The Caterpillar got down off the mushroom … remarking as it went, ‘One side will make you grow taller, and the other side will make you grow shorter.’

—Lewis Carroll, ‘Alice’s Adventures in Wonderland’

UCLA geneticists have identified the mutation responsible for IMAGe syndrome, a rare disorder that stunts infants’ growth. The twist? The mutation occurs on the same gene that causes Beckwith–Wiedemann syndrome, which makes cells grow too fast, leading to very large children.

The UCLA findings could lead to new ways of blocking the rapid cell division that allows tumours to grow unchecked. The discovery also offers a new tool for diagnosing children with IMAGe syndrome, which until now has been difficult to identify accurately.

The discovery holds special significance for principal investigator Dr. Eric Vilain, a professor of human genetics, paediatrics and urology at the David Geffen School of Medicine at UCLA.

Nearly 20 years ago, as a medical resident in his native France, Vilain cared for two boys, ages 3 and 6, who were dramatically short for their ages. Though unrelated, the children shared a mysterious malady marked by minimal foetal development, stunted bone growth, sluggish adrenal glands, and undersized organs and genitals.

‘I never found a reason to explain these patients’ unusual set of symptoms,’ said Vilain, who also directs the UCLA Institute for Society and Genetics. ‘I’ve been searching for the cause of their disease since 1993.’

When Vilain joined UCLA as a genetics fellow, the two cases continued to intrigue him. His UCLA mentor at the time, geneticist Dr. Edward McCabe, recalled a similar case from his previous post at Baylor College of Medicine. The two of them obtained blood samples from the three cases and analysed the patients’ DNA for mutations in suspect genes but uncovered nothing.

Vilain and McCabe approached the Journal of Clinical Endocrinology and Metabolism and in 1999 published the first description of the syndrome, which they dubbed IMAGe, an acronym of sorts for the condition’s symptoms: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia and genital anomalies.

Over the next decade, about 20 cases were reported around the world. But the cause of IMAGe syndrome remained a mystery.

Help arrived unexpectedly last year, when Vilain received an email from Argentinian physician Dr. Ignacio Bergada, who had unearthed the 1999 journal article. He told Vilain about a large family he was treating in which eight members suffered the same symptoms described in the study. All of the family members agreed to send their DNA samples to UCLA for study.

Vilain realized that he had stumbled across the scientific equivalent of winning the lottery. He assembled a team of UCLA researchers to partner with Bergada and London endocrinologist Dr. John Achermann.

‘At last, we had enough samples to help us zero in on the gene responsible for the syndrome,’ Vilain said. ‘Sequencing technology had also advanced in sophistication over the past two decades, allowing us to quickly analyse the entire family’s DNA samples.’

Vilain’s team performed a linkage study, which identifies disease-related genetic markers passed down from one generation to another. The results steered Vilain to a huge swath of Chromosome 11.

The UCLA Clinical Genomics Center performed next-generation sequencing, a powerful new technique that enabled the scientists to scour the enormous area in just two weeks and tease out a slender stretch that held the culprit mutation. The team also uncovered the same mutation in the original three cases described by Vilain and McCabe in 1999.

‘We discovered a mutation in a tiny sliver of the chromosome that appeared in every family member affected by IMAGe syndrome,’ Vilain said. ‘This was a big step forward. Now we can use gene sequencing as a tool to screen for the disease and diagnose children early enough for them to benefit from medical intervention.

‘We were a little surprised, because the mutation was located on a famous gene recognised for causing Beckwith–Wiedemann syndrome,’ he added. ‘The two diseases are polar opposites of each other.’

Children born with Beckwith–Wiedemann syndrome — named for the two doctors who discovered it — grow very large, with big adrenal glands, elongated bones and oversized internal organs. Because their cells grow so fast, one in five children with the disorder die of cancer at a young age. The disease appears in approximately one out of 15,000 births.

‘Finding opposite functions in the same gene is a rare biological phenomenon,’ Vilain emphasised. ‘When the mutation appeared in the slim section we identified, the infant developed IMAGe syndrome. If the mutation fell anywhere else in the gene, the child was born with Beckwith–Wiedemann. That’s really quite remarkable.’ UCLA

International Osteoporosis Foundation Working Group provides guidance; urges caution in the diagnosis and treatment of osteoporosis in adults under 50 years of age
Much of the research defining osteoporosis and fracture risk has focused on older adults, i.e. postmenopausal women and men over the age of 50. While older adults are at highest risk of osteoporosis and related fractures, the disease can also affect younger adults between 20 and 50 years of age. However, the diagnosis and management of osteoporosis in young adults is complicated by special challenges, including a complex pathophysiology and the related fact that there is no clear definition of osteoporosis, or of intervention thresholds, in this age group.
An International Osteoporosis Foundation scientific working group has now published a review which outlines the pathophysiology, diagnosis and management of osteoporosis in young adults, providing a clear screening strategy that includes the use of clinical and laboratory exams.
Dr. Serge Ferrari of the University of Geneva and chair of the IOF Working Group on Osteoporosis Pathophysiology, explains the diagnostic challenge faced by clinicians, ‘Low bone mass in this age group may not necessarily represent a pathological condition, but result instead from low peak bone mass in relation to body size, late puberty, or genetic and environmental background.’
On the other hand, there are young adults who may truly have osteoporosis with bone fragility at a young age. This may result from altered bone modelling and/or remodelling during growth or later due to a chronic disorder or a genetic or idiopathic condition. Typical examples would be inflammatory bowel diseases, particularly Crohn’s disease. These diseases impair bone mass gain and/or accelerate bone loss because of mal-absorption and poor nutrient intake. In addition, low levels of physical activity, secondary amenorrhea, and in many cases the effects of corticosteroid treatment, can have an impact on bone mass.
Distinguishing between these two situations can be all the more difficult because up to 30% of young women and 50% of young men have had fractures during childhood and adolescence, usually traumatic. These are not necessarily associated with skeletal fragility.
An apparently low areal bone mineral density (T-score < -2.5 at spine or hip by DXA) must be interpreted with caution in young adults of small body size (constitutionally lean) and/or stunted growth. Inaccurate ‘diagnosis’ of osteoporosis in young subjects can lead to anxiety, unnecessary drug prescriptions, and in some countries potential restrictions of insurance coverage. Individuals with low bone mass, although possibly deserving investigation depending on the context (for instance to rule out vitamin D deficiency) should not automatically be classified as osteoporotic. This diagnosis only applies when there is evidence of skeletal fragility. Nevertheless, a truly low BMD and/or unusual fractures (such as low-trauma, multiple and vertebral) should prompt investigation for secondary causes of osteoporosis. Careful medical history, clinical and laboratory investigations can reveal an underlying disease that requires specific medical intervention, which in turn will improve bone mass. Bisphosphonates may improve BMD in young subjects with osteoporosis due to various disorders, however the evidence is scarce so far and there are no data on their anti-fracture efficacy. In any case, the indications and duration of anti-resorptive treatment in the young should be as restrictive as possible, particularly in the absence of secondary causes, multiple and/or fragility (vertebral) fractures, and high bone turnover accompanied by documented bone loss. Professor Cyrus Cooper, chair of the IOF Committee of Scientific Advisors, concluded, 'This review will be of assistance to clinicians managing this important problem. The clinical relevance of low bone mineral density in young adults is less well understood than is the case in postmenopausal women and older men. Furthermore, many treatment modalities licensed for use in postmenopausal osteoporosis have not been carefully evaluated in younger adults. Clear guidance as to the interpretation of BMD and the appropriate use of treatments is therefore most timely.' International Osteoporosis Foundation

An important step towards developing a rapid, inexpensive diagnostic method for autism has been take by Uppsala University, among other universities. Through advanced mass spectrometry the researchers managed to capture promising biomarkers from a tiny blood sample.
There are no acknowledged biomarkers for autism today. Researchers at Berzelii Centre and the Science for Life Laboratory in Uppsala who, in collaboration with colleagues at Linnaeus University in Sweden and the Faculty of Medicine in Tehran, Iran, who have discovered some promising biomarkers.
Many diseases are caused by protein alterations inside and outside the body’s cells. By studying protein patterns in tissue and body fluids, these alterations can be mapped to provide important information about underlying causes of disease. Sometimes protein patterns can also be used as biomarkers to enable diagnosis or as a prognosticating tool to monitor the development of a disease. In the current study disruptions of the nervous system were in focus when the scientists studied protein patterns in autism spectrum disorder (ASD).
To identify potential biomarkers (peptides or proteins), the researchers performed a detailed protein analysis of blood plasma from children with ASD compared with a control group. Using advanced mass spectrometric methods, they succeeded in identifying peptides consisting of fragments of a protein whose natural function is in the immune system, the complement factor C3 protein.
The study is based on blood samples from a relatively limited group of children, but the results indicate the potential of our methodological strategy. There is already a known connection between this protein and ASD, which further reinforces the findings, says Jonas Bergquist, professor of analytical chemistry and neurochemistry at the Department of Chemistry – BMC (Biomedical Centre) in Uppsala.
The hope is that this new set of biomarkers ultimately will lead to a reliable blood-based diagnostic tool. Uppsala University

Urban beach closures due to coliform outbreaks have become disturbing signs of summer, yet water-testing technology has never been fast enough to keep up with changing conditions, nor accessible enough to check all waters.
Now, researchers at McMaster University have developed a rapid testing method using a simple paper strip that can detect E. coli in recreational water within minutes. The new tool can close the gap between outbreak and detection, improving public safety.
The new strips are coated with chemicals that react to the bacteria, and are printed using inkjet technology similar to that found in standard desktop printers. Within 30 minutes of sampling, the paper changes colour to indicate the presence of E. coli, with colours coded to represent different forms and concentrations of the bacteria.
Scientists from the Sentinel Bioactive Paper Network have created and validated the viability of the test strip, which can detect potentially harmful concentrations of E. coli in water quickly and simply, with much greater accuracy than existing portable technology.
The Natural Sciences and Engineering Research Council of Canada (NSERC) funds Sentinel, a strategic research network that spans the country and is based at McMaster. Several dozen researchers are involved in its initiatives.
‘Coliforms are always a big problem,’ said the paper’s lead author John Brennan, a McMaster chemistry professor who holds the Canada Research Chair in Bioanalytical Chemistry. ‘The methods used to detect outbreaks are slow, and tend not to be portable, as they often need a lab-based amplification step prior to testing, causing a time lag between an outbreak and a beach closure.’
Bioactive paper is both old and new, Brennan says. Since the late 1950s, physicians have been using bioactive paper to test for glucose in urine. In the last several years, the area has expanded quickly and research has become very competitive as scientists work on new applications.
‘It’s always a race,’ Brennan said.
In the future, the test strips should make it possible for consumers to check their water affordably and easily, without additional equipment, scientific knowledge or long waits.
‘One of the problems right now is that there is no simple, fast and cheap way to test recreational water, and certainly nothing out there in the realm of rapid tests for drinking water,’ Brennan said.
Field testing of the prototype strips is planned or under way in Canada and across the globe, in regions where untreated water poses particular health hazards. The results of these studies will help to refine the test strips and may lead to strips that are sensitive enough to tell whether water is safe enough to drink, said Brennan.
The standards for safe drinking water are hundreds of times tighter than those for safe swimming water. Typically, limits for safe swimming allow for a maximum of 100 to 500 cells of E. coli in 100 mL of water, depending on jurisdiction. For water to be considered safe for drinking, there cannot be even one cell in 100 mL – a little less than half a cup of water.
The next stage of pre-commercial development of the test strips is already funded by NSERC through a Phase I Idea to Innovation grant. Commercialization of a final product could take as little as two to three years. McMaster University

Mammalian spermatogenesis is maintained by spermatogonial stem cells (SSCs). However, since evidentiary assays and unequivocal markers are still missing in non-human primates and man, the identity of primate SSCs is unknown. In contrast, in the mouse, germ cell transplantation studies functionally demonstrated the presence of SSCs. LIN28 is an RNA-binding pluripotent stem cell factor, which is also strongly expressed in undifferentiated mouse spermatogonia. By contrast, two recent reports indicated that LIN28 is completely absent from adult human testes. Here, we analysed LIN28 expression in marmoset monkey (Callithrix jacchus) and human testes during development and adulthood and compared it with the mouse. In the marmoset, LIN28 was strongly expressed in migratory PGCs and gonocytes. Strikingly, we found a rare LIN28-positive subpopulation of spermatogonia also in the adult marmoset testis. This was corroborated by western blotting and quantitative RT-PCR. Importantly, in contrast to previous publications, we found LIN28-positive spermatogonia also in normal adult human and additional adult non-human primate testes. Some seasonal breeders exhibit a degenerated (involuted) germinal epithelium during their non-breeding season consisting only of Sertoli cells and SSCs. The latter re-initiate spermatogenesis prior to the next breeding-season. Fully involuted testes from a seasonal hamster and NHP (Lemur catta) exhibited numerous LIN28-positive spermatogonia, indicating a SSC-identity of the labeled cells. We conclude that LIN28 is differentially expressed in mouse and non-human primate spermatogonia and might be a marker for a rare SSC population in non-human primates and man. Further characterization of the LIN28-positive population is required. European Society of Human Reproduction and Embryology