Faculty Bibliography

BACKGROUND:The occurrence of hepatitis A in the United States is heterogeneous because of disease cycles with substantial variation in incidence among states and involvement of numerous behavioral risk factors. In spite of the Advisory Committee on Immunization Practices' (ACIP) 1999 recommendation for routine hepatitis A immunization in states with high rates of disease and the fact that disease rates are at a historic low, outbreaks continue to occur. METHODS:We reviewed outbreaks of hepatitis A in the United States occurring from 1994 through 2004. We searched PubMed, ProMed, Google, and the CDC Foodborne Disease Outbreak and Epi-X Internet sites to ascertain the number and type of hepatitis A outbreaks. The CDC's MMWR publication and the Hepatitis Control Report were also searched. RESULTS:A total of 256 hepatitis A outbreaks were identified from 1994 through 2004. The mean number of outbreaks was 23 per year (median 25). The number of outbreaks in states with traditionally low/intermediate endemic rates of hepatitis A remained relatively constant during the study period. Outbreaks declined significantly (P = 0.01) in states with previously high rates of disease--most of which have implemented hepatitis A vaccination programs. CONCLUSIONS:Outbreaks of hepatitis A continue to occur in the United States despite the licensure of two safe and effective vaccines in 1995 and the apparent decline in the number of outbreaks in states with previously high rates of hepatitis A. The recent ACIP recommendation for universal hepatitis A vaccination at age 1 year in all states will contribute to a further reduction in hepatitis A outbreaks.

Oxidative stress may play a role in the pathogenesis of systemic lupus erythematosus (SLE). We examined the hypothesis that oxidative stress was associated with indices of lupus disease activity and severity of symptoms. Urinary F2 isoprostane excretion, a validated marker of oxidative stress, was measured in 95 patients with SLE and 103 healthy controls. Outcome measures included SLEDAI and SLICC scores, the modified health assessment questionnaire, the fatigue severity scale (FSS), and visual analogue scales (VAS) for fatigue, pain and overall disease activity. F2 isoprostane excretion was compared in patients and controls, and its relationship with clinical variables in SLE examined. F2 isoprostane excretion did not differ significantly among patients with lupus (2.7 +/- 2.3 ng/mg Cr) and control subjects (2.2 +/- 1.4 ng/mg Cr) (P = 0.70). In patients with lupus, F2 isoprostane concentrations were independently associated with higher patient reported disease activity (VAS) (OR = 1.52, P = 0.01), fatigue (FSS, OR = 1.52, P = 0.03) and lower quality of life (OR = 0.73, P = 0.05), but not with objective markers or inflammation or disease activity. In conclusion, F2 isoprostane excretion is associated with patient-reported symptoms in SLE but not with measures of inflammation, SLEDAI or SLICC. Oxidative stress may contribute to debilitating symptoms such as fatigue in SLE.

This study tested the hypothesis that angiotensin promotes oxidative stress and inflammation in humans via aldosterone and the mineralocorticoid receptor. We measured the effect of intravenous aldosterone (0.7 mug/kg per hour for 10 hours followed by 0.9 mug/kg per hour for 4 hours) and vehicle in a randomized, double-blind crossover study in 11 sodium-restricted normotensive subjects. Aldosterone increased interleukin (IL)-6 (from 4.7+/-4.9 to 9.4+/-7.1 pg/mL; F=4.94; P=0.04) but did not affect blood pressure, serum potassium, or high-sensitivity C-reactive protein. We next conducted a randomized, double-blind, placebo-controlled, crossover study to measure the effect of 3-hour infusion of angiotensin II (2 ng/kg per minute) and norepinephrine (30 ng/kg per minute) on separate days after 2 weeks of placebo or spironolactone (50 mg per day) in 14 salt-replete normotensive subjects. Angiotensin II increased blood pressure (increase in systolic pressure: 13.7+/-7.5 and 15.2+/-9.4 mm Hg during placebo and spironolactone, respectively; P<0.001 for angiotensin II) and decreased renal plasma flow (-202+/-73 and -167+/-112 mL/min/1.73 kg/m(2); P<0.001 for angiotensin II effect) similarly during placebo and spironolactone. Spironolactone enhanced the aldosterone response to angiotensin II (increase of 17.0+/-10.6 versus 9.0+/-5.7 ng/dL; P=0.002). Angiotensin II transiently increased free plasma F(2)-isoprostanes similarly during placebo and spironolactone. Angiotensin II increased serum IL-6 concentrations during placebo (from 1.8+/-1.1 to 2.4+/-1.4 pg/mL; F=4.5; P=0.04) but spironolactone prevented this effect (F=6.4; P=0.03 for spironolactone effect). Norepinephrine increased blood pressure and F(2)-isoprostanes but not aldosterone or IL-6. Aldosterone increases IL-6 in humans. These data suggest that angiotensin II induces IL-6 through a mineralocorticoid receptor-dependent mechanism in humans. In contrast, angiotensin II-induced oxidative stress, as measured by F(2)-isoprostanes, is mineralocorticoid receptor independent and may be pressor dependent.

BACKGROUND:Patient complaints are associated with increased malpractice risk but it is unclear if complaints might be associated with medical complications. The purpose of this study was to determine whether an association exists between patient complaints and surgical complications. METHODS:A retrospective analysis of 16,713 surgical admissions was conducted over a 54 month period at a single academic medical center. Surgical complications were identified using administrative data. The primary outcome measure was unsolicited patient complaints. RESULTS:During the study period 0.9% of surgical admissions were associated with a patient complaint. 19% of admissions associated with a patient complaint included a postoperative complication compared with 12.5% of admissions without a patient complaint (p = 0.01). After adjusting for surgical specialty, co-morbid illnesses and length of stay, admissions with complications had an odds ratio of 1.74 (95% confidence interval 1.01 to 2.98) of being associated with a complaint compared with admissions without complications. CONCLUSIONS:Admissions with surgical complications are more likely to be associated with a complaint than surgical admissions without complications. Further research is necessary to determine if patient complaints might serve as markers for poor clinical outcomes.

BACKGROUND:Intradialytic parenteral nutrition (IDPN), with or without exercise, has been shown to reverse the net negative whole-body and forearm muscle protein balances observed during hemodialysis. Pharmacologic doses of recombinant human growth hormone (rhGH) constitute another potential anabolic therapy in chronic hemodialysis patients. OBJECTIVE:Our goal was to examine the potential additive anabolic effects of rhGH compared with IDPN and exercise on protein and energy homeostasis. DESIGN/METHODS:We studied 7 chronic hemodialysis patients in a crossover design study in which each subject participated in 2 protocols: GH (rhGH + IDPN + exercise) and no GH (IDPN + exercise). During the GH protocol, the subjects were studied after 3 daily doses of rhGH. Each subject was studied 2 h before, 4 h during, and 2 h after a hemodialysis session with the use of a primed, constant infusion of l-[1-(13)C]leucine. RESULTS:Whole-body net protein balance was -0.50 +/- 0.07 mg x kg fat-free mass(-1) x min(-1) when the patients did not receive rhGH and -0.39 +/- 0.04 mg x kg fat-free mass(-1) x min(-1) when the patients received rhGH, a 22% improvement in prehemodialysis whole-body protein homeostasis (P < 0.05). Essential amino acid muscle loss was also significantly less during the prehemodialysis period when rhGH was administered (-18 +/- 23 compared with -71 +/- 20 mmol/L; P < 0.05). The whole-body anabolic effects of rhGH observed during the prehemodialysis period persisted throughout the entire study, as evidenced by a lack of significant interaction or main effect of treatment during hemodialysis and in the posthemodialysis period. CONCLUSION/CONCLUSIONS:rhGH improves whole-body protein homeostasis in chronic hemodialysis patients.

This study tests the hypothesis that spironolactone influences plasminogen activator inhibitor-1 (PAI-1) concentrations through mineralocorticoid receptor antagonism rather than through changes in potassium. Effects of spironolactone (50 mg per day) and triamterene (50 mg per day) on fibrinolytic balance were compared in 18 normotensive and 20 hypertensive subjects pretreated with hydrochlorothiazide (HCTZ; 12.5 mg per day). Blood pressure and serum potassium were similar in spironolactone and triamterene treatment groups. The effect of the 2 drugs on the renin-angiotensin-aldosterone system was also similar. In contrast, spironolactone and triamterene exerted opposing effects on PAI-1 antigen (P=0.006 for drug effect). In normotensive subjects, triamterene (from 10.1+/-7.8 to 16.9+/-9.9 ng/mL at 9 am, P=0.019; from 7.6+/-5.4 to 11.5+/-7.3 ng/mL at 11 am, P=0.027; from 9.3+/-7.7 to 13.7+/-8.5 ng/mL for average of all time points, P=0.054) but not spironolactone significantly increased PAI-1 antigen. In hypertensive subjects, spironolactone significantly decreased PAI-1 antigen (from 22.0+/-23.4 to 16.7+/-19.0 ng/mL at 10 am, P=0.041; from 17.5+/-21.7 to 12.7+/-16.8 ng/mL at 11 am, P=0.043; from 20.3+/-22.6 to 16.6+/-19.7 ng/mL for average of all time points, P=0.014), whereas there was no effect of triamterene. Only spironolactone significantly decreased the molar ratio of PAI-1 to tissue-type plasminogen activator (t-PA) in hypertensive subjects. By regression analysis, predictors of mean PAI-1 response were spironolactone versus triamterene (P=0.014), hypertension (P=0.002), and PAI-1 response to HCTZ (P=0.019), with a trend for aldosterone (P=0.061). Mineralocorticoid receptor antagonism prevents the effect of activation of the renin-angiotensin-aldosterone system on PAI-1 antigen in normotensive subjects and improves fibrinolytic balance in hypertensive subjects through a potassium-independent mechanism.

OBJECTIVE:In spite of numerous studies demonstrating the serious gastrointestinal (GI) toxicity associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs), many patients at high GI risk continue to receive prescriptions for these drugs, often without gastroprotective agents. Etoricoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than non-selective NSAIDs. We compared the incidence of upper GI Perforations, symptomatic gastroduodenal Ulcers, and upper GI Bleeding (PUBs) in a combined analysis of all randomized, double-blind, clinical trials of chronic treatment with etoricoxib versus NSAIDs completed by June 2003. RESEARCH DESIGN AND METHODS/METHODS:Data for 5441 individual subjects with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis were pooled from all 10 multinational etoricoxib trials completed by June 2003. Information on suspected PUBs was prospectively collected in all protocols, and all investigator-reported PUBs were judged by a blinded, external adjudication committee using pre-specified criteria. PUBs were analyzed using COX proportional hazards models using terms for treatment and known PUB risk factors. MAIN OUTCOME MEASURE/METHODS:The incidence of confirmed PUBs among patients treated with etoricoxib 60 mg, 90 mg, or 120 mg (combined N=3226) was compared to that among patients treated with ibuprofen, diclofenac, or naproxen (combined N=2215). RESULTS:The incidence of PUBs over 44.3 months was significantly lower with etoricoxib vs. NSAIDs [cumulative incidence 1.24% vs. 2.48%, p < 0.001; rate/100 patient-years 1.00 vs. 2.47; relative risk 0.48, 95% Confidence Interval (CI) 0.32, 0.73]. Results of analysis of events occurring during the first year of treatment and subgroup analyses were consistent with the primary result. CONCLUSIONS:Treatment with etoricoxib was associated with a significantly lower incidence of PUBs than was treatment with non-selective NSAIDs. The difference was consistent in subgroups of patients defined by a variety of known risk factors.

BACKGROUND:Most nonsteroidal anti-inflammatory drugs (NSAIDs) are non-selective cyclooxygenase-1 (COX-1) and COX-2 inhibitors and are associated with upper gastrointestinal (GI) dyspeptic symptoms often resulting in GI co-medication usage or treatment discontinuation. OBJECTIVE:To compare the rates of new use of gastroprotective agents and discontinuations due to dyspepsia with the COX-2 selective inhibitor etoricoxib compared with non-selective NSAIDs. RESEARCH DESIGN AND METHODS/METHODS:This pre-specified combined analysis used data from nine randomized, double-blind, controlled, clinical trials with etoricoxib in patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis. The cumulative incidences of (1) new use (new prescription or increased dose) of gastroprotective agents (GPA) and (2) discontinuation due to dyspeptic symptoms were compared among patients treated with etoricoxib (60 mg, 90 mg, or 120 mg daily) vs. non-selective NSAIDs (diclofenac 50 mg. t.i.d. or naproxen 500 mg. b.i.d.). RESULTS:The overall rates/100 patient-years for new use of GPAs were 9.1 and 13.0 for etoricoxib and NSAIDs, respectively (RR = 0.75; 95% confidence interval [CI] 0.64, 0.89; p < 0.001). A benefit with etoricoxib was seen in the first 6 months when most new GPA usage occurred; after 6 months new use of GPAs was similar between etoricoxib and NSAIDs. The rates/100 patient-years of treatment discontinuation due to dyspeptic symptoms with etoricoxib and NSAIDs were 1.5 and 2.7, respectively (RR = 0.60; 95% CI 0.41, 0.87; p = 0.007). Analyses of placebo-controlled treatment periods showed significantly more new GPA use and more discontinuations due to dyspeptic symptoms with NSAIDs vs. placebo, but not with etoricoxib vs. placebo. CONCLUSION/CONCLUSIONS:In this combined analysis of clinical trials of patients with OA, RA, chronic low back pain, or AS, new use of gastroprotective agents was significantly lower with etoricoxib than with the comparator non-selective NSAIDs during the initial 6 months of treatment and similar thereafter. There were significantly fewer discontinuations for dyspeptic symptoms with etoricoxib than with NSAIDs over the entire follow-up period.

OBJECTIVES/OBJECTIVE:Mitogen-activated protein kinases (MAPK) are important intermediates in the signal transduction pathways involved in neuronal dysfunction following cerebral ischemia-reperfusion injury. One subfamily, extracellular regulated kinase 1/2, has been heavily implicated in the pathogenesis of post-ischemic neuronal damage. However, the contribution of extracellular regulated kinase 1/2 to neuronal damage following deep hypothermic circulatory arrest and low flow cardiopulmonary bypass is unknown. We attempted to correlate the extent of neuronal damage present following deep hypothermic circulatory arrest and low flow cardiopulmonary bypass with phosphorylated extracellular regulated kinase 1/2 expression in the cerebral vascular endothelium. METHODS:Piglets underwent normal flow cardiopulmonary bypass (n=4) deep hypothermic circulatory arrest (n=6) and low flow cardiopulmonary bypass (n=5). Brains were harvested following 24 h of post-cardiopulmonary bypass recovery. Cerebral cortical watershed zones, hippocampus, basal ganglia, thalamus, cerebellum, mesencephalon, pons and medulla were evaluated using hematoxylin and eosin staining. A section of ischemic cortex was evaluated by immunohistochemistry with rabbit polyclonal antibodies against phosphorylated extracellular regulated kinase 1/2. RESULTS:Compared to cardiopulmonary bypass controls, the deep hypothermic circulatory arrest and low flow cardiopulmonary bypass piglets exhibited diffuse ischemic changes with overlapping severity and distribution. Significant neuronal damage occurred in the frontal watershed zones and basal ganglia of the deep hypothermic circulatory arrest group (P<0.05). No detectable phosphorylated extracellular regulated kinase 1/2 immunoreactivity was found in the cardiopulmonary bypass controls; however, ERK 1/2 immunoreactivity was present in the cerebral vascular endothelium of the deep hypothermic circulatory arrest and low flow cardiopulmonary bypass groups. CONCLUSIONS:Our results indicate that phosphorylated extracellular regulated kinase 1/2 may play a prominent role in early cerebral ischemia-reperfusion injury and endothelial dysfunction. The pharmacologic inhibition of extracellular regulated kinase 1/2 represents a new and exciting opportunity for the modulation of cerebral tolerance to low flow cardiopulmonary bypass and deep hypothermic circulatory arrest.

OBJECTIVES/OBJECTIVE:Etoricoxib is a selective cyclooxygenase inhibitor that in clinical studies has improved the signs and symptoms of osteoarthritis and rheumatoid arthritis and reduced the potential for GI injury. The incidence of endoscopically detected ulcers and of clinically important upper GI events (perforations, ulcers, and bleeding episodes) was compared in patients taking etoricoxib or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS:Upper GI endoscopy was performed at intervals over 12 wk in 680 patients taking etoricoxib 120 mg once daily, ibuprofen 800 mg three times daily, or placebo in a randomized, parallel-group, double-blind study. Survival analysis was used to analyze time-to-event data for the incidence of gastric or duodenal ulcers (> or =3 mm and > or =5 mm), and the log rank test was used to compare the cumulative incidence between treatment groups. A combined analysis of upper GI events in all 10 Phase II/III clinical trials of etoricoxib (60, 90, or 120 mg) versus nonselective NSAIDs (naproxen, ibuprofen, or diclofenac) for osteoarthritis, rheumatoid arthritis, and chronic low back pain was conducted. Investigators reported potential events for adjudication by an external, blinded committee, using prespecified criteria to confirm events. All events that occurred during active treatment periods (maximum 792 days) or within 14 days of stopping treatment were included in the analysis. Time to first event was evaluated using survival analysis; the Kaplan-Meier method was used to determine the cumulative incidence, and relative risk was estimated with the Cox proportional hazards model. RESULTS:In the endoscopy study, the cumulative incidence of ulcers >/=3 mm at 12 wk in the ibuprofen group (17%) was significantly higher than in the etoricoxib group (8.1%, p < 0.001); similar results were seen for ulcers >/=5 mm. In the placebo group, the rate of ulcers >/=3 mm was 1.86%. Of 3142 patients treated with once-daily etoricoxib and 1828 patients treated with a nonselective NSAID (ibuprofen, naproxen, or diclofenac), 82 patients with investigator-reported upper GI events (71 confirmed) were eligible for the combined analysis. For etoricoxib versus NSAIDs, the rate per 100 patient-yr for confirmed events was 1.16 versus 3.05 (relative risk = 0.44, 95% CI = 0.27-0.72, p < 0.001), whereas that for investigator-reported events was 1.35 versus 3.42 (relative risk = 0.47, 95% CI = 0.30-0.74, p = 0.001). Results were driven primarily by studies with naproxen as the comparator. CONCLUSIONS:The incidence of endoscopically detected ulcers was significantly lower with etoricoxib 120 mg than with ibuprofen 2400 mg. Treatment with etoricoxib reduced the incidence of investigator-reported and confirmed adverse upper GI events by approximately 50% compared with treatment with nonselective NSAIDs.