bluuebunny/crossref_metadata_2025 huggingface dataset:
Familial supernumerary nipples
Authors: Leung Alexander K. C. , Opitz John M. , Reynolds James F.
Published: September 2005

This paper reports a Chinese family among whom three members in two generations had supernumerary nipples. The supernumerary nipples were situated below the normal nipples. The father had a right renal cyst, whereas the twin daughters had normal renal ultrasonography.
G syndrome: An unusual family
Authors: Allanson Judith E. , Opitz John M. , Reynolds James F.
Published: September 2005

The G syndrome is a multiple congenital anomaly (MCA) syndrome of hypertelorism., hypospadias, stridor, and swallowing difficulties. Cleft lip and palate, cardiac defects, cranial asymmetry, and bowel obstruction are occasional manifestations. Family data suggest autosomal dominant inheritance. Males appear to have more serious manifestations, whereas most females with the G syndrome have a benign course and are ascertained through affected male relatives.

In the family reported here, the proposita was first seen at age 7 weeks because of swallowing difficulties., stridor, and unusual facial appearance, reminiscent of the G syndrome. Evaluation of the family showed striking facial changes in her father and all four of his sibs. These five individuals had megalencephaly, hypertelorism., and a broad prominent nasal root and bridge, reminiscent of the facial appearance in the BBB syndrome. There was no evidence for dysphagia, respiratory abnormality, or hoarse voice in any other relative.

These individuals with the G syndrome display two unusual manifestations. There are no males with hypospadias; the proposita has the most severe laryngotracheoesophageal symptoms. Although hypospadias is not an invariable manifestation of the G syndrome and although six females with severe dysphagia or respiratory abnormalities have been reported previously, the manifestations in this family underline the variability of this condition and provide further support that the G syndrome can be expressed with equal severity in both males and females.

Although phenotypic overlap between the BBB and G syndromes has long been recognized, many still consider them to be distinct nosologic entities. The occurrence of both BBB and G syndrome in different members of the same family has been observed previously. In this family the characteristic phenotype of the G syndrome in our proposita, coupled with traits in keeping with the BBB syndrome in her father and his sibs, adds credence to the contention that the G and the BBB syndromes are but different expressions of the same mutant gene.
Prenatal detection of 46,XY,rec(5),dup q, inv(5)(p13q33) using DNA analysis, flow cytometry, and in situ hybridization to supplement classical cytogenetic analysis
Authors: Martin A. O. , Northrup H. , Ledbetter D. H. , Trask B. , van den Engh G. , Beau M. M. Le , Beaudet A. L. , Gray J. W. , Sekhon G. , Krassikoff N. , Booth C. , Opitz John M. , Reynolds James F.
Published: September 2005

Distinguishing between balanced and unbalanced chromosome complements segregating from parental rearrangements may be difficult using only classical cytogenetic techniques if banding morphology is similar under both expectations. In these situations, supplementing cytogenetic analysis with molecular genetic techniques and flow cytometry may provide increased diagnostic accuracy. To illustrate this, we present a case in which similar band pattern morphology would be expected for both the balanced carrier (heterozygote) and the recombinant dup q chromosome complements segregating from a mother with a balanced inversion [46,XX,inv(5)(p13q33)]. The parents came to Northwestern for consultation after receiving conflicting interpretations of their first amniotic fluid cultures. An ultrasound examination was said to be normal. They inquired whether there were ways to increase their confidence that the complement was unbalanced. Their reluctance to terminate the pregnancy was due to a 6‐year history of infertility. After extensive counselling, the couple elected repeat amniocentesis. Further cytogenetic analysis of repeat amniotic fluid cultures by G‐banding and R‐banding, molecular genetic analysis with highly polymorphic DNA probes, and quantitative flow cytometry were performed. Results agreed that an unbalanced fetal complement was present. Southern blot analysis with a 5p marker definitively demonstrated a lack of maternal 5p material in the fetus, and in situ hybridization showed a 5q marker at either end of the recombinant chromosome. Flow cytometry was consistent with this interpretation, Because of the advanced gestational age, the parents elected to terminate based on cytogenetic results of the second amniocentesis, rather than to wait another 1–2 weeks for results of other methods. Although not determinative of this pregnancy outcome, this correspondence provides reassurance that, in cases when banding analysis may be more difficult or inconclusive, other methods are accurate supplements to classical cytogenetics.
Interstitial 7q deletion [46,XX,del(7)(pter → q21.1::q22 → qter)] and the location of genes for β‐glucuronidase and cystic fibrosis
Authors: Chitayat David , McGillivray Barbara C. , Wood Steven , Kalousek Dagmar K. , Langlois Sylvie , Applegarth Derek A. , Opitz John M. , Reynolds James F.
Published: September 2005

We report on a patient with a de novo chromosome abnormality del(7)(q21.1q22). The cells of this patient were used to determine the assignment of the gene for the enzyme .β‐glucuronidase and the DNA probes around the cystic fibrosis gene—pJ3.11 and metH. Both the β‐glucuronidase gene and the DNA probes pJ3.11 and metH were found in 2 copies in our patient, indicating that neither locus lies in the deleted segment.
Spontaneous expression of fra(10)(q25) in bone marrow from a patient with agranulocytosis
Authors: Haney Susan M. , Butler Fred O. , Heerema Nyla A. , Opitz John M. , Reynolds James F.
Published: September 2005

We report on the spontaneous expression of fra(10)(q25) in bone marrow from a patient with agranulocytosis. Expression of this fragile site in both bone marrow and leukocytes was enhanced by bromodeoxyuridine (BrdU), while folic‐acid‐deficient medium enhanced the expression of fra(10)(q25) only in leukocytes. Variability in the expression of fra(l0)(q25) in bone marrow and leukocyte cultures over an 18‐month period was also found.
Laterality defects in conjoined twins: Implications for normal asymmetry in human embryogenesis
Authors: Cunniff Christopher , Jones Kenneth Lyons , Jones Marilyn C. , Saunders Brian , Shepard Thomas , Benirschke Kurt , Opitz John M. , Reynolds James F.
Published: September 2005

We evaluated six pairs of conjoined twins: four pairs were dicephalus, and two were of the ischiopagus type. In three of the four dicephalus pairs, the right twin had an abnormality of laterality that included a right aortic arch, reversed great vessel orientation, bilateral right‐sided isomerism of the lungs, asplenia, and situs inversus of the viscera. The left twin had normal great vessel orientation and situs solitus in each case. The finding that was unique in these three dicephalus twin pairs was their fused hearts, which were similar in orientation and configuration. The fourth dicephalus twin pair had one normally rotated heart, which was located in the midline and had normally placed chambers and great vessels. Each twin of this pair had normal visceral situs.

In the two pairs of ischiopagus twins, each pair had two separate hearts, with normal cardiac structure and great vessel relationships. The viscera expressed normal laterality. Documentation of a defect in laterality in the right twin in three conjoined twin pairs with fusion of the hearts, combined with the presence of normal laterality in three pairs without cardiac fusion, has implications regarding the mechanisms leading to laterality of the human embryo. We suggest that rotation of the heart initiates the embryo's process of lateralization and that the laterality defects of the viscera seen in the right twin are a result of their abnormal cardiac rotation.
Identification of carriers of Duchenne muscular dystrophy: Value of molecular analysis
Authors: LeRoy Bonnie S. , Uhrhammer Nancy A. , Steere Karyn J. , Boehm Corinne D. , King Richard A. , Rich Stephen S. , Williams Preston P. , Smith Stephen A. , de Martinville Bérengère , Reynolds James F.
Published: September 2005

Currently, molecular methods are the most accurate diagnostic tools for carrier detection and prenatal diagnosis of Duchenne muscular dystrophy (DMD). This report illustrates the value of molecular diagnosis as opposed to previous diagnostic methods, the need for frequent re‐evaluations as new methodologies develop, and the necessity for in‐depth genetic counseling. In Family 1, the proposita was predicted to be a carrier by an indirect assay (abnormal in vitro muscle ribosomal protein synthesis). DNA analysis using restriction fragment length polymorphisms (RFLPs) indicated that she was not a carrier. She gave birth to a predicted non‐affected male, who inherited the gene in question. In Family 2 the proposita, an obligate carrier, was initially evaluated by RFLP analysis. Two pregnancies were monitored by first trimester chorionic villous sampling. Re‐evaluation indicated that all affected individuals, including one of the embryos, carried a deletion of the dystrophin gene. The identification of an RFLP within the region containing the deletion allowed unambiguous determination of the carrier status of all individuals.
Origin of 46,XY/46,XY,r(19) mosaicism
Authors: Yung Jar‐Fee , Sobel Daniel B. , Hoo Joe J.
Published: September 2005

We report on a case of 46,XY/46,XY,r(19) mosaicism. The patient shows minimal clinical abnormality and the terminal deletions prerequisite for the ring formation are not microscopically discernible. The origin of the mosaicism is discussed. Firstly, the mosaicism may represent chimerism with a prezygotic origin of the ring chromosome; secondly, the ring chromosome could have arisen postzygotically; and thirdly, the ring could have been of a prezygotic origin with the apparently normal cells actually containing reopened rings. The consequences of these hypothesis on genetic counselling are discussed.
Two siblings with tel Hashomer camptodactyly and mitral valve prolapse
Authors: Toriello Helga V. , Higgins James V. , Malvitz Thomas , Waterman Donald F.
Published: September 2005

A brother and sister with Tel Hashomer camptodactyly and mitral valve prolapse are described. Mitral valve prolapse is heterogenous, but appears to occur more frequently in individuals with connective tissue disorders. The presence of mitral valve prolapse as a component manifestation of Tel Hashomer camptodactyly suggests that abnormal connective tissue is a pleiotropic effect of the mutant allele.
Fanconi anemia in black African children
Authors: Macdougall Lorna G. , Greeff Michael C. , Rosendorff Jennifer , Bernstein Renee
Published: September 2005

Fanconi anemia (FA) has rarely been reported in black children either in the United States or Africa. This report describes 25 black African children with FA seen in Johannesburg over an 11‐year period. The prevalence of homozygotes was estimated to be 1:476,000. Clinical manifestations, mean age at diagnosis, and hematologic and chromosome abnormalities were similar to those described in other ethnic groups. Response to androgens was poor and most patients required regular transfusions. Seventeen (68%) of the children died during the 11‐year observation period. Leukemia was the terminal event in 2 patients. The mean age at death was 9.8 years and the mean time between diagnosis and death 2.3 years. The poor response to androgens, high mortality, and early mean age at death would favor consideration of early bone marrow transplantation in these children.
Hutchinson‐Gilford progeria: Familial occurrence
Authors: Parkash H. , Sidhu S. S. , Raghavan R. , Deshmukh R. N.
Published: September 2005

We report on 2 brothers with Hutchinson‐Gil‐ford progeria. These patients have 2 unusual findings, i.e., marked resorption of the mandible along with loss of teeth in the elder sib and prolonged survival. Both sibs are still alive and active at the age of 32 and 24 years.
Apparent postnatal onset of some manifestations of the Wiedemann‐Beckwith syndrome
Authors: Chitayat David , Rothchild Avi , Ling Emily , Friedman J. M. , Couch Robert M. , Yong Siu‐Li , Baldwin Virginia J. , Hall Judith G.
Published: September 2005

We report on 2 patients who were apparently normal at birth but later developed characteristics of Wiedemann‐Beckwith syndrome (WBS). Both had hypoglycemia neonatally and gradually developed coarse facial changes, umbilical hernia, and macroglossia. Renal sonography done after the macroglossia developed showed large kidneys in both. The placentas were carefully examined in both cases but findings described as typical of WBS were only found in one.

The clinical evolution of these infants suggests that some WBS manifestations may have their onset postnatally in some cases. We postulate that the cellular hyperplasia and hypertrophy characteristic of WBS may be caused by persistent rests of embryonal cells that secrete paracrine and/or endocrine growth factors.
Boomerang dysplasia
Authors: Winship I. , Cremin B. , Beighton P.
Published: September 2005

Boomerang dysplasia is a recently delineated form of neonatally lethal dwarfism. A fourth case has been investigated and an increased range of phenotypic manifestations is documented in this article. So far all affected infants have been males and X‐linked recessive inheritance is possible. Diagnostic criteria for Boomerang dysplasia are outlined.
Chromosome evolution and high‐resolution analysis of leucocytes, bone marrow, and tumor cells of retinoblastoma patients
Authors: Lemieux Nicole , Richer Claude‐Lise
Published: September 2005

High‐resolution cytogenetics were applied to leucocytes, bone marrow, and tumors of 8 reti‐noblastoma (Rb) patients in search of microdeletions or subtle rearrangements and in order to determine clonal evolution. Four of 9 tumors (Rb1, Rb6.1, Rb6.2, and Rb8) showed a deletion in the characteristic region on 13q while 2 others (Rb3 and Rb4) were hemizygous for chromosome 13 in approximately one‐third of the cells. Our study presents a particularly high incidence of chromosome 13 anomalies as compared to the previously published data. Furthermore, comparison of karyotypes of 3 significant cases (Rb1, Rb6, and Rb8) allows the reconstruction of the necessary steps in the evolution of retino‐blastoma. It also shows the need for a double mutation in tumor development, both in hereditary and non‐hereditary cases. High‐resolution chromosome analysis of retinoblas‐toma patients provides a rare opportunity to study the succession of events necessary for tumor development.
Fraser syndrome with renal agenesis in two consanguineous Turkish families
Authors: Francannet C. , Lefrançois P. , Dechelotte P. , Robert E. , Malpuech G. , Robert J. M.
Published: September 2005

We report on 3 girls and one boy from 2 sib‐ships with Fraser syndrome and renal agenesis. They were born to consanguineous parents, which supports an autosomal recessive mode of inheritance.
Bone dysplasias: The prenatal diagnostic challenge
Authors: Escobar Luis F. , Bixler David , Weaver David D. , Padilla Lillie‐Mae , Golichowski Alan
Published: September 2005

The prenatal diagnosis of bone dysplasias presents difficult challenges for the clinician involved in monitoring pregnancies. Such diagnoses highlight delicate ethical issues and may require difficult decision‐making when the differential diagnosis includes a lethal bone dysplasia. Despite the rapid technological advances in ultrasonography, the ability to make prenatal diagnoses within this group of disorders is limited by the restricted ultrasonographic capability to appreciate fully the detailed fetal anatomy. However, we perceive that a significant further limitation involves the lack of a systematic protocol to guide the clinician in the ultrasonographic evaluation of a fetus suspected of having a skeletal dysplasia.

In an attempt to aid the clinician who is evaluating these suspected pregnancies, we report here 8 cases and propose a model protocol for the ultrasonographic diagnostic approach to fetal skeletal problems in utero.
Karyotype/phenotype controversy: Genetic and molecular implications of alternative hypotheses
Authors: Wilson Golder N.
Published: September 2005

Alternative explanations for aneuploid phenotypes are evaluated according to clinical and experimental predictions. The additive hypothesis views the diverse manifestations of aneuploidy as the simple sum of individual gene dosage effects. The interactive hypothesis views aneuploid characteristics as network properties of genes within and outside the aneuploid segment. The importance and historical context of this debate are emphasized, and the 2 hypotheses are contrasted in terms of their experimental predictions and explanatory power. In particular, the concepts of colinearity and continuity derived from single gene action are explicitly examined in human aneuploidy with the conclusion they are likely to be false assumptions.
Ambiguous genitalia in the Proteus syndrome
Authors: Frydman Moshe , Kauschansky Arieh , Varsano Itzhak
Published: September 2005

An 11‐year‐old girl was followed up since birth because of hemihypertrophy of the left leg and thigh, multiple pigmented nevi and subcutaneous tumors typical of the Proteus syndrome. Because of clitoromegaly and scrotal‐like hypertrophy of the labia majora, she had an endocrine evaluation the results of which were normal. The findings are thought to represent local genital hypertrophy. Ambiguous genitalia have to be added to the phenotype of the Proteus syndrome.
Trisomy 13 syndrome and neural tube defects
Authors: Rodríguez José Ignacio , García Marcial , Morales Carmen , Morillo Ana , Delicado Alicia
Published: September 2005

Abnormalities of the CNS, such as arhinen‐cephaly or holoprosencephaly, are common findings in trisomy 13 syndrome. However, neural tube defects (NTDs) are rarely reported. A review of 267 patients in the literature on reported CNS developmental defects in trisomy 13 syndrome showed only 6 patients with lumbosacral NTDs. No case of en‐cephalocele or anencephaly was found. We report on 3 patients with spina bifida from the records of 34 necropsies of karyotyped tri‐somy 13 syndrome, which were found among 403, 710 births.
The Cyclopes in Odysseus' Apologos
Authors: Bazopoulou‐Kyrkanidou Euterpe
Published: September 2005

In Homer's Odyssey, Odysseus narrates the lifestyle and behavior of the Cyclopes. They were no larger than life‐sized figures and lived in a land rich in natural products but cultivated nothing. They dwelled in caves, and their sociopolitical system was based on the family unit. There were no interfamilial congregations, institutions, or laws. They had no ships, nor were there any craftsmen who might build ships to visit the cities of other men. Perhaps the land of the Cyclopes described in Homer's Odyssey may have represented a place somewhat like the hospitals or islands which were used to isolate patients with leprosy. Otherwise, we can follow Thucydides' opinion: let it suffice, as the story has been told by poets, and each man has formed his own opinion about them. © 2005 Wiley‐Liss, Inc.
Fishing gear effects and ecology of the sea whip (Halipteris willemoesi (Cnidaria: Octocorallia: Pennatulacea)) in British Columbia, Canada: preliminary observations
Authors: Troffe Peter M. , Levings Colin D. , Piercey G. (Beth) E. , Keong Victor
Published: September 2005

We conducted a preliminary study of the effects of a shrimp beam trawl and prawn traps on sea whips (Halipteris willemoesi (Cnidaria: Octocorallia: Pennatulacea)) at two bays on Clio Channel, south central coast of British Columbia, Canada. Video and grabs surveys were conducted to estimate abundance and make observations on sea whips and their habitat.

No adult sea whips were caught in six beam trawls. In 600 prawn (Pandalus platyceros) trap sets at Turnour Bay, 30 sea whips were found entangled in the gear and of these 50% of the colonies were damaged. The length of broken sea whips ranged from 0.09 to 1.03 m. At Turnour Bay, the density of adults observed in video surveys ranged from 7.1 to 14.3 m−2. Juvenile density in grab samples ranged from 53 to 123 m−2 and a few adults were also caught. The lengths of intact adult sea whips caught in traps and grabs ranged from 0.20 to 1.98 m and juveniles from 0.3 to 0.7 cm.

Fewer adult sea whips (<0.1 m−2) were seen in Bones Bay, where sediments were muddier (grain size <0.25 mm: 84.6 to 97.2%) relative to Turnour Bay (grain size <0.25 mm: 71.4 to 85.9%). Bottom water characteristics at the two bays were similar. Seasonal temperature range was 7.5–8.4°C, salinity 30.63–31.49 psu, and dissolved oxygen 2.76–5.97 mg L−1. Differences in sediment characteristics and food availability may have been a factor influencing differences in abundance of sea whips between the two bays.

Further data are needed to investigate the effects of trawling and trapping on sea whips, as sample sizes were small in the present study and only two gear types were evaluated. Studies of effects of otter trawling and heavier traps, such as those used for Dungeness crab (Cancer magister), are warranted.

Copyright © 2005 John Wiley & Sons, Ltd.
Habitat preference modelling as a conservation tool: proposals for marine protected areas for cetaceans in southern Spanish waters
Authors: Cañadas A. , Sagarminaga R. , De Stephanis R. , Urquiola E. , Hammond P.S.
Published: September 2005

As part of a project to identify marine protected areas (MPAs) in Spanish Mediterranean waters, habitat preference models were developed using 11 years of survey data to provide predictions of relative density for cetacean species occurring off southern Spain.

Models for bottlenose, striped and common dolphin described, firstly, probability of occurrence (using GLMs) and, secondly, group size (using linear models) as predicted by habitat type defined by a range of physical and oceanographic covariates. Models for Risso's dolphin, long‐finned pilot, sperm and beaked whales used only the first stage because of data limitations.

Model results were used to define the boundaries of three proposed Special Areas of Conservation (SAC) (under the EU Habitats Directive) and one proposed Specially Protected Area of Mediterranean Importance (SPAMI) (under the Barcelona Convention).

The study illustrates the value of habitat preference modelling as a tool to help identify potential MPAs. The analyses incorporate environmental data in a spatial prediction that is an improvement over simpler descriptions of animal occurrence. Contiguous areas covering a specified proportion of relative abundance can readily be defined. Areas with apparently good habitat but few observations can be identified for future research or monitoring programmes.

Models can be refitted as new observations and additional environmental data become available, allowing changes in habitat preference to be investigated and monitoring how well MPAs are likely to be affording protection.

The study represents an important contribution to the implementation of the Habitats Directive by the Spanish government by providing a robust scientific basis for the definition of SAC and providing results to inform conservation objectives and management plans for these areas. The results identified areas that are important for a number of cetacean species, thus illustrating the potential for MPAs to improve cetacean conservation generally in the Alboran Sea, a region of great importance for supporting biodiversity and ecological processes in the wider Mediterranean Sea.

Copyright © 2005 John Wiley & Sons, Ltd.
The effects of introduced tilapias on native biodiversity
Authors: Canonico Gabrielle C. , Arthington Angela , McCrary Jeffrey K. , Thieme Michele L.
Published: September 2005

The common name ‘tilapia’ refers to a group of tropical freshwater fish in the family Cichlidae (Oreochromis, Tilapia, and Sarotherodon spp.) that are indigenous to Africa and the southwestern Middle East. Since the 1930s, tilapias have been intentionally dispersed worldwide for the biological control of aquatic weeds and insects, as baitfish for certain capture fisheries, for aquaria, and as a food fish. They have most recently been promoted as an important source of protein that could provide food security for developing countries without the environmental problems associated with terrestrial agriculture. In addition, market demand for tilapia in developed countries such as the United States is growing rapidly.

Tilapias are well‐suited to aquaculture because they are highly prolific and tolerant to a range of environmental conditions. They have come to be known as the ‘aquatic chicken’ because of their potential as an affordable, high‐yield source of protein that can be easily raised in a range of environments — from subsistence or ‘backyard’ units to intensive fish hatcheries. In some countries, particularly in Asia, nearly all of the introduced tilapias produced are consumed domestically; tilapias have contributed to basic food security for such societies.

This review indicates that tilapia species are highly invasive and exist under feral conditions in every nation in which they have been cultured or introduced. Thus, the authors have concluded that, despite potential or observed benefits to human society, tilapia aquaculture and open‐water introductions cannot continue unchecked without further exacerbating damage to native fish species and biodiversity. Recommendations include restricting tilapia culture to carefully managed, contained ponds, although exclusion is preferred when it is feasible. Research into culture of indigenous species is also recommended.

Copyright © 2005 John Wiley & Sons, Ltd.
Postnatal‐related changes in the size and total number of neurons in the caudal mesenteric ganglion of dogs: Total number of neurons can be predicted from body weight and ganglion volume
Authors: Gagliardo Karina Martinez , De Carvalho Balieiro Júlio César , De Souza Romeu Rodrigues , Ribeiro Antonio Augusto Coppi Maciel
Published: September 2005

Aging is mostly characterized by a progressive decline of neuronal function that involves both the central and the peripheral nervous system. The aging process is accompanied by changes in either the number or the size of neurons. However, these data are controversial and not very well known in the sympathetic ganglia of large mammals. Hence, the present investigation aimed to study the dog's caudal mesenteric ganglion (CMG) in three different periods of postnatal development, searching for qualitative and quantitative alterations. The CMG is responsible for the large intestine, internal anal sphincter, and partially the urogenital system innervations. Nine dead male dogs from the Veterinary Hospital of the College of Veterinary Medicine at University of São Paulo were divided into three well‐defined age groups (1–2 months old, 1–2 years old, and 5–10 years old). The stereological study was pursued using the physical disector method combined to the Cavalieri principle. The postnatal development was accompanied by an increase in the nonneuronal tissue amount and in ganglion volume. Additionally, the total number of neurons also increased during aging (from 70,140 to 1,204,516), although the neuronal density showed an opposite trend (from 29,911 to 11,500 mm−3). Due to the interrelation between either body weight or ganglion volume and aging in the dogs investigated in this study, it was possible to predict the total number of neurons in CMG using both body weight and ganglion volume in an attempt to verify whether or not size and total number of neurons are both allometrically and aging ruled, i.e., if either the animal's body weight and ganglion volume or aging influence these parameters. The prediction of the total number of neurons was very close to the initially estimated values. © 2005 Wiley‐Liss, Inc.
Stereology and ultrastructure of the salivary glands of diabetic Nod mice submitted to long‐term insulin treatment
Authors: Caldeira Eduardo José , Camilli José Angelo , Cagnon Valéria Helena Alves
Published: September 2005

Insulin‐dependent diabetes mellitus compromises the salivary glands, altering their morphology and the mechanisms of salivation, which are fundamental for oral health. Thus, the aim of the present study was to determine the effects of prolonged insulin treatment on the morphology of the salivary glands in Nod mice. Forty‐five female mice were divided into five groups: nine positive diabetic Nod mice for 10 days (group 1), nine positive diabetic Nod mice for 20 days (group 2), nine diabetic Nod mice for 10 days (group 3), nine diabetic Nod mice for 20 days (group 4), and nine nondiabetic BALB/c mice (group 5). Animals of groups 3 and 4 received 4–5 U of insulin daily, whereas animals of groups 1, 2, and 5 received the same dose of physiological saline simulating the experimental conditions. Samples of the salivary glands were analyzed by light, transmission, and scanning electron microscopies. The results showed intense alterations in diabetic animals characterized by nuclear and cytoplasmic atrophy, biomembrane disorganization, an increase in fibrillar components of the extracellular matrix, and the presence of inflammatory cells. Insulin treatment exerted positive effects on the recovery of the changes resulting from the diabetic state in both parotid and submandibular glands but the pattern continued to be altered. It can be concluded that, in addition to compromising the processes of tissue maintenance and renewal, tissue destructuring leads to alterations in functional mechanisms in both diabetic animals and animals submitted to glycemic control. © 2005 Wiley‐Liss, Inc.
The Pediatric Rheumatology International Trials Organization criteria for the evaluation of response to therapy in juvenile systemic lupus erythematosus: Prospective validation of the disease activity core set
Authors: Ruperto Nicolino , Ravelli Angelo , Cuttica Ruben , Espada Graciela , Ozen Seza , Porras Oscar , Sztajnbok Flavio , Falcini Fernanda , Kasapcopur Ozgur , Venning Helen , Bica Blanca , Merino Rosa , Coto Cecilia , Ros Joan , Susic Gordana , Gamir María Luz , Minden Kirsten , See Yvonne , Uziel Yosef , Mukamel Masha , Riley Phil , Zulian Francesco , Olivieri Alma Nunzia , Cimaz Rolando , Girschick Hermann , Rumba Ingrida , Cavuto Silvio , Pistorio Angela , Lovell Daniel J. , Martini Alberto
Published: September 2005

Objective

To validate and promulgate a core set of outcome measures for the evaluation of response to treatment in patients with juvenile systemic lupus erythematosus (SLE).

Methods

In 2001, a preliminary consensus‐derived core set of measures for evaluating the response to therapy in juvenile SLE was established. In the present study, the core set was validated through an evidence‐based, large‐scale data collection process that led to the enrollment of 557 patients from 39 different countries. Consecutive patients with active disease were assessed at baseline and after 6 months. The validation procedures included assessment of feasibility, responsiveness, discriminant and construct ability, agreement in the evaluation of response to therapy between physicians and parents, redundancy, internal consistency, and ability to predict a therapeutic response.

Results

The following clinical measures were found to be feasible and to have good construct validity, discriminative ability, and internal consistency; furthermore, they were not redundant, proved responsive to clinically important changes in disease activity, and were associated strongly with treatment outcome and thus were included in the final core set: 1) physician's global assessment of disease activity, 2) global disease activity measure, 3) 24‐hour proteinuria, 4) parent's global assessment of the patient's overall well‐being, and 5) health‐related quality of life assessment.

Conclusion

The members of PRINTO propose a core set of criteria for the evaluation of response to therapy that is scientifically and clinically relevant and statistically validated. The core set will help standardize the conduct and reporting of clinical trials and assist practitioners in deciding whether a patient with juvenile SLE has responded adequately to therapy.
Remission and active disease in rheumatoid arthritis: Defining criteria for disease activity states
Authors: Aletaha Daniel , Ward Michael M. , Machold Klaus P. , Nell Valerie P. K. , Stamm Tanja , Smolen Josef S.
Published: September 2005

Objective

Several composite scores are available to assess the activity of rheumatoid arthritis (RA). Criteria for remission and active RA based on these continuous scores are important for use in clinical practice and clinical trials. We aimed to reevaluate or to define such criteria for the Disease Activity Score in 28 joints (DAS28) and the Simplified Disease Activity Index (SDAI).

Methods

We sampled patient profiles from an observational RA database that included clinical and laboratory variables. Thirty‐five rheumatology experts classified these profiles into 1 of 4 categories: remission, low, moderate, or high disease activity. Cutoff values were estimated by mapping scores on the DAS28 and SDAI to these ratings, and analyses of agreement (kappa statistics) and a diagnostic testing approach (receiver operating characteristic curves) were used to validate the estimates. The final criteria were validated using 2 observational cohorts (a routine cohort of 767 patients and an inception cohort of 91 patients).

Results

Results from the 3 analyses were very similar and were integrated. The criteria for separating remission, low, moderate, and high disease activity based on the SDAI were scores of 3.3, 11, and 26, respectively; those based on the DAS28 were scores of 2.4, 3.6, 5.5, respectively. In the routine cohort, these cutoff values showed substantial agreement (weighed κ = 0.70) and discriminated between groups of patients with clearly different functional capacities (P < 0.001). In the inception cohort, these cutoff scores differentiated responders (those with a 20% response on the American College of Rheumatology improvement criteria) from nonresponders (P < 0.01), as well as patients with and without radiologic progression (P < 0.05).

Conclusion

New criteria for levels of RA disease activity were determined and internally validated. These criteria, which are based on current and explicit expert judgment, are valuable in this era of rapidly advancing therapeutic approaches.
The presence of molecular markers of in vivo lipid peroxidation in osteoarthritic cartilage: A pathogenic role in osteoarthritis
Authors: Shah Rahul , Raska Karel , Tiku Moti L.
Published: September 2005

Objective

To investigate the role of oxidative functions in human osteoarthritic (OA) chondrocytes and to investigate the presence of in vivo molecular markers of lipoxidation in OA cartilage.

Methods

An in vitro model of cartilage collagen degradation was used. Lipid peroxidation activity and overall oxidative function in OA chondrocytes were monitored by cis‐parinaric acid and dichlorofluorescein assays, respectively. In vivo molecular markers of lipoxidation in normal and OA cartilage were studied using immunohistochemistry to detect the presence of malondialdehyde and hydroxynonenal adducts.

Results

Human OA chondrocytes showed a robust amount of 3H‐proline–labeled collagen degradation upon stimulation with lipopolysaccharide and calcium ionophore A21387, as compared with that in untreated OA chondrocytes. Primary OA chondrocytes showed both spontaneous and inducible levels of lipid peroxidation activity. However, lipid peroxidation activity was already maximally elevated in more than 50% of the OA chondrocyte samples. Overall, spontaneous and inducible oxidative activities were observed in all OA samples. Immunohistochemical analysis of control OA tissue sections that were not treated with monoclonal antibody showed little immunoreactivity. OA cartilage sections treated with monoclonal antibodies showed specific immunoreactivity on the cartilage surface, at sites of OA lesions, at the pericellular matrix, and at intra‐ and intercellular matrices. Normal cartilage sections showed faint surface reactivity.

Conclusion

Our observations suggest that human OA chondrocytes demonstrate spontaneous and inducible cell‐associated lipoxidative and nonlipoxidative activity. Lipoxidative activity appears to be enhanced in OA chondrocytes. The presence of molecular markers of in vivo lipid peroxidation was demonstrated in OA cartilage, suggesting its role in the pathogenesis of the disease.
Involvement of αvβ5 integrin–mediated activation of latent transforming growth factor β1 in autocrine transforming growth factor β signaling in systemic sclerosis fibroblasts
Authors: Asano Yoshihde , Ihn Hironobu , Yamane Kenichi , Jinnin Masatoshi , Mimura Yoshihiro , Tamaki Kunihiko
Published: September 2005

Objective

To confirm the involvement of αvβ5 in the self‐activation system in systemic sclerosis (SSc) fibroblasts.

Methods

Levels of αvβ5 expression were analyzed by immunoprecipitation. The promoter activity of the human α2(I) collagen gene was determined by transient transfection assay. Phosphorylation levels and DNA binding ability of Smad3 were investigated by immunoprecipitation and DNA affinity precipitation, respectively. The localization of active transforming growth factor β (TGFβ) was determined by coculture assay using TMLC cells (mink lung epithelial reporter cells that stably express a portion of the plasminogen activator inhibitor 1 promoter). The morphologic features of cells were determined by immunofluorescence analysis.

Results

Levels of αvβ5 expression were significantly elevated in SSc fibroblasts compared with normal fibroblasts. Treatment with anti‐αvβ5 antibody or β5 antisense oligonucleotide significantly reduced human α2(I) collagen gene promoter activity in SSc fibroblasts. In SSc fibroblasts pretreated with TGFβ1 antisense oligonucleotide, the exogenous latent TGFβ1 stimulation significantly increased human α2(I) collagen gene promoter activity; this effect was significantly reduced in the presence of anti‐αvβ5 antibody. Phosphorylation levels and DNA binding ability of Smad3 in SSc fibroblasts were significantly reduced by treatment with β5 antisense oligonucleotide. The luciferase activity of TMLC cells cocultured with SSc fibroblasts was significantly elevated compared with that of TMLC cells cocultured with normal fibroblasts and was significantly reduced in the presence of anti‐αvβ5 antibody. Anti‐αvβ5 antibody reversed the myofibroblastic features of SSc fibroblasts.

Conclusion

Up‐regulated expression of αvβ5 contributes to the establishment of autocrine TGFβ signaling in SSc fibroblasts through activation of endogenous latent TGFβ1.
Targeting interleukin‐15 in patients with rheumatoid arthritis: A proof‐of‐concept study
Authors: Baslund Bo , Tvede Niels , Danneskiold‐Samsoe Bente , Larsson Per , Panayi Gabriel , Petersen Joergen , Petersen Lars J. , Beurskens Frank J. M. , Schuurman Janine , van de Winkel Jan G. J. , Parren Paul W. H. I. , Gracie J. Alastair , Jongbloed Sarah , Liew Foo Y. , McInnes Iain B.
Published: September 2005

Objective

Interleukin‐15 (IL‐15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax‐IL15, a human IgG1 anti–IL‐15 monoclonal antibody, to neutralize exogenous and endogenous IL‐15 activity in vitro and to perform a phase I–II dose‐escalation trial with HuMax‐IL15 in patients with active RA.

Methods

Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax‐IL15. HuMax‐IL15 was administered to 30 RA patients who received no other disease‐modifying antirheumatic drugs in a 12‐week, dose‐ascending, placebo‐controlled, double‐blind, phase I–II proof‐of‐concept study.

Results

In vitro studies showed that HuMax‐IL15 suppressed proliferation and induced apoptosis in an IL‐15–dependent cell line, BDB2, and was capable of suppressing the release of interferon‐γ by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL‐15. Furthermore, HuMax‐IL15 F(ab′)2 fragments suppressed exogenous IL‐15–induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax‐IL15 can specifically neutralize several biologic effects of IL‐15 in synovial tissue in vitro. In a phase I–II clinical trial, HuMax‐IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%).

Conclusion

These clinical data suggest for the first time that IL‐15 could represent a novel therapeutic target in RA.
Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg‐Strauss syndrome
Authors: Sinico Renato A. , Di Toma Lucafrancesco , Maggiore Umberto , Bottero Paolo , Radice Antonella , Tosoni Cinzia , Grasselli Chiara , Pavone Laura , Gregorini Gina , Monti Stefano , Frassi Micol , Vecchio Filomena , Corace Caterina , Venegoni Emanuela , Buzio Carlo
Published: September 2005

Objective

Churg‐Strauss syndrome (CSS) is classified among the so‐called antineutrophil cytoplasmic antibody–associated systemic vasculitides (AASVs) because of its clinicopathologic features that overlap with the other AASVs. However, while antineutrophil cytoplasmic antibodies (ANCAs) are consistently found in 75–95% of patients with Wegener's granulomatosis or microscopic polyangiitis, their prevalence in CSS varies widely and their clinical significance remains uncertain. We undertook this study to examine the prevalence and antigen specificity of ANCAs in a large cohort of patients with CSS. Moreover, we evaluated the relationship between ANCA positivity and clinicopathologic features.

Methods

Immunofluorescence and enzyme‐linked immunosorbent assay were used to determine the presence or absence of ANCAs in 93 consecutive patients at the time of diagnosis. The main clinical and pathologic data, obtained by retrospective analysis, were correlated with ANCA status.

Results

ANCAs were present by immunofluorescence in 35 of 93 patients (37.6%). A perinuclear ANCA (pANCA) pattern was found in 26 of 35 patients (74.3%), with specificity for myeloperoxidase (MPO) in 24 patients, while a cytoplasmic ANCA pattern, with specificity for proteinase 3, was found in 3 of 35 patients (8.6%). Atypical patterns were found in 6 of 30 patients with anti‐MPO antibodies (20.0%). ANCA positivity was associated with higher prevalences of renal disease (51.4% versus 12.1%; P < 0.001) and pulmonary hemorrhage (20.0% versus 0.0%; P = 0.001) and, to a lesser extent, with other organ system manifestations (purpura and mononeuritis multiplex), but with lower frequencies of lung disease (34.3% versus 60.3%; P = 0.019) and heart disease (5.7% versus 22.4%; P = 0.042).

Conclusion

ANCAs are present in ∼40% of patients with CSS. A pANCA pattern with specificity for MPO is found in most ANCA‐positive patients. ANCA positivity is mainly associated with glomerular and alveolar capillaritis.
Serum pulmonary and activation‐regulated chemokine/CCL18 levels in patients with systemic sclerosis: A sensitive indicator of active pulmonary fibrosis
Authors: Kodera Masanari , Hasegawa Minoru , Komura Kazuhiro , Yanaba Koichi , Takehara Kazuhiko , Sato Shinichi
Published: September 2005

Objective

To clarify the clinical significance of serum levels of pulmonary and activation‐regulated chemokine (PARC) in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc) and to compare PARC levels with KL‐6 antigen or surfactant protein D (SP‐D) levels.

Methods

Serum PARC levels were determined by enzyme‐linked immunosorbent assay in 123 SSc patients. In a retrospective longitudinal study, correlation of serum PARC levels with the activity of PF was assessed in 21 SSc patients with active PF.

Results

PARC levels at the first visit were higher in patients with SSc than in patients with systemic lupus erythematosus (SLE) or healthy controls. Increased serum PARC levels were associated with involvement of PF, decreased diffusing capacity for carbon monoxide, and decreased vital capacity in SSc patients. In the longitudinal study, serum PARC levels were significantly decreased in SSc patients with inactive PF compared with those with active PF.

Conclusion

Elevated serum PARC levels correlated with PF and more sensitively reflected the PF activity than did serum KL‐6 or SP‐D levels in SSc. Serum PARC levels may be a useful new serum marker for active PF in SSc.
Use of a gonadotropin‐releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus
Authors: Somers Emily C. , Marder Wendy , Christman Gregory M. , Ognenovski Vladimir , McCune W. Joseph
Published: September 2005

Objective

Cyclophosphamide (CYC) therapy for systemic lupus erythematosus (SLE), a disease predominantly affecting women of childbearing age, causes an unacceptably high incidence of irreversible premature ovarian failure (POF). This study was performed to evaluate the effectiveness of depot leuprolide acetate, a synthetic gonadotropin‐releasing hormone analog (GnRH‐a), for protection against POF during CYC therapy.

Methods

Young women with severe SLE treated in a standardized protocol of monthly intravenous bolus CYC were offered treatment with GnRH‐a (depot leuprolide acetate; a 3.75‐mg monthly injection during the standard CYC regimen). Patients treated with GnRH‐a were compared with controls individually matched by age (±5 years) and by cumulative CYC dose (±5 gm). Reproductive status was determined after a minimum followup of 3 years after CYC therapy. The primary outcome was time to POF. Paired summary statistical analyses, Kaplan‐Meier survival estimates, and Cox regression analyses were performed to assess differences in outcome between groups.

Results

POF developed in 1 of 20 women treated with GnRH‐a (5%) compared with 6 of 20 controls (30%) matched by age and cumulative CYC dose (matched odds ratio 0.09, P < 0.05). Kaplan‐Meier estimates demonstrated improved cumulative ovarian protection over time in the GnRH‐a–treated group (P = 0.04).

Conclusion

Treatment with GnRH‐a during CYC therapy was associated with a significant reduction of POF in young women with severe SLE.