Fullest clinical report of Saudi MERS cases to date points to important differences with SARS

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: Flu / Cold / SARS
Article Date: 26 Jul 2013 - 2:00 PDT Current ratings for:
Fullest clinical report of Saudi MERS cases to date points to important differences with SARS

Saudi and UK scientists provide the most detailed picture yet of the clinical and laboratory characteristics of Middle East Respiratory Syndrome (MERS) coronavirus, revealing a wide range of clinical symptoms and an extremely high death rate among patients with co-existing medical conditions.

The new research, published in The Lancet Infectious Diseases, also reveals some important differences with severe acute respiratory syndrome (SARS).

MERS emerged a year ago in Saudi Arabia and almost all those infected have been reported there, or have been linked to people who contracted the virus there.

The new analysis, the largest case series to date, includes 47 cases (46 adults, 1 child) of confirmed MERS infections from Saudi Arabia between Sept 1, 2012, and June 15, 2013.

By combining clinical records, laboratory results, and imaging findings with demographic data, the authors noted a trend of older patients, more men, and patients with underlying medical conditions who succumb to the disease.

As with SARS, MERS infections presented with a wide spectrum of symptoms. Most patients admitted to hospital exhibited fever (98%), chills/rigors (87%), cough (83%), shortness of breath (72%), and muscle pain (32%). A quarter of patients also experienced gastrointestinal symptoms, including diarrhoea and vomiting.

However, in contrast to SARS, the majority of cases (96%) occurred in people with underlying chronic medical conditions including diabetes (68%), high blood pressure (34%), chronic heart disease (28%), and chronic renal disease (49%).

"Despite sharing some clinical similarities with SARS (eg, fever, cough, incubation period), there are also some important differences such as the rapid progression to respiratory failure, up to 5 days earlier than SARS"*, explains Professor Ziad Memish, the Deputy Minister for Public Health from the Kingdom of Saudi Arabia, who led the research.

"In contrast to SARS, which was much more infectious especially in healthcare settings and affected the healthier and the younger age group, MERS appears to be more deadly with 60% of patients with co-existing chronic illnesses dying, compared with the 1-2% toll of SARS. Although this high mortality rate with MERS is probably spurious due to the fact that we are only picking up severe cases and missing a significant number of milder or asymptomatic cases, so far there is little to indicate that MERS will follow a similar path to SARS."*

According to co-author Professor Ali Zumla from University College London, "The recent identification of milder or asymptomatic cases of MERS in health care workers, children, and family members of contacts of MERS cases indicates that we are only reporting the tip of the iceberg of severe cases and there is a spectrum of milder clinical disease which requires urgent definition. Ultimately the key will be to identify the source of MERS infection, predisposing factors for susceptibility to infection, and the predictive factors for poor outcome. Meanwhile infection control measures within hospitals seem to work."*

Writing in a linked Comment, Professor Christian Drosten from the University of Bonn Medical Centre in Germany points to the urgent need for accurate diagnostic tests to help focus control efforts and minimise the risk of spread to others, "To ascertain relevant data for MERS epidemiology, we need to develop serological assays using samples from well defined groups of patients, such as described here. Population-based antibody testing could establish the extent of MERS-CoV infection, instead of only seeing the tip of the iceberg represented by cases admitted, such as those summarised in this important paper."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our infectious diseases / bacteria / viruses section for the latest news on this subject.

*Quotes direct from authors and cannot be found in text of Article.

The Lancet

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Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy

Main Category: Parkinson's Disease
Article Date: 27 Jul 2013 - 0:00 PDT Current ratings for:
Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy

Biologists at The Scripps Research Institute (TSRI) have made a significant discovery that could lead to a new therapeutic strategy for Parkinson's disease.

The findings, recently published online ahead of print in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson's disease. Precisely how the loss of this enzyme leads to the deaths of neurons has been unclear. But the TSRI researchers showed that parkin's loss sharply reduces the level of another protein that normally helps protect neurons from stress.

"We now have a good model for how parkin loss can lead to the deaths of neurons under stress," said TSRI Professor Steven I. Reed, who was senior author of the new study. "This also suggests a therapeutic strategy that might work against Parkinson's and other neurodegenerative diseases."

Genetic Clues

Parkinson's is the world's second-most common neurodegenerative disease, affecting about one million people in the United States alone. The disease is usually diagnosed after the appearance of the characteristic motor symptoms, which include tremor, muscle rigidity and slowness of movements. These symptoms are caused by the loss of neurons in the substantia nigra, a brain region that normally supplies the neurotransmitter dopamine to other regions that regulate muscle movements.

Most cases of Parkinson's are considered "sporadic" and are thought to be caused by a variable mix of factors including advanced age, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins. But between 5 and 15 percent of cases arise specifically from inherited gene mutations. Among these, mutations to the parkin gene are relatively common. Patients who have no functional parkin gene typically develop Parkinson's-like symptoms before age 40.

Parkin belongs to a family of enzymes called ubiquitin ligases, whose main function is to regulate the levels of other proteins. They do so principally by "tagging" their protein targets with ubiquitin molecules, thus marking them for disposal by roving protein-breakers in cells known as proteasomes. Because parkin is a ubiquitin ligase, researchers have assumed that its absence allows some other protein or proteins to evade proteasomal destruction and thus accumulate abnormally and harm neurons. But since 1998, when parkin mutations were first identified as a cause of early-onset Parkinson's, consensus about the identity of this protein culprit has been elusive.

"There have been a lot of theories, but no one has come up with a truly satisfactory answer," Reed said.

Oxidative Stress

In 2005, Reed and his postdoctoral research associate (and wife) Susanna Ekholm-Reed decided to investigate a report that parkin associates with another ubiquitin ligase known as Fbw7. "We soon discovered that parkin regulates Fbw7 levels by tagging it with ubiquitin and thus targeting it for degradation by the proteasome," said Ekholm-Reed.

Loss of parkin, they found, leads to rises in Fbw7 levels, specifically for a form of the protein known as Fbw7ß. The scientists observed these elevated levels of Fbw7ß in embryonic mouse neurons from which parkin had been deleted, in transgenic mice that were born without the parkin gene, and even in autopsied brain tissue from Parkinson's patients who had parkin mutations.

Subsequent experiments showed that when neurons are exposed to harmful molecules known as reactive oxygen species, parkin appears to work harder at tagging Fbw7ß for destruction, so that Fbw7ß levels fall. Without the parkin-driven decrease in Fbw7ß levels, the neurons become more sensitive to this "oxidative stress" - so that more of them undergo a programmed self-destruction called apoptosis. Oxidative stress, to which dopamine-producing substantia nigra neurons may be particularly vulnerable, has long been considered a likely contributor to Parkinson's.

"We realized that there must be a downstream target of Fbw7ß that's important for neuronal survival during oxidative stress," said Ekholm-Reed.

A New Neuroprotective Strategy

The research slowed for a period due to a lack of funding. But then, in 2011, came a breakthrough. Other researchers who were investigating Fbw7's role in cancer reported that it normally tags a cell-survival protein called Mcl-1 for destruction. The loss of Fbw7 leads to rises in Mcl-1, which in turn makes cells more resistant to apoptosis. "We were very excited about that finding," said Ekholm-Reed. The TSRI lab's experiments quickly confirmed the chain of events in neurons: parkin keeps levels of Fbw7ß under control, and Fbw7ß keeps levels of Mcl-1 under control. Full silencing of Mcl-1 leaves neurons extremely sensitive to oxidative stress.

Members of the team suspect that this is the principal explanation for how parkin mutations lead to Parkinson's disease. But perhaps more importantly, they believe that their discovery points to a broad new "neuroprotective" strategy: reducing the Fbw7ß-mediated destruction of Mcl-1 in neurons, which should make neurons more resistant to oxidative and other stresses.

"If we can find a way to inhibit Fbw7ß in a way that specifically raises Mcl-1 levels, we might be able to prevent the progressive neuronal loss that's seen not only in Parkinson's but also in other major neurological diseases, such as Huntington's disease and ALS [amyotrophic lateral sclerosis]," said Reed.

Finding such an Mcl-1-boosting compound, he added, is now a major focus of his laboratory's work.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our parkinson's disease section for the latest news on this subject.

“Parkin-Dependent Degradation of the F-box protein Fbw7 ß Promotes Neuronal Survival in Response to Oxidative stress by Stabilizing Mcl-1,” Susanna Ekholm-Reed, Matthew S. Goldberg, Michael G. Schlossmacher and Steven I. Reed, Published ahead of print 15 July 2013, doi: 10.1128/MCB.00535-13

Funding for the study was provided in part by the National Institutes of Health (NS059904 and CA078343).

Scripps Research Institute

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'Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy'

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