Feeds:
Posts
Comments

Posts Tagged ‘Perelman School of Medicine’


Reporter: Aviva Lev-Ari, PhD, RN

 

Five Psych Disorders Have Common Genetics

By Michael Smith, North American Correspondent, MedPage Today

Published: February 27, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

share common genetic underpinnings — despite differences in symptoms and course of disease, researchers discovered.

In particular, single nucleotide polymorphisms (SNPs) in two genes involved in calcium-channel activity appear to play a role in all five, Jordan Smoller, MD, ScD, of Massachusetts General Hospital in Boston, and colleagues reported online in The Lancet.

The findings come from a genome-wide analysis of 33,332 cases and 27,888 controls in what the authors described as the largest-ever genetic study of psychiatric illness.

The results are “new evidence that may inform a move beyond descriptive syndromes in psychiatry and towards classification based on underlying causes,” Smoller said in a statement.

The findings are especially important because of revisions to the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases, which have “reinvigorated debate about the validity of diagnostic boundaries,” the authors noted.

Indeed, the findings confirm previous evidence of “abundant pleiotropy in human complex disorders” – meaning the same genetic variant plays a role in several diseases, argued Alessandro Serretti, MD, PhD, and Chiara Fabbri of the University of Bologna in Italy.

For instance, they noted in an accompanying commentary, calcium signaling, a key regulator of the growth and development of neurons, was expected to be highly pleiotropic, an expectation that “has now been confirmed.”

But while some gene variants play a role in many disorders, there are almost certainly others that contribute to the “consistent diversity among disorders,” Serretti and Fabbri argued.

“Many genes and polymorphisms are expected to confer a liability to individual psychiatric diseases,” they wrote.

Nonetheless, they concluded, one implication of the study is that genetics “can contribute to prediction and prevention of psychiatric diseases, along with the identification of molecular targets for new generations of psychotropic drugs.”

But that is not likely to happen soon, according to Randy Ross, MD, of the University of Colorado School of Medicine in Aurora, Colo.

The study is a “beginning step to give us ideas that will eventually lead to new treatments,” he told MedPage Today.

In the long run, however, this study and subsequent research will change both diagnosis and treatment, Ross said, as psychiatric diseases are put on a biological footing.

The researchers found that SNPs (single-letter changes in the genetic code) in four regions were associated with all five disorders:

The statistical significance of all four surpassed the cutoff for genome-wide significance of P<5×10-8, Smoller and colleagues reported.

The calcium-channel gene CACNA1C  has been previously linked to

  • bipolar disorder,
  • schizophrenia, and
  • major depressive disorder, they wrote, as well as to
  • Timothy syndrome, a developmental disorder that can include autism.

The other calcium-channel gene has been linked to bipolar disorder in people of Han Chinese ethnicity, they added.

“Our results suggest that voltage-gated calcium signaling, and, more broadly, calcium-channel activity, could be an important biological process in psychiatric disorders,” they argued.

The region on chromosome 3 includes more than 30 genes, Smoller and colleagues noted, but previous research has linked SNPs in the area to

  • bipolar disorder,
  • schizophrenia, and
  • depression.

They cautioned that they compared models of cross-disorder effects with widely used goodness-of-fit measures, but different criteria might yield other results.

They also noted that diagnostic misclassification in the study cohort might produce “spurious evidence of genetic overlap between disorders,” although such errors would have to be widespread to affect the results.

Another limitation: the members of the study cohort were of European ancestry, so it’s not known if the findings apply to other populations.

The study was supported by the National Institute of Mental Health, as well as grants from the NIH, government grants from other countries, and private and foundation support.

The authors declared they had no conflicts.

The comment authors declared they had no conflicts.

Primary source: Lancet

Source reference:
Smoller JW, et al “Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis” Lancet 2013; DOI: 10.1016/S0140-6736(12)62129-1.

Additional source: Lancet
Source reference:
Alessandro Serretti, Chiara Fabbri “Shared genetics among major psychiatric disorders” Lancet 2013; DOI: 10.1016/S0140-6736(13)60223-8.

 SOURCE:

Read Full Post »


Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 5/29, 2013

Renal Denervation Safe in Real-World Setting

By Todd Neale, Senior Staff Writer, MedPage Today

Published: May 25, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points:

PARIS — May 21-24, 2013

Out in everyday practice, renal denervation with the Symplicity device safely lowers blood pressure in patients with hypertension, preliminary results from the Global SYMPLICITY registry showed.

The Global SYMPLICITY registry is part of the clinical program evaluating the Symplicity device. It has been approved for use in Europe and elsewhere but remains restricted to investigational use in the U.S. Medtronic, which makes the Symplicity device, announced on Thursday that it has completed enrollment in Symplicity HTN-3, the pivotal U.S. trial.

The registry has a targeted enrollment of about 5,000 patients from about 200 centers worldwide; 149 sites spread throughout Canada, Mexico, South America, Europe, Africa, the Middle East, Asia, and Australia have already started collecting data.

Any patient who receives renal denervation can be included in the registry, and thus the study will include patients with hypertension and other conditions associated with increased sympathetic activity, including heart failure, insulin resistance, atrial fibrillation, sleep apnea, and chronic kidney disease.

European Society of Cardiology‘s recently published consensus paper on renal denervation, which recommended treatment in patients with a systolic blood pressure of 160 mm Hg or higher (or at least 150 mm Hg for type 2 diabetics) who were taking at least three antihypertensive medications, including a diuretic.

SOURCE:

Expert consensus document from the European Society of Cardiology on catheter-based renal denervation

http://eurheartj.oxfordjournals.org/content/early/2013/04/25/eurheartj.eht154.extract

Most of the first 617 patients included the registry (60%) were treated in accordance with the European Society of Cardiology’s recently published consensus paper on renal denervation, above.

About one-fifth of the patients (22%) started with a systolic blood pressure of at least 180 mm Hg, which was the average baseline blood pressure in the Symplicity HTN-1 and HTN-2 trials.

The average starting blood pressure overall was 164/89 mm Hg, and patients were taking an average of 4.35 medications. Common comorbidities included diabetes (38.2%), renal disease (30.1%), sleep apnea (16.3%), a history of cardiac disease (49%), heart failure (9.3%), and atrial fibrillation (11.9%).

The registry data showed significant drops in blood pressure measured both in the office and with 24-hour ambulatory monitoring, although the reductions were smaller than those seen in the clinical trials.

That’s not surprising, according to Mahfoud, because out in everyday practice blood pressure is not recorded as appropriately as in a clinical trial setting and poor compliance to medication becomes more of an issue. In fact, he said, a recent study showed that 47% of patients with resistant hypertension were not adherent to their medication regimens.

Also contributing to the smaller reductions in the real-world population is the fact that the average starting blood pressure was lower than in the clinical trials, Mahfoud said, adding that it is known that renal denervation induces greater reductions in blood pressure among those with the highest readings initially.

Mahfoud reported receiving institutional grant/research support from Medtronic, St. Jude, Recor, and serving as a consultant for St. Jude, Medtronic, Boston Scientific, and Cordis. Medtronic makes the Symplicity renal denervation device.

 Primary source: European Association of Percutaneous Cardiovascular Interventions

SOURCE REFERENCE:

Mahfoud F, et al “Early results following renal denervation for treatment of hypertension in a real-world population: the Global SYMPLICITY registry” EuroPCR 2013.

Adverse Events:
Of the first 617 patients included in the registry, only two had vascular complications related to access during the procedure, and none had serious events stemming from delivery of the radiofrequency energy to the renal artery; the rate of vasospasm was 9%, according to Felix Mahfoud, MD, of Saarland University Medical Center in Homburg/Saar, Germany.Through 6 months of follow-up, there were two hospitalizations for hypertensive crisis, two myocardial infarctions, one new case of end-stage renal disease from nephrotoxic overdose, and one death that was not considered to be related to the procedure, he reported at the EuroPCR meeting here.The procedure was not only safe, but also effective at lowering blood pressure, with reductions in office-based readings ranging from 13/6 mm Hg among patients with a baseline systolic blood pressure of 140 mm Hg or higher to 28/18 mm Hg among those with a baseline systolic pressure of 180 mm Hg or higher at 3 months. The findings were similar at 6 months.

“The take-home message will be hopefully … that renal denervation is a safe procedure providing blood pressure lowering in patients with high blood pressure at baseline and that that procedure might have an impact on clinical outcomes,” Mahfoud said in an interview.

Positive Effects of Renal Denervation Ablation for Hypertension in Controlled Randomized SYMPLICITY HTN-2 Trial

Renal Nerve Ablation Effects on BP Lasting

Download Complimentary Source PDF 

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: January 08, 2013
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Late-term results from a study of the safety and effectiveness of renal denervation to reduce hypertension mirrored positive results seen earlier in the randomized SYMPLICITY HTN-2 trial, researchers found.

The mean reduction in systolic blood pressure at 1 year post procedure was a significant 28.1 mmHg (P<0.001), similar to the mean 31.7 mmHg drop at 6 months (P=0.16 for the comparison), according to Murray Esler, MD, of the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, and colleagues.

Those in the control group who crossed over to the intervention at 6 months also had a significant fall in systolic blood pressure from a mean 190 to 166 mmHg (P<0.001), researchers reported in the January issue of Circulation: Journal of the American Heart Association.

The increasing prevalence of hypertension is a worldwide phenomenon, with an estimated 1.56 billion predicted to be affected in 2025, the authors noted. Yet, many of these patients cannot control their blood pressure (with control being defined as a pressure <140/90 mmHg) even when taking three or more antihypertensive medications.

Esler and colleagues cited a 2005 study that found a range of 47% to 87% of people in North America and Europe whose blood pressure is not under control (Lancet 2005; 365: 217-223).

Renal denervation has shown promise in these patients who are refractory to medication. The percutaneous procedure uses energy such as radiofrequency waves to scar the renal artery in an attempt to disrupt the sympathetic nerves, thereby affecting blood pressure.

Three-year data from the nonrandomized SYMPLICITY HTN-1 study were in line with 2- and 1-year results, showing a mean drop of 33/19 mmHg associated with the intervention.

In the current study, researchers from the multi-center randomized controlled SYMPLICITY HTN-2 trial enrolled 106 patients with essential hypertension (systolic blood pressure ≥160 mmHg, or ≥150 mmHg for diabetics). Patients were taking at least three antihypertensive medications.

The initial 1-year data from the SYMPLICITY HTN-2 trial were reported at the 2012 American College of Cardiology meeting. The primary endpoint was a change in systolic blood pressure at 6 months. Also at the 6-month mark, patients in the control group were allowed to cross over and receive the treatment; they were then followed for 6 more months.

The 6-month data were based on 101 patients (49 in the treatment group versus 51 controls). The 1-year data were based on 47 patients in the primary treatment group and 35 per-protocol controls who crossed over. The crossover patients also had to have a systolic blood pressure of ≥160 mmHg.

The significant decrease of 28.1 mmHg in systolic blood pressure in the treatment arm at 1 year was matched by significant drops in diastolic blood pressure at 6 and 12 months, as well as in the crossover group at 6 months (P<0.001 for all).

The authors reported that 84% of initial denervation patients had a decrease of at least 10 mmHg at 6 months; at 1 year, the number was 79%. In the crossover group, that rate was 63% at 6 months.

Interestingly, there was no significant difference in the changes in medication — reduced dosage or fewer drugs — between the treatment arm and controls, despite the reduction in blood pressure for the treatment arm.

“These data further substantiate the safety of renal sympathetic denervation via delivery of controlled radiofrequency energy bursts,” Esler and colleagues concluded.

They also noted that renal function remained unchanged at both 6 and 12 months. A pilot study by the Melbourne group looking specifically at patients with chronic kidney disease found renal denervation to be safe in this population.

The limitations to the current study include the lack of 24-hour blood pressure monitoring and the lack of blinding among the staff measuring blood pressure. The investigators noted that the ongoing SYMPLICITY HTN-3 trial addresses these limitations.

This study was funded by Medtronic Ardian.

Esler and three co-authors reported receiving research support from Medtronic Ardian. During the conduct of the trial, senior author Sobotka was chief medical officer of Ardian, and was a medical adviser to Medtronic.

From the American Heart Association:

 SOURCE:

Other articles on this topic on this Open Access Online Scientific Journal:

Lev-Ari, A. (2012aa). Renal Sympathetic Denervation: Updates on the State of Medicine

https://pharmaceuticalintelligence.com/2012/12/31/renal-sympathetic-denervation-updates-on-the-state-of-medicine/

 

Lev-Ari, A. (2012U). Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

https://pharmaceuticalintelligence.com/2012/09/02/imbalance-of-autonomic-tone-the-promise-of-intravascular-stimulation-of-autonomics/

Lev-Ari, A. (2012C). Treatment of Refractory Hypertension via Percutaneous Renal Denervation

https://pharmaceuticalintelligence.com/2012/06/13/treatment-of-refractory-hypertension-via-percutaneous-renal-denervation/

Read Full Post »


Aspirin a Day Tied to Lower Cancer Mortality

Reporter: Aviva Lev-Ari, PhD, RN

Aspirin a Day Tied to Lower Cancer Mortality

Download Complimentary Source PDF 

Daily aspirin use is associated with a modest decrease in mortality from cancer, particularly for malignancies of the gastrointestinal tract, a large retrospective study confirmed.

Individuals who were current daily users for 5 years or more at baseline had an 8% decrease in cancer mortality compared with non-users (RR 0.92, 95% CI 0.83 to 1.02), according to Eric J. Jacobs, PhD, and colleagues from the American Cancer Society in Atlanta.

The association was stronger, with a 16% decrease for those with daily use for 5 years or more, when the analysis included data collected periodically during 2 decades of follow-up (RR 0.84, 95% CI 0.75 to 0.95), the researchers reported in the Journal of the National Cancer Institute.

A recent pooled analysis of more than 50 trials involving aspirin use for cardioprotection found a 37% reduction in deaths from cancer among users, which was considerably greater than in observational studies and trials of alternate-day aspirin.

To clarify the magnitude of the association between aspirin use and overall cancer mortality, Jacobs and colleagues analyzed data from the Cancer Prevention Study II, which began in 1992 and included 100,139 participants who completed questionnaires with information on demographics, medical history, and behavioral influences.

Beginning in 1997, participants also provided information about aspirin use, and continued to provide updates every 2 years.

The 1997 questionnaire was considered the baseline for the analysis, at which time 23.8% of participants were using either low-dose or adult-strength aspirin.

More than half of participants were older than 60 and female, and almost all were white.

During the 20 years of follow-up, there were 5,138 deaths from cancer.

Among those who reported aspirin use in 1997, three-quarters said they were still taking it in 2003, while among those who were non-users at baseline, 25% had begun doing so.

Baseline aspirin users tended to be more educated, former smokers, and obese, as well as to have a history of cardiovascular disease and diabetes.

Male users also were more likely to have a history of prostate specific antigen (PSA) testing, and women users were more likely to have a history of mammography.

Overall mortality was slightly lower even for individuals who had been users for less than 5 years (RR 0.84, 95% CI 0.76 to 0.94).

Relative risks were similar for users of low-dose and full-strength aspirin, and for those with and without a history of cardiovascular disease, ranging from 0.82 (95% CI 0.72 to 0.91) to 0.95 (95% CI 0.86 to 1.04).

Current users who had never smoked had considerably lower mortality (RR 0.68, 95% CI 0.57 to 0.81), a reduction that was not seen for former smokers (RR 0.92, 95% CI 0.82 to 1.04) or those currently smoking (RR 0.91, 95% CI 0.70 to 1.19).

Even after discounting lung cancer deaths, the only lower mortality among aspirin users was for never-smokers (RR 0.67, 95% CI 0.56 to 0.81).

A possible explanation for the lack of effect on cancers other than those in the lung among ever-smokers is that smoking may attenuate the antiplatelet activity of aspirin, and activated platelets are thought to promote tumor metastases, the researchers explained.

Aspirin use at the 1997 baseline was not significantly associated with mortality from specific cancers, but differences were seen when data through 2008 were included in the analysis:

  • Cancers within the gastrointestinal tract, RR 0.61 (95% CI 0.44 to 0.84)
  • Cancers outside the gastrointestinal tract, RR 0.88 (95% CI 0.78 to 1)
  • Colorectal cancer, OR 0.64 (95% CI 0.42 to 0.98)
  • Esophageal and stomach cancer, RR 0.56 (95% CI 0.37 to 0.86)

“The reduction in overall cancer mortality was driven by both a substantial reduction in mortality from gastrointestinal tract cancers and a small, but statistically significant, reduction in mortality from cancers outside the gastrointestinal tract,” they stated.

They noted that their study was observational, which was an important limitation, in that confounding factors could have resulted in either an underestimate or an overestimate of the effects of aspirin on mortality.

Also, the absolute risk for cancer mortality between non-users and daily long-term aspirin users — approximately 100 per 100,000 person-years for men and about 40 per 100,000 person-years for women — would represent an important benefit of aspirin use if it were causal, the authors stated.

“However, even if causal, differences in absolute rates are likely to differ between our predominantly elderly population and younger populations at much lower risk of cancer mortality,” they warned.

They concluded that the “relatively modest benefit” seen in their analysis could “meaningfully influence the balances of risks and benefits of prophylactic aspirin use.”

In an accompanying editorial, John Baron, MD, of the University of North Carolina in Chapel Hill, offered a word of caution. Baron was the lead author of the meta-analysis on aspirin use and cancer risk.

“Just because aspirin is effective does not mean it necessarily should be used,” he argued.

“Aspirin is a real drug, with definite toxicity. As for any preventative intervention, the benefits must be balanced against the risks, particularly when the benefits are delayed whereas the risks are not,” Baron stated.

The American Cancer Society funds the Cancer Prevention Study II cohort.

The authors are employees of the American Cancer Society.

Editorialist Baron has been a consultant for Bayer, and holds a use patent for aspirin chemoprevention.

Primary source: Journal of the National Cancer Institute
Source reference:
Jacobs E, et al “Daily aspirin use and cancer mortality in a large US cohort” JNCI 2012; DOI: 10.1093/jnci/djs318.

Additional source: Journal of the National Cancer Institute
Source reference:
Baron JA, et al “Aspirin and cancer: trials and observational studies” JNCI 2012; DOI: 10.1093/jnci/djs318.

Read Full Post »