bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of immigration detention and temporary protection on the mental health of refugees
Authors: Steel Zachary , Silove Derrick , Brooks Robert , Momartin Shakeh , Alzuhairi Bushra , Susljik Ina
Published: December 2005

Background

Over the past decade, developed Western countries have supplied increasingly stringent measures to discourage those seeking asylum.

Aims

To investigate the longer-term mental health effects of mandatory detention and subsequent temporary protection on refugees.

Method

Lists of names provided by community leaders were supplemented by snowball sampling to recruit 241 Arabic-speaking Mandaean refugees in Sydney (60% of the total adult Mandaean population). Interviews assessed posttraumatic stress disorder (PTSD), major depressive episodes, and indices of stress related to pasttrauma, detention and temporary protection.

Results

A multilevel model which included age, gender, family clustering, pre-migration trauma and length of residency revealed that past immigration detention and ongoing temporary protection each contributed independently to risk of ongoing PTSD, depression and mental health-related disability. Longer detention was associated with more severe mental disturbance, an effect that persisted for an average of 3 years after release.

Conclusions

Policies of detention and temporary protection appear to be detrimental to the longer-term mental health of refugees.
Anomalies of asymmetry of pyramidal cell density and structure
in dorsolateral prefrontal cortex in schizophrenia
Authors: Cullen Thomas J. , Walker Mary A. , Eastwood Sharon L. , Esiri Margaret M. , Harrison Paul J. , Crow Timothy J.
Published: December 2005

Background

Studies suggest that neuronal density in left dorsolateral prefrontal
cortex is increased in schizophrenia.

Aims

To replicate these findings and extend them to both hemispheres.

Method

Neuronal density, size and shape were estimated in the prefrontal cortex
(Brodmann area 9) of the left and right hemispheres of brains taken
postmortem from 10 people with schizophrenia and 10 without mental
illness (6 men, 4 women in both groups).

Results

Overall neuronal density (individually corrected for shrinkage) did not
differ between the groups. In the control brains, density was generally
greater in the left than the right hemisphere, the reverse was seen in
the schizophrenia brains; this loss or reversal of asymmetry was most
significant in cortical layer 3. Pyramidal neurons in this cell layer
were significantly larger on the left and more spherical in shape than on
the right side in control brains, but size and shape did not differ
between the two sides in schizophrenia. Non-pyramidal and glial cell
densities were unchanged.

Conclusions

We failed to find an increase in neuronal density, but found evidence at
a cellular level of loss or reversal of asymmetry, consistent with the
hypothesis of a primary change in the relative development of areas of
heteromodal association cortex in the two hemispheres.
Rural/non-rural differences in rates of common mental disorders
in Britain
Authors: Weich Scott , Twigg Liz , Lewis Glyn
Published: December 2005

Background

Some UK studies have reported an urban excess in the prevalence of the
most common mental disorders of anxiety and depression.

Aims

To investigate rural/non-rural differences in the onset and maintenance
of episodes of common mental disorders, after adjusting for the
characteristics of respondents and their households.

Method

A 12-month cohort study of 7659 adults aged 16–74 years living in 4338
private households, nested within 626 electoral wards in England, Wales
and Scotland. Common mental disorders were assessed using the General
Health Questionnaire (GHQ). Electoral wards were characterised by Office
for National Statistics classification and by population density. Data
were analysed using multilevel statistical modelling.

Results

Rural residents had slightly better mental health than non-rural
counterparts. The effects of geographical location on the mental health
of participants were neither significantly confounded nor modified by
socioeconomic status, employment status or household income.

Conclusions

There are small but statistically significant differences in rates of
common mental disorders between urban and rural residents. Quantifying
between-place differences using population density alone risks missing
important contextual effects on mental health.
Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder
Authors: Green Elaine K. , Raybould Rachel , Macgregor Stuart , Hyde Sally , Young Allan H. , O'Donovan Michael C. , Owen Michael J. , Kirov George , Jones Lisa , Jones Ian , Craddock Nick
Published: December 2005

Background

Brain-derived neurotrophic factor (BDNF) influences neuronal survival, proliferation and plasticity Three family-based studies have shown association of the common Valine (Val) allele of the Val66Met polymorphism of theBDNFgene with susceptibility to bipolar disorder.

Aims

To replicate this finding.

Method

We genotyped the Val66Met polymorphism in our UK White bipolar case-control sample (n=3062).

Results

We found no overall evidence of allele or genotype association. However, we found association with disease status in the subset of 131 individuals that had experienced rapid cycling at some time (P=0.004). We found a similar association on re-analysis of our previously reported family-based association sample (P<0.03, one-tailed test).

Conclusions

Variation at the Val66Met polymorphism ofBDNFdoes not play a major role in influencing susceptibility to bipolar disorder as a whole, but is associated with susceptibility to the rapid-cycling subset of the disorder.
Men with severe learning disabilities and challenging behaviour
in long-stay hospital care
Authors: Hubert Jane , Hollins Sheila
Published: December 2005

Background

Community-based health and social care professionals have little
knowledge of the past experiences of people with severe learning
disabilities and challenging behaviour who are living in
institutions.

Aims

To gain a greater understanding of the experiences and needs of men who
are living in a locked ward.

Method

The study sample consisted of 20 men who were living in a locked ward of
a long-stay institution. Qualitative (ethnographic) methods were used,
involving participant observation (for around 250 hours) on the ward. All
traceable families were interviewed. The analysis used grounded theory,
and material was fed back into the resettlement process throughout.

Results

The men's lives were emotionally, socially and physically deprived. Their
individual, gender and social identities were not recognised, and their
general health and mental healthcare needs were inadequately
addressed.

Conclusions

People who live in long-stay institutions, segregated from society, lose
their individual and social identity, which complicates the presentation
of mental health and behavioural problems, and raises important adult
protection issues.
Prison medicine: ethics and equivalence
Authors: Birmingham Luke , Wilson Simon , Adshead Gwen
Published: December 2005

Guidelines for good medical practice do not reflect the complex reality of
the ethical problems that arise in prison. Perhaps the best a doctor working
in prison can do is realise that there are ethical dilemmas everywhere, try
to recognise them and feel the tension.
The 10/90 divide in mental health research: Trends over a
10-year period
Authors: Saxena Shekhar , Paraje Guillermo , Sharan Pratap , Karam Ghassan , Sadana Ritu
Published: December 2005

A search (precision value 94%, recall value 93%) of the ISI Web of Science
database (1992–2001) revealed that mental health publications accounted for
3–4% of the health literature. A 10/90 divide in internationally accessible
mental health literature was evident and remained undiminished through 10
years as low- and middle-income countries (n= 152)
contributed only 6%, high-income countries (n=54) 94%, and
14 leading high-income countries (with more than 1% contribution for
majority of years under consideration) contributed 90% of internationally
accessible mental health research. Steps should be taken to improve the
research infrastructure and capacity to conduct and disseminate mental
health research in general, and on a priority basis in low- and
middle-income countries.
Progress in the treatment of borderline personality
disorder
Authors: Fonagy Peter , Bateman Anthony
Published: December 2005

We outline recent evidence suggesting that the natural course of borderline
personality disorder is more benign than formerly believed. We explore
possible reasons for the change in findings which include both the
iatrogenic effects of earlier treatment models and the recent availability
of effective interventions. Clinicians should be optimistic about
improvement and long-term outcomes.
Survey of the provision of psychological therapies for older people
Authors: Evans Ceri , Reynolds Paul
Published: December 2005

Aims and Method

The aim of the present study was to assess the current state of provision of psychological therapies for older people in Wales. A postal questionnaire was sent to all consultant old age psychiatrists in Wales, requesting information regarding the consultant's community mental health team (CMHT) and access to psychological therapies.

Results

A response rate of 85% was achieved: 45% of CMHTs had team members providing psychological therapy; 31% of CMHTs had access to psychological therapy via the team and also generic services. The estimated average wait for generic services was 29 weeks. There was no access to psychological therapies for 17% of CMHTs.

Clinical Implications

In some areas of Wales there is limited or no access to psychological therapies via mental health services for older people. This may represent an important unmet need. Long-term strategies, taking into account recruitment and retention, training and new ways of working, need to be implemented.
Capacity, compliance and electroconvulsive therapy (ECT): the practice of ECT among consultant psychiatrists
Authors: Law-Min Richard , Stephens John Patrick
Published: December 2005

Aims and Method

The aim of this study was to seek the views of consultant psychiatrists on the legal framework they would use when considering treatment with electroconvulsive therapy (ECT). A questionnaire, consisting of three clinical vignettes, was sent to 70 consultants in the Wessex rotation (East Dorset/Hampshire region).

Results

A total of 56 questionnaires were returned; a response rate of 80%. Most consultant psychiatrists agree when giving ECT to capacitated and non-consenting patients. However, there was a lack of consensus when dealing with seemingly incapacitated but compliant patients.

Clinical Implications

More clarification in this area is needed. Trusts can assist clinicians by devising their own policies based on nationally agreed standards of best practice. The treatment of mentally incapacitated but compliant patients is an area of practice where uncertainty exists. If proceeding under common law in such cases, it is good practice to discuss with relatives/carers and obtain a second opinion from a consultant colleague. The most recent Bournewood judgement and the new Mental Health Bill will have further implications for clinical practice.
Survey of client satisfaction with methadone maintenance programmes
Authors: Kumar M. Raj , Rajwal Madhuri
Published: December 2005

Aims and Method

The aim of the study was to elicit clients' satisfaction with the methadone maintenance service and their views regarding opiate users not in the service. A self-completion questionnaire with 40 questions covering various aspects of service delivery was given to clients on this programme.

Results

Of a total of 52 questionnaires, 31 (60%) were returned. There was a high level of overall satisfaction (93%) with the service and staff, but there were significant problems related to prolonged waiting times and access to ancillary services. There were also practical difficulties related to prescriptions. Over half of the clients (54%) used additional illicit opiates.

Clinical Implications

It is likely that addressing identified problem areas may influence treatment outcome in this challenging group. Staff should maintain optimism in helping the clients who, as seen by this survey, value their advice.
Higher specialist training in child and adolescent psychiatry: a survey of academic programmes
Authors: Hawkins Tim , Lee Alison , Stephens Helen , Matthies Gisa , Bailey Alison
Published: December 2005

Aims and Method

Academic programmes are mandatory in child psychiatry specialist registrar training. A postal questionnaire survey was undertaken to explore the views of specialist registrars and academic programme coordinators identified nationally with regard to their local academic programme.

Results

Sixty per cent of specialist registrars (152 out of 253) and 90% of coordinators (17 out of 19) responded. All schemes offered an academic programme with protected time. Teaching methods were diverse, and satisfaction varied within and between schemes, with trainees reporting greater satisfaction associated with active involvement of coordinators.

Clinical Implications

The authors provide recommendations for local planning of academic programmes. The authors request the assistance of CAPSAC in standardising the appointment and training of coordinators and facilitating their release from clinical commitments.
Tilting the balance: the first long-term medium secure unit in the NHS in England and Wales
Authors: Power Niamh , Harwood Dawn , Akinkunmi Akintunde
Published: December 2005

Rollo May Ward, a long-term medium secure facility integrated within the West London Mental Health National Health Service (NHS) Trust, is the first dedicated long-term NHS medium secure unit to have opened in England. It caters for a group of men with complex clinical needs and risk assessment issues who had previously been inappropriately detained within high secure services owing to a lack of suitable, less secure placement facilities. We describe the background to the development of the long-term medium secure service, the referral and assessment processes, the structure of the ward and the therapeutic programmes available to patients. We also outline the characteristics of the first 21 patients to be admitted to the ward and offer advice for similar future developments.
Using the scarce resource of child and adolescent psychiatrists equitably
Authors: Lloyd Hilary , Bamforth Margaret , Eminson Mary
Published: December 2005

The authors, all consultant child and adolescent psychiatrists working in the north-west of England (an area that has experienced recruitment difficulties throughout the past decade), seek to stimulate discussion about the serious issues of recruitment and retention faced by child and adolescent psychiatry. Current thinking about staffing and models of provision is challenged.
Through the back door: the College and award of Membership without examination
Authors: Khan Murad M.
Published: December 2005

Every year the Royal College of Psychiatrists awards a number of memberships to psychiatrists without examination. This is done under Bye-Law III 2 (ii). The sub-category Bye-Law III 2 (ii) (a) states that the ‘Membership of the College may be extended to senior psychiatrists who have practised with distinction over many years and are of international repute’. Candidates should be nominated, proposed and seconded by two members or fellows of the College. If the candidate is from outside the UK, one of the sponsors must be from the applicant's home country. Nominations are accepted from all over the world (Royal College of Psychiatrists, 2001).
Evaluating qualitative papers in a multidisciplinary evidence-based journal club: a pilot study
Authors: Mukherjee Raja A. S. , Owen Katherine , Hollins Sheila
Published: December 2005

Journal clubs have traditionally been important means by which clinicians, academics and trainees appraise research that relates to their field. In recent years the evidence-based style has become more prevalent, allowing knowledge gleaned from research to be applied to clinical situations. Currently, the main approach of evidence-based journal clubs is quantitative. This paper describes the evaluation of a modified journal club format, developed in an academic department of a medical school and combining the appraisal of both qualitative and quantitative papers.
Beginning therapy: clinical outcomes in brief treatments by psychiatric trainees
Authors: Mace Chris , Beeken Sally , Embleton Joan
Published: December 2005

Aims and Method

Psychotherapy provided by inexperienced psychiatric trainees was assessed through comparison of post-treatment outcomes with a brief psychodynamic therapy and a brief integrative psychotherapy. A retrospective case–control design was applied to all patients seen by nine senior house officers (SHOs) during 6-month placements who provided follow-up data. Matching linked each patient offered simple cognitive–analytic therapy to one who had received brief psychodynamic therapy from the same SHO. Post-treatment changes were analysed by treatment received and differences between trainees were explored.

Results

Seventeen cases in each group met entry criteria. Patients receiving the integrative treatment had more severe pathology and outcomes were more variable when this model was used. Eight of the nine SHO therapists performed better with the psychodynamic intervention.

Clinical Implications

Significant clinical improvements can be achieved by inexperienced psychiatric trainees providing brief psychotherapy under supervision. Patient selection is undoubtedly important. Fundamental psychotherapy competencies need to be mastered before structured hybrid models are attempted.
The Involvement of Thioredoxin and Thioredoxin Binding Protein‐2 on Cellular Proliferation and Aging Process
Authors: YOSHIDA TORU , NAKAMURA HAJIME , MASUTANI HIROSHI , YODOI JUNJI
Published: December 2005

Recent reports on aging have revealed that many genetic loci affecting life span are closely linked to the machinery either producing or defending oxidative stress. Protective mechanisms against oxidative stress are thus important in countering the aging process. Thioredoxin (TRX) is a small thiol‐mediated protein with a redox‐active disulfide/dithiol within the conserved active site. TRX transgenic mice are more resistant than control mice to a variety of oxidative stresses including infection and inflammation. Moreover, we observed that the median life span of TRX tg mice was extended up to 135% compared to that of controls. TRX binding protein‐2 (TBP‐2), which is identical to vitamin D3 upregulated protein 1 (VDUP1), was identified as a binding molecule to TRX, and a negative regulator of TRX function. The expression of TBP‐2/VDUP1 is frequently lost in tumor tissue and cell lines, and ectopic expression of TBP‐2/VDUP1 suppresses cellular proliferation along with cell cycle arrest at the G1 phase. These findings suggest that TRX and TBP‐2/VDUP1 are involved not only in cytoprotective functions against oxidative stress, but also in the regulation of cellular proliferation and the aging process.
The Different Paths to Age One Hundred
Authors: PERLS THOMAS
Published: December 2005

Attaining age 100 is a rare event in industrialized nations, occurring in 1 person per 10,000 in the population. Becoming a centenarian does not appear to be rare because the individual genetic or behavioral factors (such as specific genetic polymorphisms or lack of specific toxic exposures) that enable such longevity are rare, but rather because having the adequate combination of these factors is rare.
Genetic Engineering of Mice to Test the Oxidative Damage Theory of Aging
Authors: MARTIN GEORGE M.
Published: December 2005

The laboratory mouse Mus musculus domesticus provides the best current mammalian models for the genetic analysis of aging. We give a brief overview of the use of transgenic manipulations to test the oxidative damage theory of aging. These manipulations are of two types: The first approach engineers mice that exhibit increased sensitivities to oxidative damage and thus produces mice that are likely to be short‐lived. The second approach engineers mice to be more resistant to such injuries, and thus may produce mice that exhibit enhanced longevities, something that is much harder to engineer. The latter result is thus more meaningful, with the caveat that it may result from some special vulnerability of a particular lab strain or lab strains in general. The first approach, most elegantly carried out by Arlan Richardson's laboratory, provides evidence against the oxidative damage theory. My colleagues and I have been engaged in the second approach and have accumulated evidence supporting the theory. These conventional transgenic experiments, however, should be supplemented by alternative genetic approaches. One that is surprisingly neglected takes advantage of the pleuripotency of embryonic stem cells and the power of somatic cell genetics. A cautionary note is that interventions that minimize oxidative stress may be complicated by unwanted compromises of physiologically adaptive actions such as superoxide signaling and the possible protective effects of certain oxidatively modified proteins.
Aging and Genome Maintenance
Authors: VIJG JAN , BUSUTTIL RITA A. , BAHAR RUMANA , DOLLÉ MARTIJN E.T.
Published: December 2005

Genomic instability in somatic cells has been implicated as a major stochastic mechanism of aging. Using a transgenic mouse model with chromosomally integrated lacZ mutational target genes, we found mutations to accumulate with age at an organ‐ and tissue‐specific rate. Also the spectrum of age‐accumulated mutations was found to differ greatly from organ to organ; while initially similar, mutation spectra of different tissues diverged significantly over the lifetime. To explain how genomic instability, which is inherently stochastic, can be a causal factor in aging, it is proposed that randomly induced mutations may adversely affect normal patterns of gene regulation, resulting in a mosaic of cells at various stages on a trajectory of degeneration, eventually resulting in cell death or neoplastic transformation. To directly address this question we demonstrate that it is now possible to analyze single cells, isolated from old and young tissues, for specific alterations in gene expression.
The Use of Genetic SNPs as New Diagnostic Markers in Preventive Medicine
Authors: CANTOR CHARLES R.
Published: December 2005

Using an automated mass spectrometric genotyping platform, we have completed more than ten whole‐genome SNP scans on phenotypically stratified population pools. The pools are usually constructed to represent one ethnicity, one gender, and one phenotype, classified as strictly as possible. From 28,000 to 91,000 different SNPs are used for each study, and the pools typically contain DNA from 300 different individuals. Significant correlations between SNP allele and phenotype are first reproduced in the pools, then replicated on individual DNA samples (deconvolution of the pools), and then where possible replicated in completely independent populations.
Decoding the Pyramid: A Systems‐Biological Approach to Nutrigenomics
Authors: KAPUT JIM
Published: December 2005

Nutritional genomics, or nutrigenomics, seeks to understand the effects of diet on an individual's genes and health. Nutrigenomics is a systems‐biological science that can be explained by five principal tenets: (1) improper diets in some individuals and under some conditions are risk factors for chronic diseases; (2) common dietary chemicals alter gene expression and/or genome structure; (3) the influence of diet on health depends upon an individual's genetic makeup; (4) some genes or their normal common variants are regulated by diet, which may play a role in chronic diseases; and (5) dietary interventions based upon knowledge of nutritional requirements, nutritional status, and genotype can be used to develop individualized nutrition plans that optimize health and prevent or mitigate chronic diseases. Optimal nutrition may also influence the aging process.
Effects of Testosterone on Cognitive and Brain Aging in Elderly Men
Authors: MOFFAT SCOTT D.
Published: December 2005

Older age is associated with functional declines throughout the body, including some aspects of cognitive performance. While dementia develops in only some elderly individuals, declines in cognitive functioning have an impact on daily living for many others. There are individual differences in age‐related cognitive changes, however, and the factors that contribute to this variability have not been well‐characterized. Recent evidence suggesting that age‐related alterations in the endocrine environment may modulate cognitive changes has generated considerable interest. Currently, there is a discordance between the rapidly expanding number of studies of the possible neuroprotective effects of estrogens in postmenopausal women, and the relative dearth of analogous research on the putative effects of testosterone on cognitive and brain function in older men. This paper reviews the extant literature and reports new findings on the effects of testosterone loss and supplementation on cognitive and brain function in elderly men. Preliminary evidence suggests that testosterone loss may be a risk factor for cognitive decline and possibly for dementia. Conversely, the maintenance of higher testosterone levels either endogenously or through exogenous supplementation may prove beneficial for cognitive and brain function in elderly men. However, most studies are associational in nature and the intervention studies are of short‐duration testosterone exposure in small samples of subjects. Large‐scale placebo‐controlled intervention studies are required to resolve ambiguities in the literature. Testosterone intervention to ameliorate cognitive decline may be warranted only when the efficacy and safety of longer‐term use is firmly established.
Controversies in Dyslipidemias: Atheroprevention in Diabetes and Insulin Resistance
Authors: BRINTON ELIOT A.
Published: December 2005

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in industrialized countries. Patients with diabetes and insulin resistance are at even greater risk than the general population. Risk factors may be even more significant in predicting risk of disease when present in diabetic patients. Interaction among the elements of the metabolic syndrome/insulin resistance (MS/IR) in atherogenesis is currently the subject of much research. Efforts to understand the elements of the dyslipidemias associated with MS/IR are now beginning to pay off. An increasing number of drugs and other interventions have been shown to be effective in clinical trials in reducing risk factors and improving outcomes. The advantages and disadvantages of possible treatments of these dyslipidemias, including the risks and benefits of combination therapy, are discussed in detail. Finally, strategies for maintaining glucose control and the role of inflammation associated with MS/IR and CVD are described.
Oxidative Stress Profiling:
Authors: CUTLER RICHARD G.
Published: December 2005

Steadily accumulating scientific evidence supports the general importance of oxidative damage of tissue and cellular components as a primary or secondary causative factor in many different human diseases and aging processes. Our goal has been to develop sensitive and reliable means to measure the oxidative damage and defense/repair status of an individual that could be easily used by a physician to determine whether there is an immediate or long‐term increased health risk to their patients with regard to oxidative damage. We also sought to try to determine how this risk can best be reduced, and whether the prescribed therapy is working and how it might be best adjusted to optimize benefits. We have found that combining both an oxidative damage profile with a defense/repair profile produces the most reliable set of information to meet these objectives. Success is indicated by demonstrating the expected inverse correlation of oxidative stress vs. antioxidant status of a population of several hundred individuals. We also find support that oxidative stress status is under tight regulatory control for most individuals over a wide range of lifestyle variables including diet and exercise. Indeed only about 10% of the individuals analyzed appear to have unusually high oxidative stress levels. Only these individuals having the higher than normal levels of oxidative stress are the best responders to antioxidant supplements to lower their oxidative stress status to normal levels. We discuss the implications of these results for human application and review how current clinical studies are carried out to evaluate the benefits of antioxidant supplements in reducing the incidence of specific age‐dependent disease.
Dietary Fat and Health: The Evidence and the Politics of Prevention: Careful Use of Dietary Fats Can Improve Life and Prevent Disease
Authors: LANDS WILLIAM E.M.
Published: December 2005

Every year, more young people start the slow progressive injury that eventually becomes cardiovascular disease and death. It could be prevented with nutrition education, but medical efforts focus more on treatments for older people than on preventing primary causes of disease in young people. Two avoidable risks are prevented by simple dietary interventions: (1) Eat more omega‐3 and less omega‐6 fats, so tissues have less intense n‐6 eicosanoid action, and (2) eat less food per meal to lower vascular postprandial oxidant stress. An empirical diet‐tissue relationship was developed and put into an interactive personalized software program to aid informed food choices.
Physical Activity and Aging
Authors: STEWART KERRY J.
Published: December 2005

Most human beings experience peak physical performance in their late teens and begin a slow decline in their early 20s, whose course is greatly affected by the activity levels undertaken by individuals in the years that follow. Many studies provide evidence that in developed nations such as the U.S., a sedentary lifestyle contributes significantly to development of the major risk factors for age‐related disease, prominent among them obesity, diabetes, and hypertension. Conversely, numerous studies document the benefits of physical activity, and in particular structured exercise programs, not only for reducing disease risk and improving physical performance, but also for enhancing substantially the quality of daily life. Aerobic and resistance training have complementary benefits, and can be undertaken at almost any age and physical condition, given appropriate medical clearance and supervision as warranted.
Would Doubling the Human Lifespan Be a Net Positive or Negative for Us, Either as Individuals or as a Society? Point‐Counterpoint
Authors: STOCK GREGORY B. , CALLAHAN DANIEL
Published: December 2005

There is a significant possibility that over the next few decades science will make discoveries of a kind that might allow the doubling of the average human life span, from roughly 76 years now to 150. This development would, for many, represent the realization of a dream: that of enabling people to live much longer lives than at present, holding back death, which has often been seen as an ancient, unbeatable enemy. It would also raise a large number of unprecedented individual and social problems: Would we really want to live to 150? Is such a goal ethical? What would this putative longevity do to our present social structures and arrangements? Would we get a better society or a worse one?
Oxidative Stress Profiling:
Authors: CUTLER RICHARD G. , PLUMMER JOHN , CHOWDHURY KAJAL , HEWARD CHRISTOPHER
Published: December 2005

Many of the most serious human diseases have a strong association with the steady‐state level of oxidative damage in tissues. On an individual level this damage is defined as the patient's oxidative stress status (OSS). OSS is associated with many of the major age‐related diseases such as cancer, heart disease, diabetes, and Alzheimer's disease, as well as with the aging process itself. In general, the greater the OSS of the individual, the higher the risk for disease development. To further understand the role that OSS has as a causative or an associated factor for these diseases, and to develop more effective personalized therapy to minimize OSS, requires a reliable means to measure the many different components contributing to an individual's OSS. This procedure is called oxidative stress profiling (OSP) and represents a new strategy to simultaneously assess an individual's OSS as well as to identify key physiological parameters, such as the hormone, lipid, antioxidant, or iron profile, that may be responsible for that individual's OSS. The OSP strategy provides physicians with information that enable them to make a more accurate diagnosis of the patient's condition and to recommend specific types of therapy based on better scientific data. Follow‐up studies of the patient would then be conducted using these same tests until the OSS of the patient has been minimized. The OSP strategy is particularly well suited for a personalized health optimization program. The procedure is based on measuring both the steady‐state levels of oxidative damage in nucleic acids, proteins, and lipids and the protective and defense processes of these components using blood, urine, and breath samples. Testing individuals before and after a controlled amount of exercise (70% VO2) may also help to obtain greater sensitivity and reproducibility. Evaluation of test results to obtain an integrated calculated OSS result for a patient represents a major challenge. One approach is to present the test results on a percentile bases, allowing results of different tests to be integrated into one or a few parameters, such as an oxidative stress and an antioxidant index. This article presents a general overview and rationale of the concept of the oxidative stress profile, tests to be used, and examples of how it may be applied.
Multiple‐Fiber Reconstruction Algorithms for Diffusion MRI
Authors: ALEXANDER DANIEL C.
Published: January 2006

This chapter reviews multiple‐fiber reconstruction algorithms for diffusion magnetic resonance imaging (MRI) and provides some initial comparative results for two such algorithms, q‐ball imaging and PASMRI, on data from a typical clinical diffusion MRI acquisition. The chapter highlights the problems with standard approaches, such as diffusion‐tensor MRI, to motivate a recent set of alternative approaches. The review concentrates on the software implementation of the new techniques. Results of the preliminary comparison show that PASMRI recovers the principal directions of simple test functions more consistently than q‐ball imaging and produces qualitatively better results on the test data set. Further simulations suggest that a moderate increase in data quality allows q‐ball, which is much faster to run, to recover directions with consistency comparable to that of PASMRI on the test data.
Vaccinia Virus Complement Control Protein Diminishes Formation of Atherosclerotic Lesions: Complement Is Centrally Involved in Atherosclerotic Disease
Authors: THORBJORNSDOTTIR PERLA , KOLKA RAGNHILDUR , GUNNARSSON EGGERT , BAMBIR SLAVKO H. , THORGEIRSSON GUÐMUNDUR , KOTWAL GIRISH J. , ARASON GUÐMUNDUR J.
Published: December 2005

Complement is known to be activated in atherosclerotic lesions, but the importance of this event in disease pathology is a matter of debate. Studies of rabbits fed a high‐fat diet have indicated complement activation as a rate‐limiting step, whereas results from genetically modified mouse strains (ApoE−/− or LDLR−/−) have failed to support this finding. To resolve whether this reflects differences between species or between genetically driven and diet‐induced disease, we studied the effect of a complement inhibitor, vaccinia virus complement control protein (VCP), on C57BL/6 mice, the background strain of ApoE−/− and LDLR−/− mice. Atherosclerosis was induced by a high‐fat diet, and VCP (20 mg/kg) was injected once per week after the eighth week. Fatty streak development was monitored at 15 weeks by microscopic examination of oil red‐O‐stained sections from the root of the aorta. VCP injections led to significant (50%) reduction of lesion size (P= 0.004). Lesions were marked by gradual accumulation of lipids and macrophages but did not develop beyond the fatty streak stage. VCP activity disappeared from serum in 4 days, and the possibility therefore exists that a higher level of protection may be achieved by more frequent injections. We conclude that the development of fatty streaks in diet‐induced atherosclerotic disease can be significantly retarded by prophylactic treatment with a complement inhibitor. These results support previous findings from complement‐deficient rabbits and suggest that the pathogenesis of atherosclerosis in diet‐induced disease differs from that induced by major defects in lipid metabolism.
Cytokine Therapy
Authors: CUTLER ANTONY , BROMBACHER FRANK
Published: December 2005

Cytokines are a unique class of intercellular regulatory proteins that play a crucial role in initiating, maintaining, and regulating immunologic homeostatic and inflammatory processes. Indeed, measurement of cytokine profiles in patients provides a useful indication of disease status. Due to their multiple functions, including regulatory and effector cellular function in many diseases, these molecules, their receptors, and their signal transduction pathways are promising candidates for therapeutic interference. The therapeutic administration of cytokines, modulation of cytokine action, or at times gene therapy is being used for a wide range of infectious and autoimmune diseases, in immunocompromised patients with AIDS, and in neoplasia.
Fighting Food Allergy: Current Approaches
Authors: NIEUWENHUIZEN NATALIE E. , LOPATA ANDREAS L.
Published: December 2005

Food allergy is defined as an adverse immunologic reaction to allergens present in food and is associated with symptoms ranging from gastrointestinal discomfort to anaphylactic shock and death. The increase in prevalence and potential fatality of disease has led to increased efforts to find effective therapies and prophylaxis. While specific immunotherapy (SIT) is effective in desensitization against inhalant allergens, it is unadvised against food allergy because of the high risk of adverse side effects. A review of the recent literature shows that various approaches have been taken to develop safer and more effective SIT regimens. Here we discuss the use of recombinant allergens, peptides, DNA vaccines, immunostimulatory DNA sequences, and other bacterial products in SIT. In addition, we review nonspecific therapies such as anti‐IgE administration and cytokine therapy as well as natural therapies such as probiotics and Chinese herbal medications. In conclusion, anti‐IgE treatment and SIT using hypoallergenic recombinant allergens in combination with Th1‐inducing adjuvants appear the most promising approaches. New initiatives to increase our understanding of the pathophysiology and immunologic mechanisms of food allergy along with the molecular characterization of food allergens should pave the way towards safer and more effective ways of combating this debilitating and potentially life‐threatening disease.
Vaccinia Virus Complement Control Protein Ameliorates Collagen‐Induced Arthritic Mice
Authors: JHA PURUSHOTTAM , SMITH SCOTT A. , JUSTUS DAVID E. , KOTWAL GIRISH J.
Published: December 2005

The main objective of this study was to investigate the therapeutic efficiency of recombinant vaccinia virus complement control protein (rVCP) on collagen‐induced arthritis (CIA) in DBA‐1/J mice. Arthritis was induced in DBA‐1J mice by injecting bovine collagen emulsified in complete Freunds adjuvant. We used rVCP to block complement activation and investigated its effect on different aspects of CIA including osteoclast formation and bone destruction. The osteoclast‐like cells were detected using immunohistochemistry. Joint destruction was studied using X‐ray of the intact knee joints. Cartilage destruction was monitored by staining the paraffin sections with toluidine blue. ELISA was used to measure the cytokine levels in the serum. Blocking complement activation in DBA/1J arthritic mice with rVCP resulted in significant inhibition of the clinical progression of the disease and reduction in joint destruction as revealed by X‐ray analysis and toluidine blue staining of the joint sections. Inhibition of complement reduced the production of proinflammatory cytokines and the number of osteoclast‐like cells in arthritic joints. In conclusion, blocking of complement in CIA by rVCP inhibits the inflammation and the formation of osteoclast‐like cells and reduces cartilage destruction.
The Vaccinia Virus N1L Protein Influences Cytokine Secretion in Vitro after Infection
Authors: ZHANG ZHOUNING , ABRAHAMS MELISSA‐ROSE , HUNT LAWRENCE A. , SUTTLES JILL , MARSHALL WILLIAM , LAHIRI DEBOMOY K. , KOTWAL GIRISH J.
Published: December 2005

The vaccinia virus N1L ORF encodes a protein that enhances virulence and replication of the virus by an unknown mechanism. It has been studied for its ability to enhance viral replication and dissemination in the brain and more recently has been linked to an immunomodulatory role in which it inhibits the activation of cytokine transcription activators in Toll‐like receptor signaling pathways after pathogen recognition. The effect of N1L on the release of cytokines from human primary monocytes was investigated. Secretion of the proinflammatory, antiviral cytokines TNF‐α, IL‐1β, IFN‐α, IFN‐β, and the anti‐inflammatory cytokine IL‐10 was found to be inhibited by the presence of the N1L protein.
The Vaccinia Virus N1L ORF May Encode a Multifunctional Protein Possibly Targeting Different Kinases, One of Which Influences ATP Levels in Vivo
Authors: ABRAHAMS MELISSA‐ROSE , ZHANG ZHOUNING , CHIEN SUFAN , SKERNS TIM , KOTWAL GIRISH J.
Published: December 2005

As the single‐most potent virulence factor of the vaccinia virus, the 13.8‐kDa protein enhances viral replication in the brain by an unknown mechanism. Due to the high energy demands of the brain and the at times inadequate energy supply and small energy reserves to support physiologic activity, the ability of this organ to support energy requirements for replication of a virus is unlikely. We investigated the possible role of the 13.8‐kDa protein in the enhancement of adenosine triphosphate (ATP) utilization in the brain to sustain viral replication. In vitro and in vivo monitoring and comparison of ATP levels in mouse brain tissue infected with a wild‐type vaccinia virus or a 13.8‐kDa deletion strain (vGK5) revealed differences in ATP utilization and a significant difference in ATP levels in vivo after 5 days of infection. Because of poor replication of the wild‐type Lister vaccinia virus in the brain, a role for the 13.8‐kDa protein in the modulation of ATP levels to support viral replication in the brain could not be conclusively implicated. Evaluation of the amino acid sequence and predicted secondary structure of the 13.8‐kDa protein and sequence and structural homologs thereof provided evidence of putative dimerization and adenine binding sites and a possible kinase‐related function for this protein.
Curcumin Inhibits the Classical and the Alternate Pathways of Complement Activation
Authors: KULKARNI AMOD P. , GHEBREMARIAM YOHANNES T. , KOTWAL GIRISH J.
Published: December 2005

Curcumin (Cur), the golden yellow phenolic compound in turmeric, is well studied for its medicinal properties. In the current investigation, Cur dissolved using sodium hydroxide solution (CurNa) was tested for in vitro complement inhibitory activity and compared with rosmarinic acid (RA) and quercetin (Qur) dissolved using sodium hydroxide (RANa and QurNa, respectively) and the vaccinia virus complement control protein (VCP). The comparative study indicated that CurNa inhibited the classical complement pathway dose dependently (IC50= 404 μM). CurNa was more active than RANa, but less active than QurNa. VCP was about 2,212, 2,786, and 4,520 times more active than QurNa, CurNa, and RANa, respectively. Further study revealed that CurNa dose dependently inhibited zymosan‐induced activation of the alternate pathway of complement activation.
Amyloid, Cholinesterase, Melatonin, and Metals and Their Roles in Aging and Neurodegenerative Diseases
Authors: LAHIRI DEBOMOY K. , CHEN DE‐MAO , LAHIRI PREETI , BONDY STEVE , GREIG NIGEL H.
Published: December 2005

The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid β peptides (Aβ), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple “hits,” including alterations in the levels of Aβ, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age‐related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Aβ peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal‐induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA‐approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms.
Arthropod‐Derived Protein EV131 Inhibits Histamine Action and Allergic Asthma
Authors: WESTON‐DAVIES WYNNE , COUILLIN ISABELLE , SCHNYDER SILVIA , SCHNYDER BRUNO , MOSER RENE , LISSINA OLGA , PAESEN GUIDO C. , NUTTALL PATRICIA , RYFFEL BERNHARD
Published: December 2005

Histamine is an important mediator of allergic responses. Arthropods express several biologically active proteins in their saliva, which may allow a prolonged blood meal on the host. Proteins identified and expressed include histamine, serotonin, tryptase, and complement binding proteins. We review here data that scavenging of endogenous histamine by the histamine‐binding protein EV131 has a profound inhibitory effect on allergic asthma. Aerosol administration of EV131 prevented airway hyperreactivity and abrogated peribronchial inflammation, eosinophil recruitment, mucus hypersecretion, and IL‐4 and IL‐5 secretion. Saturation with histamine abrogated the inhibitory effect of EV131 on bronchial hyperreactivity. The data suggest that histamine plays a role in allergies and that scavenging of histamine by EV131 may represent a novel therapeutic strategy in the treatment of allergic diseases.