Folate in age-related disease

Folic acid and homocysteine in age-related disease

Mattson MP, Kruman II, Duan W

Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, USA

It has been known for decades that babies born to women that have a dietary deficiency in folic acid (folate) are at increased risk for birth defects, and that the nervous system is particularly susceptible to such defects.

Folate deficiency in adults can increase risk of coronary artery disease, stroke, several types of cancer, and possibly Alzheimer's and Parkinson's diseases.

Recent findings have begun to reveal the cellular and molecular mechanisms whereby folate counteracts age-related disease. An increase in homocysteine levels is a major consequence of folate deficiency that may have adverse effects on multiple organ systems during aging.

Humans with inherited defects in enzymes involved in homocysteine metabolism, including cystathionine beta-synthase and 5,10-methylenetetrahydrofolate reductase, exhibit features of accelerated aging and a marked propensity for several age-related diseases. Homocysteine enhances accumulation of DNA damage by inducing a methyl donor deficiency state and impairing DNA repair. In mitotic cells such DNA damage can lead to cancer, while in postmitotic cells such as neurons it promotes cell death.

The emerging data strongly suggest that elevated homocysteine levels increase the risk of multiple age-related diseases, and point to dietary supplementation with folate as a primary means of normalizing homocysteine levels and increasing healthspan.

Ageing Res Rev 2002 Feb;1(1):95-111

Children of drug dependent parents

Predictors of internalizing and externalizing problems among children of cocaine and opiate dependent parents

STANGER Catherine (1) ; KAMON Jody (1) ; DUMENCI Levent (1) ; HIGGINS Stephen T. (1) ; BICKEL Warren K. (1) ; GRABOWSKI John (2) ; AMASS Leslie (3) ;

(1) Department of Psychiatry, University of Vermont, 1 South Prospect Street, Burlington, VT 05401-3456, ETATS-UNIS(2) Department of Psychiatry, Houston Health Science Center, University of Texas, 1300 Moursund Ave, Suite 115, Houston, TX 77030, ETATS-UNIS(3) Friends Research Institute, Inc., 11075 Santa Monica Blvd, Suite 225, Los Angeles, CA 90025, ETATS-UNIS

We tested associations in structural models among parent individual problems (severity of drug problems, medical problems, psychiatric symptoms), family problems, and children's internalizing and externalizing problems. Results were compared for cocaine versus opiate dependent parents, mothers versus fathers, boys versus girls, and older versus younger children.

Cocaine and opiate dependent parents in treatment (N = 211) were interviewed about their substance use, psychiatric symptoms, and interpersonal problems and completed a measure of family problems.

Parents also rated children's internalizing and externalizing problems. In structural models controlling for the significant correlations between parent and family problems and between children's internalizing and externalizing problems, family problems but not individual parent problems predicted children's internalizing and externalizing symptoms. Models were similar across all groups compared with the exception of parent gender, with significant relations between parent and family problems for mothers but not for fathers.

In addition, older girls were more deviant relative to their same-age and gender peers than the younger girls and boys.

These results suggest that the personal problems of drug dependent mothers may influence children's problems indirectly by increasing family problems. For drug dependent fathers, family problems were an independent predictor of children's problems.

Drug and alcohol dependence 2002, vol. 66, no2, pp. 199-212 (1 p.1/4)

HIV vaccine:large-scale clinical trial

First large-scale HIV vaccine trial in South Africa opens

A large-scale clinical trial of a candidate HIV vaccine—which previously showed promise in smaller studies in the United States and elsewhere—has now opened in South Africa. The study plans to enroll up to 3,000 HIV-negative men and women, making it the largest African HIV vaccine trial to date.

Conducted jointly by the South African AIDS Vaccine Initiative (SAAVI) and the HIV Vaccine Trials Network (HVTN), the trial is supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The study vaccine, provided by Merck & Co. Inc. (Whitehouse Station, NJ), contains copies of only three HIV genes, not the entire virus, so it is impossible for a trial volunteer to become infected from the vaccine.

"Our best hope of ending the AIDS epidemic is a safe and effective vaccine," says NIH Director Elias A. Zerhouni, M.D. "To achieve that goal requires the concerted effort of governments, scientists and private industry as well as participation by well-informed volunteers."

"We applaud the South Africans for bringing this important trial to fruition. This international partnership exemplifies the model of collaboration needed to defeat HIV/AIDS," says NIAID Director Anthony S. Fauci, M.D.In South Africa the trial is called Phambili ("moving forward"). Also known as HVTN 503, it is a Phase IIb "test-of-concept" trial, the first such vaccine study in South Africa. This type of trial is designed to provide preliminary information on vaccine efficacy and thus enable researchers to decide whether or not to conduct a larger Phase III efficacy trial that could lead to licensure.

In smaller trials, the vaccine was found to be safe and to stimulate cellular immune responses against HIV in more than half of volunteers. To date, more than 1,800 people have received at least one injection. Two years ago, the first Phase IIb trial of the vaccine opened at sites in the United States, Canada, South America, Australia and the Caribbean (see http://www3.niaid.nih.gov/news/newsreleases/2005/mercktrial.htm), areas where a subtype of HIV called clade B predominates. That trial is ongoing.As in that study, the main objectives of HVTN 503 are to determine whether the candidate vaccine can prevent HIV infection or, in those who do become infected, lower the level of HIV early on. Additionally, the new trial will determine if the vaccine, which is based on clade B HIV, has the potential to protect against the HIV clade C subtype prevalent in South Africa. Immune responses in the first several hundred volunteers will be assessed to ensure the vaccine induces promising immune responses in this population against the clade C virus before proceeding to full enrollment.

Study volunteers must be healthy, sexually active, HIV-negative men and women, ages 18 to 35 years old. Investigators will assign them at random to receive either the test vaccine or an inactive placebo injection. The trial is double-blind, meaning that neither the researchers nor the volunteers know which a participant has received. All volunteers will be regularly counseled about ways to reduce their risk of acquiring HIV, and they will be given condoms. Access to care and treatment for sexually transmitted infections will be provided, and because recent findings indicate that medical circumcision can reduce the risk of HIV transmission from women to men, access to medical circumcision will also be provided to male participants who desire it.

In South Africa, the trial is led by Glenda Gray, MBBCH, FCPaeds (SA), of the Perinatal HIV Research Unit, University of the Witwatersrand, based at the Chris Hani Baragwanath Hospital in Soweto. James Kublin, M.D., M.P.H., of Fred Hutchinson Cancer Research Center, Seattle, serves as study co-chair. The study is expected to recruit volunteers at five sites in South Africa, located in Soweto, Cape Town, Klerksdorp, Medunsa and Durban.According to Dr. Gray, the study team has actively sought community endorsement of and support for this clinical trial, both of which are critical to its success. "Our communities here in South Africa are faced with the burden of HIV on a daily basis, and the trial investigators and study team have spent years developing a rapport with the community so that together we can move forward in our quest to identify improved approaches to prevent new HIV infections."

The test vaccine contains a weakened adenovirus that serves as a carrier for three clade B HIV genes. Adenoviruses are among the main causes of upper respiratory tract ailments such as the common cold. Because the vaccine contains only three HIV genes housed in weakened adenoviruses, study participants cannot become infected with HIV or get a respiratory infection from the vaccine. The study aims to determine if the HIV genes will induce a cellular immune response, producing immune cells that recognize and kill cells infected with HIV.

The South African Medicines Control Council, the South African Department of Agriculture and the U.S. Food and Drug Administration have reviewed the trial and allowed the study to proceed. In order to conduct the trial, sites also are required to obtain institutional ethics and biosafety committee approvals.

NIH/National Institute of Allergy and Infectious Diseases

Sick Building Syndrome: epidemiological study

Building health: an epidemiological study of "sick building syndrome" in the Whitehall II study

A F Marmot1, J Eley1, M Stafford2, S A Stansfeld3, E Warwick2 and M G Marmot2
1) AMA, Linton House, London, UK; 2) Department of Epidemiology and Public Health, University College London Medical School, London, UK; 3) Centre for Psychiatry, Barts and the London, Queen Mary’s School of Medicine and Dentistry, Medical Sciences Building, London, UK

Objectives: Sick building syndrome (SBS) is described as a group of symptoms attributed to the physical environment of specific buildings. Isolating particular environmental features responsible for the symptoms has proved difficult. This study explores the role and significance of the physical and psychosocial work environment in explaining SBS.

Methods: Cross sectional data on the physical environment of a selection of buildings were added to individual data from the Whitehall II study—an ongoing health survey of office based civil servants. A self-report questionnaire was used to capture 10 symptoms of the SBS and psychosocial work stress. In total, 4052 participants aged 42–62 years working in 44 buildings were included in this study.

Results: No significant relation was found between most aspects of the physical work environment and symptom prevalence, adjusted for age, sex, and employment grade. Positive (non-significant) relations were found only with airborne bacteria, inhalable dust, dry bulb temperature, relative humidity, and having some control over the local physical environment. Greater effects were found with features of the psychosocial work environment including high job demands and low support. Only psychosocial work characteristics and control over the physical environment were independently associated with symptoms in the multivariate analysis.

Conclusions: The physical environment of office buildings appears to be less important than features of the psychosocial work environment in explaining differences in the prevalence of symptoms.
Keywords: sick building syndrome; office environment; psychosocial work characteristics

Occupational and Environmental Medicine 2006;63:283-289;
© 2006 by BMJ Publishing Group Ltd

Girls' depression

Young adolescent girls' depression is tied to more stressful life events

Children's conduct problems—skipping school, sneaking out of the house, lying to parents, shoplifting, or bullying other children—are a major source of concern for parents and teachers. As a potential cause of these problems, parents' marital conflict has received a lot of research attention. Now a new study finds that parents' fighting may not be to blame but rather that parents who argue a lot may pass on genes for disruptive behavior to their children.

A group of researchers from the University of Virginia and several other universities looked at this question, studying 1,045 twins and their 2,051 children. Some of the parents were identical twins and shared all of their genes and some were fraternal and shared only half of their genes.

The study found that parents' fighting is not likely a cause of children's conduct problems. On the other hand, parents' genes influenced how often they argued with their spouses and these same genes, when passed to their children, caused more conduct problems.

"This study suggests that marital conflict is not a major culprit, but genes are," said K. Paige Harden, the lead researcher and professor of psychology at the University of Virginia. "Our findings have potential implications for treating conduct problems: Focusing on a child's parents, as is common in family therapy, may not be as effective as focusing on the child.

"The study was supported, in part, by grants from the National Institute on Alcohol Abuse and Alcoholism and the National Alliance for Research on Schizophrenia and Depression.

The findings are published in the January/February 2007 issue of the journal Child Development.

Society for Research in Child Development