bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Aberrations of NAT2 and Chromosome 8: Their Association with Progression in Transitional Cell Carcinoma of the Urinary Bladder
Authors: Watters A.D. , Stacey M.W. , Going J.J. , Grigor K.M. , Cooke T.G. , Sim E. , Bartlett J.M.S.
Published: April 2003

Introduction/Objective: N-acetyltransferase 2 (NAT2), mapped to 8p22, is a polymorphic enzyme which metabolizes aromatic amines. Loss of heterozygosity of 8p22 is associated with an increased risk of bladder cancer. This study evaluated NAT2 and chromosome 8 in sequential tumours from bladder cancer patients to determine if NAT2 alterations increase the risk of progression. Materials and Methods: Thirty-seven sequential carcinomas from 19 patients were assessed using fluorescence in situ hybridization. Results: Five carcinomas showed loss of NAT2; 4 of these were from pTa/pT1 tumours. Polysomy 8 was observed in 4 of 14 (29%) primary carcinomas (pTa/pT1), in 4 of 12 (33%) pTa/pT1 recurrences, and in 90% (9/10) of the detrusor muscle invasive tumours (pT2+). 6 of 8 (75%) locally invasive tumours with polysomy 8 were from patients who subsequently developed disease progression (pT2+). In total, 13.5% (5/37) of the carcinomas were abnormal for NAT2, and 46% (17/37) were abnormal for chromosome 8 copy number. Polysomy 8 was associated with high grade (p = 0.01) and stage (p = 0.03) and disease progression (p = 0.03). Conclusion: Whilst there does not appear to be an association between loss of NAT2 and risk of progression in transitional cell carcinoma, the high rate of polysomy of chromosome 8 implies that other genes on this chromosome significantly influence disease progression.
Venous Pressure Dynamics of the Healthy Human Leg
Authors: Kügler Christian , Strunk Martin , Rudofsky Gottfried
Published: April 2003

The delicate interplay between the muscle-joint unit and intact venous valves is mandatory for normal venous blood return from the human leg. We have investigated the potential role of (1) muscle activity and joint mobility, and (2) anthropometric factors for peripheral venous pressure physiology. 20 healthy young subjects (10 males, 10 females; mean age: 25.6 ± 3.1 years) underwent direct venous blood pressure measurements during walking on a treadmill in 12 experimental conditions (duration, 1 min each): these resulted from a combination of two different walking velocities, two different degrees of ascent, and three different walking conditions. Anthropometric parameters (e.g., body height, weight and calf circumference) were also measured in all subjects. Outcome measures were the pressures (mm Hg) during quiet standing (resting pressure, P₀), the maximal activity-induced pressure reduction (ΔPmax), i.e., the difference between the resting pressure (P₀) and minimal pressure during exercise (Pmin), the times (s) to minimal pressure during exercise (TPmin) and to half-maximal recovery of P₀ after exercise (Tmax1/2). We found that the maximal venous pressure reduction (ΔPmax) during walking increased at the higher walking speed and decreased with restricted joint mobility (p = 0.0001). Taller and heavier subjects, or subjects with a greater calf circumference had higher P₀ (p = 0.0001), showed greater ΔPmax (p < 0.010), and took longer to achieve minimal pressure during exercise (TPmin; p < 0.010) than their corresponding counterparts. Females had lower levels of P₀ (p = 0.0001), but not of ΔPmax, and shorter TPmin (p = 0.0076) than males. These gender effects largely result from differences in body height, weight, and calf circumference (p = 0.0001 for the appropriate ANOVA interaction terms). We conclude that during walking, a higher degree of muscle activity and a greater muscle mass enhance venous emptying of the healthy human leg. Conversely, impairments of joint mobility reduce the efficacy of the muscle-vein pump. Moreover, body height and weight significantly influence venous pressure physiology under both resting and activity-related conditions. These anthropometric factors also largely explain sex differences in peripheral venous hemodynamics.
Circulating Bone Marrow Cells Can Contribute to Neointimal Formation
Authors: Han Chih-lu , Campbell Gordon R. , Campbell Julie H.
Published: April 2003

To examine the source of smooth muscle-like cells during vascular healing, C57BL/6 (Ly 5.2) female mice underwent whole body irradiation followed by transfusion with 106 nucleated bone marrow cells from congenic (Ly 5.1) male donors. Successful repopulation (88.4 ± 4.9%) by donor marrow was demonstrated in the female mice by flow cytometry with FITC-conjugated A20.1/Ly 5.1 monoclonal antibody after 4 weeks. The arteries of the female mice were then subjected to two types of insult: (1) The iliac artery was scratch-injured by 5 passes of a probe causing severe medial damage. After 4 weeks, the arterial lumen was obliterated by a cell-rich neointima, with cells containing α smooth muscle actin present around the residual lumen. Approximately half of these cells were of male donor origin, as evidenced by in situ hybridization with a Y-chromosome-specific probe. (2) In an organized arterial thrombus formed by inserting an 8-0 silk suture into the left common carotid artery, donor cells staining with α smooth muscle actin were found in those arteries sustaining serious damage but not in arteries with minimal damage. Our results suggest that bone marrow-derived cells are recruited in vascular healing as a complementary source of smooth muscle-like cells when the media is severely damaged and few resident smooth muscle cells are available to effect repair.
Possible Cytotoxic Effect of the Expression of a Connexin 43-LacZ Fusion Gene in Cells of the Vascular Wall
Authors: Liao Y. , Duling B.R.
Published: April 2003

Connexin 43 (Cx43) gap junctions are hypothesized to play a key role in many aspects of vascular function. In an effort to evaluate the importance of connexins in vascular function we took advantage of the fact that a Cx43-LacZ fusion protein has been reported to effectively reduce dye transfer in NIH 3T3 fibroblasts by acting as a dominant negative construct. We explored the use of this dominant negative construct in cultured vascular smooth muscle (VSM) cells and in transgenic mice. We examined the viability of cultured VSM cells expressing the Cx43-LacZ fusion protein under the control of a cytomegalovirus promoter. We also selectively expressed the dominant negative construct in the endothelial cells of transgenic mice under the control of a Tie 2 promoter. Transient transfection of cultured VSM cells led to good initial expression of the Cx43-LacZ fusion protein as evidenced by X-gal staining. Following 10 days of G418 selection, 300 cell clones were examined. None expressed the fusion protein, based on X-gal staining and Western blot analysis, but all contained the transgene, based on PCR analysis. The fusion protein was expressed in a few isolated cells, suggesting that cell division was inhibited by the fusion protein. In agreement with this finding was the fact that expression of the Cx43-LacZ fusion protein was not observed in any of seven Tie 2-Cx43-LacZ transgenic mouse lines. Moreover, a very low yield of mice carrying the transgene was observed (7/136; 5.1%). Analysis of 65 embryos at embryonic day 11.5 showed similar results. These data strongly suggest that the expression of the Cx43-LacZ fusion protein prevents the formation of both stable clones and transgenic animals. This may be due to a cytotoxic effect of the dominant negative construct or to the fact that successful cell propagation is not possible if gap junctional transmission is completely blocked.
Alterations in Reactivity of Small Arterioles in Rat Skeletal Muscle as a Result of Chronic Ischaemia
Authors: Kelsall C.J. , Brown M.D. , Hudlicka O.
Published: April 2003

In a model of chronic hind limb ischaemia, we examined whether impaired muscle blood flow, particularly during exercise, is partly due to modification of the reactivity of skeletal muscle resistance vessels by prolonged low blood flow. Two or 5 weeks after unilateral iliac artery ligation, terminal (A4) and preterminal (A3) arterioles of extensor digitorum longus muscle were viewed by intravital microscopy using epi-illumination, and diameter changes to topical application of endothelium-dependent (bradykinin, acetylcholine) and endothelium-independent (adenosine, sodium nitroprusside and noradrenaline) agonists measured. Chronic ischaemia had no effect on resting diameters of A3 or A4 vessels. Two weeks after ligation, dilation to bradykinin was attenuated by 75% for A3 and 50% for A4 arterioles (p < 0.01 vs. control) and responses to acetylcholine were reversed from dilation to constriction (A3: control diameter change +29%, 2-week-ligated –17%; A4: control 18%, 2-week-ligated –13%). Five weeks after ligation, these effects were still apparent and, additionally, dilation to adenosine and sodium nitroprusside and constriction to noradrenaline were reduced. Thus, impaired dilation, most likely due to endothelial dysfunction, is an early manifestation of altered reactivity in the microcirculation of chronically ischaemic muscles, with functional impairment of vascular smooth muscle as a later consequence. These changes occurred despite modest improvements in muscle blood flow and perfusion pressure over the same time. These changes will act to the detriment of blood flow in contracting muscles and could limit the outcome of interventions to restore flow such as angioplasty or surgical bypass.
Nonvasomotor Influence of Sodium Nitroprusside on Arteriolar Remote Response to Methacholine
Authors: Chen Yifan , Rivers Richard J.
Published: April 2003

Vascular communication functions to facilitate blood distribution within tissues and can be demonstrated as conducted vasomotor responses. This study was designed to determine if local application of sodium nitroprusside (SNP) would affect arteriolar function at remote sites. In the cheek pouch of anesthetized hamsters, local application of SNP and nifedipine caused arteriolar dilation only at the site of application (7.1 ± 0.5 and 7.4 ± 0.6 µm), but not at remote sites. The application of SNP enhanced subsequent remote, nitric oxide (NO)-independent dilation in response to methacholine, which was applied at a site upstream from the SNP application site (6.7 ± 0.7 versus 4.5 ± 0.7 µm for methacholine alone). This potentiating effect was also observed following application of 3-morpholinosydnonimine, but not following nifedipine. This nonvasomotor influence of SNP was not affected by Nω-nitro-L-arginine (L-NA), tetrodotoxin (TTX), Gap 27 peptide or halothane. Attenuated local dilation in response to methacholine by L-NA could be partially recovered following downstream application of SNP, suggesting that SNP-induced potentiation was associated with enhanced vasodilatory signals at the methacholine application site. Thus, our results suggest that SNP induces nonvasomotor signals in arterioles to affect the network distribution of blood flow. Intrinsic NO, TTX-sensitive Na+ channels and gap junctional communication do not seem to play a major role in the conduction of the nonvasomotor signals.
A Common Phenotype Associated with Atherogenesis in Diverse Mouse Models of Vascular Lipid Lesions
Authors: Reckless Jill , Rubin Edward M. , Verstuyft Judy B. , Metcalfe James C. , Grainger David J.
Published: April 2003

The introduction of a range of different genetic modifications in mice results in altered lipoprotein metabolism and the development of vascular lipid lesions. At present, however, it is unclear to what extent the molecular events underlying lipid lesion formation are similar in these different mouse models of atherosclerosis. The aim of this study was to compare the protein expression pattern of lipid lesions from seven different mouse lines with varying susceptibility to vascular lipid lesion development, to determine to what extent lesions induced by different genetic interventions have a similar composition. The proteins we have measured, using quantitative immunofluorescence, are proteins whose expression is known to be modulated during atherogenesis in humans, including plasminogen activator inhibitor (PAI)-1, transforming growth factor (TGF)-β1, osteopontin and the macrophage marker CD11b. In all the mice lines we have investigated, PAI-1 was elevated wherever lesions developed. Active TGF-β was depressed in the vessel wall of mice which developed lipid lesions, particularly in the intima. In contrast, TGF-β1 antigen (active plus latent TGF-β1) was increased at lesion sites. Accumulation of osteopontin and, with the marked exception of apolipoprotein(a) transgenic mice, tissue macrophages occurred at sites of lipid deposition in the vessel wall. Each lesion, irrespective of its size and the mouse strain in which it developed, had similar amounts of PAI-1, active TGF-β and osteopontin per unit area of lesion. These data are consistent with a common phenotype accompanying atherogenesis, irrespective of the genetic basis of susceptibility.
P2X Receptor Immunoreactivity in Different Arteries from the Femoral, Pulmonary, Cerebral, Coronary and Renal Circulations
Authors: Lewis C.J. , Evans R.J.
Published: April 2003

The expression of the seven P2X receptor subunits (P2X1–7) in the rat vascular system was determined using subtype-selective antibodies. Arteries of different sizes (from arterioles to conduit vessels) from a range of vascular beds were used to give an overview of receptor expression. P2X1 receptor immunoreactivity was detected in the smooth muscle layer of arteries. The relative level of P2X1 receptor immunoreactivity was dependent on the size of the artery and the vascular bed; expression was highest in small and medium arteries. P2X4 receptors were detected in all arteries; once again, the relative level of expression was dependent on the size of the artery and the vascular bed. P2X5 receptor immunoreactivity was barely detectable in most arteries studied. P2X7 receptor immunoreactivity was generally punctate and associated with the outer adventitial layer. Immunoreactivity for P2X2, P2X3 and P2X6 receptors was not detected in arteries. These results demonstrate that arteries express multiple P2X receptor subunits and that there is a heterogeneity in the level of expression. The properties of artery P2X receptors correspond to homomeric P2X1 receptors, and the function of P2X4 and P2X5 receptor subunits in arteries is unclear.
Downregulation of Angiotensin-Converting Enzyme by Tumor Necrosis Factor-α and Interleukin-1β in Cultured Human Endothelial Cells
Authors: Saijonmaa Outi , Nyman Tuulikki , Fyhrquist Frej
Published: April 2003

Angiotensin-converting enzyme (ACE) and cytokines are considered to play an important role in the pathophysiology of cardiovascular diseases such as atherosclerosis. In the present study, the effects of the cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) on ACE in cultured human umbilical vein endothelial cells (HUVECs) was studied. TNF-α (0.1–10 ng/ml) and IL-1β (0.1–10 ng/ml) caused a dose- and time-dependent decrease in the amount of ACE in intact endothelial cell membranes and decreased levels of ACE mRNA. TNF-α and IL-1β activated p44/42 and p38 mitogen-activated protein kinases (MAPKs) in HUVECs; this was inhibited by the specific inhibitors of these kinases, PD98059 and SB202190, respectively. Pretreatment of endothelial cells with the specific p38 MAPK inhibitor SB202190 (5 µM) or hydrocortisone (5 µM) partly reversed the suppression of ACE by TNF-α or IL-1β, whereas the specific p44/42 MAPK inhibitor PD98059 (40 µM) was without effect. Vascular endothelial growth factor (1 ng/ml) caused an increase in membrane-bound ACE and ACE mRNA levels which was inhibited by pretreatment of the cells with TNF-α (1 ng/ml) or IL-1β (1 ng/ml). In summary, the cytokines TNF-α and IL-1β downregulated ACE in cultured human endothelial cells, which effect was probably mediated by the p38 MAPK pathway. Downregulation of ACE by TNF-α and IL-1β locally in the vascular wall may be a counterbalancing mechanism in inflammatory processes such as atherosclerosis, leading to decreased production of angiotensin II and accumulation of bradykinin.
The β3 Integrin Antagonist m7E3 Reduces Matrix Metalloproteinase Activity and Smooth Muscle Cell Migration
Authors: Bendeck Michelle P. , Nakada Marian T.
Published: April 2003

Treatment with c7E3 (abciximab, ReoPro) has been associated with a reduction in coronary events and the need for revascularization. Some of these beneficial effects may be due to blockade of the αvβ3 integrin receptor on smooth muscle cells (SMCs), however very little is known about the mechanisms involved. The current studies were designed to test the hypothesis that β3 integrin antagonists inhibit the arterial response to injury by reducing matrix metalloproteinase (MMP) activity in the vessel wall. Male Sprague-Dawley rats were treated with daily intraperitoneal injections of the monoclonal antibody m7E3 at a dose of 6 mg/kg/day. MMP-9 activity was reduced by 73%, and MMP-2 activity by 75%, in the injured carotids of the m7E3-treated rats compared to saline-treated controls. By contrast, tissue inhibitor metalloproteinase (TIMP) activity was not changed. SMC migration assayed at 4 days after injury was reduced from 56.7 ± 14 cells/mm2 intimal surface area in controls to 17.5 ± 5 cells/mm2 in m7E3-treated rats (p = 0.02). Medial cell replication measured at 4 days and intimal cell replication measured at 7 days were not affected. Intimal cross-sectional area, measured 14 days after injury was reduced by 28% after m7E3 treatment (p = 0.05). Intimal smooth muscle cell number and the ratio of intima/media cross-section area were also reduced. By contrast, intimal SMC density was not affected by m7E3 treatment, indicating no effect on matrix accumulation. We conclude that treatment with m7E3 reduced SMC migration following vascular injury, possibly via an inhibitory effect on MMP activity, and this resulted in a decrease in intimal size at 14 days after injury.
Prenatal Screening for Aneuploidies by Quantitative Fluorescent Polymerase Chain Reaction
Authors: Adinolfi Matteo , Sherlock Jon , Cirigliano Vincenzo , Pertl Barbara
Published: April 2003

Chromosome-specific DNA small tandem repeats (STRs), amplified by quantitative fluorescent polymerase chain reactions, have been successfully employed for the rapid prenatal detection of human major numeric aneuploidies. These assays – which can be performed in a few hours – can be used either as preliminary investigations aimed at relieving the anxiety of parents waiting for the results of conventional cytogenetic analysis or as prenatal diagnostic tests on samples retrieved from mothers at high risk of having an affected fetus according to previous biochemical or ultrasound tests. Here we discuss the possibility of performing prenatal diagnosis with this method as the only approach to detect numerical disorders affecting chromosomes 21,18,13,X and Y in populations where the use of conventional cytogenetic tests is hampered by technical and economical difficulties. The advantages of the quantitative fluorescent tests are that they are accurate, relatively economic and that a single operator can perform up to 40–50 prenatal diagnoses per day. Furthermore, chromosome-specific STRs, as well as primers for the detection of single gene defects, can be included in a multiplex assay. The tests can be carried out also on a very small number of amniotic or chorionic cells.
HUGO Urges Genetic Benefit-Sharing
Authors: Knoppers Bartha Maria , Chadwick Ruth , Takebe Hiraku , Berg Kare , Cantu Jose Maria , Daar Abdallah S. , Engels Eva Marie , Kirby Michael , Macer Darryl , Murray Thomas H. , Qiu Ren-Zong , Verma Ishwar C. , Wertz Dorothy C.
Published: April 2003

In view of the fact that for-profit enterprise exceeds public expenditures on genetic research and that benefits from the Human Genome Project may accrue only to rich people in rich nations, the HUGO Ethics Committee discussed the necessity of benefit-sharing. Discussions involved case examples ranging from single-gene to multifactorial disorders and included the difficulties of defining community, especially when multifactorial diseases are involved. The Committee discussed arguments for benefit-sharing, including common heritage, the genome as a common resource, and three types of justice: compensatory, procedural, and distributive. The Committee also discussed the importance of community participation in defining benefit, agreed that companies involved in health have special obligations beyond paying taxes, and recommended they devote 1–3% of net profits to healthcare infrastructure or humanitarian efforts.
Implications of Medical Genetic Testing for Coronary Heart Disease in the Community
Authors: Tonstad Serena
Published: April 2003

Coronary heart disease (CHD) is a multifactorial complex disease that only rarely can be attributed to genetically defined conditions. Several models in the literature, including DNA testing for familial hypercholesterolemia, testing for CHD risk factors in blood relatives of patients with premature CHD and mass screening, then taking a second look at individuals who report a positive family history of CHD provide data on potential benefits and pitfalls of medical genetic testing. Consequences of testing for the individual may include stigmatization, premature start of drug treatment or too low estimation of risk, if a complete evaluation of CHD risk factors is not done. Contacting relatives involves loss of privacy. Affected relatives usually carry a lower risk than the index patient because of selection bias. Among young family members, many years of follow-up may be required. Considerations for the community include the need to resolve the legal and ethical implications of testing, its cost-effectiveness, the choice of screening tests and follow-up methods and how to achieve high attendance rates.
Method and Complexity in Bioethics: The Example of Community Genetics
Authors: Cleret de Langavant Ghislaine
Published: April 2003

This article describes the need to develop a new methodology in bioethics that can consider multiple interactions, creativity and the organisation specific to complex systems. Community genetics is taken as an example of complexity in bioethics. Community genetics involves large populations and illustrates certain characteristics of complex adaptive systems which are discussed in the article.
Community Genetics in Eastern Québec: The Experience of the Corporation for Research and Action on Hereditary Diseases
Authors: Vigneault Anne , Brisson Diane , Bélanger Céline , Gaudet Daniel
Published: April 2003

In the Saguenay-Lac St. Jean (SLSJ) region of Quebec, the high prevalence of some hereditary diseases has led concerned community members to create the Corporation for Research and Action on Hereditary Diseases (CORAMH) to take an active part in seeking and providing answers to this important health issue. CORAMH performs an important and unique role in the reciprocal transfer of information between community and researchers, as well as in the promotion and development of specialized services and research. It also provides a meeting ground for dialogue and dissemination of information. In particular, since 1983, CORAMH has been offering a Hereditary Disease Information and Prevention Program, mainly to SLSJ high-school clientele to convey basic genetic notions and provide information on specific hereditary diseases and on genetic determinants of health. By rallying various actors around a common table, CORAMH has come to be viewed as a community representative and can thus conduct effective mediations with decisional authorities for the development of proper health services. CORAMH also participates in reflection and research projects, such as ECOGENE-21, that aim to develop exportable infrastructures in preventive and community genetics and vanguard scientific, medical, ethical and social approaches capable of improving the population’s quality of life. CORAMH offers an intervention model that can be applied to specific hereditary disorders or complex diseases and serve other communities which will be requiring interventions on the genetic determinants of health in the upcoming decades.
Retaining the Confidence of the Public in Molecular Genetic Testing – Quality Assurance
Authors: Patton Simon , Barton David , Elles Rob
Published: April 2003

The introduction of molecular genetic techniques to clinical laboratories opens the possibility of public access to a wide range of tests for many different genetic disorders. This new diagnostic area is still in a transition phase from research to service. Mechanisms for ensuring the quality of genetic testing are not yet in place but need to be developed with some urgency to retain public confidence. External quality assessment (EQA), or proficiency testing, is an independent check on a laboratory’s performance. This paper describes EQA pilot schemes and guidelines for ‘best practice’ developed in Europe and some of the problems involved in introducing quality assurance measures to service providers so that these measures are sustainable. The introduction of accreditation may provide a means of sustaining these systems. Reasons to encourage an international approach to EQA and harmonisation and mutual recognition of national and regional EQA schemes are also discussed.
Benefits and Costs of Genetic Screening for Breast Cancer
Authors: Grann Victor R. , Jacobson Judith S.
Published: April 2003

Genetic testing for breast cancer will soon become widely available, but the principles for evaluating its benefits and costs, from a policy perspective, have not been described. The benefits and costs of screening for breast cancer depend on the following factors: prevalence and penetrance, the mortality associated with the disease, age at testing, and the potential effects of preventive measures on risk of developing the disease, quality of life, and costs. In this paper, the epidemiological principles that describe the relationship of testing to survival, quality-adjusted survival, and cost-effectiveness are presented and illustrated by examples drawn from decision analyses of genetic testing for breast cancer. Conclusions indicate that all the aforementioned factors may affect the health outcomes with which public policy is concerned and should be considered when evaluating genetic tests.
From Gene-Specific Tests to Pharmacogenetics
Authors: Middleton L. , Freeman A. , Brewster S. , Foster C. , Roses A.
Published: April 2003

Over the next 3–5 years pharmacogenetics will provide opportunities to enhance the efficacy and tolerability of medicines, accelerated by the ongoing rapid development of a high-density map of single-nucleotide polymorphisms (SNP) and of high-throughput SNP scoring technologies. It is important that this application of genetic technology is clearly differentiated from genetic tests for monogenic and complex diseases, which are associated with a number of ethical, legal and social implications. The ethical, legal and social issues associated with pharmacogenetics need to be identified and clearly differentiated from those associated with gene-specific tests for disease.
Current Challenges to Appropriate Clinical Use of New Genetic Knowledge in Different Countries
Authors: Baird Patricia A.
Published: April 2003

Objective: To describe the challenges facing countries all over the world regarding the appropriate clinical use of genetics in their health care systems. Methods and Results: Aspects of the economic and social contexts in different countries which are of particular relevance to shaping the existing challenges are outlined. Issues which are relevant (but of different prominence) in all countries in providing genetic services are discussed. Conclusions: The challenges facing the provision of appropriate genetic services differ markedly in four major groups of countries. These challenges range from controlling inappropriate commercialization and the overuse of genetic approaches to putting in place even minimal basic community genetics services in countries where the infant mortality rate has fallen to a range where genetic and congenital disorders contribute substantially to ongoing handicap and early mortality.
The Tyr978X BRCA1 Mutation in Non-Ashkenazi Jews: Occurrence in High-Risk Families, General Population and Unselected Ovarian Cancer Patients
Authors: Shiri-Sverdlov Ronit , Gershoni-Baruch Ruth , Ichezkel-Hirsch Galit , Gotlieb Walter H. , Bruchim Bar-Sade Revital , Chetrit Angela , Rizel Shulamith , Modan Baruch , Friedman Eitan
Published: April 2003

Background: In Jewish individuals of Ashkenazi (East European) decent, three predominant mutations, 185 delAG and 5382insC (BRCA1) and 6174delT (BRCA2), seem to account for a substantial portion of germline mutations in high-risk breast/ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG and the Tyr978X mutations, as well as several ‘private’ mutations have been reported within the BRCA1 gene. Objective: Assessing the occurrence rate of the Tyr978X BRCA1 germline mutation in Jewish non-Ashkenazi individuals: high-risk familial cases, unselected ovarian cancer patients and the general average risk Jewish Iraqi population. In addition, finding proof that this is a founder mutation. Methods: PCR amplification of the relevant fragment of the BRCA1 gene from constitutional DNA followed by restriction enzyme digest that differentiates the wild type from the mutant allele. In addition, BRCA1-linked markers were used for haplotype analysis. Results: The Tyr978X BRCA1 mutation was detected in 3/289 (1%) of the average-risk Jewish Iraqi population, in 7/408 (1.7%) high-risk Jewish non-Ashkenazi individuals (representing 332 unrelated families) and in 1/81 (1.2%) of unselected Jewish non-Ashkenazi ovarian cancer patients. Allelotyping using BRCA1-linked markers revealed an identical allelic pattern in all mutation carriers with the intragenic markers. Conclusions: Our findings suggest that this mutation is prevalent in Iraqi Jews, represents a founder mutation, and should be incorporated into the panel of mutations analyzed in high-risk families of the appropriate ethnic background.
The Role of Family History in Personal Prevention Practices among US Women Physicians
Authors: Saraiya Mona , Coughlin Steven S. , Burke Wylie , Elon Lisa K. , Frank Erica
Published: April 2003

Objective: To document the role of physicians’ family history of cancer in terms of personal use of cancer preventive services and in recommending that patients receive such services. Methods: We examined the Women Physicians’ Health Study, a questionnaire-based study of a representative sample of 4,501 female physicians in the United States. Results: Among the physicians surveyed, 38.9% (95% confidence interval 37.1–40.7) reported a family history of cancer. A physician’s self-reported family history of a specific cancer was positively associated with the physician having had a more recent screening exam for that cancer. Family history of any cancer was positively associated with older age, white race, recent sigmoidoscopy, recent mammogram, digital rectal exam, a blood stool test, history of cigarette smoking and history of recent alcohol use. Physicians’ family histories did not significantly influence the reported frequency of recommendations of screening services for their patients. Conclusions: The observed association between a positive physician family history and personal cancer prevention practices suggests that physicians are receptive to the concept of a positive family history of cancer as a risk factor for cancer. This could present an educational opportunity for physicians to emphasize the importance of cancer family history in patients, particularly with respect to underutilized services such as screening for colorectal cancer.
Clinical Etiological Survey of a Population of 471 Mentally Retarded Patients Living in an Institution in the Southern Part of the Netherlands
Authors: van Buggenhout G.J.C.M. , Trommelen J.C.M. , Brunner H.G. , Hamel B.C.J. , Fryns J.-P.
Published: April 2003

Objective: Investigation of etiological factors in mental retardation (MR). Methods: On 471 adults (mean age 46 years; 92.6% males) living in an institution for the mentally retarded, clinical examination, cytogenetic and molecular studies and basic metabolic screening were performed. Results: Chromosomal abnormalities were found in 100 patients (21.2%). Of these, 87 had numerical autosomal abnormalities (all Down syndrome), 7 structural autosomal abnormalities and 6 numerical abnormalities of sex chromosomes. Monogenic disorders were diagnosed in 61 patients (13%): 14 autosomal dominant, 25 autosomal recessive and 22 X-linked conditions. In 1.7% (n = 8) of the patients a central nervous system (CNS) malformation was documented. Acquired CNS disorders were diagnosed in 69 patients (14.6%): a prenatal cause was found in 15 patients, a perinatal in 27 and a postnatal cause in 27. In 233 patients (49.5% of the total sample; 215 males and 18 females) idiopathic MR was present. In this group there were 2 patients with a high degree of consanguinity (incest). In one third (n = 73; 31.3%) of these patients there was a family history of MR (MR in first and second-degree relatives). Pedigree data were most compatible with X-linked MR in 35 males from 32 different families, i.e. 47.9% of the patients with idiopathic MR and family history of MR, and 15% of the total group of patients with idiopathic MR. Thus, X-linked inheritance was considered in a total group of 57 males, accounting for 12.1% of the total population: known X-linked disorders in 22 males and non-specific X-linked MR in 35 males. Minor anomalies were present in 41 patients (17.6%). Their presence was significantly associated with the severity of the MR. Neurological abnormalities were present in 47 patients (20.2%), with CNS dysfunction (central paresis, dyskinesia, ataxia) in 45 (19.3%). Seizures were present in one third of the patients (n = 78) and a statistically significant correlation between the level of MR and the presence of seizures was found. In the group of males with idiopathic MR, the number of males with the combination of microcephaly and micro-orchidism was higher than expected, but not statistically significant and the number of males with the combination of macrocephaly and macro-orchidism was statistically significantly increased (n = 5; 2.3%). Before systematic evaluation, only 21.8% (103/471) of the patients had a known diagnosis. After this survey, 50.5% (238/471) of the investigated patients had a definite diagnosis. Conclusion: Establishing the diagnosis in older mentally retarded patients is important in the prevention of medical complications and in the development of management strategies for the institution. Finally, it is the conditio sine qua non for genetic counseling of the respective families.
Distribution of Two X-Linked Trinucleotide Polymorphisms in Greece
Authors: Syrrou Maria , Yapijakis Christos , Bouba Ioanna , Adamidis Konstantinos , Vassilipoulos Dimitris , Georgiou Ioannis
Published: April 2003

Objective: To determine the distribution of allele frequencies of two X-linked trinucleotide repeat polymorphisms in five major geographic areas of Greece. Methods: We have studied the distribution of the CGG repeat in the FMR-1 gene and of the CAG repeat in the androgen receptor (AR) gene in 194 and 175 unrelated blood donors, respectively. Results: The distribution of (CGG)n was not significantly different between the four main areas of the Hellenic peninsula, with the exception of an island area in southern Greece, while the distribution of (CAG)n was similar among the groups. The mean repeat number in the FMR-1 gene is 30 and the mean in the AR gene is 21. Conclusions: The Hellenic population is rather homogeneous regarding the X-linked polymorphisms studied.
Blood Pressure and Risk of Dementia: Results from the Rotterdam Study and the Gothenburg H-70 Study
Authors: Ruitenberg Annemieke , Skoog Ingmar , Ott Alewijn , Aevarsson Olafur , Witteman Jaqueline C.M. , Lernfelt Bodil , van Harskamp Frans , Hofman Albert , Breteler Monique M.B.
Published: April 2003

The association between blood pressure and dementia is debated. Results from population-based studies on blood pressure and dementia are inconclusive, and most are performed in subjects younger than 80 years of age. We examined the relation between blood pressure and dementia and the possible effect modification of this relation by age in a pooled dataset based on two prospective population-based studies. Subjects came from the Rotterdam study (n = 6,668), a longitudinal population-based study among subjects aged 55 years and over, and from the Gothenburg H-70 Study (n = 317), a study on subjects aged 85 years at baseline. Screening and diagnostic procedures for assessment of dementia were similar at baseline and follow-up and comparable between studies. We estimated relative risks of dementia using Cox proportional hazards regression analysis, adjusted for age, gender and study location. The average follow-up was 2.1 years. During this period, 196 subjects developed dementia. The risk of dementia decreased with increasing blood pressure level (per 10 mm Hg systolic blood pressure: RR = 0.93, 95% CI = 0.88–0.99; per 10 mm Hg diastolic blood pressure: RR = 0.89, 95% CI = 0.79–1.00). This association was confined to subjects who used anthypertensive medication. Persons who were demented at baseline had a stronger blood pressure decline during follow-up than those who were non-demented. This study suggests an inverse association between blood pressure and dementia risk in elderly persons on antihypertensive medication. Possibly, they may need higher blood pressure levels to maintain an adequate cerebral perfusion. Alternatively, lower blood pressure may be secondary to brain lesions in preclinical stages of dementia.
Biological Activities of Topical Retinaldehyde
Authors: Didierjean L. , Tran C. , Sorg O. , Saurat J.-H.
Published: April 2003

Background: We had hypothesised that retinaldehyde (RAL) should be an interesting precursor for topical use. Aim: We review our observations about its biological activities. Methods: We performed pilot studies to explore its biological effects and tolerability in human skin and compared the effects of topical RAL to that of all-trans-retinoic acid (RA) in the mouse tail test. Results: The biological activities of RAL were found to be qualitatively identical to that of RA: (i) induction of cellular RA-binding protein type 2 mRNA and protein, (ii) increase in epidermal proliferation (increase in DNA synthesis, epidermal thickness, induction of 50-kD keratin mRNA and reduction in 70-kD keratin mRNA), and (iii) metaplastic effects (induction of orthokeratosis, reduction of 65-kD keratin mRNA, increase in filaggrin and loricrin mRNAs). When associated with RAL, citral (known for its capacity to inhibit the oxidation of retinol to RA in epidermis) counteracted the effects induced by RAL indicating that RAL exerts biological activities through transformation to RA. Hypothesising that keratinocytes would metabolize 9-cis-RAL to 9-cis-RA, we compared the biological effects induced by topical 9-cis-RAL and found that hyperplastic and metaplastic responses were lower than those induced by all-trans-RAL or all-trans-RA at similar concentrations. This suggests that 9-cis-RAL has no advantage over all-trans-RAL for specific delivery of natural retinoids into the skin. As in clinical studies conducted in human skin, we also found topical RAL less irritant than RA. Conclusion: These studies indicate that topical RAL has biological activity and is well tolerated.
Endothelin and Other Mediators in the Pathophysiology of Portal Hypertension
Authors: Gerbes Alexander , Gülberg Veit , Bilzer Manfred
Published: April 2003

Hyperdynamic circulation as well as increased hepatic resistance contribute to portal hypertension in cirrhosis of the liver [1]. Hyperdynamic circulation with increased cardiac output, heart rate and plasma volume and decreased arterial blood pressure and systemic vasodilatation is pivotal for the hyperdynamic circulation. This has prompted intense research of a number of endogenous neurohumoral mediators with vasodilating properties (NO, natriuretic peptides, glucagon, etc.) [2, 3].
The Role of Octreotide and Somatostatin in Acute and Chronic Pancreatitis
Authors: Uhl W. , Anghelacopoulos S.E. , Friess H. , Büchler M.W.
Published: April 2003

Acute pancreatitis may follow a mild or a severe course. Whereas mild or edematous pancreatitis is a self-limiting disease with a low complication rate and low death rate, morbidity and mortality in severe or necrotizing pancreatitis are still unacceptably high. The major problem is the lack of a specific drug, especially in the early phase of the disease, to interfere with the systemic inflammatory response syndrome and to limit or prevent complications of the disease. Although the initiating pathophysiological process is not known, the destruction of the gland (‘autodigestion’) by digestive enzymes may be responsible for disease progression. Inhibition of pancreatic activity, which reduces exocrine secretion and further prevents the release and activation of enzymes, was therefore suggested as a specific treatment concept. The results of clinical investigations using somatostatin or its analogue are controversial, since all these trials had low statistical power. In a recent multicenter randomized controlled study with a large number of patients (n = 302) (and an adequate level of disease severity), no benefit of octreotide on progression or outcome was found. Chronic pancreatitis is characterized by an irreversible destruction of the exocrine and endocrine pancreatic parenchyma leading to maldigestion and diabetes. Pain, which may be caused by increased ductal pressure, is one of the most dominant symptoms in chronic pancreatitis. However, no beneficial effects on pain with pancreatic exocrine secretion-inhibiting drugs have been demonstrated. Treatment of other complications of the disease (pseudocyst formation, fistula and pancreatic ascites), with somatostatin or octreotide has given conflicting results. However, in a prophylactic clinical setting (e.g. elective pancreatic surgery) the inhibition of exocrine pancreatic secretion reduces complications.
Lipodystrophia centrifugalis abdominalis infantilis – Immunohistochemical Demonstration of an Apoptotic Process in the Degenerating Fatty Tissue
Authors: Okita H. , Ohtsuka T. , Yamakage A. , Yamazaki S.
Published: April 2003

We report a case of lipodystrophia centrifugalis abdominalis infantilis (LCAI) showing apoptosis during the lipoatrophic process by immunohistochemical staining. A 3-year-old boy was seen with a 3-month history of a centrifugally spreading depressed eruption without pain and pruritus on his abdomen. He had fever, diarrhea and vomiting for a week at the beginning of his eruption. Physical examination revealed a palm-sized well-demarcated atrophic plaque on his lower abdomen and left inguinal fold. His plaque showed fine erythema peripherally. A skin biopsy specimen showed remarkably decreased subcutaneous fatty tissue. Inflammatory cell infiltration including lymphocytes and histiocytes was noted in the degenerating fatty tissue. In the degenerating subcutaneous fatty tissue, positive staining for HLA-DR, Fas, bcl-2, p53 and transferase-mediated uridine nick end labeling in mononuclear cells were observed. He was diagnosed as having LCAI. The present case showed the possible involvement of apoptosis in the fatty tissue degeneration in LCAI.
Protective Effects of Tanning on Cutaneous DNA Damage in situ
Authors: Bykov Vladimir J. , Marcusson Jan A. , Hemminki Kari
Published: April 2003

Background: The incidence of skin cancer, the most common type of cancer in the Western world, has been shown to be associated with the degree of exposure to solar radiation. However, little is known on how human skin can be protected against UV-induced DNA damage by constitutive and induced pigmentation. Objective: To study the effect of skin pigmentation induced by a sunbed-type of treatment on the formation of UV-induced DNA damage in human skin in situ. Methods: A photoproduct assay was performed in untanned and tanned skin of healthy volunteers. Results: There is no significant difference in the induction of photoproducts between untanned and tanned skin. Conclusion: Our data demonstrate that constitutive skin pigmentation is more efficient than the induced one in protection against formation of photoproducts.
Beneficial Effects of Softened Fabrics on Atopic Skin
Authors: Hermanns Jean-François , Goffin Véronique , Arrese Jorge E. , Rodriguez Carlos , Piérard Gérald E.
Published: April 2003

There is general concern about the possible cutaneous adverse effects of wearing garments treated with household laundry products, particularly on atopic skin. Our objective was to compare softened and non- softened fabrics in a forearm wet and dry test, under conditions simulating real-life conditions. Twenty atopic volunteers entered a single-blind 12-day (3 sessions per day) forearm wetting and drying test. Cotton fabrics were machine washed and liquid fabric conditioner was added or not to the final rinse. To simulate conditions of skin damage, a dilute solution of sodium lauryl sulphate was applied under occlusion to the forearm of each volunteer before the start of the study. Skin effects were evaluated by visual grading (redness, dryness and smoothness), squamometry and in vivo instrumental measurements (capacitance, transepidermal water loss and colorimetry). Rubbing of atopic skin with fabrics generally resulted in discrete to moderate alterations of the structure of the stratum corneum. Both for control and pre-irritated skin, all measured parameters indicated that softened fabric was less aggressive to the skin than unsoftened fabric. In the case of pre-irritated skin, the recovery of the skin was significantly faster when rubbed with softened than with unsoftened fabrics. In conclusion, softened fabrics help mitigate the skin condition in atopic patients.
The Heterogeneous Clinical Spectrum of Genital Herpes
Authors: Lautenschlager Stephan , Eichmann Alfred
Published: April 2003

Background and Objective: Most data of genital herpes have been collected in STD clinics in the USA where unrecognized forms accounted for 80% of HSV-2 infections. Our aim was to study the clinical features in an outpatient clinic of dermatology. Methods: The charts of 170 patients, previously monitored prospectively for a HIV prevalence study, with culture-confirmed genital herpes or herpetic infection with HSV-2 at any other site presenting between 1995 and 1999 were analyzed. Results: 111 (65%) men and 59 (35%) women were identified with a mean age of 44 years. Only 49% had a typical cluster of genital lesions. Eighty-six (51%) presented with either lesions at extragenital sites [mostly the buttocks 33/170 (19%), thigh 10/170 (6%), anal region 9/170 (5%) and fingers 8/170 (5%)] or showed morphologically atypical forms of isolated genital lesions [single ulcer 16/170 (9%), erosion 6/170 (4%), crust 3/170 (2%) and fissure, edema or erythema each 1/170 (1%)]. Women significantly presented more often with extragenital infections of HSV-2 [36/59 (61%)] than men [18/111 (16%)]. Conclusions: More than half of the patients with genital herpes of a mainly immunocompetent population presented with atypical manifestations. The underdiagnosis of genital herpes seems largely due to misinterpretation of atypical genital and extragenital lesions.
Vasculitis Occurring during Leflunomide Therapy
Authors: Holm E.A. , Balslev E. , Jemec G.B.E.
Published: April 2003

Leflunomide has recently been introduced for systemic treatment of rheumatoid arthritis. It has both immunosuppressive effects and anti-inflammatory properties. We report a patient treated with leflunomide who developed vasculitis as an adverse side effect. As far as we are aware, this is the first published report of vasculitis associated with leflunomide therapy.