Study Led By Stanford Scientists Links Schizophrenia To Chromosome Region For The First Time

Stanford University School of Medicine scientists have played a major role in an international effort that has shown, for the first time, that modern genetic technologies can solve the riddle of how gene variations lead to schizophrenia.

Researchers at Stanford and 14 other institutions carried out a study of common DNA variations throughout the genome, and then combined forces with two independent studies to complete a pooled analysis of 27,000 individuals. The largest genetic differences between the study participants with and without schizophrenia were found on a stretch of chromosome 6 containing numerous genes associated with immune response (and some with other roles). This raises the possibility that immune function plays a role in schizophrenia.

Stanford’s Jianxin Shi, PhD, and Douglas Levinson, MD, are first and second authors of one of three linked papers to be published online together in Nature on July 1. Their paper reports on the Molecular Genetics of Schizophrenia Project. This undertaking implicated a region of the human genome not previously suspected as a risk factor for schizophrenia. That finding was bolstered by another of the simultaneously published papers, which showed an even stronger association when the number of subjects was increased to almost 48,000, and identified significant association in two additional genes. The third paper shows that there are likely to be many common gene variations, perhaps hundreds or more, that have small effects in the risk of schizophrenia.

Taken together, “the papers present the first highly significant findings of gene regions associated with schizophrenia risk,” said Levinson, professor of psychiatry and behavioral sciences, director of that department’s Program on the Genetics of Brain Function, and the Walter E. Nichols, MD, Professor in the School of Medicine.

It is already known that schizophrenia – which strikes close to one in every 100 people – has a very strong genetic component, probably accounting for at least 80 percent of risk for this disease. However, unlike sickle-cell anemia or Huntington’s disease, in which a defect at a single genetic location is responsible, most cases of schizophrenia are believed to involve interactions among a multitude of genes, with a variant of any single gene contributing only a tiny bit to a person’s risk.

“That makes it hard to tease out, in a statistically significant way, any of these schizophrenia-associated genes,” said Levinson. But it is feasible with very large numbers of subjects, he said. Finding genes involved in a multigenic trait can, at least in theory, be accomplished by means of so-called genome-wide association studies, in which DNA variations are measured in two large groups of people, one with a common pathology and the other without it.

To achieve the needed sample size, data from three independent studies were pooled and analyzed in a special way that corrected for differences in how those disparate studies were designed and run. Such a methodology is called a meta-analysis. Shi, a research scientist in Levinson’s laboratory, designed and performed the meta-analysis on the resulting pooled-subject group, some 8,000 individuals with schizophrenia and 19,000 normal controls of European ancestry. (Restricting the study population to people of similar ancestry excludes numerous non-disease-related genetic differences that would otherwise be observed, Shi said.)

In 1999, when Levinson and Shi’s study began, genomic technologies were nowhere near as advanced as they are today. But the recent hybridization of Silicon Valley-style microelectronics with biotechnology-bred DNA assay techniques has resulted in powerful new microarrays capable of scanning entire genomes for tiny variations called “single base-pair polymorphisms,” or SNPs.

A DNA base pair is effectively the genome’s smallest possible accounting unit – the penny, as it were, of genetic variation. As a simplified analogy, think of your genetic inheritance as a stack of 3 billion pennies, with each coin bearing one of four mint marks. If you set two such stacks (representing two individuals’ genomes) side by side and compare two adjacent pennies’ mint marks at any given height, they’ll usually be the same. We’re all descendants of a common ancestor, so the similarities in our genomic sequences shouldn’t surprise anyone.

But evolution happens. Every few hundred “pennies” or so, you will observe a divergence, or SNP – one chemical “mint mark” on this genome, another on that one. With the human genome being so huge, this comes to something like 10 million SNPs, of which about a million occur with frequencies of at least 5 percent.

Using commercially available “SNP chips” designed to detect those more-common variants, the investigators looked for differences between the DNA of people with schizophrenia versus the DNA of those without the disease. The scientists required that such differences achieve “genome-wide statistical significance.” Here’s why: If you flip a million coins, one at a time, you’re going to see all kinds of seemingly miraculous events – say, 15 heads in a row – that may seem significant but are typical when you toss even a perfectly balanced coin so many times.

Shi’s job was to devise analytical techniques to determine whether the “finding” of a SNP’s greater likelihood among schizophrenics was real or spurious. The genomic region on chromosome 6 survived this rigorous statistical test.

“These findings show that our genetic methods are working, and that the genetic underpinnings of schizophrenia can be understood,” said Levinson. “Similar methods have produced critical new discoveries in many other common diseases, once very large numbers of people could be studied. Now we see that the same approach works for psychiatric disorders like schizophrenia.”

Pablo Gejman, MD, of Northwestern University was the senior author of the paper. Stanford co-author Alice Whittemore, PhD, professor of health research and policy, consulted on the study’s meta-analytic methodology. The study was funded by the National Institute of Mental Health and by the National Alliance for Research on Schizophrenia and Depression.

Source:
Bruce Goldman

Stanford University Medical Center

Countries Representing 75% World’s Population Meet To Plan Effective Implementation Of The Tobacco Control Treaty

Countries around the world are taking effective measures to curb tobacco use, including strong legislation, graphic warning labels and advertising bans. These positive changes reinforce the commitment made by the more than 110 countries meeting this week to decide on the detailed implementation of the World Health Organization Framework Convention on Tobacco Control (WHO FCTC).

Many of the countries joining this first Conference of the Parties (COP) in Geneva have already implemented some of the measures in the convention. Ireland, Norway and Spain, for example, have recently banned smoking in indoor public places. India has comprehensive tobacco advertising bans. Brazil, Canada, Thailand and Singapore print graphic warnings on cigarette packages. These are just some of the examples of efforts which will contribute to a major reduction in tobacco deaths.

“This group has already changed history,” said Dr LEE Jong-wook, Director-General of the World Health Organization. “The convention is something that we all committed to. Its provisions are bold. They are based on knowledge of what is effective. We will make it work.”

Dr Lee made his comments to the first Conference of the Parties (COP) meeting this week in Geneva. The COP is the governing body of the Treaty. It serves as the authority to oversee, monitor and evaluate progress of the Treaty, in order to reduce tobacco consumption and tobacco-related deaths globally.

Concrete measures included in the Treaty could help save 200 million lives by the year 2050, if a progressive 50% reduction in uptake and consumption rates is achieved. Many measures in the WHO FCTC have deadlines and clear guidelines. For example, from the Treaty’s entry into force, countries have three years to enforce health warnings on tobacco products, and five years to implement comprehensive bans on tobacco advertising, promotion and sponsorship.

Other measures, such as those regarding illicit trade or cross-border advertising, have not yet been detailed in the Treaty. The COP could decide to develop protocols and specific guidelines and requirements for countries to implement these measures.

The COP will likely also consider other measures to ensure the effective implementation of the rest of the treaty provisions. These might include financial support for developing countries, or mechanisms to ensure that countries do not fall behind in their implementation progress.

In February 2007, the first Contracting Parties will submit to the COP initial reports on their progress, specifying what actions they have taken to implement the tobacco control measures established in the Treaty. “This is a crucial time for people suffering the consequences of tobacco use,” said Dr Yumiko Mochizuki-Kobayashi, Director of the WHO Tobacco Free Initiative. “Tobacco is still the top preventable cause of death. The goal is to see it fall from that position in our lifetime.With continued commitment from Member States, we will achieve that goal.”

WORLD HEALTH ORGANISATION

House Passes Bill That Would Allow ‘Paired’ Kidney Donations

The House on Wednesday unanimously approved legislation (HR 710) to specify that “paired” kidney donations do not violate laws prohibiting compensation for organ donations, the AP/Long Island Newsday reports. The bill — named the Charlie W. Norwood Living Organ Donation Act, after the former Georgia representative who died of cancer last month — was introduced in January by Norwood (R) and Rep. Jay Inslee (D-Wash.) to increase the number of paired kidney donations performed at hospitals each year. In paired donations, a patient in need of an organ transplant with a willing, but medically incompatible, friend or family member is matched with a similarly incompatible pair so that both patients can receive a transplant. Current law makes the legality of such donations questionable because of the concern that trading organs constitutes compensation. Some hospitals refuse to perform paired donations and there is no formal matchmaking system to expand their use, AP/Newsday reports (Evans, AP/Long Island Newsday, 3/7). Norwood estimated that the bill could save Medicaid an estimated $220,000 per transplant patient in dialysis costs (Kemper, Atlanta Journal-Constitution, 3/7). The Congressional Budget Office has estimated that paired donations could save Medicare $500 million over 10 years in dialysis costs (AP/Long Island Newsday, 3/7).

“Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Long-Term Marijuana Smoking Leads To Respiratory Complaints

Long-term exposure to marijuana smoke is linked to many of the same health problems as tobacco smoke, such as increased respiratory symptoms like cough, phlegm and wheeze, according to a new study by researchers at Yale School of Medicine.

Marijuana is the most widely used illicit drug in the United States, and abuse of the drug is on the rise. The study is published in Archives of Internal Medicine. First author Jeanette M. Tetrault, M.D., and colleagues sought to find the relationship between marijuana smoking and pulmonary function or respiratory complications.

“While there is convincing data on the effects of tobacco smoke on pulmonary clinical outcomes, the effect of marijuana smoke has been poorly understood,” said Tetrault, ambulatory care fellow at Yale School of Medicine and the Department of Veterans Affairs Connecticut Healthcare System.

Tetrault and colleagues systematically reviewed articles from 1966 through 2005 identified from the MEDLINE, PsychINFO and EMBASE databases that evaluated the effect of marijuana smoking on pulmonary function and respiratory complications. Of the 34 articles that met selection criteria, 12 were classified as challenge studies because they examined the link between short-term marijuana use and airway response. Eleven of the 12 studies found an association between short-term marijuana use and relaxation and opening of the air passages.

The study’s physiologic data failed to show an association between long-term marijuana smoking and airflow obstruction (emphysema). However, all 14 studies that assessed long-term marijuana smoking and respiratory complications noted an association with increased respiratory symptoms, suggesting obstructive lung disease.

The authors noted several common limitations among the studies, including inadequate control of the complicating effect of tobacco smoking; lack of standardized measures for the amount or duration of marijuana use; and lack of standardized measures of the outcomes that were evaluated.

“Despite these limitations, clinicians should advise their patients of the potential negative impact of marijuana smoking on overall lung health,” said Tetrault.

###

Other authors on the study included Kristina Crothers, M.D., Brent A. Moore, Reena Mehra, M.D., John Concato, M.D., and David Fiellin, M.D.

Citation: Archives of Internal Medicine, Vol. 167, (February 12, 2007)

Contact: Karen N. Peart

Yale University

New Estimates on Extent of Malaria, Wellcome Trust

A new comprehensive investigation into the extent of the deadliest form of malaria shows there were over half a billion
cases in 2002.

More than two-thirds of these occurred in Africa, where Plasmodium falciparum malaria mostly affects children under-five. But
far more cases than previously thought take place in SE Asia.

The latest estimate of 515m episodes, is described in today’s edition of Nature and emphasises that malaria treatment
requires more investment for more people in more areas of the world than governments and health agencies might have
anticipated.

This research is timely because the United Nations has set-up initiatives targeting malaria. The Millennium Development Goal*
aims to halt the spread of the disease by 2015 and Roll Back Malaria ** is designed to halve mortality in the next six years.

Scientists from the University of Oxford, based at the Kenya Medical Research Institute- Wellcome Trust Research Programme***
used contemporary and historical epidemiological, geographical and demographic information to model where people live, the
likelihood of infection from malaria parasites and susceptibility to developing the disease. New methods in Geographic
Information Systems and data from earth orbiting satellites were used.

Professor Bob Snow, who led the research, which suggests 2.2 billion people are at risk from malaria, said : “We have taken a
conservative approach to estimating how many attacks occur globally each year but even so the problem is far bigger than we
previously thought.

“We have taken a science- driven approach to working out who is at risk, where they are located and what their chances would
be of developing an attack of malaria.

“Our work has demonstrated that nearly 25% of worldwide cases occur in South East Asia and the Western Pacific – whereas most
people regard Plasmodium falciparum disease a problem particular to Africa.

“Getting numbers right is important. Not knowing the size of the problem limits our ability to articulate how much money we
need to tackle the problem – not knowing where the problem is located means you can’t spend wisely.

“This is particularly important for new drugs needed to fight malaria. These are expensive and difficult to produce and
production capacity and financing can be driven by speculation, poor data or simply best-guesses.

“We need to do a better job – driven by data – on working out the burden posed by this killer parasite if we are serious
about international goals and targets set by development partners.

“World leaders are now seriously focusing on malaria as a problem that can be tackled with tools we know work and are
comparatively cheap. Hopefully these data will provide not only more ammunition as to why they should take it seriously but
help them decide where to spend their money to best effect.”

International malaria expert, Professor Nick White, Director of the Wellcome Trust’s SE Asia unit, said : “If we are going to
Roll Back Malaria then we need to know the size of the problem- and where it is. Falciparum malaria has increasingly been
thought of as an African problem. These estimates challenge that notion and suggest there is a lot more falciparum malaria in
SE Asia than previously thought.”

Dr Richard Feachem, Executive Director of the Global Fund to Fight AIDS Tuberculosis and Malaria, said : “The work by Snow
and his colleagues is important. Many have believed that existing data grossly under-estimates malaria, morbidity and
mortality in Africa and Asia. We now have confirmation of this.

“Accurate numbers are essential to the Global Fund, which is charged by the international community with financing the
counter-attack against malaria, especially through purchases of effective drugs and insecticide-treated bednets. We must now
significantly increase our estimates of resources needed.

*Millennium Development Goals.

In 2000 The United Nations announced eight goals to help the developing world. One of these was to begin to reverse the
number of malaria cases by 2015.
developmentgoals.

** The Roll Back Malaria initiative was announced by the WHO, UNICEF, UNDP and the World Bank in November 1998. It aims to
halve the number of malaria deaths by 2010.
mosquito.who.int/malariacontrol..

*** Kenya Medical Research Institute- Wellcome Trust Research Programme

kemri-wellcome

jr2.ox.ac/ndm/Tropical_Medicine

Department of Zoology Oxford
zoo.ox.ac

Wellcome Trust
183 Euston Rd.
London NW1 2BE
United Kingdom
Phone 44 171 611 8846
wellcome.ac/en/1/awtpre.html

Response To Alcohol Advertising Study – The Stroke Association, UK

In response to the alcohol advertising study in the BMJ, Joe Korner, Director of Communications at The Stroke Association said:

“Drinking too much alcohol is known to cause long-term harm to your health. So it is of great concern if companies are pushing against the boundaries of advertising guidelines on alcohol, as this report suggests.

We know that heavy drinking can raise blood pressure, which is one of the main risk factors for stroke. People who regularly drink a large amount of alcohol have an increased risk of stroke and it’s important people are more aware of the chance they are taking with their health.”

Source
The Stroke Association

Sperm Nuclear DNA Fragmentation In Adolescents With Varicocele

UroToday – Bertolla and colleagues performed this study from Brazil to see if sperm from adolescents with a varicocele had an increased rate of DNA fragmentation when compared with adolescents without varicocele. It is a controlled, prospective study. They included adolescent patients with a clinically diagnosed bilateral varicocele, grades II and III, and adolescent patients without a varicocele.
The rate of sperm DNA fragmentation was assessed by the Comet assay. It was graded as: class I (no DNA fragmentation); II (little DNA fragmentation); III (meaningful DNA fragmentation); or IV (high DNA fragmentation).

They found that a higher percentage of cells with no DNA fragmentation (class I) were seen in the nonvaricocele group (47.62 ± 7.69) when compared with the varicocele group (27.52 ± 10.73). A higher percentage of sperm with class III and class IV DNA fragmentation were found in the varicocele group (20.43 ± 8.97, and 19.57 ± 10.68) when compared with the nonvaricocele group (11.38 ± 5.55, and 5.71 ± 2.35).

The group concluded that although standard semen analysis showed no difference between the groups, adolescents with bilateral varicoceles have an increase in sperm nuclear DNA fragmentation, and it is possible that DNA fragmentation evaluation could be important in deciding treatment options for adolescent patients.

By Pasquale Casale, MD

Reference:
Fertility and Sterility 85(3): 625-628, March 2006.
Link Here.
Bertolla RP, Cedenho AP, Hassun Filho PA, Lima SB, Ortiz V, Srougi M

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Compound Found In Cruciferous Vegetables Associated With A Decreased Risk Of Bladder Cancer

Isothiocyanates (ITC) are compounds found in cruciferous vegetables such as broccoli, cauliflower, kale, turnips, collards, Brussels sprouts, cabbage, radish, turnip and watercress.

They exert their anti-oxidant effect via down regulation of cytochrome p450 enzyme levels and induce apoptosis by activating Phase II detoxifying enzymes. Experimental data has suggested that these compounds may protect against the genesis of bladder cancer.

In the May 15th issue of the International Journal of Cancer, Zhao and colleagues from the Departments of Epidemiology and Urology at the M.D. Anderson Cancer Center report on an epidemiological study evaluating the relationship between ITC intake and bladder cancer risk.

The cohort consisted of 697 patients with newly diagnosed bladder cancer and 708 healthy controls matched by age, sex, and race. Dietary questionnaires were available for all patients. The dietary intake of ITCs was compared with bladder cancer risk and with the expression of genetic polymorphisms for the arylamine N-acetyltransferases 2 (NAT) and glutathione S-transferase genes.

Median ITC intake per day was significantly lower in bladder cancer patients than in controls (0.23 vs. 0.33, p < 0.001). High ITC intake was associated with 29% lower risk of bladder cancer (odds ratio = 0.71, 95% CI 0.57 to 0.89). This anti-cancer effect was seen more commonly in men, in patients age 64 or older, and in smokers. NAT2 slow acetylators exhibited an increased risk of bladder cancer in Caucasians compared with rapid acetylators (OR = 1.31, 95% CI 1.02 to 1.69). The decrease in bladder cancer risk associated with ITC intake was not associated to NAT2, GSTM1, or GSTT1 genotype expression.

This well-conducted study for the first time demonstrates that consumption of cruciferous vegetables with a high content of isothiocyanates such as broccoli, cauliflower, kale, turnips, collards, Brussels sprouts, cabbage, radish, turnip and watercress may offer a protective advantage against bladder cancer. Whether increasing ITC intake in bladder cancer patients improves treatment response and prevents recurrence remains to be studied.

Int J Cancer. 2007 May 15;120(10):2208-13.

By Ricardo Sanchez-Ortiz, MD

About UroToday

UroToday attracts more than 45,000 readers monthly. The website covers over 22 urology disease categories and provides the most in depth Urological conference reports available online. UroToday is the world leader in delivering a quality, global online publication providing accurate and timely education that is clinically relevant in the practice of Urology. All scientific content is developed by urologists committed to translating research into clinically relevant science, including all genitourinary cancers, pediatric and geriatric urological dysfunctions for urologists, medical oncologists, advanced nurse practitioners and other medical professionals.

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How Smoking Accelerates Ageing

Wrinkly skin, breathlessness and a chesty cough are regularly associated with heavy smoking. They can belie a person’s age by making someone seem older than they actually are. But until now, scientists have known little about the biological mechanisms that appear to accelerate the ageing process.

Professor William MacNee from the University of Edinburgh has been investigating chronic obstructive pulmonary disease (COPD) that is usually caused by smoking and other environmental pollutants. COPD progressively and irreversibly damages lungs and kills around 30,000 people a year in the UK.

Speaking at a meeting of the Biochemical Society held in Charnwood today (5 March) he told delegates about new evidence for accelerated aging linked to COPD. “We believe that there is a relationship between inflammation seen in COPD and ageing. Accelerated ageing could also be a process that links damage to the lungs with other diseases, such as heart disease,” he said.

Natural ageing and the eventual death of cells are hastened and these processes are now thought to be central to the development of COPD. Professor MacNee continued, “There is new evidence that cigarette smoke and other pollutants may accelerate the ageing process by making the inflammation in the lungs worse and impairing the healing process.”

The function of our lungs deteriorates with age in the same way as our skin, bones and blood vessels. Throughout life, cells divide to maintain and renew the cells that make up our whole body. Gene components, known as telomeres, protect chromosomes and play an important role in cell division. Telomeres get shorter each time a cell divides and if it becomes too short, DNA may be damaged and this results in ageing.

Similar accelerated ageing processes are now thought to be linked with heart and circulatory diseases that often occur in people with COPD. The disease continues even when people give up smoking. Professor MacNee presented the evidence that normal ageing processes are altered in patients with COPD.

Looking ahead, Professor MacNee said, “If we can discover how to intervene, we could find a way to help prevent accelerated ageing.”

Biochemical Society

Induced Pluripotent Stem Cells Rescue Visual Function In Rats

An international team of scientists has rescued visual function in laboratory rats with eye disease by using cells similar to stem cells. The research shows the potential for stem cell-based therapies to treat age-related macular degeneration in humans.

A team led by Dennis Clegg, of UC Santa Barbara, and Pete Coffey, of University College London (UCL), published their work in two papers, including one published this week in the journal PloS One. The first paper was published in the October 27 issue of the journal Stem Cells.

The scientists worked with rats that have a mutation which causes a defect in retinal pigmented epithelial (RPE) cells and leads to photoreceptor death and subsequent blindness. Human RPE cells were derived from induced pluripotent stem cells – embryonic stem cell-like cells that can be made from virtually any cell in the body, thus avoiding the controversy involved in using stem cells derived from embryos. Pluripotent means that the cells can become almost any cell in the body.

In experiments spearheaded by UCL’s Amanda Carr, the team found that by surgically inserting stem cell-derived RPE into the retinas of the rats before photoreceptor degeneration, vision was retained. They found that the rats receiving the transplant tracked their visual focus in the direction of moving patterns more efficiently than control groups that did not receive a transplant.

“Although much work remains to be done, we believe our results underscore the potential for stem-cell based therapies in the treatment of age-related macular degeneration,” said Sherry Hikita, an author on both papers and director of UCSB’s Laboratory for Stem Cell Biology.

Dave Buchholz, first author of the article in Stem Cells, explained that by using induced stem cells that can be derived from patients, the scientists avoid immune rejection that might occur when using embryonic stem cells.

According to Buchholz, “RPE cells are essential for visual function. Without RPE, the rod and cone photoreceptors die, resulting in blindness. This is the basic progression in age-related macular degeneration. The hope is that by transplanting fresh RPE, derived from induced pluripotent stem cells, the photoreceptors will stay healthy, preventing vision loss.”

The research is the result of a collaboration between research groups led by Clegg, professor in the Department of Molecular, Cellular & Developmental Biology and co-director of UCSB’s Center for Stem Cell Biology and Engineering, and Pete Coffey, professor of Cellular Therapy and Visual Sciences at University College London and director of the London Project to Cure Blindness. Other authors include Amanda Carr, Anthony Vugler, Jean Lawrence, Carlos Gias, Li Li Chen, Ahmad Ahmado, Ma’ayan Semo, Matthew Smart, Shazeen Hasan, and Lyndon da Cruz at UCL, and Buchholz, Hikita, Teisha Rowland, Amy Friedrich, Cassidy Hinman, and Lincoln Johnson at UCSB.

Source: Gail Gallessich

University of California – Santa Barbara