Acetaminophen: Repeated Use of Slightly Too Much Can Be Fatal

From Medscape Medical News Laurie Barclay, MD November 22, 2011 — Repeated doses of slightly too much acetaminophen (known as paracetamol in the United Kingdom and elsewhere in Europe) can be fatal, according to the results of a large, single-center cohort study published online November 22 in the British Journal of Clinical Pharmacology. "On admission, these staggered overdose patients were more likely to have liver and brain problems, require kidney dialysis or help with breathing and were at a greater risk of dying than people who had taken single overdoses," senior author Kenneth J. Simpson, MBChB (Hons), MD, FRCP (Edin), from the University of Edinburgh and Scottish Liver Transplant Unit in the United Kingdom, said in a news release. "They haven't taken the sort of single-moment, one-off massive overdoses taken by people who try to commit suicide, but over time the damage builds up, and the effect can be fatal," he adds. In the United Kingdom, acetaminophen hepatotoxicity is the leading cause of acute liver failure (ALF). However, the effect of a staggered overdose pattern or delayed hospital presentation on mortality or need for emergency liver transplantation was previously unknown. Of 663 patients admitted with acetaminophen-induced severe liver injury between 1992 and 2008, 161 (24.3%) had taken a staggered overdose. Compared with patients who took an overdose at a single time, patients with staggered overdose were significantly older and more likely to abuse alcohol. When asked why they repeatedly ingested more than the recommended dose of acetaminophen, patients with staggered overdose most often cited pain relief as their rationale (58.2%). Compared with patients who took an overdose at a single time, those who took staggered overdoses had lower total ingested doses and lower serum alanine aminotransferase (ALT) levels on admission. Nonetheless, they were more likely to be encephalopathic and to require renal replacement therapy or mechanical ventilation. Although mortality was higher in staggered overdoses than in single-time overdoses (37.3% vs 27.8%; P = .025), the staggered overdose pattern was not an independent predictor of mortality. For staggered overdoses, sensitivity of the King's College poor prognostic criteria was reduced (77.6%; 95% confidence interval [CI], 70.8% - 81.5%). Delayed presentation to medical services more than 24 hours after single-time overdose occurred in 44.9% of those in whom accurate timings could be determined, and was independently associated with death or liver transplantation (odds ratio [OR], 2.25; 95% CI, 1.23 - 4.12; P = .009). In their logistic regression analysis, the investigators controlled for signs and symptoms, such as hepatic encephalopathy and prothrombin time, as well as various demographic factors. "Staggered overdoses or patients presenting late after an overdose need to be closely monitored and considered for the paracetamol antidote, N-acetylcysteine [NAC], irrespective of the concentration of paracetamol in their blood," Dr. Simpson said. Because both these groups are at increased risk of developing multiorgan failure, they should be considered for early transfer to specialist liver centers. Limitations of this study include reliance on patient recall regarding the time of last ingestion, total paracetamol dose, and suicidal intent; limited data regarding the use of concomitant P450 enzyme inducers or recent fasting; and selection bias for the more severe cases of acetaminophen toxicity in Scotland. "[T]his large cohort study demonstrates the deleterious effects of delayed presentation and staggered overdose pattern upon outcome following paracetamol-induced acute liver injury," the study authors conclude. "Both delayed presentation > 24 hours and staggered overdoses are strongly associated with multiorgan injury and the need for [liver transplantation]. Patients presenting with these overdose patterns should be treated as high risk for progression to ALF, and should receive NAC in their presenting hospital whilst awaiting serial ALT and PT levels." This study received no external funding. The authors have disclosed no relevant financial relationships. Br J Clin Pharmacol. Published online November 22, 2011.

Pomegranate Juice Lowers Cardiovascular Risk Factors

From Medscape Medical News Daniel M. Keller, PhD November 12, 2011 (Philadelphia, Pennsylvania) — Patients on hemodialysis consuming a moderate amount of pomegranate juice for a year saw a continuous, cumulative, beneficial effect on their lipid profile, their blood pressure, and the number of antihypertensive medications they required, Batya Kristal, MD, MHA, from the Nephrology Department at the Western Galilee Hospital in Nahariya, Israel, reported here at Kidney Week 2011: American Society of Nephrology 44th Annual Meeting. In addition to water, sugars, and pectin, pomegranates contain the antioxidants ascorbic acid and polyphenolic flavonoids. Hemodialysis patients were randomized to receive 100 mL of pomegranate juice (n = 66) or an equivalent-tasting placebo (n = 35) 3 times a week for 12 months. End points of the trial were lipid profile, including triglycerides (TGs), low-density-lipoprotein cholesterol, high-density-lipoprotein cholesterol (HDL), systolic and diastolic blood pressure, and the number of antihypertensive drugs required. At 12 months, all components of the lipid profile improved in the pomegranate juice group but not in the placebo group. In the juice group, there were statistically significant decreases in TGs from baseline to 12 months (P = .01), especially in patients with a baseline TG level of at least 200 mg/dL (P < .001). Over the same time period, HDL rose significantly (P = .005) in the juice group. There was no significant change in any of these parameters in the placebo group. During the study period, there was a significant decrease in systolic blood pressure in the juice group overall (P < .006), especially in patients who had a baseline systolic pressure of at least 140 mm Hg (P < .005); this was not the case in the placebo group. At 12 months, those in the juice group were taking significantly fewer antihypertensive drugs than those in the placebo group (P < .05). In the juice group, 22% of the subjects were taking fewer and 12.2% were taking more antihypertensive drugs; in the placebo group, 7.7% were taking fewer and 34.6% were taking more antihypertensive drugs. Dr. Kristal speculated that the consumption of pomegranate juice might lower the risk for cardiovascular disease in patients on hemodialysis, and recommended that it be added to diets that improve cardiometabolic risks, including low-salt diets, Dietary Approaches to Stop Hypertension (DASH), and the Mediterranean diet. One safety concern is that pomegranate juice contains a high level of potassium, so potassium overload is a risk, especially in patients with chronic kidney disease and dietary potassium restrictions. Dr. Kristal recommended that such patients be monitored by a dietician and a nephrologist. In addition, pomegranate juice intake can interfere with the metabolism of certain drugs, raising their levels in the blood. However, no adverse effects were detected in the group taking pomegranate juice. Katherine Tuttle, MD, executive director for research at Providence Sacred Heart Medical Center and professor of medicine at the University of Washington School of Medicine in Spokane, who was not involved in the study, told Medscape Medical News that "it's an interesting preliminary study.... I think before we conclude that we should be giving our patients pomegranate juice, we need to do bigger studies in other settings [with] more diverse populations and, of course, look beyond just the risk factors that they measured." In light of the high levels of potassium in pomegranate juice, Dr. Tuttle advised that "if [patients] decide to use it, [they should] be sure to let their healthcare professionals know." The study had no commercial funding. Dr. Kristal and Dr. Tuttle have disclosed no relevant financial relationships. Kidney Week 2011: American Society of Nephrology 44th Annual Meeting. Abstract FR-PO1660. Presented November 11, 2011.

Statins Can Make Asthma Worse

From Medscape Medical News Fran Lowry November 14, 2011 (Boston, Massachusetts) — Statins are among the most widely prescribed drugs in the world and help to stave off cardiovascular disease, but results from a small study suggest that they might worsen asthma control, researchers said here at the American College of Allergy, Asthma & Immunology 2011 Annual Scientific Meeting. Statin drugs, which are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are effective at lowering cholesterol, but they also influence allergic inflammation with immunomodulatory activities, said lead author Safa Nsouli, MD, director of the Danville Asthma and Allergy Clinic in California. These include the downregulation of the T helper (TH)1 phenotype response and the upregulation of the TH2 phenotype response. Dr. Nsouli said he noticed that some of his patients with asthma had exacerbations and worsening control. When he investigated, he observed that they were using statins. The observation prompted him to conduct this small study. He compared 20 patients with asthma who were taking statins with 20 matched patients who were not taking statins. "The patients were very carefully selected and did not have any other medical factors that could interfere with asthma exacerbation," Dr. Nsouli told Medscape Medical News. The patients were seen at 3, 6, and 12 months. At each follow-up visit, measures of the following asthma factors were taken: forced expiratory volume in 1 second (FEV1), the use of beta agonists, nocturnal wakening, and daytime exacerbation symptoms. The investigators found that at 3 months, patients in the statin group had a 20% decrease in FEV1 from baseline, compared with patients in the nonstatin group, who had a 10% decrease. At 6 months, the decreases were 28% and 12%, respectively; at 12 months, the decreases were 35% and 14%. The use of beta-agonist rescue inhalers was also higher in the statin group than in the nonstatin group, Dr. Nsouli said. At 12 months, beta-agonist use was up by 72% in the statin group, compared with 9% in the nonstatin group. At 3 months, peak expiratory flow was decreased by 18% in the statin group, and by 4% in nonstatin group. At 6 months, it was decreased by 25% and 9%, respectively, and at 12 months, it was decreased by 39% and 11%. Finally, statin users had more nighttime wakening and a greater increase in daytime symptoms than nonusers. At 12 months, the increase in nighttime wakening was 31% and 3%, respectively, and the increase in daytime asthma symptoms was 35% and 3%. "More studies are needed to demonstrate that statins cause possible immune changes that promote allergic diseases such as asthma," Dr. Nsouli said. "Statins inhibit proinflammatory cytokines, which is good for the cardiovascular system, but they also suppress the major histocompatibility complex, class II, which is detrimental for patients with asthma," he explained. Physicians who notice that their patients' asthma is worsening should find out if they are taking statins. Dr. Nsouli suggested. He also said that patients with asthma who are prescribed statins should be informed that, because of the adverse immunomodulatory effects that statins produce, their asthma might get worse. "This does not mean that patients with asthma who need to take statins should stop taking these drugs. But it does mean that they should be treated more aggressively," Dr. Nsouli said. Chitra Dinakar, MD, from the University of Missouri School of Medicine in Kansas City, told Medscape Medical News that she thinks the observations from this study are interesting, but stressed their preliminary nature. "He had 20 patients in each group. The dose of statins wasn't clear, neither was the patient profile, but the study is thought provoking," said Dr. Dinakar, who was comoderator of the oral session. "It tells us that we need to be watching out for patients with asthma who are on statins to see if the statins do indeed affect their control. The data are preliminary at this point, but they do raise doubt. The subject merits further study." Dr. Nsouli has disclosed no relevant financial relationships. Dr. Dinakar reported financial relationships with AstraZeneca and GlaxoSmithKline. American College of Allergy, Asthma & Immunology (ACAAI) 2011 Annual Scientific Meeting: Abstract 30. Presented November 6, 2011.

Diabetes Epidemic on 'Relentlessly Upward Trajectory'

From Medscape Medical News Martha Kerr September 13, 2011(Lisbon, Portugal) — The number of people diagnosed with and dying from diabetes continues "on a relentlessly upward trajectory," with no signs of abating, according to officials from the International Diabetes Federation (IDF) and the European Association for the Study of Diabetes (EASD) 47th Annual Meeting. Data from international studies demonstrate that the number of people with diabetes in 2011 has reached 366 million. This year, 4.6 million deaths will be attributed to diabetes, with 1 person dying from diabetes every 7 seconds. Healthcare spending on diabetes has reached $465 billion. The warning comes a week before the United Nations Summit on Non-Communicable Diseases, to be held September 19 and 20 in New York City, where world leaders will meet to discuss the global issues posed by diabetes, cancer, heart, and respiratory diseases. IDF president Jean Claude Mbanya and EASD vice president Andrew Boulton state that "without urgent research into improved care and prevention models, we stand little chance of meeting any long-term targets that arise from the summit." "Implementation of current knowledge will bring some improvements to [noncommunicable disease] care and prevention, but further research is essential if we are to truly defeat these diseases," the officials say, adding that increased funding for research is critical. The findings will be published in the 5th edition of the Diabetes Atlas. The figure of 366 million people with diabetes in 2011 is up almost 30% from the 285 million cited for 2010 in the 4th edition of the Atlas. More information on the call for action can be obtained at www.idf.org or www.easd.org.

Neuromuscular Warm-Ups Reduce Injuries in Female Athletes

From Medscape Medical News Jennifer Garcia November 7, 2011 — Coach-led neuromuscular warm-up training (NMT) reduces lower-extremity injuries in female high school basketball and soccer players in a low-income, mixed-ethnicity, urban setting, according to data from a large, cluster-randomized, controlled trial published in the November issue of the Archives of Pediatric and Adolescent Medicine. To find out whether NMT training could reduce lower-extremity injuries in this setting, Cynthia R. LaBella, MD, from the Children's Memorial Hospital, Chicago, Illinois, and colleagues invited girls' soccer and basketball head coaches from all Chicago high schools to participate in the study during the 2006-2007 season. Of the 258 coaches invited, 95 enrolled, and 90 completed the study, representing 105 teams. The study was approved by the Chicago Public Schools research review board and the Children's Memorial Hospital review board. After learning how to implement a 20-minute neuromuscular warm-up before team practices and a shorter pregame version, the coaches in the intervention group used the prescribed warm-up before an average of 80% (standard deviation [SD], 21%) of practices, with a median of 87%. The control coaches stuck to their standard warm-up protocol, including no warm-up exercises and having athletes jog or warm up on their own. Overall, 96 lower-extremity injuries occurred (4.19/1000 athlete exposures; 95% confidence interval, 3.35 - 5.02 per 1000 athlete exposures) in the control group and 50 lower-extremity injuries (1.78/1000 athlete exposures; 95% confidence interval, 1.29 - 2.28 per 1000 athlete exposures) in the intervention group. Compared with athletes in the control group, Dr. LaBella and colleagues noted a 44% decrease in acute noncontact lower-extremity injuries and a 34% decrease in noncontact ankle sprains among players in the intervention group. Moreover, 7 athletes in the control group sustained anterior cruciate ligament (ACL) injuries during the study, and 6 of those required surgery. Two athletes in the intervention group sustained ACL injuries; neither required surgery. NMT combines progressive strengthening with plyometric, balance, and agility exercises. Coaches instructed the athletes to avoid dynamic knee valgus and to land jumps with flexed hips and knees. The investigators taught coaches how to distinguish proper from improper form and how to use verbal cues to promote proper form. The study authors calculated that 189 athletes would need to be trained to use neuromuscular warm-up exercises to prevent 1 noncontact lower-extremity injury. This would require training 11 soccer coaches or 16 basketball coaches, which, at $80 per coach per session, would be far less expensive than the estimated treatment cost for 1 surgically treated ACL injury. A potential limitation of the study, the researchers note, is that it encompassed only 1 season, so whether compliance can be maintained for several seasons is unknown. In addition, parental consent to include personal health and background information was available for only 855 of the 1492 participating athletes; therefore the data may not be representative of the entire sample. Despite the limitations, Dr. Labella and colleagues conclude: "[T]o our knowledge, this is the first randomized controlled study to demonstrate that (1) high school coaches in a mixed-ethnicity, predominantly low-income, urban population can implement a neuromuscular warm-up; (2) the warm-up reduces noncontact [lower-extremity] injuries, including ACL injuries, in female basketball and soccer athletes in this population; (3) the effect is likely dose related; and (4) coach training seems cost-effective." M. Alison Brooks, MD, MPH, from the Department of Orthopedics and Pediatrics, and Timothy A. McGuine, PhD, ATC, from the University of Wisconsin Health Sports Medicine Center, University of Wisconsin–Madison, write in an accompanying editorial: "This study is indeed novel for targeting a group that is often ignored and understudied because of logistical barriers and lack of resources." Although the study does confirm that neuromuscular training programs can reduce lower-extremity injuries, Dr. Brooks and Dr. McGuine point out that a longer follow-up would be needed to evaluate whether coaches continue to implement NMT consistently for several seasons, or whether retraining will be needed. The editorialists also note that many of the coaches in the control group did not include any type of warm-up routine in their training. Whether this behavior extends to the large percentage of coaches who declined to participate in the study could provide qualitative information that may help identify barriers to successful implementation of injury prevention strategies. Additionally, the authors of the editorial point out that including cost analysis of other, more common lower-extremity injuries beyond ACL would actually demonstrate an even greater cost-savings if coaches were trained in how to implement a neuromuscular warm-up as part of their training regimen. Both the study authors and the editorialists point out that physical activity has significant benefits in adolescent girls, including improved academic success and lower rates of obesity, diabetes, pregnancy, and depression. This association underscores the importance of sports injury prevention, particularly in girls from mixed-ethnicity, predominantly low-income, urban populations who are at higher risk for adolescent obesity, diabetes, and pregnancy. This study was supported by grants from Children's Memorial Research Center and Office of Child Advocacy. Dr. Brooks and Dr. McGuine have disclosed no relevant financial relationships. Arch Pediatr Adolesc Med. 2011;165:1033-1040. Abstract

Some Probiotics Effectively Reduce Common GI Symptoms

From Medscape Medical News Sandra Yin November 8, 2011 (National Harbor/Washington, DC) — Mounting evidence is building a strong case for the use of probiotics, or "good" bacteria, to alleviate common gastrointestinal (GI) symptoms, such as diarrhea, bloating, and inflammation, according to several studies highlighted during a press briefing here at the American College of Gastroenterology 2011 Annual Scientific Meeting and Postgraduate Course. In one meta-analysis, researchers from the Maimonides Medical Center in Brooklyn, New York, found that in 22 studies of more than 3000 patients, probiotic prophylaxis significantly reduced the odds of developing antibiotic-associated diarrhea and Clostridium difficile–associated diarrhea by about 60%. In another meta-analysis, researchers from Beth Israel Deaconess Medical Center and Harvard Medical School, in Boston, Massachusetts, analyzed 28 randomized controlled trials in which more than 3000 patients received a single or a combination of antibiotics for various indications. In adult and pediatric populations, the preventive effect of probiotic use was significant, regardless of the species used and regardless of the antibiotic administered. In the largest study to date on probiotics in a nonpatient population, researchers from the University of North Carolina at Chapel Hill evaluated the efficacy of Bifidobacterium infantis 35624, a probiotic that has relieved symptoms in patients with irritable bowel syndrome, to see how well it relieved abdominal discomfort and bloating in nonpatients. The double-blind randomized placebo controlled study involved a 2-week placebo phase followed by a 4-week intervention phase, and was conducted at 10 clinical centers in the United States. More than 300 nonpatients who had experienced abdominal discomfort and bloating more than twice weekly, on average, for at least 3 months were included in the study. They had not seen a physician or received prescribed medication for their symptoms in the previous 12 months. In contrast to previous clinical studies of irritable bowel syndrome patients, the researchers saw no statistically significant improvement in mean severity of abdominal discomfort or bloating after the nonpatient population took B infantis 35624. However, an Irish group found that a nonpatient population receiving B infantis 35624 experienced significantly more bloat-free days. The researchers hypothesized that microbial imbalance could explain the increased incidence of a wide range of inflammatory disorders. To test whether altering the balance between good and bad bacteria in the gut raises the immune regulatory response, which could lower inflammation, researchers from the Alimentary Pharmabiotic Centre at University College Cork, and Alimentary Health Ltd in Cork, Ireland, conducted a double-blind placebo controlled study. Their goal was to see if B infantis affects systemic proinflammatory biomarkers in patients with inflammatory disease. The results of their study suggest that probiotics exert antiinflammatory effects. "By giving a specific probiotic orally, we could actually reduce the levels of these proinflammatory cytokines and actually enhance the production of an anti-inflammatory cytokine, which is the exact replication of what we identified in animal models and more basic models," said principal investigator Eamonn Quigley, MD, FACG, professor of medicine at the National University of Ireland in Cork. Plasma levels of the anti-inflammatory cytokine interleukin (IL)-10 rose significantly in healthy volunteers and patients with psoriasis, but not in those who took the placebo for 8 weeks. Plasma levels of 2 proinflammatory cytokines — tumor necrosis factor-alpha and IL-6 — dropped in all patients who received B infantis. C-reactive protein levels were also significantly lower in patients with psoriasis, ulcerative colitis, and chronic fatigue after treatment with the bacterium than after treatment with placebo. Although not everybody who takes an antibiotic should also take a probiotic, the institutionalized elderly should, to minimize the chance of getting something like antibiotic-associated diarrhea or antibiotic-associated C difficile, said Fergus Shanahan, MD, FACG, a researcher involved in the Irish B infantis 35624 study, and professor and chair of the Department of Medicine at University College Cork. Certain subsets of patients, such as those with cystic fibrosis or chronic urinary infections, who must take recurring courses of antibiotics might benefit from taking probiotics to minimize antibiotic-associated diarrhea. "It's ironic that we would worry about taking an organism when we've got billions of organisms in the GI tract" and the amount is relatively small, Dr. Shanahan observed. Instead of worrying about drug toxicity in that population, "we're worried about something that has vanishingly low side effects. It can't be zero, but it is very, very low." "If we paid more attention to prescribing antibiotics, we wouldn't have a lot of these problems," added Dr. Quigley. According to Mark Mellow, MD, FACG, director of the Digestive Health Center at INTEGRIS Baptist Medical Center in Oklahoma City, Oklahoma, physicians aren't the only ones to blame for the indiscriminate use of antibiotics. Edicts from hospital compliance committees often establish rules that patients who come in with community-acquired pneumonia be placed on antibiotics soon after admission. These rules can have unintended consequences. "Someone comes in with a fever and a cough and because there's not enough time to sort it out, they get put on an antibiotic," he said, whether or not they have a bacterial infection. Dr. Quigley reports financial relationships with Alimentary Health, Norgine, Merck, Procter and Gamble, Movetis/Shire, Shire, Yakult, and Ironwood/Almirall. Dr. Shanahan reports a financial relationship with Alimentary Health Ltd. Dr. Mellow has disclosed no relevant financial relationships. American College of Gastroenterology (ACG) 2011 Annual Scientific Meeting and Postgraduate Course: Abstracts P650, P120, P60, P283. Presented November 1, 2011.

TNF Blockers and Cancer: FDA Requires Increased Surveillance

From Medscape Medical News > Alerts, Approvals and Safety Changes > Medscape Alerts Emma Hitt, PhD November 3, 2011 (UPDATED November 4, 2011) — The US Food and Drug Administration (FDA) announced today that it is requiring the manufacturers of tumor necrosis factor (TNF)-α blockers to perform enhanced safety surveillance of these drugs because of the potential risk for cancer in children and adults aged 30 years or younger. Manufacturers will be required to submit reports of all malignancies and, in the case of malignancy in pediatric and young adult patients, expedited reports (provided within 15 days). "This type of safety surveillance is important for our improved understanding of malignancies in pediatric and young adult patients treated with TNF blockers because it will allow FDA to more completely capture and analyze all reported malignancies based on more complete and consistent reports," the FDA states in an alert sent today from the Division of Drug Information of the FDA's Center for Drug Evaluation and Research'. The FDA recommends that healthcare professionals "remain vigilant" for TNF blocker–related malignancies and report them to the FDA's MedWatch program or to the manufacturer. They add that "healthcare professionals may be queried by FDA or the manufacturer for additional clinical and diagnostic information related to the malignancy cases." On November 4, 2011, MedWatch, the FDA's safety information and adverse event reporting program, sent out a new alert asking healthcare professionals to include specific information in its reports of malignancy in patients treated with TNF blockers. This information includes: patient characteristics (age, sex, no patient identifiers); risk factors for malignancy; exposure to other immune-suppressing products or products with risk for malignancy; indication for TNF blocker treatment; TNF blocker exposure (duration, dose); cancer diagnosis (date of diagnosis, stage); biopsy results; and outcomes of malignancy (treatments, event outcome) The FDA first warned of the increased risk for childhood and adolescent cancers associated with TNF blockers in 2008, and warnings were added to the product labels of these drugs in 2009. Today's announcement comes in the wake of several somewhat conflicting findings about TNF blockers and cancer risk. One report in the August 2010 issue of Arthritis & Rheumatism found that children treated with TNF-α blockers may have increased cancer risk but that cancer cases reported in these children were confounded by underlying illnesses and concomitant use of immunosuppressants. Likewise, another report found that TNF inhibitors used to treat rheumatoid arthritis (RA) may increase the risk for skin cancer (including melanoma) but did not appear to be associated with increased risk for other malignancies. The pooled analysis, published in the September 1, 2011, issue of the Annals of the Rheumatic Diseases, found negligible increase or no increase in overall risk of developing any cancer. However, several studies have demonstrated an increased risk with these agents. In the August 2011 issue of Rheumatology, a study including data from over 20,000 US military veterans showed that nonmelanoma skin cancer risk is about one third higher for patients with RA treated with TNF inhibitors than for similar patients treated with nonbiologic disease-modifying antirheumatic drugs. In addition, in April of this year, the FDA reported an association between hepatosplenic T-cell lymphoma in adolescents and young adults treated with TNF blockers, azathioprine, and/or mercaptopurine. Drugs included in the TNF blocker class include infliximab (Remicade, Centocor), etanercept (Enbrel, Amgen and Pfizer), adalimumab (Humira, Abbott Laboratories), certolizumab pegol (Cimzia, UCB), and golimumab (Simponi, Centocor Ortho Biotech Inc). Even in the absence of immunosuppressive drugs, a higher incidence of lymphomas has been found in patients being treated for RA, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. More information about the announcement is available on the FDA Web site and on the MedWatch Web site. Adverse events related to use of TNF blockers should be communicated to the MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.

Distinguishing Alzheimer Disease From Other Major Forms of Dementia

From Expert Review of Neurotherapeutics Stella Karantzoulis, PhD; James E. Galvin, MD, MPH 10/20/2011 http://www.medscape.org/viewarticle/751357?src=cmemp Abstract and Introduction Distinguishing AD Dementia From Other Major Forms of Dementia Memory Language Visuospatial Skills Attention & Executive Functions Lack of Insight/Unawareness/Anosognosia Behavior, Mood, Personality & Psychiatric Symptoms Personality Extrapyramidal Symptoms Expert Commentary & Five-year View Key Issues Abstract Alzheimer’s disease (AD) is the most common and most studied cause of dementia. Significant advances have been made since the first set of clinical criteria for AD were put forth in 1984 that are now captured in the new criteria for AD published in 2011. Key features include recognition of a broad AD spectrum (from preclinical to mild cognitive impairment to AD dementia) and requirement of AD biomarkers for diagnosis. Correctly diagnosing dementia type is increasingly important in an era when potential disease-modifying agents are soon to be marketed. The typical AD dementia syndrome has at its core, an amnestic syndrome of the hippocampal type, followed by associated deficits in word-finding, spatial cognition, executive functions and neuropsychiatric changes. Atypical presentations of AD have also been identified that are presumed to have a different disease course. It can be difficult to distinguish between the various dementia syndromes given the overlap in many common clinical features across the dementias. The clinical difficulty in diagnosis may reflect the underlying pathology, as AD often co-occurs with other pathologies at autopsy, such as cerebrovascular disease or Lewy bodies. Neuropsychological evaluation has provided clinicians and researchers with profiles of cognitive strengths and weaknesses that help to define the dementias. There is yet no single behavioral marker that can reliably discriminate AD from the other dementias. The combined investigation of cognitive and neurobehavioral symptoms coupled with imaging markers could provide a more accurate approach for differentiating between AD and other major dementia syndromes in the future. Key Issues Alzheimer’s disease (AD) is the most common form of dementia. There are 35 million individuals worldwide currently affected by the disease; and AD is projected to affect 115 million by 2050. Generally speaking, AD neuropathology initially involves medial temporal lobe structures (e.g., hippocampus and entorhinal cortex) and subsequently extends to temporal, parietal and frontal lobe association areas as the disease progresses. Neuropsychiatric symptoms are present throughout the course of AD. New diagnostic criteria for AD emphasize the importance of biomarker data in the definition of prodromal AD. The typical dementia syndrome continues to be described by prominent episodic memory impairment linked to early changes in the hippocampus and entorhinal cortex, with secondary deficits in word-finding skills, spatial cognition and executive functions. Atypical presentations of AD include posterior cortical atrophy, logopenic progressive aphasia and focal frontal variant AD. In posterior cortical atrophy, the onset is characterized by early, higher-order visual deficits and a higher density of neurofibrillary tangles in the occipital regions than in typical AD. Logopenic progressive aphasia is an atypical language variant defined as a primary phonological loop deficit leading to impaired memory, sentence repetition and comprehension, with sparse spontaneous speech and frequent prolonged word-finding pauses. Greater numbers of neurofibrillary tangles within the frontal lobes are seen in frontal variant AD, resulting in a more severe disease course. Episodic memory scores do not differ between behavioral variant frontotemporal dementia patients and AD patients, although the neural correlates of the memory impairment differs between the two patient groups. Lewy body dementia (LBD) tends to co-occur with AD in 80% of cases, with only 20% having pure LBD. Patients with pure Lewy body pathology have better verbal memory skills than those with pure AD or mixed LBD/AD. A fluctuating or step-wise course and history of strokes may help clinicians differentiate AD from mixed AD with cerebrovascular disease when their clinical profiles are otherwise indistinguishable. Subcortical vascular dementia is associated with primary deficits in information processing speed and executive functions, and secondary milder effects on memory. Personality changes are common among the dementias. They can occur in the very earliest stages of AD, prior to the onset of any obvious cognitive decline and can discriminate between AD and LBD (more passive traits in the LBD group). Personality changes appear to be more common in behavioral variant frontotemporal dementia than in AD. Current treatments for AD provide symptomatic relief either by improving symptoms or by delaying decline. Improving our understanding of the molecular mechanisms of AD has led to the identification of multiple potential targets for disease-modifying agents.

Pancreatic Cancer Possibly Detected by Salivary Bacteria

From Medscape Education Clinical Briefs News Author: Janis Kelly CME Author: Charles P. Vega, MD 10/20/2011 Clinical Context Pancreatic cancer is a solid tumor with particularly poor outcomes for patients, as reviewed by the authors of the current study. The 5-year survival rate of pancreatic cancer is only 5%, although this rate increases to approximately 20% among individuals with surgically resectable disease at the time of presentation. Cigarette smoking appears to be the most significant known risk factor for pancreatic cancer. Diabetes, insulin resistance, and obesity might also contribute to the risk for pancreatic cancer. The lack of biomarkers for early detection of pancreatic cancer contributes to its poor prognosis. The current study examines the value of changes in oral microbiota as an early warning sign for pancreatic cancer. Study Synopsis and Perspective A pair of bacteria in the saliva are associated with pancreatic cancer and chronic pancreatitis, according to a study published online October 12 in Gut. Although a press release from the journal attributes the suggestion that this finding "opens up the possibility of curbing the progress of one of the most difficult cancers to treat, by altering the balance of bacteria," to the researchers, they were, in fact, much more circumspect. According to lead author James J. Farrell, MD, MD, from the division of digestive diseases at the UCLA David Geffen School of Medicine in Los Angeles, California, the key finding is that the study provides proof of principle that differences in the microbiota in saliva can serve as noninvasive biomarkers for diagnosing and differentiating pancreatic cancer and chronic pancreatitis. Dr. Farrell told Medscape Medical News that "we need to validate the panel of salivary biomarkers, both bacterial and transcriptomic, in a larger prospective study, enrolling patients suspected of having pancreatic disease and cancer and following them over time. This is currently underway. The big unanswered question is: Are these bacteria causing or the result of the cancer? Most data from previous studies and studies in other disease suggest that the bacteria are directly or indirectly contributing to the development of pancreatic disease, likely through inflammation." Identifying Bacteria The researchers used the human oral microbe identification microarray (HOMIM) to examine salivary microbiota in 10 patients with resectable pancreatic cancer and 10 matched healthy control subjects. They then used real-time quantitative polymerase chain reaction (qPCR) to identify the bacterial species or clusters that were notably different in the saliva of patients with pancreatic cancer and that of control subjects. Finally, they validated the candidate marker bacteria with qPCR on saliva from 28 patients with pancreatic cancer, 27 with chronic pancreatitis, and 28 control subjects. The initial analysis identified 31 bacterial species or clusters that were higher in the saliva of patients with pancreatic cancer than in control subjects, and 25 that were lower. Two of the 6 candidate bacteria validated in the independent samples were present at significantly different levels in the patient and control groups: Neisseria elongata and Streptococcus mitis. Furthermore, 2 bacteria (Granulicatella adjacens and S mitis) were present at different levels in patients with chronic pancreatitis and in control subjects. Causative Rather Than Reactive? Dr. Farrell's group then combined N elongata and S mitis and determined that the pair distinguished patients with pancreatic cancer from control subjects with 96.4% sensitivity and 82.1% specificity. The authors write that "whether a variation in bacterial abundance is a causative factor for cancer carcinogenesis or a derivational reflection of cancer onset due to the change of oral niches needs to be further explored in longitudinal.... Taken together [with the association between chronic pancreatitis and pancreatic cancer], these data suggest that the association between variations in oral microbiota and pancreatic disease may likely be causative rather than reactive." The authors note that they were unable to test for possible changes in oral bacteria after pancreatic cancer resection. They also note that "none of the bacterial biomarkers validated in this study was significantly altered in the microflora profile of lung cancer." Limitations in Study Design However, Dominique Michaud, ScD, associate professor of community health at Brown University in Providence, Rhode Island, who reviewed the paper for Medscape Medical News, is more cautious. Dr. Michaud, whose research centers on causes of pancreatic and brain cancers, and who has studied periodontal disease and pancreatic cancer (J Natl Cancer Inst. 2007;99:171-175), said that although "this is an interesting preliminary study, it is far from conclusive. There are many limitations to the study design, including small numbers and lack of other diseased control subjects. These findings need to be replicated and cannot provide any information on causality. It is very possible that any immunocompromised patient would have the same profile of saliva bacteria, which means this would test would not be a useful clinical screening tool." Community Health Dr. Farrell told Medscape Medical News that his group is currently enrolling patients in a nested, case–control study to see how these biomarkers behave in a large general population to detect pancreatic disease, and that efforts are underway to convert the HOMIM, which is currently only a research tool, for patient and clinic-based salivary diagnostics. Dr. Farrell and Dr. Michaud have disclosed no relevant financial relationships. Coauthor David T.W. Wong, from the David Geffen School of Medicine, reports ownership of intellectual property related to the saliva diagnostics field. Gut. Published online October 12, 2011. Abstract

Thyroid Cancers Commonly Found Incidentally

From Medscape Medical News Nancy A. Melville October 31, 2011 (Indian Wells, California) — A significant increase in the incidence of thyroid cancer in recent decades might be largely attributable to cancers incidentally found with ultrasound and other types of imaging, according to research presented here at the American Thyroid Association 81st Annual Meeting. From 1975 to 2008, the incidence of thyroid cancer nearly tripled, increasing from 4.85 to 12.97 cases per 100,000. This increase is "more rapid than any other type of cancer," said coauthor Michael Malone, BS, a medical student at New York University Langone Medical Center in New York City. Recent studies have suggested that increasing diagnostic scrutiny largely explains the apparent rise in cancers. To evaluate the issue, Mr. Malone and his colleagues conducted a chart review of 404 patients who underwent initial surgery for well-differentiated thyroid cancer at the Langone Medical Center from January 2007 to August 2010. They found that of 307 (76%) patients with stage 1 or 2 thyroid cancer, 46% had their tumors initially detected with an imaging study; the rest were detected because the patient or physician felt a mass in the neck. Imaging studies were also the method of detection in 46 (47%) of the 97 (24%) patients with stage 3 or 4 well-differentiated thyroid cancer. Among the tumors detected with imaging, 58% were less than 1 cm, 53% were 1 to 2 cm, 31% were 2 to 4 cm, and 39% were greater than 4 cm, Mr. Malone noted. When tumors were detected with imaging, ultrasound was the leading modality, used in 104 (55%) patients, followed by computed tomography in 37 (20%) patients, magnetic resonance imaging in 19 (10%) patients, carotid duplex scan in 13 (7%) patients, and positron emission tomography or other imaging in 15 (8%) patients. "It is important to note that these were sonograms that were not performed to evaluate something that was palpated on physical exam, but instead were performed for a variety of reasons, some appropriate and some not." Patients whose tumors were detected with imaging were more likely to be male (32% vs 21%; P = .013) and were older (median age, 52 vs 46; P = .0004) than those whose tumors were detected without imaging. The findings support the argument that imaging studies indeed heavily influence the rise in thyroid cancer incidence rates, Mr. Malone concluded. "We feel that a substantial number of thyroid cancers are discovered by imaging rather than by palpation alone," he said. "This observation is true for small and large cancers, as well as early and advanced cancers." "As with small cancers, the increasing incidence of larger and more advanced thyroid cancers may be the result of increasing diagnostic scrutiny and may not necessarily represent a true increase in disease," he observed. Kenneth B. Ain, MD, professor of medicine and chair of cancer research at the University of Kentucky Medical Center, in Lexington, questioned whether the findings would hold true in a patient population outside of the New York City demographic. "I think before you attempt to generalize, you should take into account the evidence of geography and different populations," said Dr. Ain. "For example, the study deals with urban patients in population centers that have well-equipped medical centers, and many practitioners have unused ultrasound machines in their offices that have to generate money." "In that situation, I assure you that you'll have a huge number of case findings by ultrasound and not by palpation," he said. However, "if you take a rural population in eastern Kentucky, for instance, who have issues such as oxycontin use, smoking, and don't usually have ultrasound machines available, patients will generally present with palpable cancers and you will see the same increase in thyroid cancers among these patients as those in the big cities." He added that some of the data used for this study have also shown that thyroid cancer has the "second highest increasing cancer death rate among all ages and all sexes, and to merely state this increased case finding and not account for the fact that these cases are killing more people despite with our advanced therapeutics makes it a little curious." Kathryn G. Schuff, MD, of the Oregon Health & Science University in Portland, who moderated the session, said the study and the ensuing comments reflect a larger debate regarding the role of imaging in increasing thyroid cancer incidence rates. "There are thyroidologists arguing on both sides of the issue," noted Dr. Schuff. "Some say it's just imaging, others say it is a real increase, arguing that the increasing death rates indicate that this is not just an increase in 'small incidentally found' tumors. I don't think we have the answer to that particular question yet." Mr. Malone, Dr. Ain, and Dr. Schuff have disclosed no relevant financial relationships. American Thyroid Association (ATA) 81st Annual Meeting: Abstract 94. Presented October 28, 2011.

Yoga Improves Back Function in Patients With Low Back Pain

From Medscape Medical News > Neurology Megan Brooks October 31, 2011 — A study released today provides more evidence that yoga can help patients who suffer from chronic low back pain. Conducted in the United Kingdom, the study found that a 12-session, 3-month yoga program led to greater improvements in back function than usual care. However, yoga did not yield greater reductions in pain or improvements in overall health compared with usual care. "Although there was no evidence of pain reduction at 12 months, confidence in performing normal activities despite pain improved more in the yoga group than usual care group at 3 and 6 months," the study team notes. In terms of yoga studies for low back pain, this study is "the largest to date, with over 300 participants, and it has the longest follow-up of any trial," investigator David J. Torgerson, PhD, from the University of York's Department of Health Sciences, United Kingdom, told Medscape Medical News. "We followed them up for 12 months (9 months after they had finished the yoga), and found that the benefit of yoga was sustained for this length of time, probably because a proportion of participants continued to practice yoga after they had completed their formal course," he said. Based on the findings in this study, "yoga could be recommended as a therapy for chronic low back pain," Dr. Torgerson said. The study was published November 1 in the Annals of Internal Medicine. Benefit "Sustained" The study involved 313 adults with chronic or recurrent low back pain. All of them received a back pain education booklet and usual care. In addition, 156 were offered Iyengar yoga classes (12 classes total, once weekly). The yoga classes were given by 12 yoga teachers who had extra training in back care. Each class lasted 75 minutes. In a statement, Iyengar yoga teacher and study investigator Alison Trewhela, DBL, said: "Yoga aims to treat the whole person — not just the physical." The yoga program offers "poses for pain-relief and mental calming; mobilizing, stretching, strengthening and relaxation; improving awareness of posture; education about how a healthy back functions; and positive mental focus," she explained. Sixty percent of patients in the yoga group attended at least 3 of the first 6 sessions and at least 3 other sessions. In the first 3 months, 82% said they practiced yoga at home on their own, 65% were practicing yoga at home at 6 months, and 60% were practicing yoga at home at 12 months. The researchers report that the yoga group had better back function at 3 months (the primary outcome) and at 6 and 12 months (secondary outcomes) than the usual care group. "Although there is no consensus, a change of 1.1 to 2.5 on the RMDQ has been recommended as clinically important," the investigators note in their report. "In this trial, we found that individuals offered yoga benefited from, on average, 2.17 fewer limited activities at 3 months and by 1.57 fewer limited activities at 12 months." They note that they were missing data for the primary outcome for 21 yoga participants and 18 usual care participants, and differential missing data were observed (more so in the yoga group) for secondary outcomes. The yoga and the usual care groups had similar back pain and general health scores at 3, 6, and 12 months, and the yoga group had higher scores on the Pain Self-Efficacy Questionnaire at 3 and 6 months, but not at 12 months. Twelve (8%) of the 156 yoga patients reported adverse events; 1 adverse event was deemed as serious and possibly or probably related to yoga (the patient had experienced severe pain but had a history of severe pain after any physical activity). The other 11 adverse events in the yoga group were nonserious and were mostly related to increased pain. Adverse events were reported in 2 (1%) of the 157 patients in the usual care group (1 accident/injury, 1 death). Yoga Comparatively Effective Other interventions for low back pain that have been evaluated in randomized controlled trials include exercise and manipulation, the Alexander technique, and cognitive behavioral therapy, Dr. Torgerson and colleagues note in their report. Comparing the findings of their study with these other techniques, they say, "suggests that group yoga may improve back function (as measured by the RMDQ) more than exercise and manipulation, cognitive behavioral treatment, and 6 sessions of 1-on-1 Alexander technique but not as much as 24 sessions." They caution, however, against "overanalyzing these results because the comparisons are indirect." Further research is needed to compare yoga directly with these other treatments, they say. Additional support for yoga in chronic back pain comes from a study published online October 24 in the Archives of Internal Medicine. As reported by Medscape Medical News, the study found that stretching, regardless of whether it is achieved via yoga classes or conventional stretching exercises, has moderate benefits in adults with moderately impairing chronic low back pain. In a comparative effectiveness study, the researchers found that yoga classes were more effective than a self-help book, but not more effective than stretching classes, in improving function and reducing symptoms resulting from chronic low back pain, with benefits lasting at least several months. The author of a comment on the article in the Archives of Internal Medicine called the results from this trial "actionable" for practice because they reinforce the evidence that exercise is safe and moderately beneficial for chronic low back pain. "Health care providers should feel comfortable referring patients to either yoga or [physical therapy–]led classes; either seems to be helpful," writes Timothy S. Carey, MD, MPH, from the Sheps Center for Health Services Research, University of North Carolina, Chapel Hill. The current study was supported by Arthritis Research UK. Disclosures can be viewed on the journal's Web site. Ann Intern Med. 2011;155:569-578. Abstract