Scientists have identified which strains of the Toxoplasma gondii parasite, the cause of toxoplasmosis, are most strongly associated with premature births and severe birth defects in the United States. The researchers used a new blood test developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, to pinpoint T. gondii strains that children acquire from their acutely infected mothers while in the womb.
Pregnant women can become infected with T. gondii through contact with cat faeces that contain infectious forms of the parasite or by eating undercooked meat. Women who become infected while pregnant may miscarry, give birth prematurely, or have babies with eye or brain damage.
‘If undetected or untreated, congenital toxoplasmosis can have serious consequences for a child’s quality of life,’ noted NIAID Director Anthony S. Fauci, M.D. ‘The findings from this study support the value of screening for toxoplasmosis to identify patients who could benefit from treatment.’
Currently available blood tests can determine whether a person has ever been infected with any strain of Toxoplasma parasite. The experimental test developed at NIAID improves upon the older tests because it can detect the presence of strain-specific antibodies that distinguish infecting strains from one another. The test was developed by Michael Grigg, Ph.D., of NIAID’s Laboratory of Parasitic Diseases, and his colleagues. It was applied to blood samples collected between 1981 and 2009 as part of the National Collaborative Chicago-Based Congenital Toxoplasmosis Study. The study of congenitally infected children was initiated by NIAID grantee Rima McLeod, M.D., of the University of Chicago, who is the first author of the new study.
At least 15 distinct T. gondii strain types have been found throughout the world. In France, where research has been done to establish which strains are most common, a strain called type II predominates. Type II parasites can be distinguished from all other strains, which are collectively termed not exclusively type II strains (or NE-II).
Using the new test, the researchers found evidence of either type II or NE-II infections in 183 of the mother-child pairs in the national congenital toxoplasmosis study. Statistical analysis revealed that NE-II parasites were more likely to be associated with premature birth, and infants infected with these strains were more likely to have severe manifestations of disease than infants infected by type II parasites. For example, severe eye damage was seen in 67 percent of NE-II cases (59 out of 88), while such eye damage was present in only 39 percent of type II cases (18 out of 46). The researchers noted, however, that the association is not absolute, and that mild, moderate or severe disease can result regardless of the infecting strain.
‘We knew that, in mice, certain parasite strains are clearly associated with severe disease,’ said Dr. Grigg. ‘But we didn’t know if the same association between strain type and disease severity would hold true for people. Until now, we had not systematically determined whether infected people in the United States had European-type strains or other types, and we also hadn’t determined whether strains found here would have more severe disease symptoms associated with them.’
When she helped start the congenital toxoplasmosis study in 1981, optimal drug treatment regimens were unknown, said Dr. McLeod. Now, thanks in part to controlled clinical trials run under the auspices of the study, the condition can be successfully treated and many babies who are diagnosed before or shortly after birth and who are treated suffer few or no ill effects. When the researchers looked at the clinical histories of those children in the long-term study who had been diagnosed with congenital toxoplasmosis during gestation and whose mothers had received drug treatment prior to giving birth, the association between NE-II and severe disease at birth vanished. ‘Our study demonstrates that outcomes are equally good following postnatal treatment for type II and NE-II parasites, although not all outcomes are favorable for all children,’ she said.
In France, all pregnant women are screened for Toxoplasma infection. Prompt treatment is offered to any woman who becomes infected while pregnant, thus lessening the chance that the parasite will damage the fetus, Dr. McLeod noted. ‘In the United States, obstetrical screening for Toxoplasma infection is rarely practiced. This new study underscores the value of identifying all patients who will benefit from treatment and suggests that widespread screening and treatment of pregnant women who are infected could prevent infants from suffering eye and brain damage due to congenital toxoplasmosis,’ she said. EurekAlert

The study is the first to directly show how low testosterone levels in fat tissue can be instrumental in the onset of Type 2 diabetes.
Testosterone is present throughout the body. Low testosterone levels are linked to obesity, a known risk factor for diabetes. It acts on fat cells through molecules known as androgen receptors. These enable the testosterone to activate genes linked to obesity and diabetes.
The research showed that mice in which the function of testosterone in fat tissue was impaired were more likely to be insulin resistant than mice in which the role of testosterone was not hindered.
As men age their testosterone levels lower. This, along with increasing obesity, will increase the incidence of diabetes.
The findings from the University of Edinburgh could also help explain why older men are more at risk of developing diabetes, because testosterone levels fall in men as they age.
It showed that mice, which did not have androgen receptors in fat tissue for testosterone to attach to, were more likely to show signs of insulin resistance than other mice.
Researchers found that mice without androgen receptors in fat tissue also became fatter than other mice and developed full insulin resistance when both types were fed a high-fat diet.
The study showed that insulin resistance occurred in mice when the function of testosterone was impaired regardless of body weight.
Scientists believe that a protein called RBP4 plays a crucial role in regulating insulin resistance when testosterone is impaired. They found that levels of RBP4 were higher in mice in which the role of testosterone was impaired. The Edinburgh team say that its findings could lead to the development of new treatments that regulate production of RBP4. This could reduce the risk of diabetes in men with lower levels of testosterone.
Researchers are now planning to study patients with Type-2 diabetes to see if their levels of testosterone correlate with levels of RBP 4.
‘We already know that low testosterone levels are associated with increased obesity and therefore with increased risk of developing Type 2 diabetes, but this study provides evidence that there can be increased risk even when body mass is not affected. Yet while testosterone-impaired mice developed insulin resistance whatever diet they were given, the effect was considerably more pronounced on those fed on a high fat diet. This reinforces Diabetes UK advice that a healthy balanced diet is important for everyone and particularly for those already at high risk of developing Type 2 diabetes.’ says Dr Iain Frame, Director of Research at Diabetes UK. University of Edinburgh

A research study led by the Peninsula College of Medicine and Dentistry, University of Exeter, and Boston University School of Medicine, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating oestrogen and testosterone levels in the bloodstream.
The results also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.
The study was carried out in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.
Sex hormone binding globulin (SHBG) is the key protein that carries testosterone and oestrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.
Previous family studies have demonstrated that approximately 50 per cent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.
Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. Although these genetic variants only explain a small fraction of the sex hormone variability seen between individuals, they could provide insight into the diseases connected to sex hormone regulation.
The results showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.
‘These findings highlight the diverse range of biological processes that may be impacted by sex hormone regulation,’ said Dr. John Perry of the Peninsula College of Medicine and Dentistry, University of Exeter. EurekAlert

Transposon-mediated insertional mutagenesis accelerates the progression of ductal pancreatic cancer in mice.
In a study researchers have identified a potential new therapeutic target for pancreatic cancer.
The team found that when a gene involved in protein degradation is switched-off through chemical tags on the DNA’s surface, pancreatic cancer cells are protected from the bodies’ natural cell death processes, become more aggressive, and can rapidly spread.
Pancreatic cancer kills around 8,000 people every year in the UK and, although survival rates are gradually improving, fewer than 1 in 5 patients survive for a year or more following their diagnosis.
Co-lead author Professor David Tuveson, from Cancer Research UK’s Cambridge Research Institute, said: ‘The genetics of pancreatic cancer has already been studied in some detail, so we were surprised to find that this gene hadn’t been picked up before. We suspected that the fault wasn’t in the genetic code at all, but in the chemical tags on the surface of the DNA that switch genes on and off, and by running more lab tests we were able to confirm this.’
The team expects this gene, USP9X, could be faulty in up to 15 per cent of pancreatic cancers, raising the prospect that existing drugs, which strip away these chemical tags, could be an effective way of treating some pancreatic cancers.
.’ This study strengthens our emerging understanding that we must also look into the biology of cells to identify all the genes that play a role in cancer. ‘
…’Drugs which strip away these tags are already showing promise in lung cancer and this study suggests they could also be effective in treating up to 15 per cent of pancreatic cancers,’ continues Professor Tuveson.
The researchers used a mouse model of pancreatic cancer to screen for genes that speed up pancreatic cancer growth using a technique called ‘Sleeping Beauty transposon mutagenesis’. This system uses mobile genetic elements that hop around the cell’s DNA from one location to the next. Cells that acquire mutations in genes that contribute to cancer development will grow out and ‘driver’ cancer genes may be identified.
By introducing the Sleeping Beauty transposon into mice pre-disposed to develop pancreatic cancer, the researchers were able to screen for a class of genes called a tumour suppressor that, under normal circumstances, would protect against cancer. These genes are a bit like the cell’s ‘brakes’, so when they become faulty there is little to stop the cell from multiplying out of control.
This approach uncovered many genes already linked to pancreatic cancer. But unexpectedly, USP9X, was identified. Wellcome Trust Sanger Institute

Each year, tens of thousands of patients have all or part of their thyroids removed to rule out cancer because of suspicious, but uncertain, cytology test results. In the majority of cases, the suspicious thyroid nodules are determined to be ultimately benign.
Now, new research led by Brigham and Women’s Hospital (BWH) finds that a novel, genomic diagnostic test that measures the expression of 167 genes has shown promise in improving pre-operative risk assessment by re-classifying otherwise indeterminate results from thyroid biopsies as either benign or suspicious.
‘Our findings show that the gene expression test can substantially reclassify otherwise inconclusive results from thyroid biopsies, said Erik Alexander, MD, lead author of the paper and a physician-researcher in the Division of Endocrinology, Diabetes and Hypertension at Brigham and Women’s Hospital. ‘Currently, indeterminate thyroid nodules are usually referred for thyroid surgery given the unanswered question of thyroid cancer. While all care should be personalised, our findings suggest that this test has the potential to drastically reduce unnecessary surgery and allow physicians to monitor many patients in a more conservative fashion.’
Thyroid nodules are common and ultrasound-guided needle biopsies (fine needle aspiration) have been shown to accurately identify about 65-75 percent of nodules as benign. Approximately five-10 percent of diagnostic biopsies are malignant. The remaining biopsies produce indeterminate results – occurring about fifteen to thirty percent of the time. For these patients, there remains substantial concern for thyroid cancer, though the diagnosis is uncertain. Because of the concern for cancer, in most cases, all or part of the thyroid is removed for final diagnosis. However, the nodule is ultimately benign in seventy to eighty percent of cases. For these patients, surgery was not needed and the patient was unnecessarily exposed to the cost, risk and morbidity associated with this intervention.
In this research study, researchers enrolled 3,789 patients and collected 4,812 thyroid samples from nodules larger than 1 cm and evaluated the effectiveness of a novel gene expression test in 265 thyroid samples that were cytologically indeterminate (suspicious for cancer, though not conclusive) from 49 different academic and community hospital sites around the United States. Samples were simultaneously collected for the standard-of-care cytology analysis, as well as one or two additional needle sticks for inclusion in the study. If the cytology result was indeterminate, the study sample was then analysed using the gene expression test. Thyroid surgery was performed based on the judgement of the treating physician who was blinded to the test results. At completion of the study, the gene expression test results were compared to final histopathology diagnosis (the gold-standard diagnosis) provided by two blinded pathology experts following their review of the surgical tissue sample.
For all cytologically indeterminate nodules, the researchers found that when the gene expression test was benign, histopathological analysis of the nodule proved it benign 93 percent of the time. And when applied to lower risk subgroups of indeterminate thyroid samples labelled ‘atypia (or follicular lesion) of an undetermined significance’ or ‘follicular neoplasm,’ the accuracy improved to 94 and 95 percent, respectively.
‘This very high negative predictive value is comparable to that of a cytologically benign cytology result. Therefore, such a result will allow clinicians to recommend a more conservative approach of watching waiting in lieu of diagnostic surgery,’ said Alexander. ‘It is estimated that over 50 percent of current thyroid surgeries are performed unnecessarily (for cytologically indeterminate, though histopathologically benign nodules), and therefore could be impacted by the gene expression test.’ Brigham and Women’s Hospital