Blood Cultures Positive for Coagulase-Negative Staphylococci: Antisepsis,Pseudobacteremia, and Therapy of Patients

A blood culture cohort study investigating issues related to isolation of coagulase-negative staphylococci (CoNS) and other skin microflora is reported. Data were collected over 12 weeks to determine the incidence of significant CoNS bacteremia versus that of pseudobacteremia (contaminants) and to evaluate drug therapy in patients with cultures positive for CoNS. In addition, the effectiveness of 0.2% chlorine peroxide as a bactericidal disinfectant was compared to that of 10% providone iodine. A total of 3,276 cultures of blood from 1,433 patients were evaluated in the study. Eighty-nine cultures were positive for skin flora, with 81 of 89 (91%) involving CoNS. The incidence of significant CoNS bacteremia was 20 of 81 (24.7%), that of indeterminate bacteremia was 10 of 81 (12.3%), and that of contamination was 59 of 81 (72.8%). The incidence of significant bacteremia involving CoNS was double the 10 to 12% rate based on previous estimations at our institutions. In tests with the two bactericidal disinfectants, 22 of 1,639 cultures (1.3%) in the chlorine peroxide group versus 37 of 1,637 (2.3%) in the providone iodine group were considered contaminated (P = 0.065). Rates of contamination for venipuncture versus catheter collection were not significantly different (P = 0.46). The overall contamination rate was 59 of 3,276 (1.8%), which is consistent with the lower end of published quality assurance benchmark standards. The low rate was believed to be due to the professional phlebotomy staff in our institutions. There was excellent agreement between retrospective analysis by reviewers, when formal criteria were used, and the attending physicians’ intuitive clinical impressions in the classification of significant bloodstream infections (100% agreement) or contamination (95% agreement). However, physicians still used antimicrobial agents to treat nearly one-half of the patients with contaminated blood cultures, with vancomycin being misused in 34% of patients. In addition, 10% of patients with significant bacteremia were treated with inappropriate agents. There were no significant adverse events or prolonged hospital stays due to the unnecessary use of vancomycin; however, the additional costs of treating patients whose cultures contained CoNS contaminants was estimated to be $1,000 per patient. Measures to limit the unnecessary use of vancomycin (and other agents) are important.Coagulase-negative staphylococci (CoNS), the most frequent blood culture isolates, are predominantly blood culture contaminants, but they are also a significant cause of bacteremia (2–5, 7, 9, 13). Institution-specific contamination rates vary from 2 to more than 6% (3, 5, 23, 26, 27). In the past 5 years, estimated contamination rates at our hospitals ranged from 2.5 to 3.5%. During this period, CoNS accounted for 45 to 60% of total blood isolates, and we estimated, using laboratory criteria, that 10 to 12% of CoNS isolates from blood were implicated in significant bloodstream infections. A relatively large proportion of the patient population with presumed false-positive blood cultures due to contaminants (pseudobacteremia) were treated with antimicrobial agents, in particular, vancomycin.Clinical and microbiologic guidelines for the differentiation of true bacteremia from pseudobacteremia or contamination have been published (5, 13, 15). Suggested laboratory criteria for true bacteremia include growth within 48 h and multiple blood cultures positive for the same organism. In contrast, increased duration of time before positivity, polymicrobial growth of skin organisms, or growth during antibiotic treatment suggest contamination. Others recommended that the addition of clinical guidelines is essential for the appropriate classification of bacteremia (4, 8, 9, 15, 18).We conducted a cohort study to evaluate clinical and laboratory data for adult patients with blood cultures positive for CoNS. The study was done at two tertiary-care teaching centers, Deaconess Medical Center (DMC) and Sacred Heart Medical Center (SHMC), with a combined capacity of 900 beds. We examined problems associated with false-positive bacteremia and determined the incidence of significant bacteremia. Our goal was to make recommendations to improve clinicians’ ability to recognize the significance of potentially contaminating organisms and to evaluate treatment given to patients with CoNS-positive blood cultures. To attempt to minimize contamination, we evaluated the nontoxic, antiseptic and disinfectant chlorine peroxide in comparison to a standard disinfectant.(This work was previously presented in abstract form at the 96th General Meeting of the American Society for Microbiology, New Orleans, La., 19 to 23 May 1996 [24a].)     

A de novo mutation affecting human TrkB associated with severe obesity and developmental delay

An 8-year-old male with a complex developmental syndrome and severe obesity was heterozygous for a de novo missense mutation resulting in a Y722C substitution in the neurotrophin receptor TrkB. This mutation markedly impaired receptor autophosphorylation and signaling to MAP kinase. Mutation of NTRK2, which encodes TrkB, seems to result in a unique human syndrome of hyperphagic obesity. The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system.     

Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies

Platyspondylic lethal skeletal dysplasia (PLSD) Torrance type (PLSD-T) is a rare skeletal dysplasia characterized by platyspondyly, brachydactyly, and metaphyseal changes. Generally a perinatally lethal disease, a few long-term survivors have been reported. Recently, mutations in the carboxy-propeptide of type II collagen have been identified in two patients with PLSD-T, indicating that PLSD-T is a type 2 collagen-associated disorder. We studied eight additional cases of PLSD-T and found that all had mutations in the C-propeptide domain of COL2A1. The mutational spectrum includes missense, stop codon and frameshift mutations. All non-sense mutations were located in the last exon, where they would escape non-sense-mediated RNA-decay. We conclude that PLSD-T is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain (as opposed to a null allele). Similar mutations have recently been found to be the cause of spondyloperipheral dysplasia, a non-lethal dominant disorder whose clinical and radiographical features overlap those of the rare long-term survivors with PLSD-T. Thus, spondyloperipheral dysplasia and PLSD-T constitute a novel subfamily within the type II collagenopathies, associated with specific mutations in the C-propeptide domain and characterized by distinctive radiological features including metaphyseal changes and brachydactyly that set them apart from other type 2 collagenopathies associated with mutations in the triple-helical domain of COL2A1. The specific phenotype of C-propeptide mutations could result from a combination of diminished collagen fibril formation, toxic effects through the accumulation of unfolded collagen chains inside the chondrocytes, and alteration of a putative signaling function of the carboxy-propeptide of type 2 collagen.     

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.     

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.