Archief Roodbont

Some researchers have postulated that, by facilitating bacterial colonization of the stomach and upper intestine, suppression of gastric acid increases the risk for community-acquired pneumonia (CAP). Proton-pump inhibitors (PPIs) are among the most potent suppressors of gastric-acid secretion and are commonly prescribed — often without clear indications. Attempts to prove an association between PPI exposure and CAP have yielded inconsistent results. Now, researchers have conducted a retrospective, nested case-control study to explore this issue further.

Analysis of linked pharmacy and administrative databases from the New England Veterans Healthcare System yielded 71,985 patients who were newly prescribed PPIs between October 1997 and September 2007. Within this group, 1544 patients developed CAP after PPI initiation. These case patients were matched by age and follow-up duration with 15,440 controls who received new PPI prescriptions during the same period but did not develop CAP. PPI use was categorized as current if the prescription end date was after the index CAP date and past if it preceded this date.

Cases were significantly more likely than controls to have one or more medical comorbidities (in addition to gastroesophageal reflux), to have been hospitalized 90 days before the diagnosis of CAP, and to have been prescribed other medications possibly linked to CAP. The risk for developing CAP was higher in patients with current PPI use than in those with past use (adjusted odds ratio, 1.29; 95% confidence interval, 1.15–1.45). PPI prescription at a dose exceeding the standard daily dose (significantly more common in case patients than in controls) was also associated with CAP (P=0.012).

Comment: Because the study was retrospective and did not involve review of medical records, the results must be interpreted cautiously. However, the findings do suggest a modest effect of PPIs on the risk for CAP.

— Neil M. Ampel, MD

Published in Journal Watch Infectious Diseases January 18, 2012

Trials of anticoagulants for stroke prevention generally involve patients with frequent and symptomatic atrial fibrillation (AF); however, the growing population of patients with implanted cardiac devices has enabled the detection of subclinical AF. The manufacturer-sponsored ASSERT trial in patients with a dual-chamber pacemaker or implantable cardioverter-defibrillator was designed to evaluate whether a special pacing algorithm would prevent AF and whether subclinical AF is associated with clinical events. All 2580 participants had hypertension and no history of AF.

Three months after enrollment, device detection algorithms had recorded subclinical atrial tachycardia (defined as an atrial rate >190 beats/minute for >6 minutes) in 10% of patients. At this point, participants with pacemakers were randomized to receive or not to receive continuous overdrive atrial suppression.

During a mean of 2.5 years of follow-up, use of the special pacing algorithm did not significantly reduce AF. Clinically documented AF occurred in only 16% of patients with device-documented atrial tachycardia in the first 3 months. Subclinical atrial tachycardia in the first 3 months was significantly associated with both clinically documented AF and stroke or systemic embolism. However, the association with stroke or systemic embolism was no longer significant when patients with atrial tachycardia detected after the first 3 months (an additional 24.5%) were included in the analysis.

Comment: Clinical atrial fibrillation is not only associated with stroke but is almost certainly causative; moreover, no evidence suggests that symptomatic AF is more prothrombotic than asymptomatic AF. Although the current findings are by no means definitive for guiding anticoagulation decisions, they do support taking device-documented subclinical AF seriously. If an asymptomatic patient's CHADS₂ score is high and subclinical episodes are frequent or prolonged, I would consider anticoagulation. These findings also support aggressively screening patients with cryptogenic stroke for occult AF and initiating anticoagulation if any AF is detected.

— Mark S. Link, MD

Published in Journal Watch Cardiology January 18, 2012

Several lines of evidence suggest that in adults, antidepressant therapies enhance neurogenesis in the hippocampus, but how this process occurs has been unclear. These researchers studied the effects of fluoxetine in mice and in humans. They worked out several pathways that begin with the stimulation by fluoxetine of the microRNA miR-16 in serotonergic neurons in raphe and ultimately result in hippocampal neurogenesis.

In a series of experiments in mice, fluoxetine activated raphe miR-16, which decreased raphe levels of the serotonin reuptake transporter (SERT). In turn, these events directly caused brain-derived neurotropic factor (BDNF) and two other signaling molecules to act on the hippocampus. Indirectly, the same events resulted in release of another protein from the raphe nuclei, S100β, which in turn stimulated the locus coeruleus to induce SERT and secrete serotonin. Both the direct and indirect pathways caused decreases in hippocampal miR-16, which sequentially led to increases in both hippocampal SERT and the bcl-2 protein (which promotes neurotrophic function), which in turn stimulated neurogenesis. In nine patients with major depression, 12-week fluoxetine treatment increased levels of the three signaling molecules in cerebrospinal fluid. The interventions were accompanied by improvements in several mouse models of depression, as well as in the patients. See accompanying figure.

Comment: These findings draw together several seemingly unconnected lines of research. The authors identify miR-16 as a "missing link" between serotonin reuptake inhibitor treatment and hippocampal neurogenesis and as a "micromanager" of the intervening changes in the raphe nucleus, locus coeruleus, serotonin receptor transporter, serotonin secretion, and hippocampal neurogenesis. The processes appear to work through the cooperative and integrated activities of several signaling molecules. Further clarification of these pathways may help refine therapeutic strategies for depressive disorders.

— Joel Yager, MD

Published in Journal Watch Psychiatry January 13, 2012