Myopia, also known as short-sightedness or near-sightedness, is the most common disorder affecting the eyesight and it is on the increase. The causes are both genetic and environmental. The Consortium for Refractive Error and Myopia (CREAM) has now made important progress towards understanding the mechanisms behind the development of the condition. This international group of researchers includes scientists involved in the Gutenberg Health Study of the University Medical Center of Johannes Gutenberg University Mainz (JGU). The team has uncovered nine new genetic risk factors which work together with education-related behaviour as the most important environmental factor causing myopia to generate the disorder. The results of the study ‘Genome-wide joint meta-analyses of genetic main effects and interaction with education level identify additional loci for refractive error: The CREAM Consortium’ have recently been published in the scientific journal Nature Communications.
There has been a massive rise in the prevalence of short-sightedness across the globe in recent decades and this upwards trend is continuing. It is known from previous studies of twins and families that the risk of acquiring short-sightedness is determined to a large extent by heredity. However, the myopia-causing genes that had been previously identified do not alone sufficiently explain the extent to which the condition is inherited. In addition to the genetic causes of myopia there are also environmental factors, the most significant of which are education-related behaviour patterns. “We know from the Gutenberg Health Study conducted at Mainz that the number of years of education increases the risk of developing myopia,’ said Professor Norbert Pfeiffer, Director of the Department of Ophthalmology at the Mainz University Medical Center.

With the aim of identifying genetic mutations relating to myopia and acquiring better insight into the development of the condition, the international research group CREAM carried out a meta-analysis of data collected from around the world. The data compiled for this analysis originated from more than 50,000 participants who were analysed in 34 studies. The second largest group of participants was formed by the more than 4,500 subjects of the Gutenberg Health Study of the Mainz University Medical Center. ‘In the field of genetic research, international cooperation is of particular importance. This is also borne out by this study, to which we were able to make a valuable contribution in the form of data from our Gutenberg Health Study,’ continued Professor Norbert Pfeiffer. ‘And in view of the fact that a survey undertaken by the European Eye Epidemiology Consortium with the help of the Gutenberg Health Study shows that about one third of the adult population of Europe is short-sighted, it is essential that we learn more about its causes in order to come up with possible approaches for future treatments.’

Aware that environmental effects and hereditary factors reinforce one another in the development of myopia, the scientists devised a novel research concept for their investigations. They used a statistical analysis technique that takes into account both the effects of the environmental and hereditary factors and does so in equal measure and simultaneously. Their efforts were crowned with success as they were able to classify nine previously unknown genetic risk factors.

Risk-associated gene involved in the development of short-sightedness
These newly discovered genetic variants are associated with proteins which perform important functions when it comes to the transmission of signals in the eye. One of these genes is of particular interest because it plays a major role in the transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the eye. Previous studies have shown that there is greater activation of the gene in question in eyes that are myopic. The results of current research substantiate this conclusion. The CREAM researchers interpret this as evidence that this newly discovered risk-related gene is actually involved in the development of short-sightedness. This represents significant initial headway towards understanding how genetic causes interact with the level of education as an environmental factor to produce the heterogeneity of myopia. Further research will be needed to clarify the details of how the mechanisms actually work and interact with one another.

The spread of short-sightedness is a worldwide phenomenon. Particularly in South East Asia the incidence of myopia in school children has increased notably over the last decades. This is likely due to an improvement in educational attainment. People who read a great deal also perform a lot of close-up work, usually in poor levels of daylight. The eye adjusts to these visual habits and the eyeball becomes more elongated than normal as a result. But if it becomes too elongated, the cornea and lens focus the image just in front of the retina instead of on it so that distant objects appear blurry. The individual in question is then short-sighted.

Johannes Gutenberg University Mainz
www.uni-mainz.de/presse/20232_ENG_HTML.php

Researchers at the University of Rochester Medical Center recently discovered a genetic link between Long QT Syndrome (LQTS), a rare cardiac rhythm disease, and an increased risk for seizures. The study also found that people with LQTS who experience seizures are at greater risk of sudden cardiac death.

According to research, there is a clear association between the heart and the brain of LQTS patients. Patients carrying LQTS genetic mutations were three times more likely to have experienced seizures in their past, compared to their family members who did not carry those mutations. Interestingly, LQTS patients who had a history of seizures also tended to have worse cardiac symptoms.

David Auerbach, Ph.D., senior instructor of Medicine in the Aab Cardiovascular Research Institute of the University of Rochester Medical Center, and lead author of the study found seizure status to be the strongest predictor of cardiac arrhythmias – the abnormal heart rhythms characteristic of LQTS. In fact, about 20% of the LQTS patients in the study who had a history of seizures had survived at least one lethal cardiac arrhythmia. 

You could begin applying these findings to patients today by telling physicians treating LQTS patients to look outside the heart.
Auerbach’s study set a new clinical precedence for the link between seizures and LQTS and provides a case for doctors to pay more attention to what is happening in LQTS patients’ brains or, more broadly, to “look outside the classic organ of interest” in any disease.

As a postdoctoral fellow, Auerbach studied the heart-brain connection in a severe genetic form of epilepsy, and found that cardiac arrhythmias were one cause of sudden unexplained death in people with epilepsy. Now, he investigates the converse – whether a genetic heart disorder is also associated with issues in the brain. 

Auerbach tapped into the Rochester-based LQTS Patient Registry to answer this question. This unique resource was developed 40 years ago by the senior author of the study, Arthur Moss, M.D., the Bradford C. Berk, MD, PhD, Distinguished Professor of Medicine at URMC. The registry contains information about more than 18,000 people including LQTS patients and their affected and unaffected family members, who provide a nearly ideal group of controls. “In essence, they have the same genetic makeup, except theoretically, the LQTS-causing mutation,” says Auerbach.

To ensure that the seizures reported in the registry were not merely misdiagnosed cardiac arrhythmias, Auerbach investigated the effect of beta blockers, drugs often prescribed to LQTS patients to prevent cardiac arrhythmias. While the drugs effectively reduced patients’ arrhythmias, they had no effect on seizures, minimizing the chance that the seizures were simply misdiagnosed cardiac side effects.

Looking at the patients’ genetic information, Auerbach and his colleagues found that patients with the three different types of LQTS (LQTS1-3) showed similar heart rhythm symptoms, but vastly different prevalence of seizures. LQTS1 and LQTS2 patients had much higher prevalence of seizures than LQTS3 or no mutation – with LQTS2 at the greatest risk.

Further investigation of the LQTS-causing mutation showed that the specific location of the mutation greatly affected the risk of cardiac arrhythmias and seizures.  In one location on the gene, the mutation protected against these symptoms, but in another location on the same gene, the mutation increased the risk of those symptoms. Understanding what each of these mutations does may shed new light on a basic mechanism of seizures and may provide viable therapeutic targets to treat LQTS.

The University of Rochester Medical Center www.urmc.rochester.edu/news/story/4612/the-heart-brain-connection-the-link-between-lqts-and-seizures.aspx

Autism is an agonizing puzzle, a complex mixture of genetic and environmental factors. One piece of this puzzle that has emerged in recent years is a biochemical cascade called the mTOR pathway that regulates growth in the developing brain. A mutation in one of the genes that controls this pathway, PTEN (also known as phosphatase and tensin homolog), can cause a particular form of autism called macrocephaly/autism syndrome.

Using an animal model of this syndrome, scientists from the Florida campus of The Scripps Research Institute (TSRI) have discovered that mutations in PTEN affect the assembly of connections between two brain areas important for the processing of social cues: the prefrontal cortex, an area of the brain associated with complex cognitive processes such as moderating social behavior, and the amygdala, which plays a role in emotional processing.

 “When PTEN is mutated, we find that neurons that project from the prefrontal cortex to the amygdala are overgrown and make more synapses,” said TSRI Associate Professor Damon Page. “In this case, more synapses are not necessary a good thing because this contributes to abnormal activity in the amygdala and deficits in social behavior.”

The study also showed that targeting the activity of the mTOR pathway shortly after birth, a time when neurons are forming connections between these brain areas, can block the emergence of abnormal amygdala activity and social behavioral deficits. Likewise, reducing activity neurons that project between these areas in adulthood can also reverse these symptoms.

‘Given that the functional connectivity between the prefrontal cortex and amygdala is largely conserved between mice and humans,” said TSRI Graduate Student Wen-Chin Huang, the first author of the study, “we anticipate the therapeutic strategies suggested here may be relevant for individuals on the autism spectrum.”

Although caution is warranted in extrapolating findings from animal models to humans, these findings have implications for individualized approaches to treating autism. “Even within individuals exposed to the same risk factor, different strategies may be appropriate to treat the symptoms of autism in early development versus maturity,” said Page.

The Scripps Research Institute www.scripps.edu/news/press/2016/20161115page.html

Changes in benign tissues next to prostate tumours may provide an early warning for patients at higher risk for biochemical recurrence after a radical prostatectomy, a study by researchers at Case Western Reserve University and Johns Hopkins Medical Institutions shows.

Biochemical recurrence, which is increasing prostate-specific antigen (PSA) levels, can be used to predict which prostate cancer patients will develop local recurrence, distant metastases and death.
In a small sampling, image analysis of the adjacent tissue was a better predictor than the current standard for prognosis following the prostatectomy.
If preliminary findings are confirmed by further studies, they may help doctors decide sooner which patients need more follow-up therapies after surgery or should return for more regular monitoring.
“In a sense, this study is validating what a lot of people think regarding these cancers—that there is a field effect, as if the tumour has hard-to-see tentacles that can affect the patient and outcomes,” said Anant Madabhushi, the F. Alex Nason professor II of biomedical engineering at Case Western Reserve and leader of the research.

Madabhushi worked with Case Western Reserve’s George Lee, a research assistant professor, and Sahirzeeshan Ali, a PhD student, and Johns Hopkins Medical Institutions’ Robert W. Veltri, associate professor of urology, and Jonathan I. Epstein, the Reinhard Professor of Urologic Pathology. Their study is published in the journal European Urology Focus.

The researchers analyzed records from 70 patients who underwent radical prostatectomies from 2000 to 2004 with up to 14 years follow-up. They digitized images of the resected prostate specimens and analysed the tumour regions and surrounding tissue that appeared to be benign.
Of the group studied, 22 suffered from biochemical recurrence, metastasis or died.

The scientists used computers to search for and identify image features that may be undetectable with the human eye, but which may correlate with a biochemical recurrence. They used the top 10 features to develop a risk score.

They were surprised to find that nuclear shape and architecture in the benign-looking tissue were greater predictors of recurrence than features found in the tumour, Madabhushi said. “Its an amazing finding, completely unexpected.”
Among the risk calculators used to assess prostate cancer recurrence is a nomogram of variables known to influence recurrence, and a Gleason score, which is based on the cancer tissue pattern compared to normal tissue.
“We were able to do better than nomograms and the Gleason score,” Madabhushi said.
But by combining the benign-field features with tumour features extracted from patient’s pathology images and Gleason scoring, they were able to further improve the prediction of recurrence.

Case Western Reserve University blog.case.edu/think/2016/07/06/changes_in_benign_tissue_next_to_prostate_tumours_may_predict_biomedical_recurrence_of_cancer_scientists_find

Identifying and treating metabolic deficiencies in patients with treatment-resistant depression can improve symptoms and in some cases even lead to remission, according to new research from the University of Pittsburgh School of Medicine.

“What’s really promising about these new findings is that they indicate that there may be physiological mechanisms underlying depression that we can use to improve the quality of life in patients with this disabling illness,” said David Lewis, M.D., Thomas Detre Professor and Chair of Pitt’s Department of Psychiatry.

Major depressive disorder, also referred to simply as depression, affects nearly 15 million American adults and is one of the most common mental disorders. Unfortunately, at least 15 percent of patients don’t find relief from conventional treatments such as antidepressant medications and psychotherapy, explained lead study investigator Lisa Pan, M.D., professor of psychiatry, and clinical and translational science, Pitt School of Medicine. Depression also is the cause of more than two-thirds of suicides that occur annually.

The groundwork for the current study was laid five years ago when Dr. Pan and David Brent, M.D., Endowed Chair in suicide studies at Pitt, treated a teen with a history of suicide attempts and long-standing depression. “Over a period of years, we tried every treatment available to help this patient, and yet he still found no relief from his depression symptoms,” she explained.

Searching for answers, Dr. Pan contacted Jerry Vockley, M.D., Ph.D., chair of genetics, Children’s Hospital of Pittsburgh of UPMC, and David Finegold, M.D., professor of human genetics at Pitt’s Graduate School of Public Health, and through a series of biochemical tests, the three discovered that the patient had a cerebrospinal fluid deficiency in biopterin, a protein involved in the synthesis of several brain signalling chemicals called neurotransmitters.

After receiving an analogue of biopterin to correct the deficiency, the patient’s depression symptoms largely disappeared and today he is a thriving college student.

The success prompted the researchers to examine other young adults with depression who were not responding to treatment, explained Dr. Pan.

In the published trial, the researchers looked for metabolic abnormalities in 33 adolescents and young adults with treatment-resistant depression and 16 controls. Although the specific metabolites affected differed among patients, the researchers found that 64 percent of the patients had a deficiency in neurotransmitter metabolism, compared with none of the controls.

In almost all of these patients, treating the underlying deficiency improved their depression symptoms, and some patients even experienced complete remission. In addition, the further along the patients progress in the treatment, the better they are getting, Dr. Pan added.

University of Pittsburgh School of Medicine www.upmc.com/media/NewsReleases/2016/Pages/l-pan.aspx