Safely Fixed Hip Prostheses

Artificial hip joints are firmly anchored to the patient’s damaged bone by screws. But which parts of the bone will safely hold the screws in place? A simulation model is to calculate the strength of the bone from computer tomography images.Hip prostheses do not hold forever. If an implant comes loose, the doctors have to replace it. Most patients need this second operation after about 15 years. By then, the first prosthesis has often worn down the pelvic bone in several places. Moreover, the bone density, and thus also its strength, changes with increasing age. Medics therefore have to work out where best to place the screws that connect the artificial joint to the bone, and what shape the hip prosthesis needs to be in order to fit the surrounding bones as well as possible.

At present, doctors examine patients using computer tomography (CT), and determine the rough density of the bones from the images. On the basis of various assumptions, they then calculate how strong the bones are in different places. The problem is that, although there are various theories on which the simulations can be based, the results often deviate significantly from reality. The consistency of the damaged bones is usually different from what the simulation leads to believe.

This is set to be changed by researchers at the Fraunhofer Institute for Machine Tools and Forming Technology IWU in Dresden and their colleagues at the biomechanics laboratory of the University of Leipzig. They are developing a model with which doctors can reliably and realistically calculate the density and elasticity of the bone from the CT scanner images. To this end, the researchers are transferring methods usually used for component testing to human hip bones, which involve inducing oscillations in the bone. This type of examination cannot be carried out on the patient. The bone has to be clamped into an apparatus.

“The nature of the oscillations enables us to deduce local properties of the bone – such as its density and elasticity,” explains IWU group manager Martin Quickert. The researchers compare these results with scanned images of the bone and describe the correlations on the basis of a mathematical model. This should make it possible in future to determine the strength of a bone directly from the CT scanner images. The scientists have already performed the first examinations on prepared and thus preserved bones, and plan to induce oscillations in unprepared bones left in their natural state over the coming months. The researchers hope that in about two years’ time, doctors will be able to obtain a realistic simulation model of unprecedented quality from computer tomography data. The prostheses can then be perfectly anchored, and will be held safely in place for longer.

Structure Of TIGAR, A Possible Cancer Flag, Discovered

Two Brown University researchers have determined the three-dimensional structure of an enzyme whose presence in the body could help doctors detect cancer earlier or develop more targeted treatments
Hua Li and Gerwald Jogl detail their progress with the enzyme known as TIGAR in a paper to be published Jan. 16, 2009, in The Journal of Biological Chemistry.

“It will help us to understand where else we should be looking for good [anti-cancer] targets,” said Jogl, assistant professor of biology in the Department of Molecular Biology, Cell Biology and Biochemistry at Brown. Jogl is the study’s principal investigator and corresponding author. Li is a fifth-year Ph.D. student based in Jogl’s lab and is the lead author.

Jogl and Li wanted to determine the structure of TIGAR. After more than a year of research, they discovered that it is has a more substantive active site than they had expected. To map the structure, the pair used a method called X-ray crystallography.

The process involved using intensive X-ray light produced at the National Synchroton Light Source in Brookhaven, N.Y., to analyze crystals grown from samples of the TIGAR enzyme.

A separate study by researchers from St. Jude’s Children’s Research Hospital first identified the existence of TIGAR. Those results were published in CELL in 2006.

TIGAR, which helps regulate energy production in the cell, is activated after cell damage. Because of this, the presence of the enzyme can indicate potential problems that may lead to cancer. But TIGAR itself is positive. Once activated, TIGAR slows all processes in the cell, allowing time to repair cell damage. This process is also intended to prevent further damage that could lead to cancer.

Jogl and Li believe their finding may suggest that TIGAR has additional functions in the cell.

Understanding TIGAR is important, Jogl said, because the enzyme is “one of the good guys” in the battle against cancer. Because its presence can come in tandem with cellular damage, TIGAR is an important clue for scientists that could indicate cancer may follow. Knowing more about TIGAR could lead to earlier cancer detection or even preventative treatments.

“We are looking at the good guys,” Jogl said. “Studying the good guys will lead us to the bad guys and where the places are to interfere.”

A National Institutes of Health grant helped support the study.

MRSA’s 'Weak Point' Visualized By Scientists

An enzyme that lives in MRSA and helps the dangerous bacterium to grow and spread infection through the human body has been visualised for the first time, according to a new study.Now, armed with detailed information about the structure of this enzyme, researchers hope to design new drugs that will seek it out and disable it, providing a new way of combating MRSA and other bacterial infections.

The enzyme, a ‘worker-protein’ called LtaS, produces an important component of the protective outer-layer that surrounds all Staphylococcus aureus cells as well as many other bacteria that cause disease.

Staphylococcus aureus is a type of bacterium that causes a variety of infections in the human body, including skin infections and abscesses, sometimes leading to blood poisoning and life-threatening lung or brain infections. MRSA is a particular strain of Staphylococcus aureus, which has evolved to be resistant to the antibiotic methicillin and a large number of other antibiotics, and can be life threatening.

To counter this drug resistance and ensure that it is possible to treat MRSA infection in the future, new antibiotics are needed that work differently, for example by attacking parts of the pathogen that are not targeted by current drugs.

The team from Imperial College London behind today’s study, funded by the Medical Research Council, thinks that LtaS might be a good candidate target for a new antibiotic to which MRSA will not be resistant. This is because its job is to build a polymer called lipoteichoic acid (LTA), which is an important structure found on the surface of Staphylococcus aureus cells.

Although the role of the cell surface polymer LTA is not fully understood, lab tests carried out by the same researchers have shown that if the LtaS enzyme is depleted, production of LTA on the cell surface draws to a halt. As a result growth of the Staphylococcus aureus cell is blocked. So in a patient infected with MRSA, inhibiting this enzyme could clear up the infection because the bacterial cells would be unable to grow properly. Many existing antibiotics work in a similar way by inhibiting the production of other such important structures on the surface of bacterial cells.

The trick, according to one of the paper’s lead authors, Dr Angelika Grundling from Imperial College London’s Division of Investigative Science, is to now find a way of using the new knowledge to develop a drug for use in real world scenarios:

“We’re not quite sure how it works, but we know that this surface structure called LTA is involved in cell growth and cell division – we have shown that without it the cell cannot grow properly, and eventually dies. Because LtaS is the ‘machine’, which builds LTA, developing a drug that knocks out the machine will provide us with a new way to disable the growth of these cells, which would represent a novel new treatment for MRSA and other Staphylococcus aureus infections.”

Dr Grundling and her colleagues have produced a detailed image of the molecular structure of the LtaS enzyme using X-ray crystallography techniques. The image includes a map of LtaS’s active binding site: the part of the enzyme which plays a key role in building LTA. This is the very part that researchers now need to home in on with a drug, in order to prevent the LtaS enzyme from doing its job.

Professor Paul Freemont from Imperial’s Division of Molecular Biosciences, co-lead-author of the paper, explains the importance of the information they have gained about this particular part of the enzyme:

“If we’re to develop a drug which disables LtaS from doing its job, then we need to make sure the drug molecule is as perfectly matched as possible to the enzyme’s binding site, so it can trick the enzyme into taking it up. Once the drug is bound to the enzyme it will be able start its job of sabotage.

“So the more detailed information about the binding site we have, the better we’ll be able to develop an effective drug to match it,” he said.

The two Imperial teams led by Professor Freemont and Dr Grundling now hope to work with the College’s Drug Discovery Centre to search for a biological agent that interacts with the LtaS binding site, as the basis for a new antibiotic drug.

They hope that in the future such a drug could be used to treat not just MRSA, but a whole host of infections caused by bacterial pathogens.

Additional funding for the research was obtained through the US National Institute of Health.