bluuebunny/crossref_metadata_2025 huggingface dataset:
High-mobility group A2 gene expression is frequently induced in non-functioning pituitary adenomas (NFPAs), even in the absence of chromosome 12 polysomy
Authors: Pierantoni Giovanna Maria , Finelli Palma , Valtorta Emanuele , Giardino Daniela , Rodeschini Ornella , Esposito Francesco , Losa Marco , Fusco Alfredo , Larizza Lidia
Published: December 2005

The high-mobility group A2 (HMGA2) gene has a critical role in benign tumors where it is frequently rearranged, and in malignant tumors, where it is overexpressed in the absence of structural modification of the HMGA2 locus. By previous fluorescence in situ hybridization (FISH) and reverse transcriptase PCR analyses on human prolactin-secreting pituitary adenomas we detected rearrangement of the HMGA2 gene and amplification of its native region associated with activated expression. These data indicated a role for the HMGA2 gene in the development of human pituitary prolactinomas, since they are consistent with the appearance of prolactin/growth hormone adenomas in transgenic mice overexpressing the HMGA2 gene. To assess a more general role for HMGA2 in pituitary oncogenesis, we investigated HMGA2 amplification and expression in a panel of non-functioning pituitary adenomas (NFPAs) which account for 25% of all pituitary adenomas. We provide evidence that out of 18 NFPA tumors tested, 12 expressed HMGA2, but, different from prolactinomas, only in two cases the upregulation of the gene could be associated with amplification and/or rearrangement of the HMGA2 locus. Increased dosage of chromosome 12 was found in the expressing and non-expressing NFPAs, confirming that this sole event is insufficient to drive up activation of the HMGA2 gene. A role for chromosome 12 polysomy to promote structural instability of HMGA2 is confirmed, but the mechanism via trisomy is less prevalent in the frequently diploid NFPAs than in the usually hyperdiploid prolactinomas. Micro-rearrangements of HMGA2 gene not detectable by FISH analysis and/or sequence alterations could contribute to upregulation of HMGA2 gene in pituitary adenomas of the NFPA subtype. However, it cannot be excluded that the HMGA2 overexpression may be due, in some NFPA patients, to the same, still mainly unknown, mechanisms responsible for HMGA2 overexpression in malignant neoplasias.
Zoledronic acid cooperates with a cyclooxygenase-2 inhibitor and gefitinib in inhibiting breast and prostate cancer
Authors: Melisi Davide , Caputo Rosa , Damiano Vincenzo , Bianco Roberto , Veneziani Bianca Maria , Bianco A Raffaele , De Placido Sabino , Ciardiello Fortunato , Tortora Giampaolo
Published: December 2005

Biphosphonates (BPs) are widely used to inhibit osteoclastic activity in malignant diseases such as bone metastatic breast and prostate carcinoma. Recent studies reported that BPs could also cause a direct antitumor effect, probably due to their ability to interfere with several intracellular signalling molecules. The enzyme cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) play an important role in the control of cancer cell growth and inhibitors of COX-2 and EGFR have shown antitumor activity in vitro and in vivo in several tumor types. We, and others, have previously shown that EGFR and COX-2 may be directly related to each other and that their selective inhibitors may have a cooperative effect. In the present study we have evaluated the combined effect of zoledronic acid, the most potent nitrogen-containing BP, with the COX-2 inhibitor SC-236 and the selective EGFR-tyrosine kinase inhibitor gefitinib, on breast and prostate cancer models in vitro and in xenografted nude mice. We show that combination of zoledronic acid with SC-236 and gefitinib causes a cooperative antitumor effect accompanied by induction of apoptosis and regulation of the expression of mitogenic factors, proangiogenic factors and cell cycle controllers both in vitro and in xenografted nude mice. The modulatory effect on protein expression and the inhibitory effect on tumor growth is much more potent when the three agents are used together. Since studies are ongoing to explore the antitumor effect of zoledronic acid, our results provide new insights into the mechanism of action of these agents and a novel rationale to translate this feasible combination treatment strategy into a clinical setting.
Emerging role of the endothelin axis in ovarian tumor progression
Authors: Bagnato Anna , Spinella Francesca , Rosanò Laura
Published: December 2005

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and the ET receptors, ETAR and ETBR, represents a novel target in tumor treatment. ET-1 may directly contribute to tumor growth and indirectly modulate tumor–host interactions in various tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, Kaposi’s sarcoma, brain tumors and melanoma. Extensive experimental evidence links ETAR overexpression with tumor progression in ovarian cancer. ETAR engagement can in fact activate multiple signal transduction pathways including protein kinase C, phosphati-dylinositol 3-kinase, mitogen-activated protein kinase and transactivate epidermal growth factor receptor, which play a role in ovarian tumor growth and invasion. The effects of ETAR signaling are wide ranging and involve both cancer cells and their surrounding stroma, including the vasculature. Upon being activated, the ETAR mediates multiple tumor-promoting activities, including enhanced cell proliferation, escape from apoptosis, angiogenesis, epithelial–mesenchymal transition and increased motility and invasiveness. These findings indicate that activation of ETAR by ET-1 is a key mechanism in the cellular signaling network promoting ovarian cancer growth and progression. The predominant role played by ETAR in cancer has led to the development of small molecules that antagonize the binding of ET-1 to ETAR. The emerging preclinical data presented here provide a rationale for the clinical evaluation of these molecules in which targeting the related signaling cascade via ETAR blockade may be advantageous in the treatment of advanced stage ovarian carcinoma.
Increased risk of ovarian cancer in integrin β3 Leu33Pro homozygotes
Authors: Bojesen S E , Kjær S K , Høgdall E V S , Thomsen B L , Høgdall C K , Blaakær J , Tybjærg-Hansen A , Nordestgaard B G
Published: December 2005

We previously demonstrated that integrin β3 Leu33Pro homozygotes have an increased risk of cancer, possibly most pronounced for ovarian cancer. We now test the latter hypothesis in case-control and prospective studies. We genotyped 463 Danish women with ovarian cancer, and 4291 women from the Danish general population. Calculation of odds ratios by conditional logistic regression was performed in the case-control study (n=463 + 3543), and of ovarian cancer incidence, log-rank statistics and hazard ratios by Cox regression in the prospective study (n=4291) with 9.5-year follow-up. In the case-control study matched for age and marital status, the odds ratio for ovarian cancer in homozygotes versus non-carriers was 1.6 (95% confidence interval: 1.0–2.6). In the prospective study with 28 incident ovarian cancers, non-carriers and homozygotes had incidences of 7 (4–11) and 30 (10–92) per 10 000 person-years (log-rank P=0.02). The age-adjusted hazard ratio for ovarian cancer in homozygotes versus non-carriers was 3.9 (1.1–13). Risk of ovarian cancer did not differ between heterozygotes and non-carriers in either study. Integrin β3 Leu33Pro homozygotes have an increased risk of ovarian cancer.
Advanced level‐adaptive overdrive (ALAO) method applicable to full‐HD LC TVs
Authors: Okumura Haruhiko , Baba Masahiro , Taira Kazuki , Kinno Akira
Published: December 2005

Abstract— In this paper, we report on the development of an advanced level‐adaptive overdrive (ALAO) method applicable to full‐HD LC TVs, which makes it possible not only to reduce the gray‐level response time to less than one fourth, but also to improve the S/N ratio for still images by 10 dB; and further to reduce the circuit cost for the LAO method to almost half that of the prior LAO circuit. We have applied the ALAO method to a full‐HD LC front projector with 1.84 Mpixels and a screen size larger than 100 in., and we obtained high‐quality full‐HD moving images.
Refractive‐index matching between liquid crystals and photopolymers
Authors: Li Jun , Baird Greg , Lin Yi‐Hsin , Ren Hongwen , Wu Shin‐Tson
Published: December 2005

Abstract— Refractive indices of two photocurable polymers, NOA65 and NOA81 (Norland Optical Adhesive), and two series of Merck liquid crystals, E‐series (E44, E48, and E7) and BL‐series (BL038, BL003 and BL006), and two UCF high‐birefringence liquid‐crystal mixtures were measured using an Abbe refractometer in the visible spectral region and 15–55°C temperature range. Some liquid crystals have excellent index matching with NOA65 in the red, while some fit better in the blue spectral region. To validate this index‐matching property found in the material level, we prepared some polymer‐dispersed liquid‐crystal devices. Good correlations between material and device performances are obtained.
Altitude control in simulated flight using 3‐D objects and terrain texture
Authors: Patterson Robert , Geri George A. , Dyre Brian P. , Akhtar Shama C. , Covas Christine M. , Pierce Byron J.
Published: December 2005

Abstract— In this study, the effects of manipulating the properties of 3‐D objects and terrain texture on the control of altitude in simulated flight has been investigated. 3‐D objects were found to be as effective as terrain texture for controlling altitude, and this result was interpreted as suggesting that both terrain texture and 3‐D objects can serve as effective carriers of information about motion parallax and optical expansion and contraction. The present results, which were obtained using a vertically defined flight task, are inconsistent with the findings of Patterson et al., who reported that 3‐D objects were more effective than terrain texture for controlling a horizontally defined heading task. The present results indicate that, when terrain texture is present, the motion parallax or optical expansion associated with the presence of 3‐D objects does not improve altitude control.
Trastuzumab
Authors: Smith Ian E , Cross Susan G
Published: December 2005

Breast cancer is a heterogenous disease with several clinical and biologic subtypes. Human epidermal growth factor receptor 2 (HER 2) is overexpressed in approximately 20% of breast cancers. This overexpression is usually due to HER 2 gene amplification, and results in a more aggressive tumor with a worse prognosis. Trastuzumab (Herceptin®) is the first humanized monoclonal antibody to be commercially available for the treatment of breast cancer and it is directed against HER 2. Trials have demonstrated trastuzumab's activity in metastatic breast cancer both as a single agent and in combination with a number of chemotherapy agents. Recently, benefits for trastuzumab have also been shown in the neoadjuvant and adjuvant setting.
The Levonorgestrel Intrauterine System: Long-Term Contraception and Therapeutic Effects
Authors: Sitruk-Ware Regine , Inki Pirjo
Published: December 2005

The levonorgestrel intrauterine system (Mirena®) has been developed as a long-acting method of contraception. This medicated device, inserted into the uterus, delivers a small daily dose of a progestin, levonorgestrel, into the uterine cavity. It is one of the most effective methods of contraception and is approved in more than 100 countries for 5 years of use.
First-Generation Vaccines against Human Papillomavirus
Authors: Paavonen Jorma , Lehtinen Matti
Published: December 2005

There has been considerable progress in the development of a prophylactic human papillomavirus vaccine in the past 10 years, since the discovery of human papillomavirus virus-like particles. Licensure of the human papillomavirus vaccine is probably not far away. This would make it the first licensed vaccine against a common sexually transmitted infection. Although hepatitis B is a sexually transmitted infection for which there is an effective prophylactic vaccine, it is often not perceived as such by individuals taking the vaccine. Preclinical studies have already produced attractive vaccine candidates and recent clinical trials have yielded strikingly promising results. The candidate vaccines are generally well tolerated, induce high titers of serum antibodies to the human papillomavirus types and effectively prevent acquisition of infection and early clinical disease caused by common human papillomavirus types.
Anastrozole: A New Gold Standard of Hormonal Treatment for Breast Cancer?
Authors: Howell Anthony
Published: December 2005

Tamoxifen has long been the standard endocrine therapy for postmenopausal women with hormone-sensitive breast cancer. However, data now suggest that the third-generation aromatase inhibitors have emerged as superior alternatives for advanced disease. In early disease evaluation of initial adjuvant therapy, data from the Arimidex®, Tamoxifen, Alone and in Combination trial has shown that anastrozole is more effective than tamoxifen with a better risk–benefit profile. This trial provides the most mature data of any aromatase inhibitor study and suggests that anastrozole should be considered the preferred initial adjuvant therapy for postmenopausal women with hormone-responsive early breast cancer. The emergence of aromatase inhibitors as an alternative to tamoxifen for the treatment of breast cancer is challenging the management of the disease and influencing the change of regulatory guidelines.
Darifenacin for the Treatment of Overactive Bladder
Authors: Haab François
Published: December 2005

Overactive bladder is a debilitating disorder affecting 16.5% of adults and increasing in prevalence with age. Symptoms, including urgency, urge incontinence and frequency can result from detrusor overactivity with contraction of the bladder mediated primarily by activation of muscarinic M3 receptors. Antimuscarinic agents are therefore an important approach to treating overactive bladder, but a lack of M3 receptor subtype selectivity with these agents can generate a range of side effects that limits their effectiveness. This review describes an alternative approach to treating overactive bladder using the selective muscarinic M3 receptor antagonist darifenacin. The M3 receptor selectivity of darifenacin improves the symptoms of overactive bladder while reducing the potential for deleterious effects of non-M3 muscarinic receptor antagonism in the brain or heart. The pharmacology and pharmacokinetics of darifenacin are summarized, and the its clinical efficacy and demonstrated safety profile are described.
The Role of Proteomics in the Diagnosis and Treatment of Ovarian Cancer
Authors: Tchabo Nana E , Guancial Elizabeth A , Czechowicz Josephine A , Kohn Elise C
Published: December 2005

Ovarian cancer is the leading cause of gynecologic cancer death in the Western world and more than 70% of patients are diagnosed with advanced stage disease. The high mortality rate is due to the difficulty in the early detection of ovarian cancer. Current screening strategies lack the necessary sensitivity and specificity to reliably and accurately diagnose affected women, prompting investigators to seek alternative means of analysis found in protein pathways and networks. Proteomics seeks to advance the understanding of how proteins interact in cancer and may provide a mechanism for early stage diagnosis. The proteomic techniques of laser capture microdissection, mass spectrometry and tissue lysate arrays have led to the discovery of new biomarkers and the identification, development and approval of a number of targeted therapeutic agents. Following validation through clinical trials, the application of these techniques will contribute to the changing paradigm of cancer detection and treatment toward personalized medicine.
A Western Primer of Chinese Herbal Therapy in Endometriosis and Infertility
Authors: Burks-Wicks Carla , Cohen Misha , Fallbacher Josef , Taylor Robert N , Wieser Fritz
Published: December 2005

Endometriosis is a disease that affects approximately 10% of all reproductive-aged women and the prevalence rises to 20–50% in infertile women. There is growing evidence that medicinal Chinese herbs with pain-alleviating and anti-inflammatory properties may be useful in the treatment of endometriosis and infertility, but the mechanisms of action of these herbs have yet to be investigated. In addition, studies of adequate design, sample size and appropriate control are lacking. Therefore, prospective randomized, controlled studies to evaluate the efficacy, mechanism of action and toxicities of Chinese herbs in the treatment endometriosis and infertility are needed.
Overview on Rodent Models of Alzheimer's Disease
Authors: Dodart Jean‐Cosme , May Patrick
Published: December 2005

In Alzheimer's disease (AD), characteristic lesions develop in brain regions that subserve cognitive functions, ultimately leading to dementia. There are now several lesioned or transgenic small‐animal models of the disease that model select aspects of cognitive deficits and/or recapitulate many, but not all, of the characteristic pathologic lesions observed in AD. This overview describes the most common approaches used to model AD in rodents, highlights their utility, and discusses some of their deficiencies.
Parenteral Injections
Authors: Donovan John , Brown Patricia
Published: December 2005

This unit describes the techniques for the following routes of injection for mice, rats, hamsters and rabbits: intramuscular, intradermal, subcutaneous, intravenous, intraperitoneal, footpad, and intrathymic. Guidelines are also given regarding injection volumes and temperatures, and the use of proper restraints.
Blood Collection
Authors: Donovan John , Brown Patricia
Published: December 2005

Blood is most frequently sampled for evaluation of serum antibodies or analysis of surface markers on peripheral blood cells. The protocols offered in this unit describe collection of blood from the orbital sinus or plexus of the mouse, rat, or hamster. With appropriate techniques, small amounts of blood can be obtained with little ill effect on the animal. Collection from the auricular vein or artery of the rabbit is also relatively unstressful to the animal. Bleeding procedures that should be performed on the anesthetized animal include collection from the mouse axillary plexus, cardiac puncture of the mouse, rat, hamster, or rabbit, and collection from the hamster abdominal aorta or vena cava.
Brief communication: The collection of identified human skeletons housed at the Bocage Museum (National Museum of Natural History), Lisbon, Portugal
Authors: Cardoso Hugo F.V.
Published: December 2005

A large collection of identified human skeletons curated at the Bocage Museum (National Museum of Natural History, Lisbon, Portugal) has remained in relative anonymity since its collecting protocol was initiated in the 1980s. This collection originates from modern cemetery sources and is comprised of 1,692 skeletons with basic documentary data (age at death, place of birth, occupation, place of residence, and date and cause of death). At present, this information is more readily available for 699 individuals. The remaining 993 are in the process of being fully documented. The skeletons consist largely of Portuguese nationals who lived in the 19th and 20th centuries (1805–1975) in Lisbon. Both sexes are equally represented, and ages at death range from birth to 98 years, including 92 subadults (<20 years old). Am J Phys Anthropol, 2006. © 2005 Wiley‐Liss, Inc.
Dental fluctuating asymmetry in the Gullah: Tests of hypotheses regarding developmental stability in deciduous vs. permanent and male vs. female teeth
Authors: Guatelli‐Steinberg Debbie , Sciulli Paul W. , Edgar Heather H.J.
Published: December 2005

In this investigation, deciduous teeth (canines, c; first molars, m1; second molars, m2) and their permanent successors (canines, C; first premolars, P1; second premolars, P2) were used to test two related hypotheses about fluctuating asymmetry (FA). First, based on the biology of the developing dentition, it was predicted that deciduous teeth would be more developmentally stable and thus exhibit less dimensional FA than their permanent successors. Second, based on sex differences in tooth development, it was predicted that female canines would have greater developmental stability (less FA) than male canines. Bucco‐lingual measurements were made on dental casts from a single Gullah population. Using a repeated‐measures study design (n = 3 repeated measures), we tested these hypotheses on sample sizes ranging from 63–82 antimeric pairs. Neither hypothesis was supported by our data. In most cases, Gullah deciduous teeth did not exhibit statistically significantly less FA than their permanent successors; indeed, statistically significant differences were found for only 3 of 12 deciduous vs. permanent contrasts, and in two cases, the deciduous tooth had greater FA. Female mandibular canines exhibited statistically significantly greater FA than those of males, while there was no statistically significant sex difference in FA for the maxillary canine. FA in these Gullah samples is high when compared to Archaic and late prehistoric Ohio Valley Native Americans, consistent with historical and archaeological evidence that environmental stress was relatively higher in the Gullah population. We suggest that when environmental stress in a population is high, the impact of differences in tooth formation time spans and developmental buffering upon FA may be minor relative to the effect of developmental noise. Am J Phys Anthropol, 2006 © 2005 Wiley‐Liss, Inc.
Edge effects and their influence on lemur density and distribution in Southeast Madagascar
Authors: Lehman Shawn M. , Rajaonson Andry , Day Sabine
Published: December 2005

Edge effects are caused by the penetration of abiotic and biotic conditions from the matrix into forest interiors. Although edge effects influence the biogeography of many tropical organisms, they have not been studied directly in primates. Edge effects are particularly relevant to lemurs due to the loss of 80–90% of forests in Madagascar. In this study, data are presented on how biotic edge effects influenced the distribution and density of lemurs in the Vohibola III Classified Forest in southeastern Madagascar. In total, 415 lemur surveys were conducted during June–October 2003 and May–September 2004 along six 1,250‐m transects that ran perpendicular to the forest edge. Data were also collected on lemur food trees along the six transects (density, height, diameter at breast height, area, volume, and distance to forest edge). Four nocturnal species (Avahi laniger, Cheirogaleus major, Lepilemur microdon, and Microcebus rufus) and four diurnal species (Eulemur rubriventer, Eulemur fulvus rufus, Hapalemur grisesus griseus, and Propithecus diadema edwardsi) were sighted during surveys. Regression analyses of lemur densities as a function of distance to forest edge provided edge tolerances for A. laniger (edge‐tolerant), M. rufus (edge‐tolerant), E. rubriventer (edge‐tolerant or omnipresent), and H. g. griseus (omnipresent). The density and distribution of M. rufus and their foods trees were correlated. Edge‐related variations in food quality and predation pressures may also be influencing lemurs in Vohibola III. Tolerance for edge effects may explain, in part, how lemurs have survived extreme habitat loss and forest fragmentation in southeastern Madagascar. Am J Phys Anthropol, 2006. © 2005 Wiley‐Liss, Inc.
Thermal constraints on activity scheduling and habitat choice in baboons
Authors: Hill Russell A.
Published: December 2005

The importance of thermoregulation as a constraint on behavior has received comparatively little attention in relation to other ecological factors. Despite this, a number of studies suggested that high temperature may represent an important ecological constraint. This paper examines the impact of temperature on activity scheduling in a troop of chacma baboons (Papio hamadryas ursinus) at De Hoop Nature Reserve, South Africa. Once the daily, seasonal, and individual effects were controlled for, the “perceived environmental temperature” (PET), which accounts for the relative contributions of solar radiation, wind speed, and humidity on shade temperature, was a significant constraint on behavior. With high PET, feeding declines, and there is an increase in grooming and particularly resting behavior. Baboons thus engage in more sedentary behaviors as temperature increases, with significantly higher levels of resting and grooming when temperature exceeds the approximate thermal neutral zone for baboons. Seeking shade is an important behavioral response to thermal stress, and PET was a significant determinant of whether an animal was in shade while engaged in either resting or grooming behavior. Furthermore, the proportion of time spent in shade increased across air temperatures that were below, within, and above the thermal neutral zone for baboons. Finally, since resting and grooming are conducted preferentially in certain habitat types, thermoregulatory considerations also impact on patterns of habitat choice and day‐journey routes. This suggests that the thermal environment is an ecological variable that should be given greater consideration in future studies of primate behavior. Am J Phys Anthropol, 2006. © 2005 Wiley‐Liss, Inc.
Skeletal manifestations of infantile scurvy
Authors: Brickley Megan , Ives Rachel
Published: December 2005

Recent investigations of human skeletal material from the historic St. Martin's cemetery, England, found a range of abnormal lesions in six infants that are almost certainly related to scurvy. Porous and proliferative bone lesions affecting the cranial bones and scapulae were found, and this paper presents images obtained using both macroscopic and scanning electron microscope examination of the lesions. Previous work on infantile scurvy (Ortner et al., 1997–2001) relied heavily on changes at the sphenoid, which is often missing in archaeological bone, so the identification of changes attributable to scurvy on other cranial bones and the scapulae is encouraging. The ability to recognize changes related to scurvy on a range of bones will ensure an enhanced potential for recognition of this disease in future research involving archaeological bone. Research on historical documents from Birmingham dating to the eighteenth and nineteenth centuries, combined with the probable cases of scurvy identified, supports the view that the paucity of cases of infantile scurvy from the archaeological record reflects a lack of understanding and recognition of bone manifestations, rather than a lack of occurrence in this period. Changes linked to scurvy were only found in infants from the poorer sections of the community from St. Martin's, and this is almost certainly linked to patterns of food consumption and may be related to shortages of potatoes, due to blight, experienced during this period. Am J Phys Anthropol, 2006. © 2005 Wiley‐Liss, Inc.
Superquadric modeling of cranial and cerebral shape and asymmetry
Authors: Sommer H.J. , Eckhardt R.B. , Shiang T.Y.
Published: December 2005

A new method for quantifying cranial and cerebral shape and asymmetry fits symmetric superquadric geometric models to three‐dimensional coordinate measurements. Asymmetry is quantified as radial residuals of the surface data points from their best‐fit superquadric models. Twenty human crania, 10 magnetic resonance imaging (MRI) exocranial surfaces, and 10 corresponding MRI cerebral surfaces as well as two infant head casts were digitized and modeled using superquadrics. Superquadric parameters have simple geometric interpretation, are very reproducible, and demonstrated statistically significant differences between crania of Amerindian ancestry and MRI exocranial surfaces of European ancestry used in this study. Superquadric models demonstrated strong congruence between MRI exocranial and cerebral surfaces. Typical asymmetry was 1–5 mm. Lastly, polar contour plots of radial residuals for head casts before and after orthotic cranioplasty demonstrated the efficacy of using superquadrics to quantify positional plagiocephaly and synostosis of infant crania. Am J Phys Anthropol, 2006. © 2005 Wiley‐Liss, Inc.
Differential maternal and paternal contributions to the genetic pool of Ibiza Island, Balearic Archipelago
Authors: Tomàs C. , Jiménez G. , Picornell A. , Castro J.A. , Ramon M.M.
Published: December 2005

We report on a comparison of the genetic diversity between Ibiza and the population of the other Balearic islands and also between the archipelago with respect to circum‐Mediterranean populations. For such a comparison, autosomal and Y‐chromosome STRs, as well as mtDNA sequence data analyzed from the same individuals, were studied. Analysis of 14 autosomal STRs showed that Ibiza had significant differentiation with respect to other Balearic populations and also with respect to insular and continental populations from the Mediterranean area. Nevertheless, the results obtained from the analysis of eight Y‐STRs showed a high level of genetic homogeneity for eight western Mediterranean populations. On the other hand, these populations did not show a compacted group when mtDNA diversity was analyzed, since they showed genetic differentiation among them. The analyses of haplotypes shared between populations indicated that mtDNA haplotypes have drifted to higher frequencies than the Y chromosome. This fact could be due to a shared recent history between Ibiza and other western Mediterranean populations, with numerous male displacements originated by wars and, especially, commercial relations. The results of mtDNA from the Ibiza population could be due to a maternal Carthaginian/Phoenician founder effect, together with genetic drift, in accordance with the historical and demographic data of the area. Am J Phys Anthropol, 2006. © 2005 Wiley‐Liss, Inc.
Genetic structure of the Aleuts and Circumpolar populations based on mitochondrial DNA sequences: A synthesis
Authors: Zlojutro Mark , Rubicz Rohina , Devor Eric J. , Spitsyn Victor A. , Makarov Sergei V. , Wilson Kristin , Crawford Michael H.
Published: December 2005

The mtDNA variation of 198 Aleuts, as well as North American and Asian populations drawn from the literature, were analyzed to reconstruct the Aleuts' genetic prehistory and to investigate their role in the peopling of the Circumarctic region. From median‐joining network analysis, three star‐like clusters were identified in the Aleuts within the following subhaplogroups: A3, A7 (an Aleut‐specific subclade of A3), and D2. Mismatch analyses, neutrality test scores, and coalescent time estimates for these three components provided evidence of two expansion events, one occurring at approximately 19,900 B.P. and the other at 5,400 B.P. Based on these findings and evidence from the archaeological data, four general models for the genetic prehistory of the Aleutian Island chain are proposed: 1) biological continuity involving a kin‐structured peopling of the archipelago; 2) intrusion and expansion of a non‐native biface‐producing population dominated by subhaplogroup D2; 3) amalgamation of Arctic Small Tool tradition peoples characterized by D2 with an older Anangula substratum; and 4) biological continuity with significant gene flow from neighboring populations of the Alaskan mainland and Kodiak Island. The Aleut mtDNAs are consistent with the Circumarctic pattern by the fixation of A3 and D2, and the exhibition of depressed diversity levels relative to Amerind and Siberian groups. The results of this study indicate a broad postglacial reexpansion of Na‐Dene and Esko‐Aleuts from reduced populations within northern North America, with D2 representing a later infusion of Siberian mtDNAs into the Beringian gene pool. Am J Phys Anthropol, 2006. © 2005 Wiley‐Liss, Inc.
mtDNA microevolution in Southern Chile's archipelagos
Authors: García Federico , Moraga Mauricio , Vera Soledad , Henríquez Hugo , Llop Elena , Aspillaga Eugenio , Rothhammer Francisco
Published: December 2005

The genetic variability of four predominantly Indian populations of southern Chile's archipelagos was examined by determining the frequencies of four mitochondrial DNA haplogroups that characterize the American Indian populations. Over 90% of the individuals analyzed presented Native American mtDNA haplogroups. By means of an unweighted group pair method with arithmetic mean (UPGMA) dendrogram, a principal component analysis (PCA) derived from a distance matrix of mtDNA, and the exact test of population differentiation, we are able to prove the existence of a North‐South cline. The populations in the northern part of the archipelagos are genetically similar to the Huilliche tribe, while the groups from the South are most closely related to the Fueguino tribe from the extreme South of Chile, and secondarily to the Pehuenche and Mapuche, who are found to the North and East of Chiloé archipelago. These results are consistent with a colonization of the southern archipelagos from Tierra del Fuego. We evaluate the evolutionary relationships of the population of the Chiloé area to groups from other geographic areas of Chile, using analysis of molecular variance (AMOVA). Three Amerindian clusters are identified: one formed by the Aymará and Atacameño, a second by the Huilliche, and a third including the Mapuche, Pehuenche, and Fueguino tribes, and the population inhabiting the South of the Chiloé arcipelago. These groups exhibit a North‐South gradient in the frequency of haplogroup B, confirmed by FST tests. Am J Phys Anthropol, 2006 © 2005 Wiley‐Liss, Inc.
Is antibody clustering predictive of clinical subsets and damage in systemic lupus erythematosus?
Authors: To C. H. , Petri M.
Published: December 2005

Objective

To examine autoantibody clusters and their associations with clinical features and organ damage accrual in patients with systemic lupus erythematosus (SLE).

Methods

The study group comprised 1,357 consecutive patients with SLE who were recruited to participate in a prospective longitudinal cohort study. In the cohort, 92.6% of the patients were women, the mean ± SD age of the patients was 41.3 ± 12.7 years, 55.9% were Caucasian, 39.1% were African American, and 5% were Asian. Seven autoantibodies (anti–double‐stranded DNA [anti‐dsDNA], anti‐Sm, anti‐Ro, anti‐La, anti‐RNP, lupus anticoagulant (LAC), and anticardiolipin antibody [aCL]) were selected for cluster analysis using the K‐means cluster analysis procedure.

Results

Three distinct autoantibody clusters were identified: cluster 1 (anti‐Sm and anti‐RNP), cluster 2 (anti‐dsDNA, anti‐Ro, and anti‐La), and cluster 3 (anti‐dsDNA, LAC, and aCL). Patients in cluster 1 (n = 451), when compared with patients in clusters 2 (n = 470) and 3 (n = 436), had the lowest incidence of proteinuria (39.7%), anemia (52.8%), lymphopenia (33.9%), and thrombocytopenia (13.7%). The incidence of nephrotic syndrome and leukopenia was also lower in cluster 1 than in cluster 2. Cluster 2 had the highest female‐to‐male ratio (22:1) and the greatest proportion of Asian patients. Among the 3 clusters, cluster 2 had significantly more patients presenting with secondary Sjögren's syndrome (15.7%). Cluster 3, when compared with the other 2 clusters, consisted of more Caucasian and fewer African American patients and was characterized by the highest incidence of arterial thrombosis (17.4%), venous thrombosis (25.7%), and livedo reticularis (31.4%). By using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, the greatest frequency of nephrotic syndrome (8.9%) was observed in patients in cluster 2, whereas cluster 3 patients had the highest percentage of damage due to cerebrovascular accident (12.8%) and venous thrombosis (7.8%). Osteoporotic fracture (11.9%) was also more common in cluster 3 than in cluster 2.

Conclusion

Autoantibody clustering is a valuable tool to differentiate between various subsets of SLE, allowing prediction of subsequent clinical course and organ damage.
Amelioration of autoimmune nephritis by imatinib in MRL/lpr mice
Authors: Sadanaga Atsushi , Nakashima Hitoshi , Masutani Kohsuke , Miyake Katsuhisa , Shimizu Sakiko , Igawa Takashi , Sugiyama Naonobu , Niiro Hiroaki , Hirakata Hideki , Harada Mine
Published: December 2005

Objective

To examine whether the platelet‐derived growth factor (PDGF) receptor antagonist imatinib ameliorates glomerulonephritis in MRL/lpr mice, a condition that is similar to severe lupus nephritis in humans.

Methods

Sixteen‐week‐old MRL/lpr female mice having an advanced stage of glomerulonephritis were divided into 3 groups according to treatment: 1) 50 mg/kg or 2) 10 mg/kg of imatinib (administered orally 4 times a week up to 24 weeks of age) or 3) vehicle solution (untreated group). The histopathologic condition of the kidneys and salivary glands of each mouse as well as the cumulative survival rates, extent of lymphadenopathy and splenomegaly, and serum chemistry and immunologic values were assessed.

Results

In mice treated with 50 mg/kg imatinib, neither proliferation of glomerular cells nor crescent formation occurred. A drastic decrease in mesangial matrix was noted. Mice treated with 50 mg/kg imatinib had a prolonged life span compared with mice treated with 10 mg/kg imatinib and untreated mice. Expression of PDGF receptor and transforming growth factor β messenger RNA in the kidneys was significantly reduced in the 50 mg/kg imatinib–treated mice compared with that in the 10 mg/kg imatinib–treated mice (P < 0.05) and the untreated mice (P < 0.01). Intriguingly, lymphadenopathy and salivary gland inflammation were also attenuated in imatinib‐treated mice, in a dose‐dependent manner. Serum levels of IgG and anti–double‐stranded DNA antibodies were also reduced in the imatinib‐treated mice.

Conclusion

These findings indicate that imatinib has a pleiotropic therapeutic effect, namely, the inhibition of PDGF signaling and immunosuppression, on the glomerulonephritis of MRL/lpr mice, which suggests a potential application of this drug in the treatment of human lupus nephritis.
Cyclooxygenase‐ and lipoxygenase‐derived eicosanoids in bronchoalveolar lavage fluid from patients with scleroderma lung disease: An imbalance between proinflammatory and antiinflammatory lipid mediators
Authors: Kowal‐Bielecka Otylia , Kowal Krzysztof , Distler Oliver , Rojewska Joanna , Bodzenta‐Lukaszyk Anna , Michel Beat A. , Gay Renate E. , Gay Steffen , Sierakowski Stanislaw
Published: December 2005

Objective

Eicosanoids play a key role in the regulation of inflammation and fibrosis. Recently we showed that levels of 5‐lipoxygenase (5‐LOX)–derived proinflammatory/profibrotic leukotrienes are elevated in bronchoalveolar lavage (BAL) fluid from patients with scleroderma lung disease (SLD). The present study was undertaken to investigate whether increased levels of leukotrienes are balanced by the antiinflammatory/antifibrotic cyclooxygenase (COX)– and 15‐LOX–derived eicosanoids in the lungs of patients with SLD.

Methods

Levels of 5‐LOX–derived leukotriene B4 (LTB4), COX‐derived prostaglandin E2 (PGE2), and 15‐LOX–derived 15‐hydroxyeicosatetraenoic acid (15‐HETE) and lipoxin A4 (LXA4) in BAL fluid from systemic sclerosis (SSc) patients with SLD (n = 32) and without SLD (n = 16) and from healthy individuals (n = 12) were measured by enzyme‐linked immunosorbent assay.

Results

Levels of LTB4 (mean ± SEM 248 ± 29 pg/ml) and PGE2 (51 ± 10 pg/ml) in SSc patients with SLD were significantly higher compared with patients without SLD (LTB4 119 ± 35 pg/ml, PGE2 17 ± 3 pg/ml; P < 0.05 for both) and with healthy controls (85 ± 12 pg/ml and 19 ± 2 pg/ml, respectively; P < 0.05 for both). Accordingly, the mean ± SEM PGE2:LTB4 ratio was similar in SSc patients with SLD (0.30 ± 0.05), SSc patients without SLD (0.29 ± 0.07), and controls (0.31 ± 0.07). In contrast, levels of 15‐HETE and LXA4 in patients with SLD did not differ significantly from levels in patients without SLD or in controls. The ratio of LXA4:LTB4 in SLD patients (0.16 ± 0.03) was significantly lower (P < 0.05) than that in patients without SLD (0.40 ± 0.10) or controls (0.34 ± 0.08).

Conclusion

Increased production of LTB4 in the lungs of patients with SLD is not balanced by an up‐regulation of 15‐LOX–derived antiinflammatory/antifibrotic eicosanoids such as 15‐HETE or LXA4. Targeting the 5‐LOX/15‐LOX balance may be of practical value in the treatment of SLD.
Early detection of pulmonary arterial hypertension in systemic sclerosis: A French nationwide prospective multicenter study
Authors: Hachulla Eric , Gressin Virginie , Guillevin Loïc , Carpentier Patrick , Diot Elisabeth , Sibilia Jean , Kahan André , Cabane Jean , Francès Camille , Launay David , Mouthon Luc , Allanore Yannick , Tiev Kiet Phong , Clerson Pierre , Groote Pascal de , Humbert Marc
Published: December 2005

Objective

Screening allows for early management of pulmonary arterial hypertension (PAH), a severe complication of systemic sclerosis (SSc). Since no consensus has been reached on the method and criteria for optimal screening, we sought to develop an algorithm based on symptoms, Doppler echocardiography, and right heart catheterization (RHC) for application to a nationwide multicenter SSc population in France.

Methods

This prospective study was conducted from September 2002 to July 2003 by experts at 21 SSc centers. At each center, SSc patients without severe pulmonary function abnormalities underwent Doppler echocardiography by an experienced cardiologist. Patients with a peak velocity of tricuspid regurgitation (VTR) of >3 meters/second or 2.5–3 meters/second with unexplained dyspnea were asked to undergo RHC to confirm PAH according to international guidelines.

Results

Of the 599 patients analyzed, 29 had known PAH and 33 had suspected PAH, based on Doppler echocardiography, and underwent RHC. Of these 33, 18 were found to have PAH, 3 had left ventricular dysfunction, and 12 had no PAH. Newly diagnosed cases of PAH were of mild severity (mean ± SD pulmonary artery pressure [mPAP] 30 ± 9 mm Hg, mean ± SD total pulmonary resistance [TPR] 524 ± 382 dynes × second/cm5). Hemodynamic findings in patients with known PAH were mPAP 49 ± 17 mm Hg and TPR 1,007 ± 615 dynes × second/cm5. The estimate of PAH prevalence was 7.85% (95% confidence interval 5.70–10.00).

Conclusion

This screening algorithm, based on dyspnea, Doppler echocardiographic evaluation of VTR, and RHC, enabled early detection of PAH at a mild stage. Whether mild PAH will evolve to severe PAH in reported cases and whether this early diagnosis translates into improved prognosis for patients with mild PAH will be evaluated in the ongoing 3‐year followup of this cohort.
Synergistic interaction between methotrexate and a superoxide dismutase mimetic: Pharmacologic and potential clinical significance
Authors: Cuzzocrea Salvatore , Mazzon Emanuela , di Paola Rosanna , Genovese Tiziana , Muià Carmelo , Caputi Achille P. , Salvemini Daniela
Published: December 2005

Objective

To investigate the effects of combination therapy with M40403 and methotrexate (MTX) on collagen‐induced arthritis (CIA) in rats.

Methods

CIA was elicited in Lewis rats that had been assigned to different experimental groups, and the rats were treated daily, starting at the onset of arthritis (day 26), with M40403 2 mg/kg intraperitoneally, MTX 0.15 mg/kg orally, or combination therapy (M40403 2 mg/kg plus MTX 0.015 mg/kg).

Results

The histopathologic features of CIA in type II collagen–challenged rats included erosion of the articular cartilage and bone resorption. Treatment of rats with MTX 0.15 mg/kg orally delayed the development of clinical signs (days 26–35) and improved histologic status in the knee and paw, as clearly demonstrated by a significant reduction in erosion of the articular cartilage at the joint margins and subchondral bone resorption. Furthermore, radiographic evidence of protection against bone resorption and soft tissue swelling was apparent in the tibiotarsal joints of rats treated with MTX 0.15 mg/kg daily. Furthermore, combination therapy with M40403 2 mg/kg plus MTX 0.015 mg/kg exerted significant protection against the development of arthritis, similar to that observed with MTX alone at a dose of 0.15 mg/kg. In contrast, no significant protection was observed in animals treated with M40403 2 mg/kg alone or with MTX 0.015 mg/kg alone.

Conclusion

This study provides the first evidence that M40403, a potent superoxide dismutase mimetic, exerts a significant synergistic effect with MTX in rats with CIA.
Arthritis in mice that are deficient in interleukin‐1 receptor antagonist is dependent on genetic background
Authors: Zhou Fang , He Xiaowen , Iwakura Yoichiro , Horai Reiko , Stuart John M.
Published: December 2005

Objective

To determine the effect of deletion of interleukin‐1 receptor antagonist (IL‐1Ra) protein in an animal model of rheumatoid arthritis.

Methods

BALB/c mice deficient in IL‐1Ra (IL‐1Ra−/−) were bred with collagen‐induced arthritis (CIA)–susceptible DBA/1 mice and B10 mice transgenic for HLA–DRB1*0101 (B10.DR1). After generation of IL‐1Ra−/− mice on the DBA/1 and B10.DR1 backgrounds, the mice were observed for the development of spontaneous arthritis and immunized for induction of CIA.

Results

We found that although BALB/c mice deficient in IL‐1Ra (BALB/c−/−) spontaneously developed chronic inflammatory arthritis, DBA/1 IL‐1Ra–deficient (DBA/1−/−) and B10.DR1 IL‐1Ra–deficient (B10.DR1−/−) mice did not. Splenocytes from BALB/c−/− mice produced elevated levels of IL‐2, IL‐4, IL‐6, IL‐10, IL‐17, and granulocyte–macrophage colony‐stimulating factor in response to anti‐CD3 stimulation. After immunization with type II collagen (CII), DBA/1−/− and B10.DR1−/− mice had a significantly earlier onset of CIA, and with increased severity compared with IL‐1Ra+/+ mice. Immunization of BALB/c−/− mice with CII did not aggravate spontaneous arthritis. All of the immunized mice developed antibodies to CII that correlated with arthritis severity. Levels of antibody to CII in the BALB/c−/− strain were relatively low.

Conclusion

These data indicate that the spontaneous arthritis of IL‐1Ra deficiency is highly dependent on non–major histocompatibility complex genes and that autoimmunity to CII is not the major disease‐inducing event. Class II immune response genes are more important for the regulation of CIA, and although these 2 models of arthritis share many pathogenic mechanisms, they also have significant differences.