Day: 01/12/2011

Alzheimer’s blood test ‘most accurate’ so far

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The blood of patients with the brain disease contains antibodies not found in healthy people.

Ewen Callaway

Computer graphic of a vertical (coronal) slice through the brain of an Alzheimer patient (at left) compared with a normal brain (at right).A new screen could be the most accurate test yet for Altzheimer’s disease.PASIEKA / SCIENCE PHOTO LIBRARY

A new blood test diagnoses Alzheimer’s disease by sensing molecules produced by the immune systems of people with the neurodegenerative condition.

So far, the test has been applied to just a small number of blood samples, but if proven on a larger scale, the assay could help diagnose Alzheimer’s disease in combination with other tests, says Thomas Kodadek, a professor of chemistry at the Scripps Research Institute in Jupiter, Florida. It could also be used to identify patients for trials of experimental Alzheimer’s drugs, he adds. His team published its results online today in Cell1.

Currently, the only way to conclusively distinguish Alzheimer’s from other dementias is by examining the gnarled plaques and tangles of protein found in the brains of those with the condition. This can only be done after death. A furious search is under way for earlier, less-invasive tests using brain scans, blood draws and spinal taps, for instance.

Globally, over 35 million people suffer from Alzheimer’s. There are no effective treatments for the disease or proven means of preventing it.

Most trawls for blood biomarkers typically whittle down a list of potential molecules to a few that differ between people with a condition and healthy people. For instance, Tony Wyss-Coray’s team at Stanford University in California screened 120 proteins involved in cell communication and found 18 of the proteins present at higher levels in the blood of people with Alzheimer’s disease than others2.

However, such ‘candidate’ screens rely on assumptions about which molecules are likely to be affected by a disease. They also rely on sensing vanishingly small levels of proteins and other molecules.

Slide screen

Antibodies — immune molecules in blood that stick to specific foreign and disease proteins — offer a solution, says Kodadek. If specific to a disease, they are likely to be found in high levels in those with the condition, yet be absent in healthy people.

Typically, a scientist would fish out such antibodies using the disease proteins they attack. However, Kodadek’s team reasoned that antibodies should also recognize other kinds of molecules. They created glass slides coated with thousands of differently shaped peptoid molecules — chemical cousins of peptides that are likely to be recognized by antibodies.

“One could imagine our test being used a cheap front line screen.”

Thomas Kodadek
Scripps Research Institute

As a proof of principle, Kodadek’s team searched for antibodies produced by mice that have a multiple sclerosis-like condition caused by their antibodies attacking the fatty sheaths surrounding nerves. Among the 4,600 peptoids on the slide, several latched onto antibodies in the blood of mice with the disease, but this did not happen for controls. “It was a night-and-day difference, it wasn’t a subtle thing,” he says.

Next, the researchers tested the peptoid slides on blood from six likely Alzheimer’s patients, six similarly aged healthy people, and six patients with a different neurodegenerative condition, Parkinson’s disease.

They identified three peptoids that recognized antibodies from people suspected to have Alzheimer’s. Tested against 16 different people with the condition, each peptoid proved more than 93% accurate at diagnosing Alzheimer’s, meaning they missed only one Alzheimer’s case out of 16.

Antibody issue

In unpublished work, Kodadek says his team has applied the test to about 300 people, correctly diagnosing 98% of the people thought to have Alzheimer’s. Meanwhile, the test proved 95% accurate at distinguishing healthy people from those suspected to have Alzheimer’s, yet Kodadek doubts all 5% are true false positives. “I’m really pretty sure what we’re seeing is pre-symptomatic Alzheimer’s,” he says.

Current tests for Alzheimer’s relying on brain imaging and spinal tap accurately diagnose about 90% of patients, says Kodadek. “One could imagine our test being used a cheap front line screen, and at least if you test positive there, you could go for these more expensive things that couldn’t be used as a general screen.”

Kaj Blennow, an expert on Alzheimer’s biomarkers at Sahlgrenska University Hospital in Mölndal, Sweden, calls the findings “very promising” but says they need to be replicated in a larger group of patients, including those at early stages of Alzheimer’s and with other forms of dementia.

Wyss-Coray says it is still an open question as to whether or not people with Alzheimer’s produce antibodies that are specific to their condition. However, the small number of peptoids unique to those with the disease could point to a very specific immune response against an unknown disease molecule. “If true, that would most certainly change the current view of this disease.”

Kodadek’s team is hoping to find the molecule or molecules recognized by the Alzheimer’s antibodies. They also plan to apply the peptoid screen to discovering antibodies against various cancers.

A company he is involved with, Opko Health based in Miami, Florida, plans to work with a large pharmaceutical firm to identify people suitable for its clinical trials. “If we’re ever going to get an Alzheimer’s drug, we need a much better early diagnostic. Otherwise these trials are doomed to failure,” Kodadek adds.

source: nature medicine

Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

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To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs.

Design Network meta-analysis.

Data sources Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data.

Study selection All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility.

Data extraction The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data.

Data synthesis 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death.

Conclusions Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.

source: BMJ

Curing HIV?

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An HIV-infected man who underwent stem-cell transplantation for leukemia continues to be free of the virus more than 3.5 years later, without any antiretroviral therapy.

In early 2009, researchers described an HIV-infected man with acute myeloid leukemia (AML) who had achieved drug-free virologic control for at least 20 months after receiving a stem-cell transplant from a donor who was homozygous for the CCR5 {Delta}32 allele (JW AIDS Clin Care Feb 13 2009). Now, investigators describe this patient at 45 months of follow-up.

Prior to transplantation, the patient underwent conditioning with cytotoxic agents, total body irradiation, and antithymocyte globulin. On the day of transplantation, he stopped all antiretroviral therapy (ART) and has not reinitiated it. At 13 months, his AML relapsed, he received another intensive conditioning regimen (this time including gemtuzumab, an anti-CD33 monoclonal antibody that was withdrawn from the U.S. market in 2010), and he received a second transplant from the same donor.

In the 45 months since the initial transplantation, the patient’s blood and gut mucosa have been reconstituted with CCR5-negative donor CD4 cells. Notably, his new immune system is not impervious to HIV infection: His CD4 cells express the CXCR4 coreceptor and can be infected ex vivo with an exogenous X4-tropic HIV clone. Nevertheless, the investigators have not found any signs of HIV in his blood, gut mucosa, bone marrow, cerebrospinal fluid, or brain (the last of which was biopsied because of leukoencephalopathy, which turned out to be transplant-related). Moreover, his titer of HIV-specific antibodies has continued to decline over time, providing further evidence that viral antigen is no longer present.

Comment: This singular case raises important questions. Did the intensive conditioning regimens that the patient received prior to transplantation somehow eradicate HIV? Was transplantation of CCR5-negative stem cells the key to this success? Can stem cells from infected patients be manipulated to resist HIV infection and thereby abrogate viral replication after ART is stopped? The answers to these difficult questions could inform the development of safer and more practical strategies for curing HIV infection.

— Rajesh T. Gandhi, MD

Published in Journal Watch HIV/AIDS Clinical Care January 10, 2011

Herpes Zoster Vaccine Found Effective in Community Setting

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A study conducted in a clinical practice setting confirms the effectiveness of herpes zoster vaccine, according to a report in JAMA.

In a retrospective cohort study of health plan members, researchers examined the incidence of herpes zoster among some 75,000 vaccinees aged 60 and older and 225,000 age-matched controls who did not receive the vaccine. After a follow-up averaging about 2 years, the incidence of herpes zoster was twice as high among controls as among vaccinees (13.0 vs. 6.4 per 1000 person-years). The difference remained after adjustment for sex, race, presence of chronic disease, and health care utilization. There was also a significant reduction in risk for ophthalmic herpes zoster.

The authors estimate that one episode of herpes zoster would be prevented for every 71 patients vaccinated. They write that their results “support recommendations to offer herpes zoster vaccine to eligible patients of all ages, including the oldest population.”

source: JAMA

The FDA Approves Clinical Trials Using Embryonic Stem Cells to Treat Dry Age-Related Macular Degeneration

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Advanced Cell Technology, Inc.  (ACT) announced today that the US Food and Drug Administration (FDA) has cleared the Company’s Investigational New Drug (IND) application to treat dry age-related macular degeneration (AMD) using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs). ACT is now permitted to initiate a Phase I/II multicenter clinical trial to treat patients with dry AMD, the most common form of macular degeneration in the world. There are currently no treatments available for this prevalent disease of an aging global population.

Age-related macular degeneration has two predominant forms, wet and dry. Dry AMD is the most common form, accounting for almost 90% of all cases. The progress of dry AMD includes a breakdown or thinning of the layer of RPE cells in the patient’s macula, the region at the center of the retina responsible for high acuity vision. Over time, the progressive loss of RPE cells and accompanying loss of photoreceptors can cause severe vision loss and even blindness.

The Phase I/II trial will be a prospective, open-label study that is designed to determine the safety and tolerability of the RPE cells following sub-retinal transplantation into patients with dry AMD. Twelve patients will be enrolled in the study at multiple clinical sites. Sites currently under consideration are the Jules Stein Eye Institute at UCLA, and the Ophthalmology Department at Stanford University School of Medicine. Additional sites may be considered.

Specific inclusion and exclusion requirements and investigator contact information will be posted shortly at clinicaltrials.gov. Patients and their caregivers should refer to this source rather than contacting ACT or its representatives.

Added Sugar May Raise Cholesterol in Teens

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Teenagers Eat Equivalent of 28 Teaspoons a Day
teen girl eating cake

Jan. 10, 2011 — All that added sugar in the diets of typical teens could increase their risk for heart disease, a new study suggests.

After analyzing data from a national health survey, researchers concluded that the average teenager eats the equivalent of 28 teaspoons — or close to 500 calories’ worth — of added sugar each day.

Added sugars are calorie-containing sweeteners present in processed foods or beverages, and spotting them on food labels is not always easy.

Sugar, corn syrup, and high-fructose corn syrup are among the most commonly used and widely recognized added sugars. Less well known are sweeteners containing fructose, sucrose, and maltose.

In a study published last April, researchers from the CDC and Atlanta’s Emory University found that adults whose diets contained the most added sugar also had the lowest HDL, or good, cholesterol and the highest LDL, or bad, cholesterol.

Their new study, published today in the American Heart Association (AHA) journal Circulation, finds the same pattern among teens.

Adding Up the Added Sugar

The study merged a 24-hour dietary recall by teens participating in the National Health and Nutrition Survey (NHANES)  between 1999 and 2004 with data from the U.S. Department of Agriculture on added sugar content in foods.

The teens’ average daily consumption of added sugar was three to five times higher that the limit deemed acceptable by the American Heart Association (AHA), which considers a “prudent upper limit” to be about 100 calories, or 6 teaspoons, for most women and 150 calories, or 9 teaspoons, for most men.

When the researchers examined data on cholesterol levels and other heart disease risk factors among the teens in relation to their added sugar consumption, they found that:

  • Those who ate the most added sugar (30% or more of total calories) had LDL cholesterol levels that were 9% higher, triglyceride levels that were 10% higher,  and HDL levels that were 9% lower than those who ate the least added sugar (less than 10% of total calories).
  • Overweight and obese teens who ate the most sugar also had the most insulin resistance.

Although the findings raise questions about whether the added sugar in processed foods contributes to poor cholesterol profiles and other heart disease risk factors, more direct research is needed to prove a link.

“We need controlled studies to really understand the role of added sugars in cardiovascular disease,” researcher Jean A. Welsh, MPH, RN, tells WebMD.  “But it is important to be aware of the added sugar in the foods we all eat.”

Message to Industry: Get Sugar Out of Food

Sugary sodas, sports drinks, and fruit- or fruit-flavored drinks containing added sugars are among the largest sources of added sugars in the diets of children and teens, Welsh says.

Teaching children and teens about healthy eating and giving them the tools they need to do so could make a big difference in childhood obesity and, potentially, heart disease rates in the future, preventive cardiologist Suzanne Steinbaum, MD, of New York’s Lenox Hill Hospital tells WebMD.

She points to public health initiatives like Michelle Obama’s Let’s Move campaign as a step in the right direction.

“Nearly a third of kids in this country are overweight or obese,” she says. “We don’t yet know what this will mean for cardiovascular risk, but it is probably a safe bet that we are going to see younger and younger people with heart disease.”

She says the public needs to send a strong message to the food industry.

“The message is to get the added sugars out of processed foods,” she says. “That isn’t likely to happen unless consumers demand it.”

Statins Ill-Advised After Brain Hemorrhage

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Statins should not be given to patients with a history of intracerebral hemorrhage, according to an Archives of Neurology decision analysis.

The researchers based their analysis on the theoretical case of a 65-year-old male survivor of intracerebral hemorrhage; they used published data on statins’ risks and benefits to calculate the patient’s expected quality-adjusted life-years of survival with, versus without, statin therapy.

When there was no history of ischemic stroke or cardiac events, statin therapy after lobar hemorrhage resulted in a net loss of about 2 life-years. When the hemorrhage was “deep” as opposed to lobar, the risk of recurrence was much lower, but statins still conferred losses in life-years.

The authors point to evidence of statins’ effects on clotting as a possible mechanism for the increased risk.

An editorialist concludes that statins “should generally be avoided” in patients with hemorrhagic stroke.

Source: Archives of Neurology article

 

Varenicline Helps Smokeless Tobacco Users to Quit

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More than half of varenicline recipients were abstinent at 12 weeks.

Use of smokeless tobacco is rising. In several trials, nicotine replacement and bupropion have been ineffective for treatment of patients who use smokeless tobacco. Varenicline (Chantix), a partial agonist of the nicotinic acetylcholine receptor, is effective in helping smokers to quit. In this double-blind randomized trial, industry-sponsored Scandinavian investigators assessed the efficacy of varenicline in helping adult smokeless tobacco users to quit.

At baseline, the 431 participants (mean age, 44; 89% men) reported average use of smokeless tobacco 15 to 16 times daily; average duration of use was longer than 20 years. Participants received varenicline or placebo for 12 weeks. The continuous abstinence rate at weeks 9 through 12 (confirmed by weekly measurement of salivary cotinine levels) was significantly higher in the varenicline group than in the placebo group (59% vs. 39%) for a number needed to treat (NNT) of 5. Continuous abstinence rates were also significantly higher in the long term (weeks 9–26) in the varenicline group than in the placebo group (45% vs. 34%) for an NNT of 9. Notably, few patients in this trial who took varenicline withdrew due to side effects, the most common of which was nausea.

Comment: Varenicline is significantly more effective than placebo in helping smokeless tobacco users to quit, at least in the short-to-intermediate term. Note that a U.S. trial is in progress (CHANCHEW) and that varenicline is not currently FDA-approved for this purpose.

— Paul S. Mueller, MD, MPH, FACP

Published in Journal Watch General Medicine January 11, 2011

Doxorubicin plus Sorafenib for Advanced Hepatocellular Cancer

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Combination therapy showed significant progression-free and overall survival advantages over doxorubicin alone.

Hepatocellular cancer (HCC) is the third leading cause of cancer-related mortality worldwide. Cases of HCC in the U.S. have nearly doubled during the past decade because of a rise in the incidence of hepatitis C virus infection. Sorafenib, a multitargeted tyrosine kinase inhibitor, improves progression-free and overall survival in patients with advanced HCC (JW Oncol Hematol Jul 23 2008) and is the only FDA-approved therapy for this disease. Conventional chemotherapy, in contrast, has little or no effectiveness for advanced HCC.

In a phase II trial, investigators randomized 96 chemotherapy-naive patients with metastatic or unresectable HCC and Child-Pugh class A liver function to receive oral sorafenib (400 mg twice daily) plus doxorubicin (60 mg/m2 every 21 days, for a maximum total dose of 360 mg/m2) or placebo plus the doxorubicin regimen. Of the participants, 59% were recruited in North America, and the vast majority of the entire cohort had received no prior therapy for HCC. The manufacturer of sorafenib funded the trial.

Early results showed a clear advantage in the combination-therapy group, thereby prompting an interim analysis. Median progression-free survival was significantly longer with sorafenib plus doxorubicin than with doxorubicin alone (6.0 vs. 2.7 months; hazard ratio, 0.54; P=0.006), as was median overall survival (13.7 vs. 6.5 months; HR, 0.49; P=0.006). The two groups achieved similar rates of partial response, although a waterfall-plot analysis revealed that a greater percentage of patients in the combination-therapy group than in the monotherapy group experienced tumor shrinkage (62% vs. 29%). Compared with recipients of doxorubicin alone, sorafenib recipients more often experienced hand–foot skin reactions, nausea, vomiting, and grade 1–2 left-ventricular dysfunction.

Comment: FDA approval of sorafenib represented a milestone, as it was the first agent to improve survival among patients with advanced HCC, a chemotherapy-resistant disease. Results from the current trial point to a potentially clinically significant synergy between chemotherapy and sorafenib. That hypothesis is being tested in a recently initiated phase III randomized trial (CALGB 80802) of the effectiveness of sorafenib with or without doxorubicin in patients with advanced HCC.

— David H. Ilson, MD, PhD

Published in Journal Watch Oncology and Hematology January 11, 2011