Study Suggests Screening Kids for Cholesterol


Researchers Say Some High-Cholesterol Cases Aren’t Found Through Current

July 12, 2010 — One in three children with dangerously high cholesterol is missed by current screening recommendations, a new study suggests.

Kids with LDL “bad” cholesterol levels of 160 mg/dL or higher are at risk of type 2 diabetes and heart attacks in early adulthood, notes William Neal, MD, professor of pediatrics at West Virginia University, Morgantown.

Such children need medical attention. Those with a genetic tendency for very high cholesterol — about one in 500 kids — need treatment. To find them, it’s recommended that pediatricians offer cholesterol screening to kids whose parents or grandparents have very high cholesterol and/or heart disease. But not all of these kids actually get tested.

“A lot of parents told us they didn’t even know kids had cholesterol, let alone high cholesterol,” Neal tells WebMD.

Screening Children for High Cholesterol

So Neal and colleagues offered comprehensive screening, including blood cholesterol tests, to every fifth-grade child in West Virginia.

Surprisingly, more than 70% of the 20,266 kids who were screened would have qualified for routine cholesterol screening, according to current National Cholesterol Education Program (NCEP) guidelines. But even more surprising was how many kids had high cholesterol even though they would not have qualified for routine screening.

“Just as many kids who would not have been screened ended up with severely high cholesterol levels as in the group that did qualify for screening based on family history,” Neal says.

For children ages 2-19, a normal level of LDL cholesterol is under 130 mg/dL.

Among the 11-year-olds who met current cholesterol screening guidelines:

  • 8.3% had LDL cholesterol levels of 130 mg/dL or higher.
  • 1.2% had LDL cholesterol levels of 160 mg/dL or higher

Among the 11-year-olds who would not have been screened under current guidelines:

  • 9.5% had LDL cholesterol levels of 130 mg/dL or higher.
  • 1.7% had LDL cholesterol levels of 160 mg/dL or higher

Neal says that when child cholesterol screening guidelines were established in the 1990s, it was thought that about 25% of kids would qualify for screening.

“But as time has gone on, one of the indicators that triggers screening is a condition such as high blood pressure or obesity in the child,” Neal says. “You may have children for whom the family history of heart disease may not be positive, but their doctors will lean more toward screening as they worry about diabetes in addition to heart disease.”

Do All Children Need to Be Checked for Cholesterol?

Neal believes it would be a good idea for pediatricians to test all children for high cholesterol. But American Heart Association President Ralph Sacco, MD, chair of neurology at the University of Miami, isn’t so sure.

“This study does call into question whether family history is a good enough indicator for screening, but whether to jump to universal screening is another question,” Sacco tells WebMD. “The rising epidemic of diabetes means we need to focus on diet, weight control, and physical activity. Putting the emphasis on this for fifth graders would be of utmost importance.”

Screening, Sacco says, isn’t enough. What should be universal for kids is a healthier diet and a lot more exercise.

“Maybe we should have more childhood screening of waist circumference, and of how well fifth graders do in controlling their weight and maintaining exercise,” Sacco says. “Those would be universal programs we would gladly adopt.”

Sacco and Neal agree that children whose cholesterol does not get lower despite changes in lifestyle may need treatment with cholesterol-lowering statin drugs. Such drugs appear to be safe for children who need them, although treatment of children should begin at very low doses.

Valproic Acid and Specific Congenital Malformations


A fresh approach to an old dilemma provides valuable detailed information about the specific risks from using valproic acid during pregnancy.

A recent evidence-based review of prospective cohort studies of major congenital malformations (MCMs) after exposure to antiepileptic drugs (AEDs) concluded that intrauterine, first-trimester exposure to valproic acid (VPA) is highly likely to increase the risk for MCMs compared with use of either no AED or a few other individual AEDs (JW Womens Health June 11 2009). However, associations with specific MCMs were statistically limited by the designs of the studies. Now, researchers have employed a reverse approach, using the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, a population-based registry of congenital anomalies from 14 countries.

Using data from eight published cohort studies of outcomes after first-trimester valproic acid exposure, the investigators identified 14 MCMs that occurred at a greater frequency in these studies than in the EUROCAT reference group (3.8 million pregnancies). Then, the investigators used the EUROCAT antiepileptic-study database to conduct a case-control study to test their hypotheses. They compared the odds of exposure to VPA monotherapy among cases (for each of the 14 MCMs) with the odds in two control groups (a group with MCMs other than those under study and a group with chromosomal abnormalities).

Pregnancies involving spina bifida had an adjusted odds ratio (OR) of 12.7 for VPA exposure versus no AED exposure and an OR of 5.7 for VPA exposure versus exposure to other-AED monotherapy. Five other MCMs — atrial septal defect, cleft palate, hypospadias, polydactyly, and craniosynostosis — had significantly higher adjusted ORs for VPA exposure versus no AED exposure (range, 2.2 to 6.8). In an analysis of the adjusted OR for VPA monotherapy versus monotherapy with another AED, the findings were almost identical, except that craniosynostosis was no longer significantly associated with VPA exposure, but ventricular septal defect was.

Comment: The consistently higher risk for MCMs with VPA, echoed throughout several pregnancy studies around the world and now supported by a different methodological approach, is remarkable. This study more clearly identifies which MCMs are likely to occur with the use of VPA. These findings further underscore the message that, by choosing to prescribe any AED other than VPA, the clinician is likely lowering the risk for some MCMs in current and future pregnancies. Avoiding VPA use should be a guiding principle when treating adolescent girls and women with epilepsy.

— Page B. Pennell, MD

Dr. Pennell is Director of Research for the Division of Epilepsy and Sleep, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston.

Published in Journal Watch Neurology July 13, 2010

Gemcitabine synergistically enhances the effect of adenovirus gene therapy through activation of the CMV promoter in pancreatic cancer cells


Adenovirus-mediated gene therapy shows remarkable promise as a new strategy for advanced pancreatic cancer, but satisfactory clinical results have not yet been obtained. To improve this gene therapy, we investigated the effects of gemcitabine (GEM) on transgene expression by adenoviral vectors and their biological effects. We used Ad-lacZ and adenoviral vector-expressing NK4 (Ad-NK4) as representative adenoviral vectors. These vectors express β-galactosidase (β-gal) and NK4 (which inhibits the invasion of cancer cells), respectively, under the control of the CMV promoter. Cells were infected with the individual adenoviruses and then treated with GEM. GEM increased β-gal mRNA expression and β-gal activity, and increased NK4 expression in both culture media and within infected cells, in dose-dependent manners. The increased expression of NK4 delivered by Ad-NK4 had biological effects by inhibiting the invasion of cancer cells. GEM also enhanced NK4 expression in SUIT-2 cells transfected with an NK4-expressing plasmid, suggesting that GEM enhanced CMV promoter activity. In in vivo experiments, NK4 expression within subcutaneously implanted tumors was increased in GEM-treated mice compared with control mice. These results suggest that adenovirus-mediated gene therapy with GEM may be a promising approach for treating pancreatic cancer, and that this combination therapy may decrease the risks of side effects.

MicroRNA and drug resistance


Chemotherapy is the preferred treatment for malignancies. However, a successful long-term use of chemotherapy is often prevented by the development of drug resistance. Many mechanisms such as gene mutation, DNA methylation and histone modification have important roles in the resistance of cancer cells to chemotherapeutic agents. Climent suggested miR-125b was involved in the development of drug resistance by microRNA (miRNA) dysregulation. miRNAs are endogenously expressed small non-coding RNAs, which are evolutionarily conserved and function as regulators of gene expression. Much effort has been exerted in analyzing the role of miRNAs in the development of drug resistance in a variety of malignancies. Several research groups have shown that the expressions of miRNAs in chemoresistant cancer cells and their parental chemosensitive ones are different. The molecular targets and mechanisms of chemosensitivity and chemoresistance are also elucidated. This article reviews the functions of miRNAs in the development of drug resistance.

source: nature

More on the Cardiovascular Risks of HIV Infection


A large observational study identifies a CD4 count <500 cells/mm3 as an important independent cardiac risk factor in some patients.

Many study groups have attempted to define the cardiac risks faced by HIV-infected patients, with an emphasis on traditional risk factors and antiretroviral exposures. In this large prospective study, investigators focused on the risk associated with the infection itself.

Using the HIV Outpatient Study (HOPS) database, the researchers identified 2005 HIV-infected patients for whom a baseline cardiac risk profile could be calculated according to the usual Framingham criteria. These individuals represented only about half the patients who were otherwise eligible.

During a median 5.5 years of follow-up, 148 patients (7%) experienced a clinical event indicative of atherosclerotic coronary disease (including cardiac events, ischemic stroke, and peripheral arterial disease). The frequency of clinical events was correlated with the Framingham risk score: Events were roughly eight times more common in high-risk patients than in low-risk ones. Baseline CD4-cell count was also independently associated with likelihood of a clinical event: The attributable risk associated with a CD4 count <500 cells/mm3 was 25.6%, around the same magnitude as the effects of cigarette smoking and hyperlipidemia, and larger than the effects of male sex and diabetes. A case-control analysis yielded similar results.

Some antiretrovirals were modestly associated with cardiac risk in univariate analyses, but the associations did not retain significance after adjustment for other factors. The study did not address what happened to cardiac risk in successfully treated patients.

Comment: Because this study did not include patients whose Framingham risk scores could not be calculated from the medical record — presumably because they were considered at low risk for cardiac events — its findings cannot be generalized to all patients. However, the study does suggest that in the subset of patients whose doctors are — for whatever reason — concerned enough about cardiac events to record all the pertinent baseline values, low CD4-cell counts worsen cardiac prognosis.


Published in Journal Watch HIV/AIDS Clinical Care July 19, 2010

Rapamycin sensitizes Akt inhibition in malignant human breast epithelial cells


Akt and mTOR are therapeutic targets for the treatment of cancer. The effects of inhibiting mTOR, with rapamycin, and Akt, with A-443654, concurrently, on cell morphology, cell proliferation, the cell cycle, and apoptosis were examined using the benign MCF10A and malignant MCF10CA1a human breast epithelial cells. Rapamycin and A-443654 in combination produced the greatest morphological changes and inhibited cell proliferation by G2/M arrest. Rapamycin and A-443654 in combination induced apoptosis at earlier times and at lower A-443654 concentrations in MCF10CA1a tumor cells than in the benign MCF10A cells. Rapamycin and A-443654 increased p53 and p15INK4B protein levels, decreased anti-apoptotic Bcl-2 levels, and increased Bad levels in the MCF10CA1a tumor cells by ∼5-fold. These results suggest that the combined inhibition of Akt and mTOR may have beneficial therapeutic and safety margin effects.

Seismology: The secret chatter of giant faults


For the past few weeks, seismologists at the University of Washington in Seattle have been on high alert. Any day now, they expect a flurry of microtremors deep under the nearby Olympic Peninsula, just as occurs roughly every 12–14 months. And when that wave of vibrations comes along, the researchers will be ready to catch it.

Over the past year, the seismology team has set up an elaborate net — an array of more than 100 seismic sensors planted in the ground throughout the peninsula’s mountains. When those instruments start picking up signs of the tremors, the researchers will rush back out to install extra seismometers above the spots where the earth is shuddering. Every few days the scientists will tend to the sensors, replacing batteries and downloading data, with the hope of capturing as much information as possible about the seismic events underfoot.

The quakes will pass within a few weeks without anybody feeling them. But for seismologists, these swarms of tremors, sometimes called non-volcanic tremors, are among the most significant discoveries of the past decade because they could yield insight into the behaviour of destructive faults. Researchers first noticed them in 2002 in Japan, and a year later teams in the Pacific Northwest detected them beneath the Cascadia region near Seattle.

“Tremor swarms can help researchers spy on dangerous faults.”


The Cascadian tremors are attracting interest because they hail from deep beneath the coast, along a massive fault that is thought to have unleashed earthquakes approaching magnitude 9. Researchers hope that the detailed measurements they are about to make will help them monitor activity along the fault. It may be possible to use the recurring swarms as a probe to track changes in stress underground; the tremors may even yield clues about the timing and location of future large quakes.

“It’s pretty exciting,” says Greg Beroza, a geophysicist at Stanford University in California, who is watching for the results from the University of Washington team. The regularity of the quakes lets researchers prepare for them, providing an exceedingly rare chance to study seismic events in great detail. “If you had told me 10 years ago that there was going to be some kind of activity, happening on deep faults, that we could predict was going to happen again soon with some regularity, I would have told you that you were crazy,” says Beroza.

Elusive signals

The seismic trace of a tremor looks different from that of a classic earthquake. The latter starts with a bang — a burst of high-frequency energy that rapidly tails off. Tremors are tamer; their vibrations are rich in low frequencies, and they come and go with less fanfare. These characteristics, and the weakness of the tremors, make them hard to spot. Preliminary observations of tremors have come from Alaska and Mexico, among other places, but information remains sketchy because only a few places have networks of seismometers sensitive enough to catch them.

Seismologist Kazushige Obara of the University of Tokyo Earthquake Research Institute was the first person to spot tremors, using signals recorded by a permanent monitoring array buried below the Earth’s surface1. The Japanese government established the country-wide network of 600 monitors after the devastating 1995 Kobe earthquake; the instruments are sunk more than 100 metres below ground, to shield them from human-made noises — such as the rumble from trucks — that can drown out the tremors’ vibrations. When Obara detected extremely deep microearthquakes lasting for several weeks, 30 kilometres beneath Japan, researchers around the world pored over their own data to see whether they could spot similar traces.

Tremors in Japan occur mostly along junctions between tectonic plates where one dives or ‘subducts’ beneath another. The same structure underlies the Pacific Northwest, along what is known as the Cascadian subduction zone, which stretches from Vancouver Island in British Columbia, Canada, to northern California (see ‘The origin of tremor swarms’). Here, the Juan de Fuca plate is slipping beneath the North American continental plate. Since the last huge quake, which is thought to have occurred in 1700, the dangerous part of the Cascadian subduction zone has remained locked, but researchers expect it to give way cataclysmically within the next century.

With that risk in the background, researchers are especially interested in capturing tremor swarms as a way to spy on what is happening deep down in the subduction zone. Last year, they missed their chance. The University of Washington team expected the swarm to occur in August, but it arrived in early May, before many of the instruments were in the field. The researchers recorded bits of the event using a permanent array, but in much less detail than they had hoped.

This year, they are better prepared. Once their permanent array picks up the first signs of the tremors, they will head out to augment the network above the swarm. Each completed array will consist of about two-dozen seismometers stationed 200–300 metres apart in remote areas, away from human noise. The team’s work is supported by a US$500,000 grant from the US National Science Foundation to Earthscope, a non-profit research consortium.

“The experiment we have out now will be unprecedented with regard to what we can see,” says John Vidale, a seismologist at the University of Washington and one of the lead scientists on the project.

The team’s network, called an ‘array of arrays’, can pinpoint the source of the tremors by comparing when the seismic waves arrive at each seismometer, says Vidale. “As with your ears, you can tell which direction a sound is coming from,” he explains.

The origin of tremor swarms is generating intense debate. In Japan, seismologists have observed that tremors come from the plane where the plates meet, the subduction-fault boundary, which also gives birth to mammoth quakes. But in Cascadia, seismic signals indicate that some tremor may also occur above the fault plane, according to Honn Kao and his colleagues, geophysicists at the Pacific Geosciences Centre in Sidney, British Columbia2.

Deep origins

Locating the source of the vibrations could help researchers to understand the physical processes that create them. The tremors originate tens of kilometres underground, where Earth’s cold crust is pulled into the warmer mantle. Rocks in the upper crust are brittle enough to break under stress, which leads to earthquakes. But those in the mantle are so hot that they warp under pressure instead of cracking. Tremors seem to happen in the complex zone where the subducting plate has warmed enough for its rocks to become malleable.

A study published this week3 could help to explain the process that produces tremors under parts of Japan. Satoshi Ide, a seismologist at the University of Tokyo, suggests that tremor behaviour beneath Shikoku island could be controlled by the types of rock present in the subduction zone there. Ide found that the locations of some tremors line up in stripes matching the direction in which the subducting plate has travelled during the past 10 million years. He hypothesizes that these bands could trace the path left by seamounts, the remnants of former volcanoes embedded in the oceanic plate that is diving under Japan.

If he is right, the seamounts could influence the behaviour of tremors in two possible ways, he says. They might snag on the overlying plate as the crust slides into the mantle, creating occasional bursts of tremors. Alternatively, their chemical composition might cause them to act as lubricants, like lumps of grease, smoothing out the movement of the plates and turning what could have been catastrophic ruptures into bumpy jitters.

Beroza calls Ide’s findings preliminary, but “a really important result” that indicates how the properties of the rocks along faults might be preserved for millions of years and affect the occurrence of tremors today. As in Japan, tremors in Cascadia sometimes occur in bands that might reflect some characteristic of the subducting rocks.

Researchers are trying to determine what conditions create tremors instead of full-blown earthquakes, using data from old and new laboratory experiments that test how friction, porosity and other attributes of rock change under pressure. These studies could help reveal what controls the movement of faults at subduction-zone depths, says geophysicist Paul Segall of Stanford University.

Quake clues

Scientists also wonder how tremors relate to larger earthquakes on the same faults. The better-observed tremor events in Japan and Cascadia tend to be close to the parts of subducting plates that produce great earthquakes; the tremors originate below the ‘locked’ areas that store up energy for future large quakes.

Joan Gomberg, a geophysicist at the University of Washington, says researchers are looking for changes in tremor patterns that may hint at stress shifts in a fault. If such connections emerge, seismologists could start to monitor tremors for signs that precede a big earthquake. They have found some intriguing clues but nothing solid so far. The San Andreas Fault in California, for example, has experienced tremor events alongside earthquakes of magnitude 1 or 2, but direct associations between the two have yet to be confirmed.

source: nature

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Meanwhile, Obara and his colleagues plan to put out an extra
monitoring system, to gather more details about tremor events beneath
Japan. And researchers in Cascadia are ready to pounce when the swarm
hits.
“These things happen almost like clockwork, but not
exactly,” says seismologist Ken Creager of the University of
Washington, recalling last year’s disappointment when the team missed
the tremors. This year, he is more confident. “We’ll catch it one way
or another.”
// ]]>