Citations

Functional values of LogSD of the ventilation distribution (σV̇) have been reported previously, but functional values of LogSD of the perfusion distribution (σq̇) and the coefficient of correlation between ventilation and perfusion (ρ) have not been measured in humans. Here, we report values for σV̇, σq̇, and ρ obtained from wash-in data for three gases, helium and two soluble gases, acetylene and dimethyl ether. Normal subjects inspired gas containing the test gases, and the concentrations of the gases at end-expiration during the first 10 breaths were measured with the subjects at rest and at increasing levels of exercise. The regional distribution of ventilation and perfusion was described by a bivariate log-normal distribution with parameters σV̇, σq̇, and ρ, and these parameters were evaluated by matching the values of expired gas concentrations calculated for this distribution to the measured values. Values of cardiac output and LogSD ventilation/perfusion (V̇a/Q̇) were obtained. At rest, σq̇ is high (1.08 ± 0.12). With the onset of ventilation, σq̇ decreases to 0.85 ± 0.09 but remains higher than σV̇ (0.43 ± 0.09) at all exercise levels. Rho increases to 0.87 ± 0.07, and the value of LogSD V̇a/Q̇ for light and moderate exercise is primarily the result of the difference between the magnitudes of σq̇ and σV̇. With known values for the parameters, the bivariate distribution describes the comprehensive distribution of ventilation and perfusion that underlies the distribution of the V̇a/Q̇ ratio.

Despite the growing demand for emergency neurological evaluations and neurohospitalists, the supply of neurologists remains relatively fixed over time. Telemedicine is a unique tool that has the ability to put a medical specialist like a neurologist in 2 places in a relatively short period of time, expanding expertise in many rural and in some underserved urban facilities that would ordinarily be devoid of such expertise. Teleneurology is a branch of telemedicine that consults and practices through remote neurological evaluation. Telestroke is defined as remote stroke evaluation. The demand for timely neurological evaluation, especially acute stroke evaluation and treatment with intravenous recombinant tissue plasminogen activator (IV rtPA), continues to fuel the growth of neurohospitalists, telestroke, and teleneurology services. Remote, rural, or underserved urban emergency departments and hospitals which are unable to successfully recruit a neurologist or neurohospitalist to provide this service are uniquely suited to a teleneurology option. The number of private practices and academic centers providing telestroke services has grown significantly in the past decade with continued growth expected. We describe the benefits and drawbacks of teleneurology/telestroke, as well as other practical aspects for the teleneurohospitalist.

Abstract Background: Activation of oncology trials is a lengthy and complex process. Recent literature has identified numerous opportunities to improve activation timelines1, 2. The Multiple Myeloma Research Consortium (MMRC) has implemented several processes to identify and overcome myeloma clinical trial activation barriers within the consortium network of 14 North American cancer centers. We examined the impact of these processes preand post- implementation and also compared activation times with published clinical trial metrics data. Methods/Results: 12 MMRC-facilitated trials had sufficient trial data available for review within the study period of May 2006 to March 2009. Activation time was defined as the time from a center's receipt of the final clinical trial protocol from the sponsor, to the time the first patient was enrolled into a trial at any MMRC participating center. The earlier group (EG) of MMRC trials (n=7) required a mean of 257 calendar days for activation, comparable to the mean published data of 251 calendar days1. The more recent group (RG) of MMRC trials (n=5) required a mean of 158 calendar days for activation, representing a 38% shortening of activation time. Additionally, implementation of standardized processes and rigorous project management resulted in a reduction in activation times for all MMRC centers in a given trial from a mean of 7.5 months to a mean of 5.1 months. Improving the mean time of several several specific steps in the process including time to initial protocol review submission from receipt (EG=37 vs. RG=19 days), scientific review committee time (EG=98 vs. RG=55 days), and the time from trial opening to first patient dosed (EG=74 vs. RG=27 days) contributed to the overall decrease in activation times. The EG metrics data are comparable to published data1 for each process step. Conclusion: The MMRC member institutions have seen substantial improvements in trial activation times and are in the process of implementing additional processes to further improve protocol development and trial conduct metrics. The efficiencies and process improvements realized from application of rigorous MMRC project management resources and the standardization of contracting and other key activities may be applied in other areas of oncology clinical trials beyond multiple myeloma. With increasing numbers of new oncology agents to be evaluated and greater pressure on trial sponsors to introduce efficiencies into trial timelines, overcoming such barriers is of critical importance. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B58.

Abstract Background and Aims: In patients with Barrett's esophagus (BE), reflux-induced injury promotes esophageal adenocarcinoma, presumably through cyclooxygenase 2 (COX-2) related pathways. Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs) may interrupt reflux-associated carcinogenesis by reducing acid exposure and subsequent inflammation. However, clinical trial data regarding the chemopreventive efficacy of a PPI + NSAID combination are limited. The aim of this multi-center, randomized, phase II trial was to assess the effects of a 28-day intervention with esomeprazole 40 mg bid and aspirin 81 mg qd, 325 mg qd, or placebo qd on tissue prostaglandin E2 (PGE2) concentrations in BE patients. Methods: Using the infrastructure of the Cancer Prevention Network, participants (> 18 years) with histologically confirmed non dysplastic BE were randomly assigned to receive one of three interventions for 28 days: (arm A) esomeprazole 40 mg bid+ aspirin 81 mg placebo qd + aspirin 325 mg placebo qd (n=42); (arm B) esomeprazole 40 mg bid+ aspirin 81 mg qd + aspirin placebo 325 qd (n=63); (arm C) esomeprazole 40 mg bid + aspirin 81 mg qd placebo + aspirin 325 mg qd (n=63). Esophageal biopsies were obtained pre- and post-intervention to assess change in PGE2 concentration as the primary endpoint. Results: In total, 122 participants were randomized, 121 (99%) completed the trial per protocol, and 115 (94%) were evaluated for the primary endpoint. Baseline characteristics were similar across intervention arms. The absolute change (mean + SD) in tissue PGE2 concentration was −67.6 (229.68) in Arm A, −120.9 (281.28) in Arm B (p = 0.10 vs Arm A) and −174.9 (263.62) in Arm C (p = 0.02 vs Arm A). Conclusions: In combination with esomeprazole 40 mg twice per day, aspirin 325 mg per day significantly reduced tissue PGE2 concentration in BE patients after a 28-day intervention, as compared to aspirin placebo. Given the relevance of PGE2 pathways in BE-associated carcinogenesis, further evaluation of this chemoprevention strategy in larger, more definitive phase III trials is warranted. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN06-03.

OBJECTIVE To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. RESEARCH DESIGN AND METHODS A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years. RESULTS Insulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). CONCLUSIONS The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.

Pelvic lymph node dissection is the gold standard for assessing nodal disease in prostate or bladder cancer and is superior to CT, MRI and PET staging. Endoscopic ultrasound (EUS) provides an alternative, less invasive method of cytohistologic material acquisition, but its performance in pelvic urologic malignancy is unknown. Therefore, our aim was to evaluate the diagnostic accuracy of EUS guided tissue sampling for these malignancies when compared to a composite cytohistologic and surgical gold standard. A median of 3 FNA passes were performed (n=19 patients) revealing a sensitivity, specificity, PPV and NPV of 94.4% (72–99), 100% (2–100), 100% (80–100) and 50% (1–98) respectively. The perirectal space was the most frequently sampled location irrespective of the primary urological cancer origin. Final diagnosis established by EUS tissue sampling included bladder cancer (n=1), bladder cancer local recurrence (n=8), bladder cancer extra pelvic metastases (n=1), prostate cancer (n=2), prostate cancer local recurrence (n=4), prostate cancer extra pelvic metastases (n=1), testicular cancer extra pelvic metastases (n=1) and a benign seminal vesicle (n=1). EUS guided sampling of the gut wall, lymph nodes, or perirectal space yields suitable diagnostic material to establish the presence of primary, local recurrence or extra pelvic metastases of pelvic urologic malignancy.

Abstract —The Hypertension Optimal Treatment Study is a prospective trial conducted in 26 countries. The aims are to (1) evaluate the relationship between three levels of target office diastolic blood pressure (BP) (≤80, ≤85, or ≤90 mm Hg) and cardiovascular morbidity and mortality in hypertensive patients and (2) examine the effects on cardiovascular morbidity and mortality of 75 mg aspirin daily versus placebo. A total of 19 193 patients between 50 and 80 years of age had been randomized by the end of April 1994. Treatment was initiated with felodipine 5 mg daily, and additional therapy was given in accordance with a set protocol. The present substudy of 926 patients performed in nine countries aimed to (1) compare home with office BP in a representative subsample of the HOT population after the titration of treatment was completed and (2) clarify whether the separation into the target groups could be expanded into the out-of-office setting. The differences between office and home measurements in diastolic BP of 0.2 mm Hg (SD, 9; 95% confidence interval, −0.36 to 0.81; P =.40) and systolic BP of 0.5 mm Hg (SD, 15; 95% confidence interval, −0.53 to 1.46; P =.21) were not significant. The group differences in home BP were 1.9 mm Hg (≤80 versus ≤85) and 1.2 mm Hg (≤85 versus ≤90) for diastolic BP (F=11.69; ANOVA, P <.0001) and 2.6 and 2.1 mm Hg for systolic BP (F=8.44, P =.0002). Thus, office and home BPs measured with the same semiautomatic device are comparable in treated hypertensive subjects in the HOT Study, and the separation into the target groups based on office readings prevails at home.

Background —The objectives of our study were to determine the frequency of supraventricular tachyarrhythmias (SVTAs) among modifications of the Fontan operation and identify risk factors for developing SVTA. Methods and Results —The population consisted of all patients who had any modification of the Fontan operation at the Mayo Clinic between 1985 and 1993. Clinically significant SVTAs were those requiring initiation or change of antiarrhythmic treatment, and they were divided into early SVTAs (<30 days after the operation) and late SVTAs (≥30 days after the operation). Clinical histories were reviewed, and health status questionnaires were sent. Four hundred ninety-nine patients had various modifications of the Fontan operation. Frequency of early SVTA was 15%. Risk factors identified by multivariate analysis for early SVTA were AV valve regurgitation, abnormal AV valve, and preoperative SVTA. Frequency of late SVTA was 6% by 1 year, 12% by 3 years, and 17% by 5 years. Risk factors for late SVTA were age at operation (<3 or ≥10 years) and systemic AV valve replacement. By univariate and multivariate analysis, the type of Fontan operation was not a significant risk factor for late SVTA when all 6 modifications were considered. However, when we analyzed the frequency of late SVTA for the 2 recently used modifications, we found a lower frequency of late SVTA in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection. Conclusions —Postoperative SVTA continues to be a significant problem. Risk factors for SVTA are AV valve regurgitation, abnormal AV valve, preoperative SVTA, and age at operation. Frequency of SVTA does not appear to be related to type of Fontan procedure except for slightly lower frequency in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection.

BackgroundRecent studies suggest that neurohumoral mechanisms including decreased renal responses to increases in atrial natriuretic factor (ANF) play a central role in the progression from asymptomatic cardiac dysfunction to advanced congestive heart failure (CHF) with sodium retention, vasoconstriction, and reduced exercise tolerance. Recognizing that neutral endopeptidase 24.11 degrades ANF and may be enhanced in CHF, we hypothesized that chronic neutral endopeptidase inhibition (NEP-I) would potentiate renal responses to exogenous ANF and alter the temporal evolution of sodium retention in evolving CHF by potentiation of increased endogenous ANF.Methods and ResultsWe studied 13 conscious dogs with evolving CHF produced by rapid ventricular pacing at 250 beats per minute. Six of these dogs received NEP-I with candoxatril, 10 mg/kg PO BID, throughout evolving CHF. Responses to exogenous ANF, 10 μg/kg IV bolus, were assessed at baseline and after 6 days of CHF. Daily metabolic studies during evolving CHF with chronic NEP-I showed increased sodium excretion and renal cGMP generation consistent with enhanced renal activity of endogenous ANF compared with untreated controls. In addition, renal natriuretic and cGMP responses to exogenous ANF were intact in CHF with chronic NEP-I in contrast to markedly attenuated renal responses to exogenous ANF in untreated CHF. Despite enhanced ANF responsiveness and improved sodium balance in evolving CHF, a moderate degree of sodium retention was observed during chronic NEP-I in evolving CHF.ConclusionsEnzymatic degradation by neutral endopeptidase limits local renal responses to increases in endogenous and exogenous ANF in CHF independent of changes in systemic hemodynamics or augmented plasma concentrations of ANF. The moderate sodium retention observed during evolving CHF despite chronic NEP-I probably reflects the antinatriuretic effects of hemodynamic and humoral factors independent of ANF activity.