Peroxisome proliferator-activated receptor-α and liver cancer: where do we stand?

The peroxisome proliferator-activated receptor- (PPAR), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPAR is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPAR occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPAR agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPAR also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPAR. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPAR target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPAR in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPAR agonist-induced hepatocarcinogenesis.     

On Quantifying Surprise: The Variation of Event-Related Potentials With Subjective Probability

Two factors are known to determine the waveform of event-related potentials (ERP) elicited by task-relevant stimuli: the a priori probability of the stimuli and the sequence of immediately preceding stimuli. The relative contribution of these factors to the ERP waveform was assessed at nine levels of a priori probability (from .10 to .90). Random sequences of high (1500 Hz) and low (1000 Hz) tones were presented to 10 male subjects at each level of probability, both when the events were task-relevant and when the subjects were performing an alternate task to which the tones were irrelevant. The EEG was recorded from five midline electrode sites referred to linked mastoids. The amplitude of the P300 and Slow Wave components was inversely proportional to the a priori probability of task-relevant events. At every level of a priori probability, the magnitude of the P300 complex (N200-P300-Slow Wave) was diminished when the eliciting tone repeated the preceding tone, and was enhanced when it was preceded by the other tone. Thus, a priori probability and sequential structure appear to be independent determinants of the P300 complex.     

Comparison of the intensity and duration of effects of inhaled bitolterol and albuterol on airway caliber and airway responsiveness to histamine

Inhaled beta-agonists can produce bronchodilatation and reduce airway hyperreactivity in patients with asthma. Using these two measures, we compared inhaled bitolterol (three puffs, 1110 micrograms), albuterol (two puffs, 180 micrograms), and placebo administered by metered-dose inhaler in a blinded, crossover study of 40 subjects with chronic asthma. On each study day, subjects underwent histamine challenges at 1 1/2 hours before, and 1/2, 2, 4, 6, and 8 hours after inhaling one of the three test-drug treatments. Both drugs produced significant bronchodilatation at 30 minutes through 4 hours and significant effects on airway reactivity at 30 minutes through 2 hours (p less than 0.05). Bitolterol also produced small but significant bronchodilator effects at 6 hours and effects on airway reactivity at 4 hours (p less than 0.05). Effects of bitolterol on airway reactivity diminished significantly more slowly than effects of albuterol in subjects with baseline provocative concentration causing a 20% fall in FEV1 greater than or equal to 1.0 mg/ml of histamine (half-life of biologic effect 1.37 versus 0.92 hours; p less than 0.05) but not in subjects with baseline provocative concentration causing a 20% fall in FEV1 less than or equal to 1.0 mg/ml (half-life of biologic effect of 1.01 versus 1.00 hours; p greater than 0.05).     

A Web-based compendium of clinical questions and medical evidence to educate internal medicine residents.

The authors designed an electronic database of clinical questions (CQs) and medical evidence and implemented it in 2001-02 at Duke University Medical Center and the Veterans Administration Medical Center in Durham, North Carolina. This Web-based data collection system is called the Critical Appraisal Resource (CAR) and is still in operation. This report is of ten months of the system's operation. During their medicine ward rotations, residents entered CQs into the CAR; they also entered Medline reference links and validated article summaries. Residents' utilization of the CAR database, Medline, and other electronic resources was prospectively measured. In addition, residents were prospectively surveyed regarding the impact of each question and associated reference on medical decision making for individual patients. Over ten months, residents entered 625 patient-based CQs into the CAR and were able to obtain useful information from the medical literature on 82% of the CQs they searched. The two most prevalent CQ types were therapy and diagnosis questions (53% and 22%). Sixty percent of the therapy articles considered useful were reports of randomized controlled trials. Residents obtained 77% of their useful data from Medline. They reported that obtaining useful data altered patient management 47% of the time. Residents used the CAR as a resource, searching the database for information 1,035 times over the study period. In summary, the use of an evidence-based critical appraisal resource led residents to engage the medical literature on behalf of their patients and influenced approximately half of their patient-care decisions. Residents benefited from questions previously searched by other residents, allowing them to address a wider spectrum of CQs during ward rotations.     

Increased WDR spontaneous activity and receptive field size in rats following a neuropathic or inflammatory injury: implications for mechanical sensitivity

Spontaneous activity and receptive field size for spinal wide dynamic range (WDR) neurons were measured and related to the mechanical allodynia in both neuropathic (L5-L6 ligation, 14 days post-injury) and complete Freund's adjuvant-inflamed rats (CFA, 2 days post-injury). The size of the WDR receptive field located on the hindpaw expanded significantly (p<0.01) following both modes of injury, with no difference between CFA and neuropathic animals. Likewise, the spontaneous firing of WDR neurons was significantly elevated following both the CFA (4.4+/-0.6 spikes/s, p<0.01) and neuropathic (3.2+/-0.3 spikes/s, p<0.05) injuries compared to naive (2.1+/-0.2 spikes/s) and sham-neuropathic (1.9+/-0.3 spikes/s) rats. Furthermore, the spontaneous WDR activity recorded from CFA rats was also significantly greater (p<0.05) than neuropathic rats. Mechanical allodynia, as measured by application of a von Frey hair stimulus, was observed from both CFA and neuropathic rats, however, the degree of sensitivity was significantly greater (p<0.01) for the CFA animals. These data suggest that the differences in mechanical sensitivity between CFA and neuropathic rats may be related to their respective changes in WDR spontaneous activity, but not to the changes in receptive field size, and is further demonstration of the importance of spontaneous WDR activity in determining mechanical sensitivity following injury.     

Decision-making styles of dietitians

Four decision-making styles (technician, planner, teacher, artist) were distinguished with Myers-Briggs Type Indicator (MBTI) results for 61 dietitians and 55 dietetic students. The "technician" style (impersonal, matter-of-fact analysis expressed in technical skills) was preferred to other styles by the greatest percentage of subjects studied. Subgroups of clinical dietitians, those 40 years old or older, and dietetic internship graduates preferred the "technical" style that is related to academic achievement in applied and physical sciences. Dietitians in administration, consulting, education, and public health indicated a preference for the "artistic" style (an insightful approach to possibilities expressed in an ability to communicate well with others). CUP graduates indicated the most diversity in style preferences. The "planner" style identified with researchers was preferred to the "artistic" style by students. Available data from groups of dietitians studied by other investigators supported these findings and indicated similarities among dietitians, school administrators, and medical technicians. Comparison between students in this and other samples indicated more differences than similarities, which may be due to differences in programs. Since all styles are useful within the profession, it is suggested that the identification and adaptation of style be included in education programs for dietetic students and practitioners.     

Novel 6-Month Treatment for Drug-Resistant Tuberculosis,United States

The US Food and Drug Administration approved a 6-month regimen of pretomanid, bedaquiline, and linezolid for extensively drug-resistant or multidrug-intolerant tuberculosis after a trial in South Africa demonstrated 90% effectiveness 6 months posttreatment. We report on a patient who completed the regimen using a lower linezolid dose.