Publications

BACKGROUND

Network analysis techniques allow a more accurate reflection of underlying systems biology to be realized than traditional unidimensional molecular biology approaches. Using gene coexpression network analysis, we define the gene expression network topology of cardiac hypertrophy and failure and the extent of recapitulation of fetal gene expression programs in failing and hypertrophied adult myocardium.

METHODS AND RESULTS

We assembled all myocardial transcript data in the Gene Expression Omnibus (n=1617). Because hierarchical analysis revealed species had primacy over disease clustering, we focused this analysis on the most complete (murine) dataset (n=478). Using gene coexpression network analysis, we derived functional modules, regulatory mediators, and higher-order topological relationships between genes and identified 50 gene coexpression modules in developing myocardium that were not present in normal adult tissue. We found that known gene expression markers of myocardial adaptation were members of upregulated modules but not hub genes. We identified ZIC2 as a novel transcription factor associated with coexpression modules common to developing and failing myocardium. Of 50 fetal gene coexpression modules, 3 (6%) were reproduced in hypertrophied myocardium and 7 (14%) were reproduced in failing myocardium. One fetal module was common to both failing and hypertrophied myocardium.

CONCLUSIONS

Network modeling allows systems analysis of cardiovascular development and disease. Although we did not find evidence for a global coordinated program of fetal gene expression in adult myocardial adaptation, our analysis revealed specific gene expression modules active during both development and disease and specific candidates for their regulation.

The aim of this study is to examine how physicians use clinical practice guidelines that call for routine HIV screening in a general adolescent medicine clinic and to determine how adolescent patients respond to routine screening. Physicians offered screening to 116 of 217 patients (53%) aged 13-21 who completed a survey. Physicians' offers conformed to the latest Centers for Disease Control and Prevention (CDC) guidelines with 73% of patients because some patients not offered a test had been screened within the last year. Physicians were three times more likely (OR = 3.0; 95% CI = 1.3-6.8) to offer HIV screening to sexually active adolescents than to adolescents who reported no sexual history. Adolescent medicine physicians and their patients endorse the idea of routine screening as embodied in the latest CDC recommendations, but adolescents with no sexual history are less likely than other adolescents to accept screening when it is offered and to support a clinic policy of routine screening. Both physicians and their adolescent patients continue to test based on risk assessments.

We report a rare case of a foregut duplication cyst of the pancreas containing respiratory epithelium in a healthy adolescent male who presented with recurrent abdominal pain secondary to pancreatitis. The abnormality was revealed on computed tomography performed to evaluate severe abdominal pain radiating to the back. Further imaging (ultrasound and magnetic resonance imaging) confirmed that the lesion was a cyst with no apparent pancreatic ductal communication. Elective laparoscopic resection of the cyst was performed with complete resolution of the patient's symptoms.

There is an increase in reactive oxygen and nitrogen species in cardiomyocytes during myocardial ischemia/reperfusion injury. This leads to oxidative DNA damage and activation of nuclear repair enzymes such as poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 activation promotes DNA repair under normal conditions. However, excessive activation of PARP-1 leads to cell death. We report that PARP-1 enzymatic activity is directly inhibited by minocycline, and we propose that one mechanism of minocycline cardioprotection is the result of PARP-1 inhibition. Using cultured adult rat cardiac myocytes, we evaluated the mechanism of minocycline protection in which PARP-1 activation was induced by simulated ischemia/reperfusion injury using oxygen–glucose deprivation.We found an increase in reactive oxygen species production, PARP-1 activation, and PARP-1-mediated cell death after simulated ischemia/reperfusion. Cell death was significantly reduced by the PARP inhibitors 3, 4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (10 μM) and PJ-34 (500 nM) or by minocycline (500 nM). Cellular NAD(+) depletion and poly(ADP-ribose) formation, which are biochemical markers of PARP-1 activation, were also blocked by minocycline. Finally, simulated ischemia/reperfusion led to induction of the mitochondrial permeability transition, which was prevented by minocycline. Therefore, we propose that the protective effect of minocycline on cardiac myocyte survival is the result of inhibition of PARP-1 activity.

BACKGROUND

Laboratory monitoring has been increasingly recognized as an important area for improving patient safety in ambulatory care. Little is known about doctors' attitudes towards laboratory monitoring and potential ways to improve it.

METHODS

Six focus groups and one individual interview with 20 primary care doctors and nine specialists from three Massachusetts communities.

RESULTS

Participants viewed laboratory monitoring as a critical, time-consuming task integral to their practice of medicine. Most believed they commit few laboratory monitoring errors and were surprised at the error rates reported in the literature. They listed various barriers to monitoring, including not knowing which doctor was responsible for ensuring the completion of laboratory monitoring, uncertainty regarding the necessity of monitoring, lack of alerts/reminders and patient non-adherence with recommended monitoring. The primary facilitator of monitoring was ordering laboratory tests while the patient is in the office. Primary care doctors felt more strongly than specialists that computerized alerts could improve laboratory monitoring. Participants wanted to individualize alerts for their practices and warned that alerts must not interrupt work flow or require too many clicks.

CONCLUSIONS

Doctors in community practice recognized the potential of computerized alerts to enhance their monitoring protocols for some medications. They viewed patient non-adherence as a barrier to optimal monitoring. Interventions to improve laboratory monitoring should address doctor workflow issues, in addition to patients' awareness of the importance of fulfilling recommended therapeutic monitoring to prevent adverse drug events.