bluuebunny/crossref_metadata_2025 huggingface dataset:
US physicians' attitudes toward genetic testing for cancer susceptibility
Authors: Freedman A.N. , Wideroff L. , Olson L. , Davis W. , Klabunde C. , Srinath K.P. , Reeve B.B. , Croyle R.T. , Ballard‐Barbash R.
Published: June 2003

Genetic testing for an inherited susceptibility to cancer is an emerging technology in medical practice. Little information is currently available about physicians' attitudes toward these tests. To assess US physicians' opinions on unresolved issues surrounding genetic testing, a 15‐min survey was administered to a stratified random sample of 1,251 physicians from 8 specialties, selected from a file of all licensed physicians in the US (response rate = 71.0%). Dependent measures included physicians' attitudes toward genetic counseling and testing qualifications, availability of guidelines, patient confidentiality and insurance discrimination issues, and clinical utility of genetic tests. More than 89% of physicians reported a need for physician guidelines, 81% thought that patients with positive genetic test results are at risk for insurance discrimination, and more than 53% thought that it was difficult to ensure the confidentiality of test results. Almost 25% indicated that genetic tests for cancer susceptibility have too many inaccurate or ambiguous results; nearly 75% thought that clear guidelines are not available for managing patients with positive test results. Only 29% of physicians reported feeling qualified to provide genetic counseling to their patients. More than 84% of oncologists considered themselves qualified to recommend genetic testing to their patients compared with 40% of primary care physicians (PCPs), and 57% of tertiary care physicians (TCPs). US physicians expressed great uncertainty about issues surrounding genetic testing for cancer susceptibility. Results of this national survey underscore the need to provide physicians with clear guidelines on the use of genetic cancer susceptibility tests and effective medical training on their appropriate implementation. Published 2003 Wiley‐Liss, Inc.
Designation of the TARP syndrome and linkage to Xp11.23‐q13.3 without samples from affected patients
Authors: Kurpinski Kyle T. , Magyari Patricia A. , Gorlin Robert J. , Ng David , Biesecker Leslie G.
Published: June 2003

The Robin sequence is a well‐known cause of cleft palate and can be sporadic or familial, isolated or syndromic. We present a four‐generation family with a lethal disorder inherited in an X‐linked recessive pattern that includes Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava. We have designated this disorder “TARP” syndrome. All affected males die in infancy of unknown causes. An X‐chromosome linkage scan was performed using 14 unaffected members of a single large family and 40 STRP markers. The gene was mapped to an 11‐cM region in Xp11.23‐q13.3. Markers DXS1003 and DXS8092 flank the region and three‐point linkage analyses revealed a maximum LOD score of 2.75 at marker DXS1039. We have designated this locus as TARP. This locus was mapped without genotyping any affecteds and demonstrates that rare, lethal disorders can be evaluated by genetic linkage, even when no affected probands are available for study. Published 2003 Wiley‐Liss, Inc.
Homozygous Gly555Glu mutation in the nuclear‐encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II
Authors: Van Coster Rudy , Seneca S. , Smet J. , Van Hecke R. , Gerlo E. , Devreese B. , Van Beeumen J. , Leroy J.G. , De Meirleir L. , Lissens W.
Published: June 2003

A homozygous mutation in the flavoprotein (Fp) gene associated with complex II deficiency was demonstrated in a patient with consanguineous parents. She succumbed at 5½ months of age following a respiratory infection. The c1664G→A transition detected, predicted the substitution of the small uncharged glycine at position 555 by glutamic acid. Her clinical course was at variance with the Leigh syndrome in three previously reported patients due to Fp gene mutations. In this proband, CRM for flavoprotein as well as iron‐containing protein (Ip) was decreased, CRM for the entire complex II (130 kDa) being reduced even more. This observation prompts speculation of a labile interaction between Ip and Fp polypeptides and of a key role of the amino acid at position 555 in the interacting domain. © 2003 Wiley‐Liss, Inc.
Expression studies of two novel in CIS‐mutations identified in an intermediate case of Hunter syndrome
Authors: Ricci Verena , Filocamo Mirella , Regis Stefano , Corsolini Fabio , Stroppiano Marina , Duca Marco Di , Gatti Rosanna
Published: June 2003

Hunter syndrome (Mucopolysaccharidosis type II) is a rare X‐linked recessive lysosomal storage disorder caused by the deficiency of the enzyme iduronate‐2‐sulfatase (IDS). To date, more than 200 different mutations have been reported in the IDS gene, located on Xq27.3–q28. Here, we report two new mutations (M488I and G489A) identified in hemizygosity in an Italian Hunter patient. Their “in vitro” expression by COS 7 cells was carried out in order to evaluate their functional consequence on enzyme activity as well as their possible cumulative effect on the malfunctioning of the protein. The results obtained enabled us to confirm the G489A mutation as causative. The M488I mutation, however, could not be unequivocally considered as causing disease because of its residual activity. Although a cumulative effect of the two mutations can be excluded “in vitro,” we are cautious about drawing a conclusion with regard to the possible role that the two mutations could have played “in vivo” in modulating the phenotype of the patient. Finally, the knowledge of the molecular defect of the patient has enabled us to identify the carriers, providing reliable genetic counselling to the females of the family. © 2003 Wiley‐Liss, Inc.
Dilated cardiomyopathy and new 16 bp deletion in exon 44 of the dystrophin gene: The possible role of repeated motifs in mutation generation
Authors: Todorova Albena , Constantinova Dimitrina , Kremensky Ivo
Published: June 2003

Here we report a boy with dilated cardiomyopathy and severe Duchenne muscular dystrophy (DMD). The disease‐causing mutation was a new 16 bp deletion in exon 44 of the dystrophin gene, which led to frameshifting and premature translation termination. This deletion in exon 44 was associated with dilated cardiomyopathy. The dystrophin region in exon 44 might be considered as one of the high‐risk regions in which mutations could lead to myocardial damage, dilated cardiomyopathy, and early death. The abundance of repeated motifs was detected within the deleted segment and in the region. These sequence motifs might be involved in secondary structure formation and thus they could participate in the mutation generation. © 2003 Wiley‐Liss, Inc.
Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”
Authors: Ruggieri Martino , Iannetti Paola , Pavone Lorenzo
Published: June 2003

The term “cutis tricolor” describes the combination of congenital hyper‐ and hypo‐pigmented lesions, in close proximity to each other with a background of normal skin. Cutis tricolor represents twin spotting and has been reported as an isolated skin disorder or as part of a neurocutaneous malformation syndrome. We report on an 11‐year‐old girl with diffuse pigmentary changes of the cutis tricolor type, facial anomalies, mental retardation, epileptic seizures, EEG anomalies, small skull, progressive double‐curved thoracolumbar/lumbar scoliosis with vertebral scalloping and dysplastic vertebral pedicles and ribs, and tibial bowing. These abnormalities are similar to those observed in cases reported by Happle et al. [1997: J Med Genet 34:676–678] and Ruggieri [2000: Eur J Pediatr 159:745‐749]. Additionally, our patient had altered behavior and hypoplasia of the corpus callosum. This constellation of abnormalities represents a newly recognized neurocutaneous malformation syndrome. The phenotype could be explained by somatic mutation. Loss of heterozygosity at an early developmental stage would give rise to one single mosaic skin disorder (e.g., generalized skin manifestations of the cutis tricolor type in association to extracutaneous anomalies). Postzygotic recombination occurring later during embryogenesis would give rise to solitary lesions confined to the skin. © 2003 Wiley‐Liss, Inc.
Variable phenotype in Greig cephalopolysyndactyly syndrome: Clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations
Authors: Debeer Philippe , Peeters H. , Driess S. , De Smet L. , Freese K. , Matthijs G. , Bornholdt D. , Devriendt K. , Grzeschik K.‐H. , Fryns J.‐P. , Kalff‐Suske M.
Published: June 2003

Greig cephalopolysyndactyly (GCPS) (OMIM 175700) is an autosomal dominant disorder characterized by a distinct combination of craniofacial, hand and foot malformations. In this report, clinical and radiological findings of 12 patients with GCPS derived from 4 independent families and 3 sporadic cases with documented GLI3 mutations are presented with particular emphasis on inter‐ and intrafamilial variability. In a particularly instructive family in which 9 members of 4 generations could be studied clinically and molecularly, a missense mutation (R625W) is transmitted and shows a partially penetrant pattern. In a branch of the family, the GCPS phenotype skips a generation via a normal female carrier without clinical signs providing evidence that GCPS does not always manifest full penetrance as generally supposed. © 2003 Wiley‐Liss, Inc.
Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children
Authors: Kleta Robert , Aughton David J. , Rivkin Michael J. , Huizing Marjan , Strovel Erin , Anikster Yair , Orvisky Eduard , Natowicz Marvin , Krasnewich Donna , Gahl William A.
Published: June 2003

The differential diagnosis of developmental delays and growth retardation in early childhood includes the allelic lysosomal sialic acid storage disorders, Salla disease and infantile free sialic acid storage disease (ISSD). These diseases, due to defective free sialic acid transport out of lysosomes, derive from mutations in theSLC17A5gene coding for the protein sialin. We present two patients with clinical, biochemical, and molecular data indicative of lysosomal free sialic acid storage disorders. One patient, with a severe clinical course typical of ISSD, had 86‐fold elevated levels of fibroblast free sialic acid, with 62% in the lysosomal fraction. HisSLC17A5mutations include a 148‐bp deletion of exon 9, due to a G > A splice site mutation in position 1 of intron 9, and a 15‐bp deletion (del 801–815) in exon 6. Another patient, with “intermediate severe” Salla disease, had 9‐fold elevated levels of free sialic acid in cultured fibroblasts, of which 87% resided in the lysosomal fraction. This girl is compound heterozygous for theSLC17A5mutation commonly found in Finnish Salla disease patients (R39C) and a 15‐bp deletion found in ISSD patients (del 801–815). These observations emphasize the importance of considering free sialic acid disorders in infants with developmental delays and growth retardation, regardless of whether they are of Finnish ancestry. © 2003 Wiley‐Liss, Inc.
Molecular characterization of a patient with central nervous system dysmyelination and cryptic unbalanced translocation between chromosomes 4q and 18q
Authors: Gunn Shelly R. , Mohammed Mansoor , Reveles Xavier T. , Viskochil David H. , Palumbos Janice C. , Johnson‐Pais Teresa L. , Hale Daniel E. , Lancaster Jack L. , Hardies L. Jean , Boespflug‐Tanguy Odile , Cody Jannine D. , Leach Robin J.
Published: June 2003

We report on a 12‐year‐old boy who presented with delayed development and CNS dysmyelination. Genetic studies showed a normal 46,XY karyotype by routine cytogenetic analysis, and 46,XY.ish del(18)(q23)(D18Z1+, MBP−) by FISH using a locus‐specific probe for the MBP gene (18q23). Though the patient appeared to have normal chromosome 18s by repeated high resolution banding analysis, his clinical features were suggestive of a deletion of 18q. These included hearing loss secondary to stenosis of the external auditory canals, abnormal facial features, and foot deformities. FISH studies with genomic probes from 18q22.3 to 18qter confirmed a cryptic deletion which encompassed the MBP gene. In an attempt to further characterize the deletion, whole genome screening was conducted using array based comparative genomic hybridization (array CGH) analysis. The array CGH data not only confirmed a cryptic deletion in the 18q22.3 to 18qter region of approximately 7 Mb, it also showed a previously undetected 3.7 Mb gain of 4q material. FISH studies demonstrated that the gained 4q material was translocated distal to the 18qter deletion breakpoint. The 18q deletion contains, in addition to MBP, other known genes including CYB5, ZNF236, GALR1, and NFATC1, while the gained 4q material includes the genes FACL1 and 2, KLKB1, F11 and MTNR1A. The use of these combined methodologies has resulted in the first reported case in which array CGH has been used to characterize a congenital chromosomal abnormality, highlighting the need for innovative molecular cytogenetic techniques in the diagnosis of patients with idiopathic neurological abnormalities. © 2003 Wiley‐Liss, Inc.
Long‐term follow‐up of a new case of liver glycogen synthase deficiency
Authors: Laberge Anne Marie , Mitchell Grant A. , van de Werve Gerald , Lambert Marie
Published: June 2003

We report a new case of hereditary hepatic glycogen synthase (GS) deficiency (MIM 240600) in a French Canadian girl referred at 7 years of age for a family history of hyperlipidemia. Her initial evaluation incidentally revealed fasting hypoglycemia and ketonuria after a 10‐hr fast with normal growth, development, and physical examination. Additional biochemical findings included fasting hypoalaninemia with elevated plasma branched chain amino acids and postprandial hyperlactatemia. Liver glycogen synthase activity was reduced. Unlike most other reported patients, we observed on three different occasions an increase in fasting plasma glucose levels after glucagon administration during episodes of hypoglycemia. At 13 years of age, her growth and intellect are normal; however, she still has hypoglycemia after 18 hr of fasting. From our patient's course and a review of the literature, we conclude: (A) Usual modes of presentation of GS deficiency are non‐specific symptoms after overnight fasting (7/17), incidental findings (3/17), or positive family history (7/17); (B) Most patients maintain normal growth (8/11) and intellectual abilities (12/15); (C) Fasting hypoglycemia (17/17) and reduced liver glycogen content (9/9) are constant features; (D) Biochemical findings also include postprandial hyperlactatemia (13/13), fasting hyperketonemia (12/12), and fasting hypoalaninemia (8/9); (E) Glucagon response following fasting hypoglycemia is usually reduced or absent (7/8) but can be repeatedly present (1/8); (F) Liver steatosis is frequent (6/6). Although rare, GS deficiency results in a characteristic biochemical profile that, if recognized, should lead promptly to its diagnosis. © 2003 Wiley‐Liss, Inc.
Unique insertional translocation in a childhood Wilms' tumor survivor detected when his daughter developed bilateral retinoblastoma
Authors: Punnett Angela , Teshima Ikuko , Heon Elise , Budning Andrew , Sutherland Joanne , Gallie Brenda L. , Chan Helen S.L.
Published: June 2003

Retinoblastoma and Wilms' tumor are rare childhood embryonic tumors associated with loss or inactivation of tumor suppressor genes, RB1 located within 13q14, and WT1 located within 11p13. Interchromosomal insertional translocations occur rarely, and such rearrangements within RB1 or WT1, even rarer. We report a unique family in which an insertional translocation of a chromosomal segment that included band 13q14 inserted into 11p13 caused childhood Wilms' tumor in the father, and whose child developed bilateral retinoblastoma. This is the first case of an insertional translocation that caused both tumors. This insertional translocation had significant consequences for genetic counseling and in utero diagnosis. The estimated risk for an offspring of this father to develop Wilms' tumor is up to 50%, to develop retinoblastoma up to 25%, to have neither tumor 25%, and to have both tumors 0%. © 2003 Wiley‐Liss, Inc.
Hennekam syndrome presenting as nonimmune hydrops fetalis, congenital chylothorax, and congenital pulmonary lymphangiectasia
Authors: Bellini Carlo , Mazzella Massimo , Arioni Cesare , Campisi Corradino , Taddei Gioconda , Tomà Paolo , Boccardo Francesco , Hennekam Raoul C. , Serra Giovanni
Published: June 2003

We report a female infant with congenital lymphedema, facial anomalies, intestinal lymphangiectasia consistent with a diagnosis of Hennekam syndrome. At birth the patient presented with severe respiratory distress due to nonimmune hydrops fetalis, a congenital chylothorax (CC), and pulmonary lymphangiectasia. Hydrops fetalis may be present in newborns with the Hennekam syndrome. Lymphoscintigraphy can be useful in explaining pleural‐pulmonary involvement of this generalized lymph vessel malformation syndrome. © 2003 Wiley‐Liss, Inc.
Analysis of cystic fibrosis transmembrane conductance regulator gene mutations in patients with congenital absence of the uterus and vagina
Authors: Timmreck Lorna S. , Gray Mark R. , Handelin Barbara , Allito Bernice , Rohlfs Elizabeth , Davis Ann J. , Gidwani Gita , Reindollar Richard H.
Published: June 2003

The relationship between cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations and congenital absence of the uterus and vagina (CAUV) was examined. CFTR mutations have previously been associated with congenital bilateral absence of the vas deferens (CBAVD). CBAVD is caused by a disruption in the vas deferens, a Wolffian duct derivative. Because the embryologic development of the Müllerian ducts directly depends on the prior normal development of the Wolffian ducts, the same gene products may be necessary for normal embryologic development of both ductal systems. This study evaluated the role of CFTR mutations in the development of CAUV. DNA samples from 25 patients with CAUV were tested for the presence of 33 of the most common CFTR mutations. Protein‐coding DNA fragments from the CFTR gene were amplified in vitro by the polymerase chain reaction (PCR) and analyzed for mutations using allele‐specific oligonucleotide (ASO) probes. Two patients were heterozygous for CFTR mutations. One was heterozygous for the W1282X mutation and the other was heterozygous for the ΔF508 mutation. The incidence of the 33 CFTR mutations found in the patients with CAUV (8%) was twice that found in the general population (4%), but much less than the incidence of CFTR mutations in men with CBAVD (80%). This data suggests that it is unlikely for CFTR mutations to cause CAUV in females as they cause CBAVD in some males. Furthermore, the data suggest that CAUV in females may be the same disorder as CBAVD in males who do not have CFTR mutations. © 2003 Wiley‐Liss, Inc.
Fetus with an unusual form of nonrhizomelic chondrodysplasia punctata: Case report and review
Authors: Wessels Marja W. , Den Hollander Nicolette J. , De Krijger Ronald R. , Nikkels Peter G.J. , Brandenburg Helen , Hennekam Raoul , Willems Patrick J.
Published: June 2003

Chondrodysplasia punctata (CDP) is a heterogeneous condition mainly characterized by premature and ectopic calcification of cartilage. Many genetic and nongenetic causes have been described leading to a preliminar etiological classification into defects of peroxisomal metabolism, defects in cholesterol metabolism, and vitamin K (vit K) metabolism. However, numerous cases of CDP still remain unclassified. The difficulties in reaching a causal diagnosis are illustrated here by a 23‐week‐old fetus with nonrhizomelic CDP characterized by extensive cartilage stippling, brachyphalangy, and nasal hypoplasia. © 2003 Wiley‐Liss, Inc.
Inv dup del(4)(:p14 → p16.3::p16.3 → qter) with manifestations of partial duplication 4p and Wolf‐Hirschhorn syndrome
Authors: Kondoh Yuki , Toma Takaya , Ohashi Hirofumi , Harada Naoki , Yoshiura Ko‐ichiro , Ohta Tohru , Kishino Tatsuya , Niikawa Norio , Matsumoto Naomichi
Published: June 2003

An 8‐year‐old girl with a combination of clinical manifestations of partial duplication 4p and the Wolf–Hirschhorn syndrome was studied. Chromosomal G‐banding and FISH analyses showed a 33.2‐Mb segment of inverted duplication at 4p14‐p16.3 and a 2.8‐Mb segment of deletion at 4p16.3‐pter (including the Wolf–Hirschhorn syndrome critical region). The chromosomes of the parents were normal. Her karyotype was thus 46,XX, inv dup del(4)(:p14 → p16.3::p16.3 → qter) de novo. The inverted duplication deletion was assumed to have arisen through chromatid breakage at 4p16.3, U‐type reunion at the breakpoints to produce a dicentric intermediate, breakage of the dicentric to result in a monocentric, and telomere capture/healing of the broken end. Olfactory receptor gene clusters at 4p16.3 were ruled out as an intermediary of the duplication deletion process. © 2003 Wiley‐Liss, Inc.
Total field magnetic prospection: are vertical gradiometer measurements preferable to single sensor survey?
Authors: Tabbagh Jeanne
Published: June 2003

When two sensors are available the prospector can use them either in a gradiometer arrangement or dispose them at the same horizontal level to record two different profiles simultaneously. The processing of one‐sensor data presented here for both synthetic and actual cases gives slightly better results than gradient measurements, which justifies the second solution. Copyright © 2002 John Wiley & Sons, Ltd.
Aerial remote‐sensing techniques used in the management of archaeological monuments on the British Army's Salisbury Plain Training Area, Wiltshire, UK
Authors: Barnes Ian
Published: June 2003

Salisbury Plain Training Area, covering 38 000 ha in Wiltshire, southern England, is the UK's largest military training area. Military ownership has protected, from modern agricultural practices, over 2300 archaeological monuments dating from the late prehistoric and Romano‐British periods. Consequently the majority of sites still survive as earthworks.

The Defence Estates is tasked with managing this landscape, balancing military, agricultural, archaeological and nature conservation priorities within a national and international legislative framework.

The Defence Estates is evaluating the use of airborne LIDAR (light detection and ranging) and CASI (compact airborne spectrographic imager) surveys to map ‘condition’, results being directly transferable to a geographical information system. It is hoped, by comparing successive surveys, that trends can be identified, allowing management decisions to be reached. The work, funded by Headquarters Army Training Estate, is being conducted in partnership with the Environment Agency's National Centre for Environmental Data and Surveillance.

An initial trial, covering 40 km2, was held in 2001. The capacity of LIDAR and CASI to identify areas of, and trends in, formation of bare ground, grazing, disturbance (military and animal digging) and scrub infestation was evaluated.

Results showed that CASI imagery, particularly when processed as a normalized difference vegetation index (NDVI) image, was ideal for showing bare ground, scrub and levels of grazing, whereas LIDAR provided a means of measuring the magnitude of change. The techniques were less successful at distinguishing disturbed ground such as back‐filled military trenches. Combined LIDAR and CASI images were shown to be ideal media for identifying archaeological earthworks. The potential for the development of automated trend analysis was proved but manual systems were shown to be more appropriate.

Development work is continuing and it is hoped to have a remote‐sensing‐based monitoring system in place on Salisbury Plain Training Area in the foreseeable future. Copyright © Crown Copyright 2002. Recorded with the permission of the controller of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.
Archaeomagnetic investigations of Iron Age slags in Denmark
Authors: Abrahamsen Niels , Jacobsen Bo Holm , Koppelt Uwe , de Lasson Philip , Smekalova Tatiana , Voss Olfert
Published: June 2003

In Denmark iron production, by means of reducing bog‐iron ore with charcoal, was carried out at least between the second and seventh century AD. Since the 1960s magnetic mapping of iron slag remains have been used extensively at several sites in the southwestern part of Jutland in Denmark (e.g. at Drengsted, Snorup, Krarup and Yderik). A description of some of the magnetic surveying results, ideas of magnetic modelling, and magnetic and chemical analysis of slag from some of these areas are given. The Danish Iron Age slag pits are strongly magnetic, and consequently they are quite easy to locate magnetically. The slag, however, is often magnetically non‐homogeneous, and accordingly the remanent magnetic direction of the original magnetization is not uniform. Hence individual slag pits are not good recorders of the direction of Earth's magnetic field. Therefore dating of individual slag pits by means of a magnetic mastercurve, using either inversion and modelling of the magnetic field anomaly from the slag, or by using conventional palaeomagnetic techniques by orientated cores, are still difficult to make with sufficient resolution. Copyright © 2002 John Wiley & Sons, Ltd.
Cawthorn Camps, North Yorkshire—a photogrammetric approach
Authors: Stone Jane
Published: June 2003

Cawthorn Camps is a Roman site of probable late first and early second century date comprising two forts, one with a later annexe, and a camp. The site survives as earthworks and, within the main defences, there are many slight embanked structures. The current programme of research at Cawthorn is a joint initiative between the North York Moors National Park and English Heritage, the aim being to produce a revised management plan for this nationally important site. It is a multidisciplinary project combining the following disciplines: excavation, geophysical prospection, ground and aerial survey. Digital photogrammetry has been used to produce a plan, scale 1 : 500, of the earthworks to a precision of ±10 cm. Copyright © 2002 John Wiley & Sons, Ltd.
The identification of Roman buildings from the air: recent discoveries in Western Transylvania
Authors: Hanson W. S. , Oltean Ioana A.
Published: June 2003

An ongoing programme of archaeological aerial reconnaissance in southwestern Transylvania, the first time such a programme has been conducted in Romania, revealed quite large numbers of negative cropmarks or parchmarks, particularly in the dry summer of 2000. These areas of restricted crop growth indicated the presence of buried stone‐walled buildings, predominantly of Roman date, which were previously unknown. Important discoveries included much of the internal plan of the auxiliary fort at Cigmau; an extensive civil settlement to the east of that fort; buildings within the civil settlements outside the forts at Vetel (Micia) and Razboieni; buildings and property boundaries within the municipium at Apulum (Alba Iulia); and villas at Oarda and Vintu de Jos. By contrast, positive cropmarks, enhanced growth reflecting the existence of buried pits or enclosure ditches, were observed only rarely. Explanations for this phenomenon linked to a bias in the reconnaissance programme or to a general absence of enclosed sites within the archaeological record in the area are rejected. The preferred explanation relates to local soil conditions, whereby the widespread, deep alluvial soils reduce the contrast in moisture content between buried archaeological ditches or pits and the surrounding soil matrix so that positive cropmarks are rarely formed. Copyright © 2003 John Wiley & Sons, Ltd.
A high‐resolution magnetic mosaic at the Kyme archaeological site (Turkey)
Authors: Ciminale Marcello
Published: June 2003

An extended high‐resolution magnetic investigation was undertaken at the archaeological site in Kyme (Turkey). In order to obtain highly resolved digital raster images, the gradient data sets were processed by using digital image processing techniques. In addition to these sets of data, the magnetic field measurements acquired by the bottom sensor alone were also processed. A careful comparison between the gradient data magnetograms and the bottom sensor magnetograms revealed how the entire mosaic, elaborated by processing the bottom sensor data, could fruitfully integrate and improve the information inferred by the vertical gradient magnetograms. Finally, the main archaeological features outlined from this magnetic investigation, as well as the results of a first guided excavation, are presented. Copyright © 2003 John Wiley & Sons, Ltd.
Multidimensional prospecting in North American Great Plains village sites
Authors: Kvamme Kenneth L.
Published: June 2003

Geophysical survey results are described for four prehistoric and historic fortified earthlodge settlements located in the Middle Missouri River basin of North and South Dakota, USA. One impetus for this work is the upcoming bicentennial of the Lewis and Clark expedition of 1804–1806 that used the Missouri as its route of travel. Celebrated as an event that helped to open the American West to Euroamerican settlement, tourism at archaeological parks is expected to markedly increase. Multidimensional geophysical surveys were used to pin‐point cultural anomalies for archaeological excavation and interpretation, but more importantly, the wide‐area mapping of the subsurface at these villages allowed visualization of their structure and organization, yielding many new insights. At Menoken Village (AD 1240) previously unknown houses, oval in form, were revealed magnetically owing to their intense burning, as was an intravillage trail system seen in resistivity data. At Whistling Elk Village (AD 1300) the first glimpse of the nature of this deeply buried settlement was achieved by resistivity and conductivity surveys, with magnetic indications that half of the houses had been burned. The geophysical evidence also hints at a second village, much more compact, that may lie within the primary settlement, supporting an attack theory established by limited excavation evidence. At Huff Village (AD 1450) the magnetometry survey revealed the presence of vast numbers of previously unsuspected food storage pits outside of the numerous dwellings that lie within this settlement. At Mitu'tahakto's (1822–1861), an early historic Mandan/Arikara settlement, resistivity and GPR surveys discovered the presence of new and overlapping houses, and magnetometry indicated large differences in the number of iron artefacts between households, pointing to possible variations in access or status. Copyright © 2003 John Wiley & Sons, Ltd.
Anti–c‐Mpl (thrombopoietin receptor) autoantibody–induced amegakaryocytic thrombocytopenia in a patient with systemic sclerosis
Authors: Katsumata Yasuhiro , Suzuki Takahiro , Kuwana Masataka , Hattori Yutaka , Akizuki Satoshi , Sugiura Hitoshi , Matsuoka Yasuo
Published: June 2003

Amegakaryocytic thrombocytopenia (AMT) associated with systemic sclerosis (SSc) has been described in several case reports, but the underlying mechanisms have not been identified. Here we describe a rare case of SSc accompanied by thrombocytopenia and megakaryocytic hypoplasia, in which autoantibody against thrombopoietin receptor (c‐Mpl) was detected. A 61‐year‐old woman with limited SSc was admitted to our hospital because of severe thrombocytopenia (platelet count 0.2 × 104/mm3) with gingival bleeding. Her bone marrow was hypocellular with absent megakaryocytes, consistent with AMT. Treatment with corticosteroids and intravenous immunoglobulin infusions resulted in an increased platelet count, and she sustained a remission over a 1‐year period, with a platelet count averaging 10.0 × 104/mm3. Her serum was strongly positive for anti–c‐Mpl antibody, and IgG fraction purified from her serum inhibited thrombopoietin‐dependent cell proliferation in vitro. Our case report suggests that AMT in patients with SSc could be mediated by the anti–c‐Mpl antibody, which functionally blocks an interaction between thrombopoietin and c‐Mpl.
Growth plate damage, a feature of juvenile idiopathic arthritis, can be induced by adenoviral gene transfer of oncostatin M: A comparative study in gene‐deficient mice
Authors: de Hooge Alfons S. K. , van de Loo Fons A. J. , Bennink Miranda B. , Arntz Onno J. , Fiselier Theo J. W. , Franssen Marcel J. A. M. , Joosten Leo A. B. , van Lent Peter L. E. M. , Richards Carl D. , van den Berg Wim B.
Published: June 2003

Objective

To investigate the involvement of proinflammatory and destructive mediators in oncostatin M (OSM)–induced joint pathology, using gene‐deficient mice.

Methods

An adenoviral vector expressing murine OSM was injected into the joints of naive wild‐type mice and mice deficient for interleukin‐1 (IL‐1), IL‐6, tumor necrosis factor α (TNFα), or inducible nitric oxide synthase (iNOS). Reverse transcription–polymerase chain reaction was used to study gene expression. Inflammation and cartilage proteoglycan (PG) depletion were assessed by histology. OSM and IL‐1 levels in synovial fluid from patients with juvenile idiopathic arthritis (JIA) were measured by enzyme‐linked immunosorbent assay.

Results

Adenoviral expression of murine OSM led to joint inflammation, bone apposition, chondrophyte formation, articular cartilage PG depletion, and VDIPEN neoepitope expression in wild‐type mice. A unique and consistent observation was the focal PG depletion and disorganization of the growth plate cartilage during the first week of inflammation. Synovial IL‐1β, IL‐6, TNFα, and iNOS gene expression was strongly induced. Of these factors, only deficiency in IL‐1 markedly reduced inflammation and PG depletion and completely prevented growth plate damage. In addition, this is the first study in which OSM was detected in JIA synovial fluid. Most samples were also IL‐1β positive.

Conclusion

IL‐1, but not IL‐6, TNFα, or iNOS, plays an important role in joint disease induced by intraarticular gene transfer of OSM in mice. The effect of OSM on murine connective tissue and the presence of OSM in human synovial fluid make involvement of OSM in human arthropathies very likely.
Association of widespread body pain with an increased risk of cancer and reduced cancer survival: A prospective, population‐based study
Authors: McBeth John , Silman Alan J. , Macfarlane Gary J.
Published: June 2003

Objective

To determine whether reported widespread body pain is related to an increased incidence of cancer and/or reduced survival from cancer, since our previous population surveys have demonstrated a relationship between widespread body pain and a subsequent 2‐fold increase in mortality from cancer over an 8‐year period.

Methods

A total of 6,565 subjects in Northwest England participated in 2 health surveys during 1991–1992. The subjects were classified according to their reported pain status (no pain, regional pain, and widespread pain), and were subsequently followed up prospectively until December 31, 1999. During followup, information was collected on incidence of cancer and survival rates among those developing cancer. Associations between the original pain status and development of cancer and cancer survival were expressed as the incidence rate ratio (IRR) and mortality rate ratio (MRR), respectively. All analyses were adjusted for age, sex, and study location, the latter being a proxy measure of socioeconomic status.

Results

Among the study population, 6,331 had never been diagnosed with cancer at the time of participation in the survey. Of these subjects, 956 (15%) were classified as having widespread pain, 3,061 (48%) as having regional pain, and 2,314 (37%) as having no pain. There were a total of 395 first malignancies recorded during followup. In comparison with subjects reporting no pain, those with regional pain (IRR 1.19, 95% confidence interval [95% CI] 0.94–1.50) and widespread pain (IRR 1.61, 95% CI 1.21–2.13) experienced an excess incidence of cancer during the followup period. The increased incidence among subjects previously reporting widespread pain was related, most strongly, to breast cancer (IRR 3.67, 95% CI 1.39–9.68), but there were also cancers of the prostate (IRR 3.46, 95% CI 1.25–9.59), large bowel (IRR 2.35, 95% CI 0.96–5.77), and lung (IRR 2.04, 95% CI 0.96–4.34). Subjects reporting widespread pain who subsequently developed cancer, in comparison with those previously reporting no pain, had an increased risk of death (MRR 1.82, 95% CI 1.18–2.80). This decreased survival was highest among subjects with cancers of the breast and prostate, although the effects on site‐specific survival were nonsignificant.

Conclusion

This study has demonstrated that widespread pain reported in population surveys is associated with a substantial subsequent increased incidence of cancer and reduced cancer survival. At present there are no satisfactory biologic explanations for this observation, although several possible leads have been identified.
Selective inhibition of cyclooxygenase 2–generated prostaglandin E2 synthesis in rheumatoid arthritis synoviocytes by taurine chloramine
Authors: Kontny Ewa , Rudnicka Weronika , Kowalczewski Jacek , Marcinkiewicz Janusz , Maslinski Wlodzimierz
Published: June 2003

Objective

To investigate the effects of taurine chloramine (Tau‐Cl), a chlorinated derivative of the amino acid taurine, on the expression of cyclooxygenase (COX) isoenzymes and prostaglandin E2 (PGE2) synthesis in rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS).

Methods

FLS, isolated from the synovial tissue of RA patients, were treated in vitro with either interleukin‐1β (IL‐1β; 1 ng/ml) alone or together with 200–500 μM Tau‐Cl. The expression of COX isoenzymes was evaluated at both the protein (Western blotting) and the messenger RNA (mRNA) (reverse transcriptase–polymerase chain reaction) levels. The concentration of PGE2 was measured by competitive acetylcholinesterase enzyme immunoassay.

Results

Resting FLS expressed mRNA encoding both COX‐1 and COX‐2, but only COX‐1 was present at the protein level. These cells produced negligible amounts of PGE2. Upon stimulation with IL‐1β, elevation of COX‐2, but not COX‐1, mRNA and protein preceded the enhancement of PGE2 synthesis. In the presence of 300–400 μM Tau‐Cl, significant inhibition of IL‐1β–triggered COX‐2 mRNA and protein, and a related decrease in PGE2 production, was observed. In contrast, no significant changes in COX‐1 mRNA and protein levels were noted.

Conclusion

Tau‐Cl inhibits IL‐1β–triggered elevation of COX‐2 and generation of PGE2 by RA FLS. These results expand the spectrum of known antiinflammatory activities of this compound.
Blockade of parathyroid hormone–related protein prevents joint destruction and granuloma formation in streptococcal cell wall–induced arthritis
Authors: Funk J. L. , Chen J. , Downey K. J. , Davee S. M. , Stafford G.
Published: June 2003

Objective

To determine whether parathyroid hormone–related protein (PTHrP), an interleukin‐1β–inducible, bone‐resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA.

Methods

PTHrP expression and the effect of PTHrP 1–34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW)–induced arthritis, an animal model of RA.

Results

As has been reported in RA, while serum levels of PTHrP did not change during SCW‐induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW‐treated animals. However, PTHrP antibody significantly inhibited SCW‐induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor–positive neutrophils and in SCW‐induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1–34.

Conclusion

These findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders.
Effect of minodronic acid (ONO‐5920) on bone mineral density and arthritis in adult rats with collagen‐induced arthritis
Authors: Yamane Itsuro , Hagino Hiroshi , Okano Toru , Enokida Makoto , Yamasaki Daisuke , Teshima Ryota
Published: June 2003

Objective

To study the effect of minodronic acid (ONO‐5920) on bone loss and arthritis in rats with collagen‐induced arthritis (CIA) treated according to 2 different schedules.

Methods

Four groups of female Sprague‐Dawley rats (7 months old) were studied: rats without CIA treated with vehicle (controls), CIA rats treated with vehicle (CIA‐V), CIA rats treated therapeutically with minodronic acid (CIA‐T), and CIA rats treated prophylactically with minodronic acid (CIA‐P). Minodronic acid was administered orally at 0.2 mg/kg 3 times a week, beginning 2 weeks after initial sensitization in the CIA‐T rats and beginning the day after initial sensitization in the CIA‐P rats. Bone mineral density (BMD) was measured by peripheral quantitative computed tomography in the proximal metaphysis and diaphysis of the tibia every 2 weeks until week 8, when the rats were killed. The BMD and bone microstructure of the excised femur were evaluated by dual x‐ray absorptiometry and microfocal computed tomography, respectively. Histomorphometry of the proximal tibia was also performed.

Results

In CIA‐P rats, the incidence of arthritis and the severity of posterior limb swelling were reduced early after sensitization, and the decrease in BMD was prevented throughout the observation period. Bone and joint destruction evaluated by radiography of the foot was reduced in CIA‐P rats. The eroded surface was reduced and the microstructure was maintained in CIA‐P rats compared with CIA‐V rats. The mineral apposition and bone formation rates were not reduced in the CIA‐P rats. In CIA‐T rats, however, the inflammation was not suppressed and the inhibitory effect on bone loss was smaller than that in CIA‐P rats.

Conclusion

Minodronic acid suppressed the decrease in BMD and the deterioration of the bone microstructure caused by arthritis. Prophylactic administration of minodronic acid had a preventive effect on arthritis at the early stage, although not throughout the observation period.
Increased perivascular synovial membrane expression of myeloid‐related proteins in psoriatic arthritis
Authors: Kane David , Roth Johannes , Frosch Michael , Vogl Thomas , Bresnihan Barry , FitzGerald Oliver
Published: June 2003

Objective

To analyze S‐100 protein expression, in the form of myeloid‐related protein 8 (MRP8), MRP14, and the heterodimer MRP8/MRP14, in psoriatic arthritis (PsA) patients compared with rheumatoid arthritis (RA) and spondylarthropathy (SpA) patients, and to determine the effect of methotrexate (MTX) on the MRP antigen expression in PsA patients.

Methods

Serum, synovial fluid (SF), and synovium (taken at arthroscopy) samples were obtained from PsA (before and after MTX treatment), RA, and SpA patients. Concentrations of MRP8/MRP14 in serum and SF were measured by enzyme‐linked immunosorbent assay. Expression of MRP8, MRP14, and MRP8/MRP14 in synovium was determined by immunohistochemistry.

Results

MRP8, MRP14, and MRP8/MRP14 levels were increased in serum, SF, and synovium from PsA, RA, and SpA patients. In all 3 groups, paired samples of serum and SF showed significantly higher MRP8/MRP14 levels in SF (mean ± SD 15,310 ± 16,999 ng/ml [median 11,400]) than in serum (908 ± 679 ng/ml [median 695]) (P = 0.0001). MRP8/MRP14 levels in serum correlated with systemic parameters of disease activity (erythrocyte sedimentation rate [ESR] r = 0.55, P = 0.005; C‐reactive protein [CRP] level r = 0.55, P = 0.005), whereas levels in SF correlated with local parameters of disease activity (white blood cell count r = 0.45, P = 0.01; acute‐phase serum amyloid A level r = 0.32, P = 0.03). MRP expression was significantly higher in the synovial sublining layer (SLL) of PsA patients compared with RA and SpA patients. MRP antigens were predominantly expressed in perivascular areas of the SLL in PsA patients. Following MTX treatment, MRP expression in serum and synovium from PsA patients was significantly reduced. Serum levels of MRP were more sensitive to the effects of MTX than were the ESR, CRP, or clinical joint scores.

Conclusion

MRP levels in serum and SF correlate with local and systemic inflammation and are equally increased in PsA, RA, and SpA patients. In contrast, MRP8, MRP14, and MRP8/MRP14 expression in the SLL of PsA patients is increased, particularly in perivascular regions, compared with that in RA and SpA patients, suggesting a central role of MRP proteins in transendothelial migration of leukocytes in PsA. Moreover, MRP expression is reduced following MTX treatment. MRP proteins may represent a novel therapeutic target in inflammatory arthritis.
In vivo selective inhibition of mitogen‐activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes
Authors: Pelletier Jean‐Pierre , Fernandes Julio C. , Brunet Julie , Moldovan Florina , Schrier Denis , Flory Craig , Martel‐Pelletier Johanne
Published: June 2003

Objective

The primary aim of this study was to investigate, using an experimental rabbit model of osteoarthritis (OA), the effect of a selective mitogen‐activated protein kinase kinase 1/2 (MEK‐1/2) inhibitor, PD 198306, on the development of structural changes. Additional aims were to assess the effects of the inhibitor on levels of phosphorylated extracellular signal–regulated kinase 1/2 (phospho–ERK‐1/2) and matrix metalloproteinase 1 (MMP‐1; collagenase 1) in OA chondrocytes.

Methods

After surgical sectioning of the anterior cruciate ligament of the right knee joint, rabbits with OA were separated into 3 experimental groups: oral treatment with placebo or with PD 198306 at a therapeutic concentration of 10 mg/kg/day or 30 mg/kg/day. Each treatment started immediately after surgery. The animals were killed 8 weeks after surgery. Macroscopic and histologic studies were performed on the cartilage and synovial membrane. The levels of phospho–ERK‐1/2 and MMP‐1 in OA cartilage chondrocytes were evaluated by immunohistochemistry. Normal, untreated rabbits were used as controls.

Results

OA rabbits treated with the highest dosage of MEK‐1/2 inhibitor showed decreases in the surface area (size) of cartilage macroscopic lesions (P < 0.002) and in osteophyte width on the lateral condyles (P = 0.05). Histologically, the severity of synovial inflammation (villous hyperplasia) was also reduced (P < 0.02). In cartilage from placebo‐treated OA rabbits, a significantly higher percentage of chondrocytes in the superficial layer stained positive for phospho–ERK‐1/2 and MMP‐1 compared with normal controls. Rabbits treated with the highest dosage of PD 198306 demonstrated a significant and dose‐dependent reduction in the level of phospho–ERK‐1/2 and a lower level of MMP‐1.

Conclusion

This study demonstrates that, in vivo, PD 198306, a selective inhibitor of MEK‐1/2, can partially decrease the development of some of the structural changes in experimental OA. This effect was associated with a reduction in the level of phospho–ERK‐1/2 in OA chondrocytes, which probably explains the action of the drug.