Publications

Enhanced external counterpulsation (EECP) is a noninvasive technique that provides beneficial effects for patients with chronic, symptomatic angina pectoris. However, the direct left ventricular effects of EECP have not been studied invasively. We examined invasive right atrial pressure and left ventricular hemodynamics during EECP. Ten patients referred for diagnostic evaluation underwent left heart catheterization from the radial artery. At baseline and during EECP, left ventricular pressure and volume were measured using a micromanometer pressure-conductance catheter, along with recording of right atrial and central aortic pressures. Hemodynamics were recorded at different lower extremity cuff configuration and cuff inflation pressures. As cuff inflation pressure increased, EECP resulted in a dose-dependent increase in right atrial and aortic diastolic pressure (P < 0.0001). The increase in ventricular preload resulted in increased left ventricular volume. Maximum positive (P = 0.0003) and negative left ventricular dP/dt (P < 0.0001) increased. Left ventricular diastolic pressure decreased. There was a neutral effect on myocardial mechanical efficiency. In conclusion, EECP acutely increased right atrial and central aortic diastolic pressure. The increase in preload attenuated the reduction in left ventricular diastolic pressure resulting from systolic unloading. The increased preload counterbalanced the afterload reduction, resulting in a neutral effect on myocardial efficiency.

Anti-TNF immunotherapy has revolutionized the treatment of some inflammatory diseases, such as RA. However, a major concern is that patients receiving this therapy have an increased risk of fungal and bacterial infection, particularly of reactivating latent tuberculosis (TB). In this issue of the JCI, in an effort to understand how anti-TNF immunotherapy affects host mechanisms required to control TB, Bruns and colleagues examined the effects of the anti-TNF therapeutic infliximab on Mycobacterium tuberculosis-specific human lymphocytes (see the related article beginning on page 1167). The authors report that a granulysin-expressing CD45RA+ subset of effector memory CD8+ T cells that contributes to the killing of intracellular M. tuberculosis is depleted in vivo by infliximab in patients with RA, and that these cells are susceptible to complement-mediated lysis in the presence of infliximab in vitro. The study provides insight into host defense mechanisms that act to control TB infection and how they are affected during anti-TNF immunotherapy for autoimmune disease.

In 2007, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America published a document that addressed the major considerations for the justification, description, and conduct of antimicrobial stewardship programs. Our document is intended to continue the dialogue of these formalized programmatic strategies. We briefly review the guidelines, including the two primary strategies (prospective auditing with feedback, and preauthorization), and the supplemental strategies (education, information technology, transitional therapy, de-escalation or streamlining, and dose optimization). Discussions are introduced or furthered in the areas of program goals, barriers and solutions, and outcome measures. Definition and training of infectious diseases pharmacists are presented in detail. We offer keys to future success, which include continued collaboration and expanded use of information technology.

Autoimmune diseases affect a significant segment of the population and are typically thought to be multifactorial in etiology. Autoimmune diseases due to single gene defects are rare, but offer an invaluable window into understanding how defects in the immune system can lead to autoimmunity. In this review, we will focus on autoimmune polyendocrinopathy syndrome type 1 and recent advances in our understanding of this disease. We will also discuss two other monogenic autoimmune diseases: immunodysregulation, polyendocrinopathy, and enteropathy, X-linked and Autoimmune lymphoproliferative syndrome. Importantly, the knowledge and principles gained from studying these diseases have been applicable to more common autoimmune diseases and have opened the door to better diagnostic and therapeutic modalities.

Human chymase is a highly efficient angiotensin II-generating serine peptidase expressed by mast cells. When secreted from degranulating cells, it can interact with a variety of circulating antipeptidases, but is mostly captured by alpha(2)-macroglobulin, which sequesters peptidases in a cage-like structure that precludes interactions with large protein substrates and inhibitors, like serpins. The present work shows that alpha(2)-macroglobulin-bound chymase remains accessible to small substrates, including angiotensin I, with activity in serum that is stable with prolonged incubation. We used alpha(2)-macroglobulin capture to develop a sensitive, microtiter plate-based assay for serum chymase, assisted by a novel substrate synthesized based on results of combinatorial screening of peptide substrates. The substrate has low background hydrolysis in serum and is chymase-selective, with minimal cleavage by the chymotryptic peptidases cathepsin G and chymotrypsin. The assay detects activity in chymase-spiked serum with a threshold of approximately 1 pM (30 pg/ml), and reveals native chymase activity in serum of most subjects with systemic mastocytosis. alpha(2)-Macroglobulin-bound chymase generates angiotensin II in chymase-spiked serum, and it appears in native serum as chymostatin-inhibited activity, which can exceed activity of captopril-sensitive angiotensin-converting enzyme. These findings suggest that chymase bound to alpha(2)-macroglobulin is active, that the complex is an angiotensin-converting enzyme inhibitor-resistant reservoir of angiotensin II-generating activity, and that alpha(2)-macroglobulin capture may be exploited in assessing systemic release of secreted peptidases.

We compared the relative sensitivity of computed tomography (CT) and myelography for identification of disk herniation in dogs. Criteria for patient selection included presurgical CT, myelography, or both and surgical or necropsy confirmation of disk herniation between the T3 and L6 vertebral articulations. Imaging findings were described as positive or inconclusive. Adverse events such as hypotension, cardiac arrhythmias, seizures, death, and lower urinary tract infection were compared between imaging groups. One hundred and eighty-two dogs met the inclusion criteria, with 116 dogs having myelography performed as the initial diagnostic imaging modality and 66 dogs having CT performed as the initial modality. The relative sensitivity for locating the site of disk herniation was 83.6% when myelography was the first test performed and 81.8% when CT was the first test performed. CT was more sensitive than myelography at detecting lesions in chronically affected dogs (P = 0.025). Myelography was more sensitive than CT at detecting lesions in smaller dogs (< 5 kg; P = 0.004). Dogs that received both imaging modalities were significantly more likely to die or be euthanized compared with myelography alone (P < 0.001). Both myelography and CT are reasonable diagnostic imaging modalities for locating the site of disk herniation. CT should be considered especially in heavier, more chronically affected dogs. The major limitations of this study include lack of randomization to imaging modality and the use of surgical exploration or necropsy as the gold standard.

BACKGROUND

Vancomycin area-under-the-concentration-time-curve (AUC) for 24 hours divided by the minimum inhibitory concentration (MIC) (AUC24/MIC) >400 optimally treats invasive methicillin-resistant Staphylococcus aureus (MRSA) infections in adults. It is unknown whether recommended vancomycin dosing regimens for children achieve this value.

METHODS

AUC24/MIC was calculated in children using vancomycin doses of 40 and 60 mg/kg/d. AUC24 was calculated as daily dose/vancomycin clearance. Vancomycin clearance in children was estimated by 2 approaches: (1) previously literature-reported vancomycin clearance, and (2) calculated vancomycin clearance using previously derived predictor models and a hypothetical population of healthy children. Representative MIC of hospital MRSA isolates was used (0.5, 1.0, and 2.0 microg/mL).

RESULTS

The MIC50/90 for pediatric MRSA isolates in the previous year was 1.0 microg/mL. With a dose of 40 mg/kg/d, both approaches consistently predicted AUC24/MIC <400 when MIC was 1.0 microg/mL. At 60 mg/kg/d, AUC24/MIC >400 was more readily achieved when MIC was 1.0 microg/mL, however, an MIC of 2.0 microg/mL resulted in AUC24/MIC <400 for both dosing regimens.

CONCLUSIONS

A vancomycin dose of 40 mg/kg/d in children is unlikely to achieve the recommended pharmacodynamic target of AUC24/MIC >400 for invasive MRSA infections even when MIC is 1.0 microg/mL. A starting dose of 60 mg/kg/d should be used in settings where isolates with MIC of 1.0 are common. Alternatives to vancomycin should strongly be considered for patients with MIC > or =2.0 microg/mL.

BACKGROUND

Patients with obstructive sleep apnea syndrome (OSAS) are known to have an increased risk for motor vehicle crashes. They suffer from sleep-related respiratory abnormality causing repetitive arousal leading to daytime sleepiness. In turn, it has been demonstrated that sleepiness can impair human psychomotor performance causing slowing of reaction times (RTs). Patients with OSAS present with RTs comparable to young adults under the influence of blood alcohol concentrations above the legally permitted level to drive a motor vehicle. Vigilance related risk levels in patients with upper airway resistance syndrome (UARS) and potential deficits in psychomotor performance are unknown.

METHODS

We designed a study to compare psychomotor performance in UARS and compared it to patients with OSAS. Forty-seven UARS patients were matched by gender and age with 47 OSAS patients. All subjects completed a standardized vigilant attention task utilizing reaction time before undergoing polygraphic sleep studies.

RESULTS

Patients with UARS presented worse psychomotor performance on most test metrics than patients with OSAS.

CONCLUSIONS

Our study results may suggest that patients with UARS may also present an increased risk for motor vehicle crashes as previously demonstrated in OSAS patients.