bluuebunny/crossref_metadata_2025 huggingface dataset:
B
enjamin
F
ranklin: From Kite to Lightning Rod
Authors: Waterway William
Published: April 2005

One stormy day in June of 1752, Benjamin Franklin took a walk into a field to go kite flying with his 21‐year‐old son, William. The field rested along the banks of the Schuylkill. Trusting in his fathers scientific know‐how, William probably had no idea that he was participating in a potentially life‐threatening experiment. At the time, little did William realize that Franklin had so much excitement and interest in studying storms that he could have been dubbed “the world's first official storm chaser.”

As the story goes, Franklin attached a piece of metal wire to the fuselage of his homemade kite to help attract electrical charges flying among the overhead clouds. The hemp string played out through Franklin's fingers, and the kite twisted and turned in the turbulent winds as it soared higher and higher. After a considerable length of the string had played out, Franklin tied a key to the taut string. Then, with a dampened silk ribbon tied to the knuckles of his free hand, Franklin and William waited to see what would happen.

Whether it was a collection of static electricity gathered along the moist hemp string or a “gentle” lightning strike, we may never know. Regardless, Ben Franklin reported that when he placed his hand with the insulating silk ribbon near the key, he received a jolt of electricity as sparks leaped from the key. Franklin's grounded body acted as a grounding path for the electrical current built up in the electric field of the storm clouds overhead. In addition to proving that thunderclouds generate electricity, Franklin also extrapolated his negative/positive electrical research from his laboratory and theorized that the lower part of the thunderclouds was mostly negatively charged.
Our Evolving Water Consciousness
Authors: Marks William E.
Published: April 2005

Since the dawn of our species, being conscious of water has been vital to our survival, health, and social behavior.

Hundreds of thousands of years before the written word, humans thought and communicated about water. Besides being essential for survival, water remains a mysterious fluid that science continues to research and study.

Prior to the invention of writing, communication about water found expression in human sign language and the spoken word.

An important turning point in the correct human grasp of the hydrologic cycle came in 1580 with the publication of Bernard Palissy's book,
Discours admirables
. Palissy, a potter by trade, was a keen observer of nature and the workings of water. In
Discours admirables
, Palissy presented a concept of the hydrologic cycle that is accurate according to today's definition. Palissy's book also provided other new hydrologic concepts such as the origin of springs and rivers, how wells are recharged from nearby rivers, the hydrodynamics of artesian wells, the use of forestation for controlling erosion, and plans for constructing fountains for domestic water supply.

It was not until the late 1600s, however, that Edmund Halley, of Halley's Comet fame, actually proved that Palissy's theory was correct. Using his sense of observation and mathematical skills, Halley roughly figured the quantity of water draining from all the rivers of North Africa and Europe into the Mediterranean. From this, Halley determined that the combined flow was about equal to the water falling as rain or snow on the region's drainage area.
B
enjamin
F
ranklin's
A
rmonica: A Water Music Instrument
Authors: Marks William E.
Published: April 2005

The art of creating music from water‐filled glass receptacles is probably as ancient as glassmaking. Some music scholars date the phenomenon of water music back to 2500
B.C
. Because this time predates recorded history, all we have as documentation are references in early folklore and tales.

In the ancient days of Pythagoras, a variety of music was composed by musicians using water‐filled bowls that held different levels of water. This use of creating water music according to a mathematical scale, resonated with Pythagorean philosophy, which believed in transmigration of the soul and a related belief in a numerical scale.

In Persia, where some methods of their glassblowing techniques remain a mystery to this day, we find accounts, as early as the fourteenth century, of water music being played from glasses. Largely because glass music was often played by amateur performers who created their own folk music, glass music has a history that is obscure and mysterious.
F
lood
C
ontrol
A
ct of 1994
Authors: Holst Arthur M.
Published: April 2005

The Flood Control Act of 1944, enacted on December 22 of that year, established federal policy regarding jurisdiction over rivers and other bodies of water, specifically watersheds. The act states that all water‐related construction and navigation projects will be approved only if they substantially improve navigational capacity and do not excessively interfere with standard water usage. The plan was proposed to prevent flooding and to allow more irrigation, easier navigation, increased river‐related recreation, and the production of hydroelectric power. The Army Corp of Engineers was designated to oversee these tasks.
G
reat
L
akes
G
overnors'
A
greement
Authors: Lasserre Frederic
Published: April 2005

The Great Lakes Commission (GLC) is the only regional organization whose statutory mandate is to represent the eight Great Lakes states on a variety of environmental and economic issues. It was created in 1955 and was granted Congressional consent in 1968. The Great Lakes Commission is now a binational agency: its members include the eight Great Lakes states—Illinois, Indiana, Michigan, Minnesota, New York, Ohio, Pennsylvania, and Wisconsin; the Canadian provinces of Ontario and Québec have had associate member status since 1999.

The Commission is dedicated to managing the waterbody of the Great Lakes: it promotes the orderly, integrated and comprehensive development, use, and conservation of the water and related natural resources of the Great Lakes Basin and St. Lawrence River. Each jurisdiction appoints a delegation of three to five members comprised of senior agency officials, legislators, or appointees of the governor or premier.
Great Lakes Water Quality Initiative
Authors: Millano Elsie F.
Published: April 2005

The Great Lakes Water Quality Initiative (the “Initiative”) is a program to improve the quality of the waters in the Great Lakes system.

The main objective of the Initiative is to reduce the discharge of bioaccumulative compounds of concern (BCCs) into the Great Lakes system. The first phase of the Initiative consisted of the development of a consistent set of water quality criteria to be applied throughout the Great Lakes system by the Great Lakes States and by any Indian Tribes that have jurisdiction over portions of the Great Lakes system.

The second phase of the Initiative, called the Great Lakes Toxic Reduction Effort (GLTRE), is under development. The GLTRE focuses on reducing BCCs contributed to the Great Lakes system by nonpoint sources.
The Safe Drinking Water Act
Authors: Von Oppenfeld Rolf R.
Published: April 2005

The Safe Drinking Water Act (SDWA) was enacted in 1974 and subsequently amended in 1986 and 1996 to protect the public from risks posed by drinking water contamination. The Act required the Environmental Protection Agency (EPA) to establish standards or treatment techniques for contaminants that could adversely affect human health, establish requirements for monitoring the quality of drinking water supplies and for ensuring the proper operation and maintenance of water systems, and protect groundwater from subsurface injection of polluting liquids. EPA posted a general guide to the SDWA provisions at
http://www.epa.gov/OGWDW/SDWAsumm.html
and posted its general approach for implementing the provisions at
http://www.OGWDW/sdwa/sdwa.html
.

The 1996 Amendments are important because Congress gave the EPA greater flexibility under the SDWA and emphasized the cost/benefit analytical approach to regulation. For an overview of the program, see the Office of Groundwater and Drinkingwater at
http://www.epa.gov/safewater.html
. The SDWA regulations can be found at 40 C.F.R. Parts 141–149 and may be accessed on the internet at
http://www.water.access.gpo.gov/nara/cfr
or
http://epa.gov/OGWDW.regs.html
.
Oil‐Field Brine
Authors: Miskovic Dusan P.
Published: April 2005

The separation of oil and OFB is a logical consequence of the oil production process due to the fact that much more OFB than oil is more often produced, especially in older oil wells. However, until recently neither the oil drillers nor any governmental agency paid much attention to disposal of OFB as a by‐product of crude oil production. A simple procedure for OFB was diluting it in streams, rivers, and natural fresh and marine waterbodies. That practice took place until interest in crude oil production and consequently consumption of derivatives dramatically increased. Widespread oil production worldwide is constantly increasing, but the pollution aspects came to a focal point of environmental concern. To keep a high profit margin in the industry and satisfy strict environmental quality regulations, more sophisticated technologies for OFB treatment are becoming viable alternatives to the conventional OFB management practice.
Water Quality Models: Chemical Principles
Authors: Ji Zhen‐Gang
Published: April 2005

Water quality represents the physical, chemical, and biological characteristics of water resources and is used to measure the ability of a waterbody to support beneficial uses. Eutrophication is a process of nutrient overenrichment of a waterbody, resulting in accelerated biological productivity (growth of algae and weeds). Symptoms of eutrophication include algal blooms, reduced water clarity, and oxygen depletion. In modeling studies, water quality and eutrophication are sometimes used interchangeably to represent the processes of waterbody enrichment by nutrients. Key state variables in water quality models include algae, nutrients, and dissolved oxygen (DO).

This entry focuses on water quality models. Information on applications of water quality models is provided in
WATER QUALITY
—
CASE STUDIES
.
Biodegradation
Authors: Frazar Christian D.
Published: April 2005

The beginnings of life on this planet arose during a time of extreme conditions. For life to arise in an inhospitable world, the first organisms needed to be simple but hearty. The life forms of today considered most similar to those early ancestors of life are bacteria and archaea—simple, primitive organisms. Despite their primitive nature, these organisms have a diverse and powerful metabolic potential.

Microorganisms are at the base of the food chain and play a key role in both secondary production and in decomposition. The ability of microorganisms to decompose or breakdown compounds is known as biodegradation. This term is often used to refer to the degradation of environmental pollutants by bacteria or fungi. This discussion will focus on the degradation process itself and the factors that influence and limit biodegradation.
Planning and Managing Water Infrastructure
Authors: Grigg Neil S.
Published: April 2005

Water infrastructure consists of the constructed elements that control water for water supply, wastewater service, flood control, hydropower, recreation, navigation, and environmental protection. Generally, these constructed elements involve conveyance systems, including channels, canals, pipes, and bridges; diversion structures; dams; reservoirs; locks; treatment plants for water supply and wastewater management; pumping stations; hydroelectric plants; spillways, valves, and gates; and wells. Planning and managing water system capital assets require provisions for capital investment, operations, and maintenance.
Water Markets: Transaction Costs and Institutional Options
Authors: Lee Terence R.
Published: April 2005

The costs involved in the transfer of property, or transaction costs, can significantly affect the capacity of any market to operate efficiently. If water marketing is to achieve its full potential, markets must be designed to minimize transaction costs. Water marketing may lead, however, to efficiency gains, even if transaction costs are high. Moreover, increasing water scarcity will raise the welfare gains from trade relative to these costs, as the value of water rights increases. Transaction costs can be lowered by technological advance and by institutional design. It can also be expected that transactions costs will fall as the market matures, as learning by doing has its effect.
Water Resources Management
Authors: Grigg Neil S.
Published: April 2005

Water resources management controls
water resources systems
, that are combinations of constructed water control facilities and natural, or environmental elements that work together to achieve water management. A constructed water resources system, consisting of structural facilities, provides control of water flow and quality and includes facilities for water supply and wastewater management; for drainage of land and control of floods; and for water control in rivers, reservoirs, and aquifers. Examples include conveyance systems (channels, canals, and pipes), diversion structures, dams and storage facilities, treatment plants, pumping stations and hydroelectric plants, wells, and all appurtenances.

Natural water resource systems comprise sets of environmental or hydrologic elements in nature that include the atmosphere, watersheds, stream channels, wetlands, floodplains, aquifers and groundwater systems, lakes, estuaries, seas, and the ocean.
The Provision of Drinking Water and Sanitation in Developing Countries
Authors: Lee Terence R.
Published: April 2005

The U.S. National Academy of Engineering includes drinking water supply as one of the great engineering achievements of the twentieth century. For those fortunate to live in a developed country, it was. However, the failure to provide universal safe drinking water and adequate sanitation is amongst the gravest contradictions of our world at the beginning of the twenty‐first century. The necessary technology has existed for at least two millennia, but there remain serious obstacles to its application. The result is that at least 1 billion people remain without access to a reliable and safe source of water, and more than 2.5 billion lack safe sanitation. This population is concentrated in countries at the lowest levels of development.
Integrated Water Resources Management (
IWRM
)
Authors: Babel Mukand Singh
Published: April 2005

Compared to traditional approaches to water resources problems, integrated water resources management (IWRM) takes a broader holistic view and examines a more complete range of solutions. It looks outside the narrow water sector for policies and activities to achieve sustainable water resources development. It also considers how different actions affect and can reinforce each other. IWRM has attracted particular attention since the International Conferences on Water and Environmental in Dublin in 1992. IWRM can be defined as follows:

“IWRM is a process which promotes the coordinated development and management of water, land and related resources in order to maximize the resultant economic and social welfare in an equitable manner without compromising the sustainability of vital ecosystems” (2).

IWRM principles place its overriding importance over economic, social, and natural facets. It draws its inspiration from the Dublin principles, culminating from the International Conference on Water and the Environment in Dublin, 1992. These are the four Dublin principles:

Freshwater is a finite and vulnerable resource, essential to sustain life, development and the environment.

Water development and management should be based on a participatory approach, involving users, planners, and policy makers at all levels.

Water has an economic value in all its competing uses and should be recognized as an economic good.

Women must play a central part in the provision, management and safeguarding of water.
Meeting Water Needs in Developing Countries with Tradable Rights
Authors: Lee Terence R.
Published: April 2005

The most serious current issue in water management is not water scarcity, but the allocation of water among competing uses and users. The issue of allocation overshadows all other aspects of water management. Unfortunately, almost everywhere, the methods used for water allocation are woefully inadequate to achieve an effective, efficient, and timely distribution of water among uses and users. This failure to allocate water efficiently is the root cause of the widespread perception that water is becoming so scarce as to amount to a crisis. Almost everywhere, water is allocated either according to tradition or by bureaucratic processes subject to political pressures. Economists have long argued that water should be treated as an economic good. If it is treated as an economic good, then its use can be allocated by creating water rights through a market.
Wastewater Reclamation and Reuse Research
Authors: Drewes Jorg E.
Published: April 2005

Water reclamation is the treatment of wastewater to make it reusable. Water reuse is the beneficial use of the treated water and can serve either nonpotable or potable applications. Nonpotable water reuse includes all water applications other than augmenting drinking water supplies. Nonpotable reuse is occurring as agricultural and landscape irrigation, recreation, wildlife habitat maintenance (stream‐flow augmentation), in‐building applications (such as toilet flushing), industrial cooling, and groundwater recharge. Potable water reuse refers to the use of highly treated reclaimed water to augment drinking water sources. Direct potable reuse, where reclaimed water after advanced treatment is piped directly into the potable water system, is limited to rare cases. For indirect potable reuse, reclaimed water can either be discharged into a surface water or infiltrated into the subsurface to augment, in part, a drinking water supply source. Infiltration into the subsurface can be accomplished by either direct injection into the aquifer or by surface spreading which provides additional soil–aquifer treatment (SAT) when water percolates through the subsurface. The majority of research activities in wastewater reclamation and reuse reflects the main concerns about potable and nonpotable water reuse, such as (1) protection of public health, (2) reliable treatment of wastewater to meet strict water quality requirements for the intended reuse, and (3) gaining public acceptance.
Wastewater Treatment—Small Scale
Authors: Langergraber Guenter
Published: April 2005

Small wastewater treatment plants are defined as those to which fewer than 2'000 people are connected or those whose flow is less than 200 m
3
/d. These are treatment plants for small communities, villages, institutions, hotels, and camping resorts.

There are a tremendous number of small wastewater treatment plants worldwide. Small treatment works are needed mainly in rural areas to treat municipal wastewater. However, technologies to treat wastewater from industry are also important. The separate treatment of wastewater from certain processes provides opportunities to reuse water and to reduce the overall consumption of freshwater.

In rural areas and also in large cities that are not yet provided with sewers, sanitation requirements can be met at a reasonable price and on a reasonable timescale by constructing small but highly compact and efficient plants to serve clusters of dwellings.

Small wastewater treatment plants are required to satisfy very different needs which can be integrated into infrastructures at very different stages of development and sophistication. Engineers are called upon to provide technologies that are reliable, easy to operate and control, and tolerant of variations in the influent. The task is difficult and needs an interdisciplinary approach that takes into account local conditions.
Methodology for modeling detailed imperfect mixing effects in complex reactors
Authors: Wells Gary J. , Ray W. Harmon
Published: April 2005

A powerful new modeling technique is presented for exploring mixing effects in reactive flow systems. The technique combines the detailed mixing representation of computational fluid dynamics (CFD) simulations with the simplicity and computational efficiency of stirred‐tank compartment models. The method can be generally applied to many reactive systems, and requires only that appropriate criteria be specified to select compartment models from a single converged CFD simulation. A 1000‐fold increase in computational speed is achieved by the new compartment model/CFD technique when modeling steady‐state operation of low‐density polyethylene (LDPE) autoclave reactors, making broad studies of operating conditions and stability possible. Results from compartment models are shown to capture the accuracy and detail of CFD simulations over a wide range of LDPE reactor operation, and the new technique provides a combination of modeling detail and computational ease not previously available for this type of reactor. © 2005 American Institute of Chemical Engineers AIChE J, 2005
Identifying particles in industrial systems using MRI susceptibility artefacts
Authors: Robson Philip , Hall Laurie
Published: April 2005

The potential uses of magnetic susceptibility effects in magnetic resonance imaging (MRI) to identify particles in industrial systems is explored. It is both a practical demonstration, and a review of the literature for experts in both MRI and in industry. The theory of magnetic susceptibility artifacts in MRI is briefly illustrated. Experimental imaging of simplified systems that have relevance to real world processes are explored, and features of those images are related to properties of the system. Data are presented for different sized objects with identical dipole moments, for sub‐pixel sized particles for which their potential use as magnetic labels are shown, and, finally, for agglomerations and powders of particles. Given the unique ability of MRI to probe complex, opaque systems, this qualitative interpretation of MRI images, demonstrates that MRI is an important technique for the investigation of material distributions within industrial systems. © 2005 American Institute of Chemical Engineers AIChE J, 2005
Effect of reactor configuration on nitric oxide conversion in nitrogen plasma
Authors: Zhao Gui‐Bing , Garikipati S. V. B. Janardhan , Hu Xudong , Argyle Morris D. , Radosz Maciej
Published: April 2005

The configuration of a nonthermal plasma reactor strongly affects the rate of electron collision reactions. Experiments involving the decomposition of NO in N2 were performed in a reactor in which the number of parallel reactor tubes varied from 1 to 10 at a constant pressure of 147.6 kPa and ambient temperature. A previously developed lumped model of the reactions accurately predicted the effects of varying the initial concentrations of NO (from 240 ppm to 593 ppm) and gas residence time (from 1.93 to 7.42 s). With an increasing number of parallel reactor tubes, the rate of electron collision reactions decreases because the energy input per unit reactor volume at unit time decreases, while the energy consumption per molecule of NO converted to N2 and O2 decreases due to electrical and geometric effects associated with the decreasing peak width of the discharge voltage pulses and increasing reactor capacitance. Therefore, increasing the number of parallel reactor tubes provides a viable scale‐up method for constructing more efficient pulsed corona discharge reactors. © 2005 American Institute of Chemical Engineers AIChE J, 2005
Midline raphé, sternal cleft, and other midline abnormalities: A new dominant syndrome?
Authors: Forzano Francesca , Daubeney Piers E.F. , White Susan M.
Published: April 2005

Sternal fusion defects are malformations that often present as an isolated finding. An association with multiple malformations has been reported, in particular with midline raphé and craniofacial hemangiomas and as part of the pentalogy of Cantrell. Most syndromic cases were sporadic with a few families reported with recurrence in sibs. We describe a mother and two daughters with midline raphé and sternal defects. Affected members also had double central incisors, congenital heart defect, neck webbing, bicornuate uterus and minor anomalies including long face with hypotelorism. None of the three affected relatives had hemangiomas. The manifestations of these patients do not fit any previously described condition, and we propose they represent a new syndrome. This family is also important as it points to a possible genetic cause for at least some cases of this disorder of the ventral midline. © 2005 Wiley‐Liss, Inc.
Attention‐deficit/hyperactivity disorder (ADHD) and variable clinical expression of Aarskog–Scott syndrome due to a novel FGD1 gene mutation (R408Q)
Authors: Orrico Alfredo , Galli Lucia , Buoni Sabrina , Hayek Giuseppe , Luchetti Anna , Lorenzini Stefania , Zappella Michele , Pomponi Maria Grazia , Sorrentino Vincenzo
Published: April 2005

Mutations of the FGD1 gene are responsible for a significant proportion of patients with Aarskog–Scott syndrome (AAS), an X‐linked disorder characterized by short stature, brachydactyly, urogenital abnormalities, and a typical dysmorphic facial appearance. Although mental retardation does not occur significantly in AAS, this condition has been described associated with various degrees of mental impairment and/or behavioral disorders in some patients. In particular, attention deficit hyperactivity disorder (ADHD) is reported as a common characteristic of AAS. However, AAS/ADHD reported patients have been only clinically described, and diagnosis never has been confirmed on molecular basis. We present here a unique case of a 16‐years‐old patient presenting with ADHD, lower intelligence quotient, and dysmorphic features. Although the clinical features were not completely typical of AAS, genetic analysis demonstrated a novel FGD1 missense mutation (R408Q). The case we report confirms the highly variable expressivity of AAS and first documents that the FGD1 gene may play a role in ADHD susceptibility. We suggest that FGD1 analysis may be adequate in ADHD patients who exhibit dysmorphic features suggestive of AAS, also in the absence of the full phenotypical spectrum. © 2005 Wiley‐Liss, Inc.
Familial recurrence rates and genetic models of multiple sclerosis
Authors: Lindsey J. William
Published: April 2005

Susceptibility to multiple sclerosis (MS) is determined by both inherited and non‐inherited factors. The importance of genetic factors is demonstrated by the increased risk of disease in relatives of MS patients. Our objective was to determine the implications of the observed familial recurrence risks for the genetic basis of MS. We developed a computer program which calculates recurrence risks for monozygotic (MZ) twins, siblings, and second degree relatives, and used it to calculate recurrence risks for a wide variety of genetic models. We investigated models with different numbers of genes, different patterns of interaction between the genes, and dominant or recessive inheritance. The models that best reproduced the observed values had multiple loci with strongly synergistic interaction and autosomal dominant (AD) inheritance. At least six loci were required, and we found no upper limit on the number of loci. Models with genetic heterogeneity, where only a fraction of the risk loci are required for disease, are possible. In models with large numbers of loci the “abnormal” alleles conferring risk of disease are the most common allele. We conclude that a variety of genetic models with multiple genes, dominant inheritance, and synergistic interaction between risk genes are consistent with the observed familial recurrence rates in MS. © 2005 Wiley‐Liss, Inc.
Reduced tumor necrosis factor signaling in primary human fibroblasts containing a tumor necrosis factor receptor superfamily 1A mutant
Authors: Siebert Stefan , Amos Nick , Fielding Ceri A. , Wang Eddie C. Y. , Aksentijevich Ivona , Williams Bryan D. , Brennan Paul
Published: April 2005

Objective

Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) is an autoinflammatory syndrome associated with mutations in the gene that encodes tumor necrosis factor receptor superfamily 1A (TNFRSF1A). The purpose of this study was to describe a novel TNFRSF1A mutation (C43S) in a patient with TRAPS and to examine the effects of this TNFRSF1A mutation on tumor necrosis factor α (TNFα)–induced signaling in a patient‐derived primary dermal fibroblast line.

Methods

TNFRSF1A shedding from neutrophils was measured by flow cytometry and enzyme‐linked immunosorbent assay (ELISA). Primary dermal fibroblast lines were established from the patient with the C43S TRAPS mutation and from healthy volunteers. Activation of NF‐κB and activator protein 1 (AP‐1) was evaluated by electrophoretic mobility shift assays. Cytokine production was measured by ELISA. Cell viability was measured by alamar blue assay. Apoptosis was measured by caspase 3 assay in the fibroblasts and by annexin V assay in peripheral blood mononuclear cells.

Results

Activation‐induced shedding of the TNFRSF1A from neutrophils was not altered by the C43S TRAPS mutation. TNFα‐induced activation of NF‐κB and AP‐1 was decreased in the primary dermal fibroblasts with the C43S TNFRSF1A mutation. Nevertheless, the C43S TRAPS fibroblasts were capable of producing interleukin‐6 (IL‐6) and IL‐8 in response to TNFα. However, TNFα‐induced cell death and apoptosis were significantly decreased in the samples from the patient with the C43S TRAPS mutation.

Conclusion

The C43S TNFRSF1A mutation results in decreased TNFα‐induced nuclear signaling and apoptosis. Our data suggest a new hypothesis, in that the C43S TRAPS mutation may cause the inflammatory phenotype by increasing resistance to TNFα‐induced apoptosis.
Homeostatic effects of the metalloproteinase disintegrin ADAM15 in degenerative cartilage remodeling
Authors: Böhm Beate B. , Aigner Thomas , Roy Barbara , Brodie Thomas A. , Blobel Carl P. , Burkhardt Harald
Published: April 2005

Objective

The membrane‐anchored metalloproteinase disintegrin ADAM15 is up‐regulated in osteoarthritis and has been implicated in proteolysis and cell–matrix interactions. To address its role in cartilage metabolism, we performed an analysis of joint morphology in aging mice with a targeted inactivation of the ADAM15 gene (ADAM15−/−). In addition, a human chondrocyte cell line overexpressing ADAM15 was used to investigate the role of ADAM15 in an in vitro model of chondrocyte–matrix interactions.

Methods

Knee joint sections from 3‐, 6‐, and 12–14‐month‐old ADAM15−/− and wild‐type (WT) 129/SvJ mice were examined for synovial hyperplasia, cartilage degradation, and osteophyte formation. Stable transfection of the human T/C28a4 chondrocyte cell line with full‐length human ADAM15 complementary DNA led to the establishment of ADAM15‐overexpressing chondrocytes that were further analyzed for their capability to adhere to and to survive on cartilage matrix molecules (fibronectin and types II and VI collagen) under conditions of serum starvation. ADAM15 expression was investigated by reverse transcription–polymerase chain reaction and Western blotting.

Results

Aging ADAM15−/− mice exhibited accelerated development of osteoarthritic lesions compared with WT mice, and the difference was statistically significant at age 12 months. The osteoarthritic changes preferentially affected male ADAM15−/− mice. ADAM15 overexpression in T/C28a4 cells led to the specific reinforcement of chondrocyte adhesion to cartilage types II and VI collagen, and this was associated with enhanced cell viability under conditions of serum starvation.

Conclusion

The accelerated development of murine osteoarthritis in ADAM15 deficiency as well as the proadhesive and cell survival–promoting in vitro effect of ADAM15 overexpression suggest a homeostatic rather than a destructive role of ADAM15 in cartilage remodeling.
Effects of treatment with small interfering RNA on joint inflammation in mice with collagen‐induced arthritis
Authors: Schiffelers Raymond M. , Xu Jun , Storm Gert , Woodle Martin C. , Scaria Puthupparampil V.
Published: April 2005

Objective

RNA interference is a process in which genes can be silenced sequence‐specifically. In mammals, RNA interference can be invoked by introduction of small (19–21‐nucleotide) double‐stranded RNA molecules known as small interfering RNA (siRNA) into cells. Thereby, siRNA offers promise as a novel therapeutic modality. However, siRNA is a relatively large, highly charged molecule and does not readily enter cells. This study was undertaken to investigate the use of electroporation for in vivo transfection of siRNA into joint tissue in arthritic mice to achieve local RNA interference.

Methods

Proof of principle that siRNA is able to inhibit gene expression in vivo in the mouse joint was studied by local injection and electroporation of siRNA designed to silence reporter genes. In mice with collagen‐induced arthritis (CIA), the disease‐modulating activity of siRNA designed to silence tumor necrosis factor α (TNFα) was investigated.

Results

Luciferase activity could be reduced by >90% with luciferase‐specific siRNA as compared with the activity measured after electroporation without siRNA or with irrelevant siRNA. The effect was observed only locally. In mice with CIA, electroporation of siRNA designed to inhibit TNFα strongly inhibited joint inflammation, whereas electroporation of irrelevant siRNA or injection of siRNA against TNFα without electroporation failed to produce therapeutic effects.

Conclusion

Local electroporation of siRNA in joint tissue can inhibit CIA in mice. These results offer promise for the use of siRNA as a new strategy for therapeutic intervention in rheumatoid arthritis and may serve as a tool to study arthritis disease pathways through loss‐of‐function phenotypes.
Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor α receptor fusion protein etanercept
Authors: Baraliakos X. , Davis J. , Tsuji W. , Braun J.
Published: April 2005

Objective

To assess spinal inflammation by magnetic resonance imaging (MRI) before and after treatment with the tumor necrosis factor receptor fusion protein etanercept compared with placebo.

Methods

As part of a recently published randomized, controlled trial, 40 patients with ankylosing spondylitis (AS) underwent MRI of the lower thoracic and lumbar spine at 4 different time points: baseline, 12 weeks, 24 weeks, and 48 weeks. Nineteen patients received subcutaneous etanercept twice weekly (25 mg twice daily) for 1 year, and 21 patients received placebo for 6 months before being switched to etanercept. The mean age of the patients was 39.7 years, 75% were male, 89% were HLA–B27 positive, and the mean disease duration was 13 years. MRI examinations included T1‐weighted sequences before and after application of gadolinium–diethylenetriaminepentaacetic acid (Gd‐DTPA) and T2‐weighted fat‐saturated sequences. MRI sequences were scored with an adjusted AS spinal MRI score, using predefined vertebral units (VUs) as a basis.

Results

After 12 weeks, spinal inflammation (as assessed by T2‐weighted MRI with fat saturation) regressed by 54% in the etanercept group (mean score 1.33 per VU at baseline and 0.61 per VU at 12 weeks; P = 0.002) but worsened by 13% in the placebo group (0.94 at baseline and 1.06 at 12 weeks) (P < 0.001 between groups). After switching to etanercept, placebo patients improved similarly. T1‐weighted Gd‐DTPA MRI sequences performed equally well in detecting spinal changes. At baseline, >50% of all active lesions were detected in the thoracic spine. Deterioration of chronic changes was significant only in patients treated with placebo.

Conclusion

Etanercept treatment of patients with active AS results in regression of spinal inflammation as assessed by spinal MRI. Inclusion of the thoracic spine in MRI examinations of patients with AS may be of particular importance.
Association of sporadic chondrocalcinosis with a −4‐basepair G‐to‐A transition in the 5′‐untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate
Authors: Zhang Yun , Johnson Kristen , Russell R. Graham G. , Wordsworth B. Paul , Carr Andrew J. , Terkeltaub Robert A. , Brown Matthew A.
Published: April 2005

Objective

Certain mutations in ANKH, which encodes a multiple‐pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal‐dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis.

Methods

ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH‐8 articular chondrocytes.

Results

Sporadic chondrocalcinosis was associated with a G‐to‐A transition in the ANKH 5′‐untranslated region (5′‐UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This −4‐bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C‐to‐T and C‐terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143‐bp T‐to‐C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild‐type ANKH and the −4‐bp ANKH protein variant promoted increased extracellular PPi in CH‐8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen.

Conclusion

A subset of sporadic chondrocalcinosis appears to be heritable via a −4‐bp G‐to‐A ANKH 5′‐UTR transition that up‐regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.
Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: A detailed subanalysis of data from the anti–tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study
Authors: Smolen J. S. , Han C. , Bala M. , Maini R. N. , Kalden J. R. , van der Heijde D. , Breedveld F. C. , Furst D. E. , Lipsky P. E. ,   ATTRACT Study Group
Published: April 2005

Objective

To assess the relationship between inflammation and joint destruction in rheumatoid arthritis (RA) patients who have not responded clinically to treatment.

Methods

Changes from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) plus methotrexate (MTX) and those who received MTX plus placebo in the Anti–Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial.

Results

At week 54, patients who did not show 20% improvement by American College of Rheumatology criteria (ACR20 nonresponders) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables, including the 28‐joint Disease Activity Score (DAS28) (P < 0.001), tender joint count (P = 0.014), swollen joint count (P < 0.001), and C‐reactive protein (CRP) level (P < 0.001). Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment, radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited (P < 0.001) compared with ACR20 nonresponders to MTX plus placebo. Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX, irrespective of ACR response status (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo–treated group, versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX–treated group). Furthermore, among patients who were ACR20 nonresponders through week 54, patients who were DAS nonresponders at weeks 30 and 54, and patients without any improvement in individual clinical variables, those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo (P < 0.05 to P < 0.001).

Conclusion

Even in patients without clinical improvement, treatment with infliximab plus MTX provided significant benefit with regard to the destructive process, suggesting that in such patients these 2 measures of disease are dissociated.
Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: Results of a fifty‐two–week, randomized, controlled study
Authors: van der Heijde Désirée , Baraf Herbert S. B. , Ramos‐Remus Cesar , Calin Andrei , Weaver Arthur L. , Schiff Michael , James Margaret , Markind Jan E. , Reicin Alise S. , Melian Agustin , Dougados Maxime
Published: April 2005

Objective

To assess the efficacy, safety, and tolerability of etoricoxib, a cyclooxygenase 2 (COX‐2) selective inhibitor, administered continuously over 52 weeks for the treatment of ankylosing spondylitis (AS).

Methods

This 2‐part, multicenter, double‐blind, parallel‐group, 52‐week study evaluated 2 doses of etoricoxib (90 and 120 mg) compared with naproxen at 1,000 mg. A 6‐week, active‐comparator– and placebo‐controlled period (part I) was followed by a 46‐week active‐comparator–controlled period (part II). The primary outcome measures (on 100‐mm visual analog scales) were patient's assessment of spine pain, patient's global assessment of disease activity, and the Bath Ankylosing Spondylitis Functional Index.

Results

Of the 387 patients randomized to receive treatment, 301 (77.8%) completed part I and 284 (75.9%) completed part II. Compared with placebo over 6 weeks, those receiving 90 mg etoricoxib, 120 mg etoricoxib, and naproxen demonstrated significantly (P < 0.001) greater improvement in all primary end points; treatment effects (expressed as the difference in least squares mean change versus placebo) were 21–29 mm for spine pain, 18–25 mm for disease activity, and 11–15 mm for function. Compared with patients receiving naproxen, significantly greater improvement in all primary end points was demonstrated in the combined group receiving either 90 mg etoricoxib or 120 mg etoricoxib over 6 weeks, in each individual etoricoxib treatment group over 6 weeks, and in the combined etoricoxib group over 1 year (all P < 0.05); results for secondary and exploratory end points were generally consistent with those from the primary analysis. Among all groups, there were no significant differences in the incidence of overall clinical, drug‐related, or serious adverse experiences (AEs) and discontinuations due to AEs. Safety observations during part II were generally consistent with those in part I.

Conclusion

Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks, and compared with naproxen over 1 year. These study results demonstrate that etoricoxib is generally safe, well‐tolerated, and efficacious for the treatment of AS.
Generation of novel covalent RNA–protein complexes in cells by ultraviolet B irradiation: Implications for autoimmunity
Authors: Andrade Felipe , Casciola‐Rosen Livia A. , Rosen Antony
Published: April 2005

Objective

To determine whether ultraviolet B (UVB) irradiation induces novel modifications in autoantigens targeted during experimental photoinduced epidermal damage.

Methods

To search for novel UVB‐induced autoantigen modifications, lysates made from UVB‐irradiated human keratinocytes or HeLa cells were immunoblotted using human autoantibodies that recognize ribonucleoprotein autoantigens. Novel autoantigen structures identified were further characterized using nucleases and RNA hybridization.

Results

Human sera that recognize U1–70 kd (U1‐70K) and La by immunoblotting also recognized multiple novel species when they were used to immunoblot lysates of UVB‐irradiated keratinocytes or HeLa cells. These species were not present in control cells and were not observed when apoptosis was induced by Fas ligation or cytotoxic lymphocyte granule contents. Biochemical analysis using multiple assays revealed that these novel UVB‐induced molecular species result from the covalent crosslinking between the U1 RNA and the hYRNA molecules with their associated proteins, including U1‐70K, La, and likely components of the Sm particle.

Conclusion

These data demonstrate that UVB irradiation of live cells can directly induce covalent RNA–protein complexes, which are recognized by human autoantibodies. As previously described for other autoantigens, these covalent complexes of RNA and proteins may have important consequences in terms of antigen capture and processing.
Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort
Authors: Alarcón‐Segovia Donato , Alarcón‐Riquelme Marta E. , Cardiel Mario H. , Caeiro Francisco , Massardo Loreto , Villa Antonio R. , Pons‐Estel Bernardo A. ,   on behalf of the Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL)
Published: April 2005

Objective

To determine whether there is familial aggregation of systemic lupus erythematosus (SLE) and/or other autoimmune diseases in SLE patients and to identify clinical differences between patients with and those without familial autoimmunity.

Methods

We interviewed members of the Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL) inception cohort of 1,214 SLE patients to ascertain whether they had relatives with SLE and/or other autoimmune diseases. Identified relatives were studied. Familial aggregation was tested using reported highest and intermediate population prevalence data for SLE, rheumatoid arthritis (RA), or all autoimmune diseases, and studies were performed to identify the genetic model applicable for SLE.

Results

We identified 116 first‐, second‐, or third‐degree relatives with SLE, 79 with RA, 23 with autoimmune thyroiditis, 3 with scleroderma, 1 with polymyositis, and 16 with other autoimmune diseases, related to 166 of the 1,177 SLE patients in the GLADEL cohort who agreed to participate. Forty‐two SLE patients had 2 or more relatives with an autoimmune disease. We found a λsibling of 5.8 and 29.0 for SLE and of 3.2–5.3 for RA, when comparing with their reported high or intermediate population prevalence, respectively. We also found familial aggregation for autoimmune disease in general (λsibling = 1.5) and determined that for SLE, a polygenic additive genetic model, rather than a multiplicative one, is applicable.

Conclusion

In SLE there is familial aggregation of SLE, RA, and autoimmune disease in general. A polygenic additive model applies for SLE. American Indian–white Mestizo SLE patients and those with higher socioeconomic level were more likely to have familial autoimmunity.