Function in Murine Mesenteric Resistance Arteries
Authors: Lagaud G.J.L. , Masih-Khan E. , Kai S. , van Breemen C. , Dubé G.P.
Published: April 2003

An arteriograph was used to assess myogenic tone, smooth muscle contractility and the influence of endothelial function on mesenteric resistance artery reactivity in insulin-resistant mice (C57BL/KsJ-db/db) and age- and gender-matched wild-type mice. Increases in transmural pressure induced myogenic tone in arteries from both control and db/db mice. At 12 and 16 weeks of age, greater tone developed in diabetic than in control mice. In control, but not in db/db mice, pretreatment of arteries with L-NAME potentiated myogenic tone. Indomethacin and SQ29548 (PGH2/TXA2 receptor antagonist) had no efffect in control, but inhibited myogenic tone in db/db mice. Endothelium-dependent vasodilation induced by acetylcholine and bradykinin, was depressed in db/db mice and potentiated by SQ29548 and LY333531 (protein kinase Cβ inhibitor). Messenger RNA expression levels for PKCβ were over-expressed 2.5-fold in db/db relative to those in control mice. However, expression levels of mRNA for eNOS, PKCα, and PKCξ were similar in the db/db and control mice. Collectively, these results suggest that the greater myogenic tone in resistance arteries from diabetic mice may be attributable, to greater amounts of one or more vasoconstricting prostanoids. Our data indicate that in diabetic mice, basal and agonist-stimulated NO releases are depressed and NO-mediated vasorelaxation in these mice may be countered by an endogenous vasoconstrictive prostanoid. This prostanoid-induced vasoconstriction is mediated by a PKCβ-dependent mechanism. Therefore, heightened activation of PKCβ and release of a vasoconstrictor prostanoid could play a role in endothelial dysfunction associated with type II diabetes.
Factors Affecting the Use of Prenatal Testing for Fetal Anomalities in a Traditional Society
Authors: Weitzman Dahlia , Shoham-Vardi Ilana , Elbedour Khalil , Belmaker Ilana , Siton Yafa , Carmi Rivka
Published: April 2003

The Bedouin Arabs of the southern part of Israel are a community at increased risk for genetic diseases and congenital anomalies as a result of frequent consanguineous marriages and underutilization of prenatal tests to detect fetal anomalies. Objective: To investigate factors affecting the use of prenatal tests to detect fetal anomalies in a traditional non-western minority who is offered modern western-type prenatal care services. Method: Demographic and obstetric data, medical family history and information about utilization of mother and child health (MCH) clinics and of prenatal tests to detect fetal anomalies was obtained for all Bedouin women living in 4 towns who gave birth in the regional hospital between September 1994 and February 1995. Univariate and multivariate analyses were used to find which factors may be contributing to increased utilization of these services. Results: Multivariate analysis among multigravidae showed that the main factors associated with undergoing at least one prenatal test to detect fetal anomalies were: having no children following pregnancy loss(es) (OR = 5.47, 95% confidence interval [2.00; 15.00]) or having only one previous child (OR = 1.67 [1.16; 2.42]), raising a child with a congenital anomaly, genetic or chronic disease (OR = 3.38 [1.81; 6.33]), chronic diseases among close relatives (OR = 1.83 [1.17; 2.87]), and holding a job (OR = 2.86 [1.00; 8.20]). Perinatal mortality in previous pregnancies or a later child loss as well as reported congenital diseases in close relatives were not significantly associated with increased uptake of prenatal tests. After controlling for age, no difference in utilization indices was found between primigravidae and multigravidae. Conclusions: Failures of previous pregnancies, personal experience of coping with a child affected by a chronic condition, exposure to western culture in general, and continued positive contact with modern health services are proposed as possible underlying factors affecting uptake of prenatal tests to detect fetal anomalies.
Development of a Primary Health Care Clinical Genetic Service in Rural South Africa – The Northern Province Experience, 1990–1996
Authors: Christianson A.L. , Venter P.A. , Modiba J.H. , Nelson M.M.
Published: April 2003

The development of medical genetic services is not considered a priority in developing nations. However, many such countries are presently undergoing an epidemiological transition resulting in genetic disorders and birth defects becoming conditions that are attaining public health significance. South Africa is one such country. This paper documents the development, patient profile and experience gained in trying to establish a primary health care genetic/disability service in the country’s rural Northern Province.
Periconceptional Care: An Experiment in Community Genetics
Authors: Czeizel Andrew E.
Published: April 2003

Periconceptional care was established in 1984 in Hungary and was expanded to a national network in 1989. Periconceptional care consisting of counseling, examinations and medical interventions for voluntary and eligible couples based on three steps: check-up of reproductive health (i.e. preconceptional screening), a 3-month preparation for conception, and best possible protection in early pregnancy for the most sensitive early development of the embryo. Periconceptional care is provided and/or supervised by qualified nurses. This care helps participants with a positive family history, case history, a genitourinary infection or infertility to have a more effective access to secondary care. Periconceptional care is optimal for introducing periconceptional folic acid/multivitamin supplementation and for reducing smoking and alcohol consumption in females prior to conception. The rate of major congenital abnormalities in the children of couples attending for periconceptional care (20.6/1,000) was significantly lower than expected (about 40/1,000) during the study period. Periconceptional care also provides an opportunity for the primary prevention of common complex diseases, e.g. coronary artery disorders; it may be called a ‘euphenic’ model. In conclusion, periconceptional care is feasible and has many benefits, because proper preparation for conception is the earliest and probably the most important approach for health promotion and for the prevention of congenital abnormalities.
From Community Genetics to Community Genomics: The Quebec Experience
Authors: Gaudet Daniel , Hudson Thomas J. , Laberge Claude
Published: April 2003

Optimal health care delivery requires an understanding of genetic diversity and its associated risks. Population genomics is a rapidly emerging field that will yield such knowledge. As we are entering the genomic era, the need to develop policies and strategies integrating genetic determinants of health into medical services, health promotion and disease prevention is becoming increasingly important, perhaps inevitable. To this end, the Quebec Network of Applied Genetic Medicine (RMGA) supports a multidisciplinary and integrative research strategy which combines Quebec’s expertise in population and community genetics. The present article briefly describes two projects developed with a view to foster such strategy. The ECOGENE-21 project is designed to develop and evaluate resources and strategies for integrating and transferring new knowledge of the human genome to individuals, families and communities. ECOGENE-21 will be capitalizing on another project called CART@GENE, which is generating a combined genetic and demographic map containing information on allelic variation in the subpopulations of Quebec. These two projects are complementary and will be integrated with the ultimate goal of transferring knowledge gained from basic research, to promote health improvement and disease prevention.
Genetic Technologies and Courts of Law
Authors: Zweig Franklin M. , Davis Andre M.
Published: April 2003

Human genetic testing, and its next logical technological plateau, gene therapy, are largely unregulated in the United States and much of the world. Since the basic science and some of the technological know-how related to such tests and therapeutic regimes cross national boundaries, the disputes that follow in the wake of popular response to such technological advances could arise in virtually any court in the world. For much of the post-industrial world, this pits the unfettered processes of medical decision-making against standards of the rule of law enforced by independent courts of law. For a substantial portion of the developing world, courts are not independent and the rule of law is precariously standardized. There the proponents of unbounded genetic test development and experimentation have greatest opportunities for mischief that can create civil, criminal and military strife. In this paper we propose and discuss methods to forecast case scenarios. We will emphasize the globalization of civil and criminal conflicts that may be spurred by the use of genetic testing. Extra-judicial dispute resolution is likely to fail in the case of genetic tests. We finally propose an international means of judicial discourse that has potential to bring objectivity and even-handedness to the just resolution of issues spurred by genetic testing and engineered evolution.
The Integration of Genomics into Public Health Research, Policy and Practice in the United States
Authors: Beskow Laura M. , Khoury Muin J. , Baker Timothy G. , Thrasher James F.
Published: April 2003

Objectives: To examine the opportunities for and responsibilities of the public health community in bridging the gap between gene discovery and the application of genetic information to improve health and prevent disease. Methods: We developed genetics-related definitions for the core functions and essential services of public health. We combined these definitions with a visual model to create one possible ‘blueprint’ for integrating genomics into public health activities. Results: The proposed blueprint and accompanying examples illustrate the important role for genomics throughout public health research, policy and practice. Further refinement and implementation of this blueprint represents an ambitious public health leadership agenda. Conclusions: Opportunities for immediate action include strategic planning for the integration of genomics across programs, developing genomics competencies among health professionals, enhancing surveillance and epidemiologic capacity to aid evidence-based policy making, building partnerships and seeking input from stakeholders and incorporating information about genomics into health communications.
Disease Knowledge and Attitudes toward Predictive Testing and Prenatal Diagnosis in Families with Machado-Joseph Disease from the Azores Islands (Portugal)
Authors: Lima M. , Kay T. , Vasconcelos J. , Mota-Vieira L. , Gonzalez C. , Peixoto A. , Abade A. , MacLeod P. , Graça R. , Santos J.
Published: April 2003

Objective: Machado-Joseph disease (MJD) reaches its highest prevalence world-wide in the Azores, thus constituting a public health problem in these islands. The aim of the study was thus to (1) determine the level of knowledge about the disease; (2) estimate the expected level of request for predictive testing, and (3) analyse the intentions of at-risk individuals concerning their reproductive decisions. Methods: A questionnaire on these points was distributed to 42 affected and 36 at-risk individuals. Results: As expected, the educational level of the respondents was significantly associated with the level of knowledge about the disease. The survey indicated that 83.3% of the at-risk individuals would make use of a predictive test and that 77.8% would make use of prenatal diagnosis. Of the latter, 36.1% would terminate the pregnancy if confronted with a positive result for the fetus. Conclusions: The level of knowledge about MJD in the Azorean families is considered to be fair. Although the actual behavior can prove to be different from the intentions put forward by at-risk individuals based solely on the results of this study we can estimate that the request for a predictive test would be quite high. The intentions expressed by at-risk individuals seem to indicate that the prenatal diagnosis will have an effect on their reproductive decisions. Results obtained certify the importance of implementing genetic testing for MJD in the Azores.
Global Perspectives of Familial Hypercholesterolemia
Authors: Fouchier Sigrid W. , Defesche Joep C. , Kastelein John J.P.
Published: April 2003

Familial hypercholesterolemia (FH), with a prevalence of 0.2%, is a common autosomal dominant disorder of lipoprotein metabolism. The hallmark of the disease is a severely elevated total and low-density lipoprotein (LDL) cholesterol level, which predisposes to premature cardiovascular disease. The molecular basis of FH is a vast array of more than 600 mutations in the LDL receptor gene. Each country seems to have its own specific panel of LDL receptor gene mutations, but many mutations are shared by different countries, an observation which can be explained in some cases by historical or demographic conditions. The disorder is severely underdiagnosed and undertreated in many countries, while identification and treatment of patients at a young age result in a considerable health benefit. For this reason a global case-finding programme, based on family investigation and sometimes assisted by genetic testing, was established.
Development, Implementation and Evaluation of Protocols for the Management of Women and Children in South Texas Who Are at Risk for Genetic and Other Birth Disorders
Authors: Kolb Sara E. , Aguilar Maricela C. , Dinenberg Maura W. , Kaye Celia I.
Published: April 2003

Objectives: The purpose of this project was to improve genetic service provision for the unserved patients in Texas Public Health Region VIII by providing primary care providers with the skills necessary to participate in the comprehensive care of patients at risk for genetic and other birth disorders. Methods: 1,737 patient charts were reviewed from the Maternity, Pediatric and Family Planning clinics of 14 sites, 2 Federally Qualified Community Health centers and 12 Maternal and Child Health primary care clinics. From this review, 10 high-frequency genetic risk indicators were identified. Protocols in the form of decision flow charts were developed, and primary care providers were educated about the use and reasoning for the flow of the protocols. Results: One year after protocol implementation, 1,713 new records were reviewed. Before protocol implementation, 12.6% of patients with an indicator of high risk were offered an appropriate referral. After implementation, 45.9% of patients with a high-risk indicator were offered appropriate referral (χ2  = 39.76, p < 0.0001). Conclusions: These findings suggest that the protocol format and content provide an effective and efficient method of identifying and managing patients with risk factors for genetic and other birth disorders.
Psychological Impact of Preconception Counseling: Assessment of Anxiety before and during Pregnancy
Authors: de Weerd Sabina , van der Bij Akke K. , Braspenning Jozé C.C. , Cikot Rolf J.L.M. , Braat Didi D.M. , Steegers Eric A.P.
Published: April 2003

Objective: Assessment of anxiety levels in women and men before and after preconception counseling and during the first trimester of pregnancy. Methods: Couples were recruited from the fertility clinic of the University Medical Center Nijmegen, the Netherlands. Anxiety was assessed using the 40-item Spielberger State-Trait Anxiety Inventory (STAI). Results: 53 women and 51 men (74%) completed the STAI both before and after counseling. Anxiety levels did not change significantly after counseling or during the first trimester of pregnancy. 83.4% would recommend preconception counseling to others. Conclusion: Preconception counseling is valued by the majority of women and men and does not lead to adverse psychological effects.