Advil, Alleve, and Tylenol Do Not Increase Stroke Risk, But Diclofenac Does

It's been shown that NSAIDS, including, notoriously, some newer, and heavily marketed ones such as the cox-2 inhibitors celecoxib (Celebrex) and the withdrawn-from-market rofecoxib (Vioxx), slightly increase the risk of MI. Because of that risk, and the general association of stroke with MI risks, it has been suspected that NSAIDs might also, as a general class, increase stroke risk.

This appears not to be the case. In the study below, the more popular NSAIDs in the US, naproxen and ibuprofen, do not seem to increase stroke risk. Diclofenac (Voltaren) does, however. Aspirin was neutral in this study, though it has been shown to to lower brain infarctions and increase bleeds in other studies.

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ABSTRACT

Risk of ischaemic stroke associated with non-steroidal antiinflammatory drugs and paracetamol: a population-based case-control study

Journal of Thrombosis and Haemostasis, 01/27/2015

GarcíaPoza P, et al.

The authors aim to assess the risk of nonfatal ischaemic stroke associated with NSAIDs and paracetamol. The effects of dose, duration of treatment, background cardiovascular (CV) risk and use of concomitant aspirin were studied. Diclofenac and aceclofenac increase the risk of ischaemic stroke while ibuprofen and naproxen do not. Dose, duration and baseline CV risk, but not aspirin use, appear to modulate the risk. Paracetamol does not increase the risk, even in patients at high background CV risk.

Methods

The authors performed a population-based case-control study. Patients were considered exposed if they were on treatment within a 30-day window before the index date. They estimated adjusted odds ratios (ORs) and their 95% CI using logistic regression.

Results

2888 cases and 20000 controls were included. No increased risk was observed with traditional NSAIDs as a group (OR= 1.03; 0.90-1.19), but results varied across individual agents and conditions of use. An increased risk was found with diclofenac (OR=1.53; 95%CI: 1.19-1.97), in particular when used at high doses (OR=1.62; 1.06-2.46), over long-term periods (>365 days; OR=2.39; 1.52-3.76) and in patients at high background CV risk (OR=1.78; 1.23-2.58), as well as with aceclofenac when used at high doses (OR=1.67; 1.05-2.67), long-term treatments (OR=2.00; 1.14-3.53) and in patients with CV risk factors (OR=2.33; 1.40-3.87).

No association was found with ibuprofen (OR=0.94; 0.76-1.17) or naproxen (OR=0.68; 0.36-1.29).

The concomitant use of aspirin did not show a significant effect modification.

Paracetamol did not increase the risk overall (OR= 0.97; 0.85-1.10), or in patients at high CV risk (OR=0.94; 0.78-1.14).

Reading in Marine Biology

I am currently reading The Cultural Lives of Whales and Dolphins, published just last month, which is a very long and thought provoking book. Thoughts in the first few chapters: What is culture, and does the passing along of learning between animals in a community constitute culture? How alike are we in our human cultures to animals which lack the rich content of human languages? I'll do a review when I'm finished. But, it's off to listen to whale song underwater here, now.

Puhi Bay: One Chaetodon quadrimaculatus (Fourspot butterflyfish) and two Chaetodon auriga (Threadfin butterflyfish)

Strelitzia nicolai

Also called the Giant White Bird of Paradise. This is the first of three plants to flower at just 2 years of age. That is really quick flower production for this type of bird-of-paradise plant.

Aspirin Ineffective in Preventing Cardiovascular Disease in Japanese General Population

So, in a population where hypertension is the major cardiovascular risk factor, aspirin is ineffective in preventing deaths due to cardiovascular disease. Aspirin should be confined in use to those who have had evidence of extra risk, such as a prior TIA or stroke.

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ABSTRACT

JAMA. 2014;312(23):2510-2520. doi:10.1001/jama.2014.15690.

Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Japanese Patients 60 Years or Older With Atherosclerotic Risk Factors A Randomized Clinical Trial

Yasuo Ikeda, MD1; Kazuyuki Shimada, MD2; Tamio Teramoto, MD3; Shinichiro Uchiyama, MD4; Tsutomu Yamazaki, MD5; Shinichi Oikawa, MD6; Masahiro Sugawara, MD7; Katsuyuki Ando, MD8; Mitsuru Murata, MD9; Kenji Yokoyama, MD10; Naoki Ishizuka, PhD11

Objective To determine whether daily, low-dose aspirin reduces the incidence of cardiovascular events in older Japanese patients with multiple atherosclerotic risk factors.

Design, Setting, and Participants The Japanese Primary Prevention Project (JPPP) was a multicenter, open-label, randomized, parallel-group trial. Patients (N = 14 464) were aged 60 to 85 years, presenting with hypertension, dyslipidemia, or diabetes mellitus recruited by primary care physicians at 1007 clinics in Japan between March 2005 and June 2007, and were followed up for up to 6.5 years, with last follow-up in May 2012. A multidisciplinary expert panel (blinded to treatment assignments) adjudicated study outcomes.

Interventions Patients were randomized 1:1 to enteric-coated aspirin 100 mg/d or no aspirin in addition to ongoing medications.

Main Outcomes and Measures Composite primary outcome was death from cardiovascular causes (myocardial infarction, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or hemorrhagic, including undefined cerebrovascular events), and nonfatal myocardial infarction. Secondary outcomes included individual end points.

Results The study was terminated early by the data monitoring committee after a median follow-up of 5.02 years (interquartile range, 4.55–5.33) based on likely futility. In both the aspirin and no aspirin groups, 56 fatal events occurred. Patients with an occurrence of nonfatal stroke totaled 114 in the aspirin group and 108 in the no aspirin group; of nonfatal myocardial infarction, 20 in the aspirin group and 38 in the no aspirin group; of undefined cerebrovascular events, 3 in the aspirin group and 5 in the no aspirin group. The 5-year cumulative primary outcome event rate was not significantly different between the groups (2.77% [95% CI, 2.40%-3.20%] for aspirin vs 2.96% [95% CI, 2.58%-3.40%] for no aspirin; hazard ratio [HR], 0.94 [95% CI, 0.77-1.15]; P = .54). Aspirin significantly reduced incidence of nonfatal myocardial infarction (0.30 [95% CI, 0.19-0.47] for aspirin vs 0.58 [95% CI, 0.42-0.81] for no aspirin; HR, 0.53 [95% CI, 0.31-0.91]; P = .02) and transient ischemic attack (0.26 [95% CI, 0.16-0.42] for aspirin vs 0.49 [95% CI, 0.35-0.69] for no aspirin; HR, 0.57 [95% CI, 0.32-0.99]; P = .04), and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization (0.86 [95% CI, 0.67-1.11] for aspirin vs 0.51 [95% CI, 0.37-0.72] for no aspirin; HR, 1.85 [95% CI, 1.22-2.81]; P = .004).

Conclusions and Relevance Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors.

Trial Registration clinicaltrials.gov Identifier: NCT00225849.

Manufacturing Memory Templates In Advance: The Hippocampal Theta Cycle in Novelty

One of the interesting findings of the rat "place cell" research into hippocampal memory of places during a rat's exploration of its surroundings is that, as the rat retraces a known route, hippocampal memory neurons fire in an order consistent with the order the rat traces its journey, in a cycle of looping memories which reflect an array of past, present, and future locations. The window of the rat's current journey is reflected in the "theta" (about 8/sec, low range alpha in humans actually) rhythms of the hippocampus as the rat follows its route.

What happens if the rat is exploring a new area? memory of the area just traveled may follow the same pattern as in the well trodden route. But what of the future areas? Do they too have a representation in hippocampal neuron firings? It seems that they do: hippocampal cells are placed in the theta sequence before the experiences they are soon to encode even occur. Furthermore, the recruitment of anticipated memory cells varies according to the anticipated distance tothe goal, as if the buffer allocated for future memory is set in size by the anticipated duration before the planned goal is expected to be reached. One wonders if people might remember better if that buffer could be made to default to larger sizes? Or perhaps such sizing is already optimal. Who knows?

Thus, it appears that the hippocampus may be continually making a framework for memory of our journeys before we finish them, with pre-made memory templating for events that we have not yet experienced, but somehow anticipate. The hippocampus thus may create a speculative version of memory, anticipating that journey's sequences before we get there. Are journeys in our imagination made, in a concrete kind of representation, in similar locations to where we make real memories of our experiences? Probably. How then do we tell the difference between memory and imagination? That has yet to be established, but it's likely that parts of the brain outside the temporal lobe, possibly the forebrain, would be involved in reality testing to determine when goals are met.

One observation regarding the role of the 8-Hz rat hippocampal "theta cycle" in spatial memory processing: the rhythmic theta here is a default cycle, a framework for the carrying of more specific information. This is in keeping with a concept of EEG waves as having a role, not as the specific information being processed by the brain, but rather as a default or carrier wave framework for synchronizing the actual use of information perceived and actions performed by the organism.

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ABSTRACT

Hippocampal theta sequences reflect current goals

Andrew M Wikenheiser & A David Redish

Nature Neuroscience (2015) doi:10.1038/nn.3909

Received 12 August 2014 Accepted 25 November 2014 Published online 05 January 2015

Hippocampal information processing is discretized by oscillations, and the ensemble activity of place cells is organized into temporal sequences bounded by theta cycles. Theta sequences represent time-compressed trajectories through space. Their forward-directed nature makes them an intuitive candidate mechanism for planning future trajectories, but their connection to goal-directed behavior remains unclear. As rats performed a value-guided decision-making task, the extent to which theta sequences projected ahead of the animal's current location varied on a moment-by-moment basis depending on the rat's goals. Look-ahead extended farther on journeys to distant goals than on journeys to more proximal goals and was predictive of the animal's destination. On arrival at goals, however, look-ahead was similar regardless of where the animal began its journey from. Together, these results provide evidence that hippocampal theta sequences contain information related to goals or intentions, pointing toward a potential spatial basis for planning.