Day: 09/21/2010

Europe Approves Deep Brain Stimulation Therapy for Refractory Epilepsy

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The European Commission (EC) has granted the Conformité Européenne (CE) Mark for deep brain stimulation (DBS) therapy (Medtronic, Inc) as adjunctive treatment for partial-onset seizures in adults with medically refractory epilepsy. DBS therapy using a Medtronic device is expected to be available in epilepsy centers across the European Union by the end of 2010.

“Epilepsy that is refractory to current medical treatment is a severe, unsolved problem,” said Professor Eugen Trinka, MD, MSc, in a company news release. “DBS therapy for epilepsy will be an important new treatment option for many patients in Europe with severe epilepsy who are not able to control their seizures with currently available drugs.” Dr. Trinka is head of neurology at the University Hospital’s Christian Doppler Klinik in Salzburg, Austria.

CE Mark approval was based on 2-year data from the prospective, randomized, multicenter, double-blind pivotal Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy study of 110 patients. As reported by Medscape Medical News, results showed that use of the DBS device decreased the frequency of seizures by a median of 56%; 14 patients (12.7%) remained seizure-free for at least 6 months.

Long-term data from the study were presented at the American Epilepsy Society meetings in December 2008 and December 2009 and were published in Epilepsia in March 2010.

Use of the DBS device for refractory epilepsy is investigational in the United States and is under review by the US Food and Drug Administration (FDA). The agency recently requested additional information to support the approval, which will require further clinical study.

“This CE Mark is the first approval by a regulatory agency for the use of DBS therapy in severe epilepsy and provides a new treatment option for patients in Europe who are in need of other options,” said Tom Tefft, senior vice president of Medtronic, Inc, and president of the neuromodulation business unit, in the news release. “In the United States, we remain committed to working with FDA to determine the most appropriate path forward.”

DBS indications previously cleared by the FDA and EC include the treatment of essential tremor and advanced Parkinson’s disease. The EC has also approved DBS for dystonia and obsessive-compulsive disorder — applications that are only approved for humanitarian use in the United States.

Nanotubes help cells pass messages

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Actin cables transmit electrical signals between cells.

Long-distance electrical coupling of animal cells via tunneling nanotubes (TNTs).Cells communicate with each other at a distance via protein nanotubes.Xiang Wang and Hans-Hermann Gerdes.

Researchers have discovered a means of cell communication that may illuminate events ranging from embryo development to brain activity.

A Norway-based team reports today in Proceedings of the National Academy of Sciences1 that electrical signals can be transmitted between distant cells by means of nanotubes — ultrathin cables containing actin proteins — and that ‘gap junctions’ are involved in the process. Gap junctions are proteins that form pores between two adjacent cells, and that can link animal cells directly. Until now, electrical signalling was considered a fast but limited mode of communication, restricted mainly to cells in the heart and brain. But because many types of cells form nanotubes and gap junctions, it seems that electrical communication could be widespread.

“The cells now have telephone cables to talk to each other,” says Hans-Hermann Gerdes, a cell biologist at the University of Bergen and a co-author on the paper.

The study suggests that “cells may use electrical communication over long distances and be more interconnected than we thought”, says cell biologist Daniel Davis of Imperial College London.

Six years ago, using light microscopy, Gerdes’ team discovered the ultrathin cables stretching between kidney cells for distances longer than the diameter of several cells combined2. They named them tunnelling nanotubes (now also called membrane nanotubes). Various kinds of cells can transport molecules by means of nanotubes in a Petri dish. For example, HIV-1 can travel along nanotubes connecting immune cells, and prions pass through nanotubes connecting neurons. However, ways in which a cell might extrude a nanotube, open the membrane of another cell and insert its cargo were unclear. Furthermore, there was no strong evidence that nanotubes are physiologically relevant, making claims for nanotubes difficult for many scientists to accept.

Bridging the gap

Walther Mothes, a microbiologist at Yale University in New Haven, Connecticut, has been critical of the nanotube field, but says he is impressed by the current paper because of its demonstration that nanotubes use gap junctions for sending signals. “I think the nanotube field has not been able to explain the phenomenon with existing biological concepts,” he explains. “But this report marks the return of the field to plausible cell-biological concepts, which are gap junctions, and that actually makes sense.”

Using electrophysiological techniques, the authors show that a current passes down the nanotubes and causes ion channels to open in the membrane of the connecting cell. The resulting influx of ions in turn may modulate pathways involved in processes such as cell movement. But the authors found that if gap junctions were inactivated or absent, the current didn’t flow.

This long-distance signalling may account for the coordinated cell migration observed in developing embryos. For example, cells congregate into two folds to form the neural tube, the precursor to the central nervous system, in vertebrate embryos. The cells are obviously communicating in order to synchronize their behaviour, says Gerdes, but how they do so has not been clear. Nanotube-mediated electrical signalling provides an alternative to other modes of cell-cell communication that require direct cell contact or soluble secretions.

Gerdes says the findings could mean extra layers of communication are present in the human brain, “drastically” increasing the complexity of the system.

“The authors of this paper have identified an exciting way that cells can communicate at a distance. That means you can no longer just think of cells touching each other to coordinate movement,” says Michael Levin of Tufts University in Medford, Massachusetts. “Understanding what physiological information these nanotubes pass on will now be a key question for the future.”

Cryotherapy and wart

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Cryotherapy with liquid nitrogen to remove common warts may be more effective than salicylic acid or a wait-and-see approach, according to the results of a randomized controlled trial reported online September 13 in the Canadian Medical Association Journal.

“Cryotherapy is widely used for the treatment of cutaneous warts in primary care,” write Sjoerd C. Bruggink, MD, from Leiden University Medical Center in Leiden, the Netherlands, and colleagues. “However, evidence favours salicylic acid application. We compared the effectiveness of these treatments as well as a wait-and-see approach.”

Between May 1, 2006, and January 26, 2007, a total of 250 consecutive, eligible patients with new cutaneous warts were recruited from 30 primary care practices in the Netherlands and were randomly assigned to 1 of 3 groups: cryotherapy with liquid nitrogen every 2 weeks, daily self-application of salicylic acid, or a wait-and-see approach. Of the 250 participants, 122 (49%) were stratified into the common wart group and 128 (51%) into the plantar wart group.

The proportion of participants with cure of all warts at 13 weeks was the main study endpoint, and analysis was by intent-to-treat. Treatment adherence, adverse effects, and satisfaction with treatment were secondary endpoints. At 4, 13, and 26 weeks, research nurses evaluated outcomes during home visits.

Age range of the participants was 4 to 79 years. At 13 weeks, 10 patients (4%) were lost to follow-up, and 240 were included in the analysis. In the cryotherapy group, cure rate was 39% (95% confidence interval [CI], 29% – 51%) vs 24% (95% CI, 16% – 35%) in the salicylic acid group and 16% (95% CI, 9.5% – 25%) in the wait-and-see group.

Because the effectiveness of treatments differed between the common wart group and the plantar wart group (P for interaction = .007), the study authors reported outcomes for all patients as well as by location of warts.

For participants with common warts (n = 116), these differences in efficacy were most pronounced. Cure rates were 49% with cryotherapy (95% CI, 34% – 64%), 15% with salicylic acid (95% CI, 7% – 30%), and 8% with the wait-and-see approach. The different treatments were not associated with significant differences in cure rates among participants with plantar warts (n = 124).

“For common warts, cryotherapy was the most effective therapy in primary care,” the study authors write. “For plantar warts, we found no clinically relevant difference in effectiveness between cryotherapy, topical application of salicylic acid or a wait-and-see approach after 13 weeks.”

Limitations of this study include self-application of salicylic acid and lack of blinding of participants, family practices, and research nurses.

“Although earlier evidence favoured salicylic acid application above cryotherapy, the present randomized controlled trial is the first that provides evidence to support the use of cryotherapy above salicylic acid, however, for common warts only,” the study authors conclude.

pancreatic stone protein (PSP) n sepsis outcome

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Serum levels of pancreatic stone protein (PSP) reflect the clinical severity of sepsis and predict outcomes in patients with severe sepsis and septic shock admitted to the intensive care unit (ICU), according to the results of a prospective study reported here at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy.

“This marker may be useful to stratify patients with sepsis and septic shock and to guide therapy in the first 48 hours after admission to the ICU. Some patients will need more aggressive therapy, or if comorbidities exist in the presence of elevated PSP, perhaps therapy should be stopped,” said Frederick DeLodder, MSN, from the Centre Hospitalier Universitaire Valdois in Lausanne, Switzerland. “Serum PSP level might be useful during the first 24 hours of admission to identify patients at risk for death,” he added.

Severe sepsis is a leading cause of death in ICU patients and poses a major challenge to healthcare workers. Reliable and early diagnostic tools could improve risk stratification, optimize treatment for these severely ill patients, and cut down on the unnecessary use of antibiotics, Mr. DeLodder explained.

The study examined 108 patients over a 24-month period. Blood levels of PSP, other cytokines, and procalcitonin (another acute-phase protein) were measured at admission, on day 3, on day 7, and weekly thereafter until discharge from the ICU or death.

Among all hospitalized patients, 33 developed severe sepsis and 75 developed septic shock. Death occurred in 2 (6%) patients with severe sepsis and in 17 (25%) with septic shock.

PSP levels were higher in all patients with sepsis and septic shock than in healthy people. Levels rising up to 2000 ng/mL correlated with severity of sepsis.

At admission, PSP, interleukin-8, and procalcitonin serum levels were significantly higher in people with septic shock than in those with sepsis (P = .002, P = .001, and P = .01, respectively, for all 3 markers). Looking at outcomes, PSP was significantly higher in patients who died than in survivors (P = .007), whereas procalcitonin was not.

“At entry to the ICU, the area under the ROC curve was higher for PSP than for other acute-phase proteins or cytokines. The wide range of PSP serum levels may explain its much better discriminative value compared with procalcitonin,” Mr. DeLodder stated.

Preliminary evidence suggests that high PSP values might correlate with specific microorganisms, but more study is needed, he said.

Commenting on the study and the potential utility of PSP as a biomarker of sepsis and septic shock, Richard Drew, PharmD, from Duke University in Chapel Hill, North Carolina, said that biomarkers, such as procalcitonin and C-reactive protein, represent an exciting concept.

“In the context of this study, PSP looks promising for the diagnosis and prognosis [of patients with sepsis and septic shock]. The more support tools we have, the better we manage patients,” Dr. Drew stated.

DASH and prevention of kidney stone

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Following a Dietary Approaches to Stop Hypertension (DASH)-style diet may help lower kidney stone risk by increasing urinary citrate and urinary volume, according to the results of a large cohort study reported online September 16 in the Clinical Journal of the American Society of Nephrology.

“We previously observed associations between a …DASH-style diet and large reductions in kidney stone risk,” write Eric N. Taylor, from Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues. “This study examined associations between a DASH-style diet and 24-hour excretions of urinary lithogenic factors.”

The study cohort consisted of 3426 adults with and without nephrolithiasis who were enrolled in the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Studies (NHS) I and II. A DASH score was calculated from self-reported dietary composition, with higher scores reflecting higher consumption of fruits, vegetables, nuts and legumes, dairy products, and whole grains, and lower consumption of sweetened beverages and red and processed meats. The investigators adjusted 24-hour urinary calcium excretion for age, history of kidney stones, body size, and other factors using analysis of covariance.

For participants in the highest vs the lowest quintiles of DASH score, multivariate-adjusted urinary calcium excretion was increased by 3% in HPFS (P for trend = .12), by 10% in NHS I (P for trend < .01), and by 12% in the NHS II (P for trend = .05). Compared with participants in the lowest quintiles of DASH score, those in the highest quintiles had 4% to 18% higher urinary oxalate (P for trend < .03 for all), 11% to 16% higher urinary citrate (P for trend < .01 for all), and 16% to 32% higher urinary volume (P for trend < .001 for all).

In addition, a higher DASH score was associated with greater urinary potassium, magnesium, phosphate, and pH, and lower relative supersaturations (RSS) of uric acid. Among women only, a higher DASH score was associated with lower RSS of calcium oxalate.

“A DASH-style diet may reduce stone risk by increasing urinary citrate and volume,” the study authors write. “The small associations between higher DASH score and lower RSS suggest unidentified stone inhibitors in dairy products and/or plants.”

Limitations of this study include use of 24-hour urine samples, which prevented identification of associations between a DASH-style diet and potentially important postprandial increases in lithogenic factors such as calcium and oxalate, and which is likely to reflect only short-term dietary intake. In addition, the participants in the study sample were all white, limiting generalizability.

“The higher oxalate content of a DASH-style diet does not lead to large increases in 24-hour urinary oxalate, a finding consistent with our previous reports of only small associations between oxalate intake and both urinary oxalate excretion and incident kidney stone risk,” the study authors conclude. “Overall, we believe our results provide a strong rationale for a randomized trial examining the effect of a DASH-style diet on kidney stone recurrence.”

Clopidogrel plus a PPI Does Not Increase Cardiovascular Risk Beyond PPIs Alone

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Concomitant use of clopidogrel and a proton-pump inhibitor (PPI) does not appear to increase cardiovascular risk beyond that seen with PPIs alone, according to an Annals of Internal Medicine study. (Previous research has suggested a drug interaction, with the FDA warning against using clopidogrel with omeprazole.)

Danish researchers examined registry data on some 56,000 patients discharged after first myocardial infarctions; 16% experienced the primary outcome (cardiovascular death or rehospitalization for MI or stroke) in the first year. In adjusted analyses, risk for the primary outcome was similarly increased (by about one third) among patients who received both a PPI and clopidogrel after MI and among those who received just a PPI, compared with those not receiving PPIs.

The authors say their findings “seem to refute concerns about increased risk for ischemic events during concomitant PPI and clopidogrel therapy.” They say, also, that the risk seen with PPIs alone was likely due to residual confounding.

Source: Annals of Internal Medicine article