bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental Neuropsychiatry: A New Model of Psychiatry for Young People With and Without Intellectual Disability?
Authors: Dossetor David R. , Santhanam Radhika , Rhodes Paul , Holland Tony J. , Nunn Ken P.
Published: July 2005

Deinstitutionalization of young people with intellectual disability means that they are now cared for by families and served by community-based professionals. Normalization, which has been the guiding philosophy for this re-integration, has challenged child psychiatry to accept its responsibility for the mental health of this special needs group. It is argued that this group, with its special mental health needs, has had an influence on the conceptual framework of child psychiatry, particularly our understanding of development. This article examines the influence of the psychiatry of intellectual disability on child psychiatry and the influence of child psychiatry on the understanding of the mental health needs of those with intellectual disability. In particular, the management of young people with intellectual disability has required child psychiatry to expand its understanding of a biopsychosocial approach. Some of the resulting changes and challenges are presented to illustrate the benefits for both child psychiatry and the psychiatry of intellectual disability. The interaction of different conceptual biases has led to a new and broader conceptual spectrum of developmental neuropsychiatry. Developmental neuropsychiatry recognizes the need to integrate social science and preventative strategies at one end of the spectrum, with the genetics, molecular biology of human behaviour and targeted pharmacology at the other, and consider the developmental and interactive nature of such models. This article argues that this emerging, dynamic and broader conceptual framework of developmental neuropsychiatry enhances our understanding of the child mental health of all children. The article looks at some of the implications for assessment, diagnosis and treatment. As mental health needs become a greater public health priority, the advances in basic sciences will reinvigorate this medical specialty and training programmes will need to reflect these.
Life-threatening Loss of Function in Refugee Children: Another Expression of Pervasive Refusal Syndrome?
Authors: Bodegård Göran
Published: July 2005

Five children from asylum-seeking families required hospital care due to serious loss of function arising in the ‘limbo’ conditions in which they were living as refugees. Hopelessness, helplessness and an uncertain time perspective dominated family life; they had not worked through the traumas of the intolerable life from which they had fled. The massive loss of functions in the children resembles that of pervasive refusal syndrome (PRS), but the purposive aspect of the refusal seemed less pronounced. Treatment applying the principles for managing PRS was rapidly successful. The fixed behaviour of the mothers - staging a delusion/fantasy that the child was dying - was interpreted as a desperate coping strategy. It made the situation ‘understandable’ and bestowed on them a role and a meaningful function. Improvements in the children were not noticed until the mothers gave up this ‘lethal’ mothering. The interplay between parents and their children seemed of greater importance to the child than the information provided by the actual circumstances of their lives. The hypothesis about ‘lethal mothering’ presented here adds a psychodynamic perspective to the theory of ‘learned hopelessness and helplessness’; both are seen as relevant in understanding the devitalization reported here, and for understanding and treating PRS more generally.
Young People’s Experience of Mentoring: Building Trust and Attachments
Authors: Dallos Rudi , Comley-Ross Penny
Published: July 2005

The study was conducted in the context of PROMISE - a voluntary scheme, in the southwest of England which provides mentors for a young person for a period of up to 2 years. Predominantly these youngsters had experienced a range of difficulties in their lives including periods in care, severe problems in their families, trouble with the police and mental health problems. Each young person is allocated a mentor who has regular contact with them offering activities, support and informal counselling. Although the general response to the scheme has been positive it was felt that there was a gap of understanding about how the young people experienced the scheme. An exploratory qualitative study was commissioned to explore how a sample of the young people, who had been involved in the mentoring scheme for a substantial period, experienced the process of mentoring. The study involved interviews with six young people and group discussions with mentors and staff. Generally, the experience was reported by the young people to be highly favourable with the development of a positive, consistent, available, trusting and caring relationship cited as key ingredients. These findings were supported by discussion with the mentors. The study suggests that attachment theory is helpful in explaining the mentoring process and in promoting ideas for future developments.
Parenting and Borderline Personality Disorder: Ghosts in the Nursery
Authors: Newman Louise , Stevenson Caroline
Published: July 2005

This article reviews parenting issues for mothers with a diagnosis of borderline personality disorder. Motivation for parenting, conflicts and challenges associated with parenting and outcomes for infant and child development are considered. Implications for current therapeutic practice with families are outlined.
‘Bad Boys’’ Bodies: The Embodiment of Troubled Lives. Body Image and Disordered Eating Among Adolescents in Residential Childcare Institutions
Authors: Skårderud Finn , Nygren Pär , Edlund Birgitta
Published: July 2005

Children residing in care (hereafter referred to as childcare residents) are a risk-group for emotional disturbances and behaviour problems. Based on existing knowledge of risk factors one would also expect this population to be a high-risk group for eating disorders and related body-image disorders. The objective of this study was to describe pathological eating behaviour, dysfunctional body focusing and psychological symptoms in a sample of childcare residents compared with a non-clinical sample. Sixty-one childcare residents (aged 14-21 years, mean 16.2) and a non-clinical comparison group ( n= 196) completed the Eating Disorders Inventory - Child version (EDI-C). The childcare residents also completed an extended questionnaire, including questions regarding the use of anabolic-androgenic steroids. Our main findings were high scores on EDI-C symptom scales for boys in the childcare resident group; few differences between girls in the two samples; and a high frequency of having used anabolic-androgenic steroids among boys in care. Body-image problems among boys have hitherto been given little attention. The results call for increased efforts in describing and detecting pathological cognitions, emotions and behaviour concerning the body in males in general and, more specifically, in high-risk male groups, such as childcare residents.
Negative Parental Treatment of the Singled-out Child: Responses to the Problem by Health Visitors, Social Services Departments and Child and Adolescent Mental Health Services
Authors: Rushton Alan , Dance Cherilyn
Published: July 2005

The focus of this three-part study was on the recognition of, and service response to, families in which negative or rejecting behaviour is shown towards one of the children, whereas the siblings are accepted. Part 1 was an interview-based survey of health visitors’ views. They were able to identify families with such problems but were seldom in a position to intervene constructively and referrals to specialist services were not easily achieved. Part 2 was a case file study based on referrals of alleged emotional abuse to social services offices. The nature of the risk-assessment process undertaken by social workers was explored and it was shown that, beyond the initial stage of seeing the families, a lack of capacity was evident to provide structured assessments of the child, formal assessment of parenting and observation of the parent-child relationship. One-third of the emotional abuse cases were subject to child protection registration but only a minority received substantial social work intervention. Although it was found that singly rather than jointly referred children were given less priority and had less-thorough assessments, this could have been related to other characteristics of these children. Part 3 explored how child mental health professionals conceptualized the families’ difficulties, devised therapeutic interventions, considered obstacles to engaging the families and assessed the benefit of psychological help. It was acknowledged that some of these families can present a considerable challenge to any child welfare system because of denial of the problem or difficulties in engaging with existing services. More attention needs to be paid in these cases to maternal mental health problems, especially depression. Recommendations are made for developing more accessible preventive services while ensuring the protection and effective treatment of the singled-out child.
Test of Time
Authors: Edwards Mark C.
Published: July 2005

Whether behavior is determined mainly by situational factors or by more stable personality characteristics has been a classic debate in the social sciences. The question of the situational specificity of behavior has important implications for the assessment of children and adolescents. Because children function in multiple settings, clinicians are faced with the task of integrating information obtained from multiple informants from different settings, as well as their own clinical observations and impressions, and making clinical judgments based on this information. This process is challenging when information from different sources is not in agreement. Clinical decision-making and, ultimately, the accuracy of clinical judgments, will be influenced by how clinicians handle such discrepancies. With clinical accuracy being the chief concern in assessment, the debate about the stability vs situational specificity of behavior is an important one. The article by Achenbach, McConaughy, and Howell (1987) entitled ‘Child/Adolescent Behavioral and Emotional Problems: Implications of Cross-Informant Correlations for Situational Specificity’ has made an important contribution to the classic debate and leads to some practical recommendations for assessing children.
Fear during Alcohol Detoxification: Views from the Clients’ Perspective
Authors: Allen Joanne , Copello Alex , Orford Jim
Published: July 2005

Little is known about fears experienced during alcohol detoxification. Using qualitative research this preliminary study analysed descriptions of fears during one-to-one interviews about the experience of undertaking alcohol detoxification. Fears about detoxification centred around four main areas: the setting in which the process takes place, the physical consequences of withdrawal, the medication given to manage detoxification and the experience of future daily living without alcohol. The findings suggest that particular attention needs to be paid to the environmental setting of detoxification and the personal meaning of receiving medical care for withdrawal. In addition, more integration of relapse prevention work into the earliest stages of alcohol-related treatment and the provision of accurate information about detoxification may prove effective in reducing fears about the process.
Exploring Religion-Health Mediators among African American Parishioners
Authors: Holt Cheryl L. , Lewellyn Laura A. , Rathweg Mary Jo
Published: July 2005

This qualitative study examined the religiosity-health association among African Americans, with particular attention to mediators through which religiosity positively impacts health. We conducted 31 interviews across seven African American churches of different Christian denominations. Semi-structured interviews were completed with male and female parishioners. Participants were asked to describe the religiosity-health association in their own terms, and if and how their beliefs and practices impact their health. They were also asked about specific mediators proposed in this literature, such as social support and coping with stress. Respondents spontaneously mentioned that church helps them through spiritual health locus of control, coping with stress, positive affect and scriptural influence on lifestyle. These mediators may hold promise for translation into church-based health interventions.
Size Matters: Experiences of Atypical Genital and Sexual Development in Males
Authors: Chadwick Paul M. , Liao Lih-Mei , Boyle Mary E.
Published: July 2005

The psychological, emotional and social consequences of disrupted reproductive and sexual development in men are poorly understood. Interview data from eight men who had experienced gender atypical sexual development were analysed using the framework of Interpretative Phenomenological Analysis. The concept of ‘discreditment’ appeared to dominate these men’s experience of themselves and others. Emotional distress was most keenly felt when doubt was cast upon the men’s identity as sexually mature males. The extent to which absent sexual development was conspicuous or visible appeared to be an important factor in negative experiences.
The Social Realities of Adherence to Protease Inhibitor Regimens: Substance Use, Health Care and Psychological States
Authors: Halkitis Perry N. , Kutnick Alexandra H. , Slater Simon
Published: July 2005

Adherence to HIV antiretroviral treatments is impacted by a variety of factors nested within the realities of people’s lives.To understand this phenomenon, we undertook an investigation to assess HIV medication adherence in a community-based sample of 300 HIV seropositive men-who-have-sex-with-men (MSM). Using multiple measurement strategies (self-report, electronic monitoring, calendar-based assessments) we assessed factors related to medication adherence. Our findings indicate that adherence to protease inhibitor regimens are highly variable and are related to contextual, intrapersonal and behavioral factors, including access to health care, the use of specific recreational substances, self-efficacy toward adherence and avoidant coping strategies. These results suggest that a complex interaction between intrapsychic and socio-cultural realities may help to explain adherence to HIV treatment medications.
Adult Genital Surgery for Intersex: A Solution to What Problem?
Authors: Boyle Mary E. , Smith Susan , Liao Lih-Mei
Published: July 2005

The desirability of routine genital surgery for infants with ambiguous genitalia is increasingly debated. But there is less discussion about intersex adults who choose genital surgery, despite evidence suggesting that the results are often unsatisfactory. This study reports on how six women with intersex conditions decided to have feminizing genital surgery and how they evaluated the outcomes. The initial analysis highlighted a chronological transition from surgery as nondilemmatic to surgery as a serious dilemma; a version of Foucauldian discourse analysis was then used to place the women’s experiences in a cultural context. The implications for psychological involvement in services for women with intersex conditions are discussed.
Factors Influencing Anticipated Decisions about Sunscreen Use
Authors: Rasmussen Susan , O’Connor Rory C.
Published: July 2005

The present study examined influences on the decision-making processes relevant to sun-damage preventive behaviour, namely sunscreen use. Participants were randomly assigned to a positive, a negative or a control group and underwent two successive experimental manipulations: (1) information and (2) focus.They made pre-experimental, post-information and post-focus ratings of likelihood of using sunscreen and susceptibility to skin cancer.The results suggested that decision making changes as a function of the information present, and the information which individuals focus on at the time of decision making.The findings are described with particular emphasis on the implications for future intervention strategies.
Predictive Genetic Test Decisions for Huntington’s Disease: Elucidating the Test/No-test Dichotomy
Authors: Taylor Sandra D.
Published: July 2005

Predictive genetic testing for serious, mature-onset genetic illness represents a unique context in health decision making. This article presents findings from an exploratory qualitative Australian-based study into the decision making of individuals at risk for Huntington’s disease (HD) with regard to predictive genetic testing. Sixteen in-depth interviews were conducted with a range of at-risk individuals. Data analysis revealed four discrete decision-making positions rather than a ‘to test’ or ‘not to test’ dichotomy. A conceptual dimension of (non-)openness and (non-)engagement characterized the various decisions. Processes of decision making and a concept of ‘test readiness’ were identified. Findings from this research, while not generalizable, are discussed in relation to theoretical frameworks and stage models of health decision making, as well as possible clinical implications.
How Long a Honeymoon? The Effect of New Stadiums on Attendance in Major League Baseball
Authors: Clapp Christopher M. , Hakes Jahn K.
Published: July 2005

Using panel data of MLB team attendance from 1950 to 2002, we determined that the attendance “honeymoon” effect of a new stadium—after separating quality-of-play effects—increases attendance by 32% to 37% the opening year of a new stadium. Attendance remains above baseline levels for only two seasons for multipurpose stadiums built during 1960 to 1974 but for 6 to 10 seasons at newer ballparks. Contrary to expectations, there is no systematic interaction between new venues and team performance on attendance or stadium revenues. This noncomplementarity implies that a profit-maximizing team owner would not use a new stadium’s revenue stream to increase team quality of play.
Baseball Strikes and the Demand for Attendance
Authors: Coates Dennis , Harrison Thane
Published: July 2005

Determinants of attendance at major league baseball games has been a question of some interest as a result of the recent labor unrest in the sport. This article estimates the demand for attendance using a panel data set covering the years 1969 through 1996 and all the teams based in the United States. The analysis finds that even lockouts and strikes that do not result in lost games have significant effects on average attendance, unlike results in the literature. In addition, the results of the major strikes are found to be much smaller than some of those reported in the literature. Finally, using instrumental variables techniques to account for measurement error and endogeneity in the price variable, attendance demand was found to be price inelastic, regardless of how the basic ticket price variable was computed.
Home-Field Effect and Team Performance
Authors: Carmichael Fiona , Thomas Dennis
Published: July 2005

This article discusses the home-field effect in professional team sports and provides further evidence of home advantage in association football as played in the English Premier League. Utilizing play data it employs match-based production function to investigate the home-field effect on within-match performance by home and away teams.
Measuring Short-Run Uncertainty of Outcome in Sporting Leagues
Authors: Dawson Alistair , Downward Paul
Published: July 2005

We note the recurrence of errors in specifying an econometric proxy for short-run uncertainty of outcome in sporting fixtures. This research note aims to prevent the spread of these errors because they are becoming embedded in a growing literature. The note also suggests how investigators might more usefully define uncertainty of outcome.
The Economic Impact of Professional Teams on Monthly Hotel Occupancy Rates of Canadian Cities
Authors: Lavoie Marc , Rodríguez Gabriel
Published: July 2005

This article presents another attempt at finding the favorable economic effects claimed by sports team owners and boosters. The article has four peculiarities. First, no attempt is made to build a model explaining the targeted dependent variable; rather, a modified Box-Jenkins procedure is used. Second, the targeted variable, the hotel occupancy rates, is specific to the tourism industry. Third, our estimations are based on monthly data over a period of 10 years. Last, the study deals with Canadian rather than American cities. Overall results are somewhat ambiguous, but there does seem to be some evidence that the hockey lock-out of 1994-1995 did have a negative impact on hotel occupancy rates.
DCD – a novel plant specific domain in proteins involved in development and programmed cell death
Authors: Tenhaken Raimund , Doerks Tobias , Bork Peer
Published: July 2005

Background

Recognition of microbial pathogens by plants triggers the hypersensitive reaction, a common form of programmed cell death in plants. These dying cells generate signals that activate the plant immune system and alarm the neighboring cells as well as the whole plant to activate defense responses to limit the spread of the pathogen. The molecular mechanisms behind the hypersensitive reaction are largely unknown except for the recognition process of pathogens. We delineate the NRP-gene in soybean, which is specifically induced during this programmed cell death and contains a novel protein domain, which is commonly found in different plant proteins.

Results

The sequence analysis of the protein, encoded by the NRP-gene from soybean, led to the identification of a novel domain, which we named DCD, because it is found in plant proteins involved in d evelopment and c ell d eath. The domain is shared by several proteins in the Arabidopsis and the rice genomes, which otherwise show a different protein architecture. Biological studies indicate a role of these proteins in phytohormone response, embryo development and programmed cell by pathogens or ozone.

Conclusion

It is tempting to speculate, that the DCD domain mediates signaling in plant development and programmed cell death and could thus be used to identify interacting proteins to gain further molecular insights into these processes.
Tim50a, a nuclear isoform of the mitochondrial Tim50, interacts with proteins involved in snRNP biogenesis
Authors: Xu Hongzhi , Somers Z Brad , Robinson Melvin L , Hebert Michael D
Published: July 2005

Background

The Cajal body (CB) is a nuclear suborganelle involved in the biogenesis of small nuclear ribonucleoproteins (snRNPs), which are vital for pre-mRNA splicing. Newly imported Sm-class snRNPs traffic through CBs, where the snRNA component of the snRNP is modified, and then target to other nuclear domains such as speckles and perichromatin fibrils. It is not known how nascent snRNPs localize to the CB and are released from this structure after modification. The marker protein for CBs, coilin, may play a role in snRNP biogenesis given that it can interact with snRNPs and SMN, the protein mutated in Spinal Muscular Atrophy. Loss of coilin function in mice leads to significant viability and fertility problems and altered CB formation.

Results

In this report, we identify a minor isoform of the mitochondrial Tim50, Tim50a, as a coilin interacting protein. The Tim50a transcript can be detected in some cancer cell lines and normal brain tissue. The Tim50a protein differs only from Tim50 in that it contains an additional 103 aa N-terminal to the translation start of Tim50. Importantly, a putative nuclear localization signal is found within these 103 residues. In contrast to Tim50, which localizes to the cytoplasm and mitochondria, Tim50a is strictly nuclear and is enriched in speckles with snRNPs. In addition to coilin, Tim50a interacts with snRNPs and SMN. Competition binding experiments demonstrate that coilin competes with Sm proteins of snRNPs and SMN for binding sites on Tim50a.

Conclusion

Tim50a may play a role in snRNP biogenesis given its cellular localization and protein interaction characteristics. We hypothesize that Tim50a takes part in the release of snRNPs and SMN from the CB.
Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK
Authors: Ruigómez Ana , Johansson Saga , Wallander Mari-Ann , García Rodríguez Luis Alberto
Published: July 2005

Background

Natural history of paroxysmal atrial fibrillation (AF) is not very well documented. Clinical experience suggests that paroxysmal AF could progress to chronic AF with estimates ranging between 15 and 30% over a period of 1–3 years. We performed an epidemiologic study to elucidate the natural history of paroxysmal AF, this study estimated its incidence in a general practice setting, identified associated factors and analyzed the progression into chronic AF as well as the mortality rate.

Methods

Using the UK General Practice Research Database (GPRD), we identified patients aged 40–89 years with a first-recorded episode of paroxysmal AF during 1996. Risk factors were assessed using 525 incident paroxysmal AF cases confirmed by the general practitioner (GP) and a random sample of controls. We follow-up paroxysmal AF patients and estimated their mortality rate and progression to chronic AF.

Results

The incidence of paroxysmal AF was 1.0 per 1,000 person-years. Major risk factors for paroxysmal AF were age and prior valvular heart disease, ischaemic heart disease, heart failure and hyperthyroidism. During a mean follow-up of 2.7 years, 70 of 418 paroxysmal AF patients with complete information progressed to chronic AF. Risk factors associated with progression were valvular heart disease (OR 2.7, 95% CI 1.2–6.0) and moderate to high alcohol consumption (OR 3.0, 95% CI 1.1–8.0). Paroxysmal AF patients did not carry an increased risk of mortality, compared to an age and sex matched sample of the general population. There was a suggestion of a small increased risk among patients progressing to chronic AF (RR 1.5, 96% CI 0.8–2.9).

Conclusion

Paroxysmal AF is a common arrhythmia in the general practice setting, increasing with age and commonly associated with other heart diseases. It sometimes is the initial presentation and then progress to chronic AF. A history of valvular heart disease and alcohol consumption are associated with this progression.
The impact of illness in patients with moderate to severe gastro-esophageal reflux disease
Authors: El-Dika Samer , Guyatt Gordon H , Armstrong David , Degl'innocenti Alessio , Wiklund Ingela , Fallone Carlo A , Tanser Lisa , van Zanten Sander Veldhuyzen , Heels-Ansdell Diane , Wahlqvist Peter , Chiba Naoki , Barkun Alan N , Austin Peggy , Schünemann Holger J
Published: July 2005

Background

Gastro-esophageal reflux disease (GERD) is a common disease. It impairs health related quality of life (HRQL). However, the impact on utility scores and work productivity in patients with moderate to severe GERD is not well known.

Methods

We analyzed data from 217 patients with moderate to severe GERD (mean age 50, SD 13.7) across 17 Canadian centers. Patients completed three utility instruments – the standard gamble (SG), the feeling thermometer (FT), and the Health Utilities Index 3 (HUI 3) – and several HRQL instruments, including Quality of Life in Reflux and Dyspepsia (QOLRAD) and the Medical Outcomes Short Form-36 (SF-36). All patients received a proton pump inhibitor, esomeprazole 40 mg daily, for four to six weeks.

Results

The mean scores on a scale from 0 (dead) to 1 (full health) obtained for the FT, SG, and HUI 3 were 0.67 (95% CI, 0.64 to 0.70), 0.76 (95% CI, 0.75 to 0.80), and 0.80 (95% CI, 0.77 to 0.82) respectively. The mean scores on the SF-36 were lower than the previously reported Canadian and US general population mean scores and work productivity was impaired.

Conclusion

GERD has significant impact on utility scores, HRQL, and work productivity in patients with moderate to severe disease. Furthermore, the FT and HUI 3 provide more valid measurements of HRQL in GERD than the SG. After treatment with esomeprazole, patients showed improved HRQL.
Influence of electrical and thermal properties on RF ablation of breast cancer: is the tumour preferentially heated?
Authors: Ekstrand Vilhelm , Wiksell Hans , Schultz Inkeri , Sandstedt Bengt , Rotstein Samuel , Eriksson Anders
Published: July 2005

Background

Techniques based on radio frequency (RF) energy have many applications in medicine, in particular tumour ablation. Today, mammography screening detects many breast cancers at an early stage, facilitating treatment by minimally invasive techniques such as radio frequency ablation (RFA). The breast cancer is mostly surrounded by fat, which during RFA-treatment could result in preferential heating of the tumour due to the substantial differences in electrical parameters. The object of this study was to investigate if this preferential heating existed during experimental in vitro protocols and during computer simulations.

Methods

Excised breast material from four patients with morphologically diagnosed breast cancers were treated with our newly developed RFA equipment. Subsequently, two finite element method (FEM) models were developed; one with only fat and one with fat and an incorporated breast cancer of varying size. The FEM models were solved using temperature dependent electrical conductivity versus constant conductivity, and transient versus steady-state analyses.

Results

Our experimental study performed on excised breast tissue showed a preferential heating of the tumour, even if associated with long tumour strands. The fat between these tumour strands was surprisingly unaffected. Furthermore, the computer simulations demonstrated that the difference in electrical and thermal parameters between fat and tumour tissue can cause preferential heating of the tumour. The specific absorption rate (SAR) distribution changed significantly when a tumour was present in fatty tissue. The degree of preferential heating depended on tissue properties, tumour shape, and placement relative to the electrode. Temperature dependent electrical conductivity increased the thermal lesion volume, but did not change the preferential heating. Transient solutions decreased the thermal lesion volume but increased the preferential heating of the tumour.

Conclusion

Both the computer model and the in vitro study confirmed that preferential heating of the tumour during RFA exists in breast tissue. However, the observed preferential heating in the in vitro studies were more pronounced, indicating that additional effects other than the difference in tissue parameters might be involved. The existing septa layers between the cancer tissue and the fatty tissue could have an additional electrical or thermal insulating effect, explaining the discrepancy between the in vitro study and the computer model.
Accuracy of hyaluronic acid level for predicting liver fibrosis stages in patients with hepatitis C virus
Authors: Halfon Philippe , Bourlière Marc , Pénaranda Guillaume , Deydier Romaric , Renou Christophe , Botta-Fridlund Danielle , Tran Albert , Portal Isabelle , Allemand Isabelle , Rosenthal-Allieri Alessandra , Ouzan Denis
Published: July 2005

Background

In patients with chronic hepatitis C virus, liver biopsy is the gold standard for assessing liver disease stage; nevertheless, it is prone to complications, some of them serious. Non-invasive methods have been proposed as surrogate markers for liver fibrosis. It was shown that serum hyaluronic acid (HA) level increases with the development for liver fibrosis. The aim of this study was to evaluate the diagnostic value of HA as well as to determine the HA level cut-off for predicting the presence or absence of fibrosis, severe fibrosis, and cirrhosis.

Results

405 patients with chronic hepatitis C were prospectively included with biomarker measurement and liver biopsy done the same day: 151 in the training set (only biopsy lengths of 25 mm or more) and 254 in the validation set. For the discrimination of significant fibrosis, severe fibrosis, and cirrhosis in the training set, the areas under curve (AUCs) were 0.75 ± 0.03, 0.82 ± 0.02, and 0.89 ± 0.03, respectively. Absence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 16, 25, and 50 μg/l, respectively (with negative predictive values of 82%, 89%, and 100%, in the same order). Presence of significant fibrosis, severe fibrosis, and cirrhosis can be predicted by HA levels of 121, 160, and 237 μg/l, respectively (with positive predictive values of 94%, 100%, and 57%, in the same order).

Conclusion

In the validation set, HA was accurate in predicting significant fibrosis, severe fibrosis, and cirrhosis with AUCs of 0.73, 0.77, and 0.97, respectively. Moreover, accurate HA level cut-offs were defined for predicting significant fibrosis, severe fibrosis, and cirrhosis. Thus, the study supports that HA level may be clinically useful as a non-invasive marker for liver fibrosis and/or cirrhosis.
Posttranslational Modifications of Self‐Antigens
Authors: DOYLE HESTER A. , MAMULA MARK J.
Published: July 2005

Abstract: Although the immune system has developed mechanisms to distinguish “self” from “non‐self,” the presence of autoimmune diseases demonstrates that these mechanisms can be bypassed. The posttranslational modification of self‐antigens is one way in which “new” antigens are created for which immune tolerance does not exist. We review some of the posttranslationally modified self‐antigens associated with autoimmune diseases, how they arise, and how they break immune tolerance.
The Mechanism of Molecular Redundancy in Autoimmune Inflammation in the Context of CD44 Deficiency
Authors: NAOR DAVID , NEDVETZKI SHLOMO , ASSAYAG NATHALIE , THURMOND ROBIN L. , HUANG JING‐FENG , TURLEY EVA A.
Published: July 2005

Abstract: Molecular redundancy refers to the ability of genes to back up damaged genes or gene loss. Although this term is widely discussed in many scientific circles, the process is still ill‐defined, as shown by reviewing examples from the literature. Exploring the collagen‐induced arthritis model in the context of CD44 knockout mice, we suggest a mechanistic explanation for molecular redundancy that depends neither on upregulation of the compensating molecule nor on structural similarity between the original molecule and the replacement molecule. The backup process is dependent, however, on two key properties shared by the two molecules: ligand binding and support of cell trafficking.
Functional Genomics in Early Autoimmunity
Authors: MELANITOU EVIE
Published: July 2005

Abstract: The molecular mechanisms initiating the autoimmune process in type 1 diabetes mellitus (T1DM) remain unknown, and studies aiming to address this question have been compromised by the difficulty of predicting the disease at an early age both in humans and in animal models. An additional hindrance in selecting individuals at an early age has been the complex genetic inheritance of autoimmune diabetes, implicating not only several genes but also environmental factors. We have previously demonstrated the predictive value of insulin autoantibodies (IAAs) at an early age, between three to five weeks in the NOD mouse. Animals positive for early appearance of IAAs (E‐IAAs) develop autoimmune diabetes earlier. We showed a correlation between the presence of IAAs in the mothers during pregnancy, E‐IAAs in the litters, and the early appearance of T1DM. NOD mice, E‐IAA‐positive, within litters from IAA‐positive mothers during pregnancy, develop diabetes earlier and at a much greater rate than animals that are IAA‐negative and from IAA‐negative mothers. The molecular mechanisms responsible for this early autoimmune subphenotype were addressed by a global approach to differential gene expression analysis in the pancreatic lymph nodes (PaLNs). Although the data analysis is currently in progress, gene expression signatures were observed that are characteristic for PaLNs with regard to the presence or absence of IAAs. Overall, these data are consistent with the hypothesis of an early environmental influence from the autoimmune maternal environment on the genetic predisposition of the offspring, characterized by specific gene signatures leading to autoimmune disease.
Interspecific Structural Differences in Nucleosome as Revealed by Heteroimmunization in Mice with Human Nucleosome
Authors: KANAI Y , WATANABE M , KUBOTA T
Published: July 2005

Abstract: Although mounting evidence suggests the association of anti‐nucleosome (NS) antibodies with lupus nephropathy in humans, the influence of interspecific differences in NS structure on the diagnosis has not been studied fully. Thus, we investigated the interspecific differences in NS structure by immunizing normal BALB/c mice with human nucleosomes (hNS). We purified hNS and mouse nucleosomes (mNS) from individual established cell lines. Purified NS was of high‐pressure liquid chromatography grade and contained less than 1% dinucleosome, if any. Immune responses to NS were tested by an enzyme‐linked immunosorbent assay. Of 6 mice, 2 responded to both hNS and mNS. However, antibodies produced in individual mice had higher affinity to mNS than to hNS. IgG response to hNS was IgG1 and IgG2b in subclass, whereas that to mNS was restricted to IgG1. Coincident with this response difference, agarose gel electrophoresis showed a mobility difference between hNS and mNS: the former was slower than the latter. In conclusion, immunodifferentiation in vivo in mice of autologous from heterologous NS together with their mobility difference in agarose gel suggest the presence of interspecific differences in NS. In humans, 2 out of 14 randomly tested patients with systemic lupus erythematosus preferred hNS over mNS; the IgG subclass in one was IgG1, and in the other IgG4. Taken together, interspecific differences in NS will provide a new area of study not only in biochemistry but also in immunology and/or autoimmunity.
Non‐Antigen‐Specific CD8+ T Suppressor Lymphocytes in Diseases Characterized by Chronic Immune Responses and Inflammation
Authors: FILACI G , RIZZI M , SETTI M , FENOGLIO D , FRAVEGA M , BASSO M , ANSALDO G , CEPPA P , BORGONOVO G , MURDACA G , FERRERA F , PICCIOTTO A , FIOCCA R , TORRE G , INDIVERI F
Published: July 2005

Abstract: Recent studies on regulatory lymphocytes demonstrate that CD8+ T suppressor (Ts) cells may have great relevance in controlling immune system homeostasis and avoiding development of chronic inflammatory diseases. Among the three subpopulations of CD8+ Ts cells so far recognized in humans, the type 2 (non‐antigen‐specific) cell is characterized by the capacity to inhibit both T cell proliferation and cytotoxic T lymphocyte activity through secretion of soluble factors. Previous work has shown the impairment of in vitro generation of type 2 CD8+ Ts cells from the peripheral blood of relapsed patients with multiple sclerosis, systemic lupus erythematosus, or systemic sclerosis. Here, similar findings are demonstrated for patients with human immunodeficiency virus or chronic hepatitis C virus infection. Furthermore, the presence of type 2 CD8+ Ts cells infiltrating diseased tissues in patients with autoimmune thyroiditis or cancer is shown. Collectively, these findings suggest that type 2 CD8+ Ts cells may be involved in the control of pathologic chronic immune responses, contributing in some cases to the pathogenesis of the disease.
The Anti‐Alpha‐Actinin Test Completes Anti‐DNA Determination in Systemic Lupus Erythematosus
Authors: CROQUEFER S , RENAUDINEAU Y , JOUSSE S , GUEGUEN P , ANSART S , SARAUX A , YOUINOU P
Published: July 2005

Abstract: In murine systemic lupus erythematosus (SLE) models, nephritogenic anti‐dsDNA IgG has been shown to cross‐react with a kidney antigen, alpha‐actinin, and to be critical in renal pathogenesis. In humans, studies of anti‐alpha‐actinin antibodies (Abs) are scarce, and these antibodies remain to be evaluated. We have thus far tested sera from patients with SLE (n= 103), rheumatoid arthritis (RA, n= 93), and primary Sjögren syndrome (pSS, n= 34), and from healthy subjects (n= 160), for the presence of anti‐alpha‐actinin and anti‐DNA Abs. The latter were tested using several methods [IIF on Crithidia luciliae (Crit) and ELISA using dsDNA]. Anti‐alpha‐actinin Abs were confirmed by Western blot. Sera from 23 of 103 SLE patients, 3 of 93 RA patients, 1 of 33 pSS patients, and 1 of 160 controls scored positive for anti‐alpha‐actinin Abs. In SLE, the positivity was significantly associated with anti‐dsDNA reactivity (22 of 23): 19 of 23 sera were alpha‐actinin‐positive/dsDNA‐positive and 13 were alpha‐actinin‐positive/Crit‐positive. Few cases were alpha‐actinin/positive/dsDNA‐negative: 1 SLE, 3 RA, and 1 control. Furthermore, anti‐alpha‐actinin Abs have been detected at high level before or at the early stage of lupus nephritis when compared with active and inactive SLE without kidney manifestations.
The Relevance of Autoantigen Source and Cutoff Definition in Antichromatin (Nucleosome) Antibody Immunoassays
Authors: VILLALTA DANILO , TOZZOLI RENATO , BIZZARO NICOLA , TONUTTI ELIO , GHIRARDELLO ANNA , DORIA ANDREA
Published: July 2005

Abstract: In the last few years, several reports have shown that chromatin (nucleosome) represents the main autoantigen‐immunogen in systemic lupus erythematosus (SLE) and that specific antibodies are an important marker of the disease. To verify the clinical sensitivity and specificity of antinucleosome autoantibodies (ANuAs), we evaluated three ELISA immunoassay methods using different autoantigen preparations: Quanta Lite Chromatin, Medizym Anti‐nucleo, and Nucleosome IgG Elisa. We compared the results with those obtained using two ELISA assays for determining anti‐native DNA (anti‐nDNA) antibodies: Axis‐Shield and EliA dsDNA. We tested sera from 321 patients: 101 with SLE and 220 controls—48 with infectious diseases; 73 with autoimmune rheumatic disease (20 with rheumatoid arthritis, 30 with systemic sclerosis, and 23 with primary Sjögren's syndrome), and 99 healthy subjects. Using the manufacturer‐recommended cutoff, the sensitivity for the three kits was 69%, 78%, and 74%, and specificity was 100%, 94.6%, and 95.0%, respectively. Using the cutoff corresponding to 95% specificity, the sensitivity of the methods for the ANuA assay was 86%, 77%, and 74%—higher than obtained with the two ELISA methods for anti‐nDNA (65% and 64%). This study demonstrates that (1) the commercial reagents employed in clinical laboratories for ANuA detection show good sensitivity and high specificity; (2) ANuAs are more sensitive than anti‐nDNA antibodies for diagnosing SLE; and (3) different solid‐phase antigen preparations and methods used to define cutoff levels may affect a test's clinical performance.
Value of a New Automated Fluorescence Immunoassay (EliA) for PR3 and MPO‐ANCA in Monitoring Disease Activity in ANCA‐Associated Systemic Vasculitis
Authors: SINICO RENATO ALBERTO , RADICE ANTONELLA , CORACE CATERINA , Di TOMA LUCAFRANCESCO , SABADINI ETTORE
Published: July 2005

Abstract: The value of anti‐neutrophil cytoplasmic antibody (ANCA) detection for monitoring disease activity in ANCA‐associated systemic vasculitis (AASV) remains controversial. The aim of our work was to rate the performance of a new automated fluorescence PR3 and MPO‐ANCA immunoassay (EliA) for monitoring disease activity in AASV. We evaluated 100 serum samples from 71 AASV patients (with Wegener's granulomatosis, microscopic polyangiitis, and Churg‐Strauss syndrome) as well as sera from 58 pathological and 35 normal controls. In addition to PR3 and MPO‐ANCA EliA, we performed indirect immunofluorescence and “homemade” PR3 and MPO‐ANCA ELISA tests. In AASV patients, ANCA levels were correlated with disease activity, according to the Birmingham Vasculitis Activity Score (BVAS). We derived cutoff limits from receiver operating characteristic (ROC) curve analysis comparing AASV with pathological controls. Our results showed that EliA and ELISA had comparable sensitivity (76%) and specificity (95%). The analysis of active versus inactive status and correlation with ANCA levels showed a clear difference between BVAS Group I (score ≤ 4) and BVAS Group II (scores > 4) (AUC = 0.86 vs. 0.72; relative risk [RR] = 2.4; P < 0.0001) for PR3‐ANCA, but not for MPO‐ANCA (AUC = 0.94 vs. 0.87; RR = 1.48; P= 0.46). Serial serum samples from 16 patients were examined in detail. For the majority of patients, for both PR3 and MPO‐ANCA, change in titer was strongly associated with change in BVAS score. Our data showed a good correlation between ANCA titer (especially for PR3) and AASV disease activity. We recommend that ANCA titer be used to monitor AASV disease activity with the caveat that a few exceptions, in particular with MPO‐ANCA, are possible.
Anti‐C1q Autoantibodies in Lupus Nephritis: Prevalence and Clinical Significance
Authors: SINICO RENATO ALBERTO , RADICE ANTONELLA , IKEHATA MASAMI , GIAMMARRESI GAIA , CORACE CATERINA , ARRIGO GIROLAMO , BOLLINI BRUNA , LI VECCHI MAURIZIO
Published: July 2005

Abstract: Recently, anti‐C1q autoantibodies have been proposed as a useful marker in systemic lupus erythematosus (SLE) since their occurrence correlates with renal involvement and, possibly, with nephritic activity. We aimed to evaluate the prevalence of anti‐C1q antibodies in patients with SLE, with and without renal involvement, and to correlate these markers' presence and levels with the activity of the disease and nephropathy. We studied 61 patients with SLE, 40 of whom had biopsy‐proven lupus nephritis; 35 patients with other connective tissue diseases; and 54 healthy controls. In addition, 18 lupus nephritis patients were followed up during the disease time course. Anti‐C1q antibodies were measured using “homemade” ELISA with high salt concentration (1 M sodium chloride). High anti‐C1q antibody titers (> 55 AU) were present in 27 of 61 (44%) SLE patients and in 4% and 0% of normal blood donors and pathologic controls, respectively. Anti‐C1q antibodies were found in 60% of patients with lupus nephritis compared with only 14% of SLE patients without nephropathy (P < 0.05). Moreover, patients who were positive for anti‐C1q antibodies had a higher European Consensus Lupus Activity Measurement (ECLAM) score (4.35 vs. 2.2); 89% of patients with active lupus nephritis showed high titers of anti‐C1q antibodies compared with 0% of patients with inactive nephritis. Anti‐C1q and anti‐dsDNA antibodies agreed in 79% of cases. Our results confirm that anti‐C1q antibodies are present in a significant percentage of SLE patients, and that their presence and levels correlate with disease activity—in particular, during renal flare‐ups.
Antibodies against Erythropoietin and Other Protein‐Based Therapeutics: An Overview
Authors: KROMMINGA ARNO , SCHELLEKENS HUUB
Published: July 2005

Abstract: Many factors influence the immunogenicity of protein‐based therapeutics. At present, it is inconceivable to manufacture a biopharmaceutical without the risk of this adverse effect. Thus, the detection and characterization of antibodies against protein‐based therapeutics is a significant task. Only clinical studies and careful monitoring of the market can be used to conclusively demonstrate rates of immunogenicity in humans for protein therapeutics. Fully validated, reliable, and robust in vitro assays, in combination with sensitive bioassays, should be used to address these topics.