Recent Publications by CFE Educators

OBJECTIVES

To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved.

METHODS

Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years.

RESULTS

VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88).

CONCLUSIONS

STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.

The vast majority of acute coronary syndrome (ACS) trials conducted over the past two decades support the view that women have persistently higher mortality and morbidity despite the introduction of new medical therapies and devices. Even after adjustment for older age, higher prevalence of diabetes, hypertension, heart failure, smaller vessel size, and late presentation, some studies still point to a persistent sex disadvantage. Even in contemporary practice, women continue to have longer delays in presentation and treatment. Selection bias in unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) trials allows inclusion of large numbers of women with clinically insignificant coronary disease and may mistakenly shift results toward apparent benefit of a less aggressive approach. This bias causes further difficulty in determining efficacy and safety of new antithrombotic agents such as direct thrombin inhibitors and glycoprotein IIb/IIa inhibitors across the spectrum of ACS. In trials of UA/NSTEMI, use of objective evidence of ischemia such as elevated troponin levels, would greatly assist the determination of efficacy and benefit in women. Enrollment of more women in clinical trials and timely sex-specific analysis would promote a better understanding of the role of female gender in ACS and would facilitate better care of all patients.

Studies of radiation-associated risks among workers chronically exposed to low doses of radiation are important, both to estimate risks directly and to assess the adequacy of extrapolations of risk estimates from high-dose studies. This paper presents results based on a cohort of 45,468 nuclear power industry workers from the Canadian National Dose Registry monitored for more than 1 year for chronic low-dose whole-body ionizing radiation exposures sometime between 1957 and 1994 (mean duration of monitoring = 7.4 years, mean cumulative equivalent dose = 13.5 mSv). The excess relative risks for leukemia [excluding chronic lymphocytic leukemia (CLL)] and for all solid cancers were 52.5 [95% confidence interval (CI): 0.205, 291] and 2.80 (95% CI: -0.038, 7.13) per sievert, respectively, both associations having P values close to 0.05. Relative risks by dose categories increased monotonically for leukemia excluding CLL but were less consistent for all solid cancers combined. Although the point estimates are higher than those found in other studies of whole-body irradiation, the difference could well be due to chance. Further follow-up of this cohort or the combination of results from multiple worker studies will produce more stable estimates and thus complement the risk estimates from higher-dose studies.

STUDY OBJECTIVES

Treatment of patients with idiopathic pulmonary fibrosis (IPF) conventionally includes corticosteroids and cytotoxic agents. No study to date has adequately evaluated the benefits of this approach. This study retrospectively compared combination corticosteroid and cyclophosphamide therapy in a large population of patients who meet the current consensus definition of IPF.

DESIGN

Patients were identified retrospectively and treatment addressed on an intention-to-treat basis. Treated and untreated patients were matched by age and percentage of predicted FVC (FVC%) at the time of the initial visit.

SETTING

Two academic tertiary referral centers.

PATIENTS OR PARTICIPANTS

The diagnosis of IPF was based on current consensus criteria. A total of 164 patients (82 treated and 82 untreated) were included.

INTERVENTIONS

Treatment consisted of combined corticosteroid and cyclophosphamide therapy using a standardized protocol.

MEASUREMENTS AND RESULTS

There was no difference in age, FVC%, gender, or smoking status between groups. No survival difference was found between patients who were treated (median survival, 1,431 days) or untreated (median survival, 1,665 days) [p = 0.58]. The lack of treatment effect persisted when only those patients with a diagnosis by surgical biopsy (n = 24) or FVC% >/= 60 (n = 107) were analyzed.

CONCLUSIONS

Our data suggest that combined corticosteroid and cyclophosphamide therapy has no impact on survival in patients with IPF. This finding supports the evolving concept that chronic inflammation plays a minimal role in the progression of IPF and reinforces the importance of careful consideration of the risks and benefits of such therapies prior to their institution.

PURPOSE

To determine the effect of pulmonary fibrosis on survival in an unselected group of patients with hypersensitivity pneumonitis.

METHODS

We identified 72 patients with hypersensitivity pneumonitis confirmed by surgical lung biopsy in the database of the Clinical Interstitial Lung Disease Program at the National Jewish Medical and Research Center. All biopsy specimens were scored according to the presence or absence of fibrosis. Comparisons were made between patients with (fibrotic group) and without (nonfibrotic group) pathologic fibrosis. Vital status was ascertained and Kaplan-Meier curves were plotted. Cox regression analysis was used to determine predictors of survival.

RESULTS

Forty-six patients were classified as fibrotic and 26 as nonfibrotic. Twenty-nine percent had exposure to a bird antigen, 33% had exposure to a microbial antigen, and 38% had unknown exposure. Patients with fibrosis were significantly older, showed greater restrictive lung physiology, and had greater all-cause and respiratory mortality. Median survival in fibrotic patients was 7.1 years, which was significantly less than survival in those without fibrosis. In an age-adjusted regression analysis, antigen class, symptom duration, and lung function had no effect on survival. Only the presence of pathologic fibrosis was predictive of increased mortality (hazard ratio = 6.01; 95% confidence interval: 1.68 to 21.45; P = 0.006).

CONCLUSION

Pulmonary fibrosis is associated with diminished survival in patients with hypersensitivity pneumonitis.

OBJECTIVES

To examine the evaluation methods of resident teaching courses and to estimate the effectiveness of these teaching courses.

DESIGN

We searched the literature from 1975 to May 2003 using the PubMed MESH terms internship and residency and teaching; 1,436 articles were identified and 77 contained information regarding teaching courses. Fourteen articles contained information regarding outcomes of resident teaching courses and were selected for intensive review.

MAIN RESULTS

Five uncontrolled pre-post studies used resident self-reported teaching skills/behaviors as outcome measures; all reported some improvement in self-reported skills. Three uncontrolled pre-post studies examined live or videotaped resident teaching encounters and all revealed improvement in some teaching skills. One uncontrolled trial and three nonrandomized controlled trials used learner evaluations of resident teaching behaviors as outcomes and all revealed an improvement in ratings of residents after course participation. Four randomized controlled trials of resident teaching curricula are included in this review. One study did not show any quantitative benefit of a resident teaching course on performance on an objective structured teaching evaluation. Two studies assessing resident teaching evaluations before and after course participation showed conflicting results. One study noted improvements in resident teaching skills assessed through videotape analysis.

CONCLUSIONS

Resident teaching courses improve resident self-assessed teaching behaviors and teaching confidence. Teaching courses are linked to improved student evaluations. Further studies must be completed to elucidate the best format, length, timing, and content of resident teaching courses and to determine whether they have an effect on learner performance.

BACKGROUND

The etiology of cardiomyopathy is usually inferred from clinical information and preliminary laboratory studies. Patients with unexplained cardiomyopathy may be referred for endomyocardial biopsy (EMBx). It is unknown whether pathological information obtained from EMBx is beneficial or alters the diagnosis established clinically. This study was undertaken to evaluate the utility of EMBx in confirming or excluding a clinically suspected diagnosis.

METHODS

We evaluated 845 patients with initially unexplained cardiomyopathy who underwent EMBx between 1982 and 1997 at The Johns Hopkins Hospital. For each patient, an initial clinical diagnosis, an EMBx diagnosis, and a final diagnosis prior to discharge based on all available data were established.

RESULTS

The final diagnosis differed from the initial clinical diagnosis in 264 (31%) of these patients; EMBx made the diagnosis in 196 (75%) of these cases. Initial diagnoses most frequently altered were myocarditis (34%) and idiopathic cardiomyopathy (25%). Initial diagnoses least likely to be altered were those in which biopsy was used to confirm or grade a previously documented illness, such as hemochromatosis (11%), amyloidosis (18%), or cardiomyopathy secondary to doxorubicin toxicity (0%). EMBx was more sensitive than clinical diagnosis in detecting myocarditis and amyloidosis, and proved to be very specific in detecting ischemic cardiomyopathy, myocarditis, amyloidosis, and hemochromatosis.

CONCLUSIONS

In patients with unexplained cardiomyopathy after a standard evaluation, the clinical assessment of the etiology is inaccurate in 31% of patients. EMBx establishes the final diagnosis in 75% of these patients with a high degree of specificity.

Streptococcus pneumoniae causes several diseases, including otitis media, pneumonia, and meningitis. Although little is known about the regulation of or how individual pneumococcal factors contribute to these disease states, there is evidence suggesting that some factors are regulated by a cell-density-dependent mechanism (quorum sensing). Quorum sensing allows bacteria to couple transcription with changes in cell density; bacteria achieve this by sensing and responding to small diffusible signaling molecules. We investigated how the LuxS signaling system impacts the biology of S. pneumoniae. An analysis of the transcriptional profiles of a serotype 2 strain and an isogenic luxS deletion strain utilizing an S. pneumoniae-specific microarray indicated that LuxS regulates gene expression involved in discrete cellular processes, including pneumolysin expression. Contrary to the paradigm for quorum sensing, we observed pronounced effects on transcription in early log phase, where gene expression was repressed in the mutant. Assessing the mutant for its ability to infect and cause disease in animals revealed a profound defect in ability to persist in the nasopharyngeal tissues. Our analysis of an S. pneumoniae transcriptome revealed a function for LuxS in gene regulation that is not dependent upon high cell density and is likely involved in the maintenance of pneumococcal load in susceptible hosts.