Citations

We previously demonstrated that skeletal muscle blood flow is restored in the exercising forearm during experimental hypoperfusion via local dilator and/or myogenic mechanisms. This study examined the role of nitric oxide (NO) in the restoration of blood flow to the active muscles during hypoperfusion. Eleven healthy subjects (10 men/1 woman; 25 ± 1 yr of age) performed rhythmic forearm exercise (10% and 20% of maximum) while hypoperfusion was evoked by balloon inflation in the brachial artery above the elbow. Each trial included baseline, exercise, exercise with inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and local (brachial artery catheter pressure, BAP) and systemic arterial pressure [mean arterial pressure (MAP); Finometer] were measured. The exercise bouts were repeated during NG-monomethyl-l-arginine (l-NMMA) infusion (NO synthase inhibition). Forearm vascular conductance (FVC; ml·min−1·100 mmHg−1) was calculated from BF (ml/min) and BAP (mmHg). FBF and FVC fell acutely with balloon inflation during all trials ( P < 0.01). Recovery of FBF and FVC [(inflation − nadir)/(steady-state exercise − nadir)] with l-NMMA administration was reduced during 20% exercise (FBF = 77 ± 7% vs. 88 ± 8%; FVC = 71 ± 8% vs. 90 ± 9%; P < 0.01) but not 10% exercise (FBF = 83 ± 4% vs. 81 ± 5%, P = 0.37; FVC = 75 ± 10% vs. 76 ± 7%; P = 0.44) compared with the respective control trial. The time to steady-state vasodilator response was substantially longer during the l-NMMA trials (10% = 74 ± 4 s vs. 61 ± 6 s; 20% = 53 ± 4 s vs. 41 ± 4 s; P < 0.05). Thus the magnitude and timing of the NO contribution to compensatory dilation during forearm exercise with hypoperfusion was dependent on exercise intensity. These observations suggest that NO is released by contracting muscles or that a portion of the dilation caused by ischemic metabolites is NO dependent.

An ultraminiature micropressure sensor to accurately measure intramuscular pressure has been developed. The MEMS sensor is fabricated through surface micromachining and consists of a capacitive array of eight 150 μm diameter sensing membranes connected in parallel. The membranes have been vacuum-sealed via a subsequent deposition and patterning batch microfabrication step. A deep reactive ion etcher (DRIE) based postfabrication self-release has been utilized to fabricate individual devices. Each device has an outline that incorporates specially designed “anchor” structures that are utilized to attach on the muscle tissue during measurements to minimize the effect of muscle contractions on sensor readings. Electrical isolation of the wire bonds and bonding pads has been accomplished by utilizing glob-topping technique. The fabricated sensor performance has been experimentally validated inside a pressure chamber. The current sensors have 0.2 mm Hg pressure resolution in the ±19 mm Hg dynamic range with negligible hysteresis and show a flat frequency response in the 0–5.5 Hz experimental test range.

Abstract Background. The Bevacizumab Regimens’ Investigation of Treatment Effects (BRiTE) study is a prospective, observational cohort study designed to elucidate safety and effectiveness outcomes associated with bevacizumab combined with chemotherapy as used in clinical practice for first-line treatment of metastatic colorectal cancer (mCRC). Patients and Methods. Baseline characteristics, prespecified bevacizumab-related adverse events, and effectiveness data were collected from 1,953 mCRC patients who were receiving first-line treatment including bevacizumab at 248 U.S. sites. Results. At database lock, the median follow-up was 20.1 months. At baseline, 46% of patients were aged ≥65 years and 49% had an Eastern Cooperative Oncology Group performance status score ≥1. Fluorouracil, leucovorin, and oxaliplatin was the most common first-line chemotherapy regimen (56%). Overall rates of bevacizumab-related adverse events in the BRiTE study, such as gastrointestinal perforation (1.9%), arterial thromboembolic events (2%), grade 3–4 bleeding (2.2%), and de novo hypertension requiring medication (22%), were consistent with those reported in randomized clinical trials (RCTs) of bevacizumab in first-line mCRC treatment. The median progression-free survival (PFS) and overall survival (OS) times were 9.9 (95% confidence interval [CI], 9.5–10.3) months and 22.9 (95% CI, 21.9–24.4) months, respectively. Conclusion. The median PFS and OS durations and safety profile of bevacizumab in the BRiTE study were similar to those in RCTs of bevacizumab plus chemotherapy in first-line mCRC patients. The observations from the BRiTE study complement and expand upon RCT data, providing clinical information in a large cohort of bevacizumab-treated patients and subgroups such as the elderly.

Objective:This guideline provides evidence‐based recommendations on managing hoarseness (dysphonia), defined as a disorder characterized by altered vocal quality, pitch, loudness, or vocal effort that impairs communication or reduces voice‐related quality of life (QOL). Hoarseness affects nearly one‐third of the population at some point in their lives. This guideline applies to all age groups evaluated in a setting where hoarseness would be identified or managed. It is intended for all clinicians who are likely to diagnose and manage patients with hoarseness.Purpose:The primary purpose of this guideline is to improve diagnostic accuracy for hoarseness (dysphonia), reduce inappropriate antibiotic use, reduce inappropriate steroid use, reduce inappropriate use of anti‐reflux medications, reduce inappropriate use of radiographic imaging, and promote appropriate use of laryngoscopy, voice therapy, and surgery. In creating this guideline the American Academy of Otolaryngology—Head and Neck Surgery Foundation selected a panel representing the fields of neurology, speech‐language pathology, professional voice teaching, family medicine, pulmonology, geriatric medicine, nursing, internal medicine, otolaryngology–head and neck surgery, pediatrics, and consumers.ResultsThe panel made strong recommendations that 1) the clinician should not routinely prescribe antibiotics to treat hoarseness and 2) the clinician should advocate voice therapy for patients diagnosed with hoarseness that reduces voice‐related QOL. The panel made recommendations that 1) the clinician should diagnose hoarseness (dysphonia) in a patient with altered voice quality, pitch, loudness, or vocal effort that impairs communication or reduces voice‐related QOL; 2) the clinician should assess the patient with hoarseness by history and/or physical examination for factors that modify management, such as one or more of the following: recent surgical procedures involving the neck or affecting the recurrent laryngeal nerve, recent endotracheal intubation, radiation treatment to the neck, a history of tobacco abuse, and occupation as a singer or vocal performer; 3) the clinician should visualize the patient's larynx, or refer the patient to a clinician who can visualize the larynx, when hoarseness fails to resolve by a maximum of three months after onset, or irrespective of duration if a serious underlying cause is suspected; 4) the clinician should not obtain computed tomography or magnetic resonance imaging of the patient with a primary complaint of hoarseness prior to visualizing the larynx; 5) the clinician should not prescribe anti‐reflux medications for patients with hoarseness without signs or symptoms of gastroesophageal reflux disease; 6) the clinician should not routinely prescribe oral corticosteroids to treat hoarseness; 7) the clinician should visualize the larynx before prescribing voice therapy and document/communicate the results to the speech‐language pathologist; and 8) the clinician should prescribe, or refer the patient to a clinician who can prescribe, botulinum toxin injections for the treatment of hoarseness caused by adductor spasmodic dysphonia. The panel offered as options that 1) the clinician may perform laryngoscopy at any time in a patient with hoarseness, or may refer the patient to a clinician who can visualize the larynx; 2) the clinician may prescribe anti‐reflux medication for patients with hoarseness and signs of chronic laryngitis; and 3) the clinician may educate/counsel patients with hoarseness about control/preventive measures.Disclaimer:This clinical practice guideline is not intended as a sole source of guidance in managing hoarseness (dysphonia). Rather, it is designed to assist clinicians by providing an evidence‐based framework for decision‐making strategies. The guideline is not intended to replace clinical judgment or establish a protocol for all individuals with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem.

AbstractPurpose: This study aimed to evaluate the safety of, immune response induced by, and efficacy of treatment with lapuleucel-T (APC8024) in patients with HER-2/neu–expressing tumors. Lapuleucel-T is an investigational active immunotherapy product consisting of autologous peripheral blood mononuclear cells, including antigen presenting cells, which are cultured ex vivo with BA7072, a recombinant fusion antigen consisting of portions of the intracellular and extracellular regions of HER-2/neu linked to granulocyte-macrophage colony-stimulating factor.Experimental Design: Patients with metastatic breast, ovarian, or colorectal cancer whose tumors expressed HER-2 were eligible. Patients underwent leukapheresis in week 0 and received lapuleucel-T infusions in weeks 0, 2, and 4. Patients who achieved a partial response or had stable disease through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment.Results: Eighteen patients were enrolled and treated. Patients showed an immune response to the immunizing antigen (BA7072) at week 8 compared with week 0 as measured by T lymphocyte proliferation and IFN-γ enzyme-linked immunospot assay. Therapy was well tolerated. The majority (94.7%) of adverse events associated with treatment were grade 1 or 2. Two patients experienced stable disease lasting &gt;48 weeks.Conclusions: Autologous active cellular immunotherapy with lapuleucel-T stimulated an immune response specific to the immunizing antigen and seemed to be well tolerated. Further clinical studies to assess the clinical benefit for patients with HER/2-neu–expressing breast, ovarian, and colorectal cancer are warranted. (Clin Cancer Res 2009;15(18):5937–44)

Background— The relationship between neutrophils and outcomes post–myocardial infarction (MI) is not completely characterized. We examined the associations of neutrophil count with mortality and post-MI heart failure (HF) and their incremental value for risk discrimination in the community. Methods and Results— MI was diagnosed with cardiac pain, biomarkers, and Minnesota coding of the ECG. Neutrophil count at presentation, reported as counts ×10 9 /L, was categorized by tertiles (lower tertile, <5.7; middle tertile, 5.7 to 8.5; upper tertile, >8.5). From 1979 to 2002, 2047 incident MIs occurred in Olmsted County, Minn (mean age, 68±14 years; 44% women). Median (25th to 75th percentile) neutrophil count was 7.0 (5.1 to 9.5). Within 3 years post-MI, 577 patients died, and 770 developed HF. Overall survival and survival free of HF decreased with increased neutrophil tertile ( P <0.001). Compared with the lower tertile, the age and sex adjusted hazard ratio for death was 1.44 (95% CI, 1.14 to 1.81) for the middle tertile and 2.60 (95% CI, 2.10 to 3.22) for the upper tertile ( P <0.001). Similarly, for HF, the hazard ratio was 1.32 (95% CI, 1.09 to 1.59) for the middle and 2.12 (95% CI, 1.77 to 2.53) for the upper tertile ( P <0.001). These associations persisted after adjustment for risk factors, comorbidities, Killip class, revascularization, and ejection fraction. Neutrophil count improved risk discrimination as indicated by increases in the area under the receiver operating characteristic curves (all P <0.05) and by the integrated discrimination improvement analysis (all P <0.001). Conclusions— In the community, the neutrophil count was strongly and independently associated with death and HF post-MI and improved risk discrimination over traditional predictors.

Background— The risk of syncope occurring while driving has obvious implications for personal and public safety. We aimed to define the clinical characteristics, causes, and prognosis of syncope while driving. Methods and Results— In this case-control study of consecutive patients evaluated for syncope from 1996 through 1998 at an academic medical center, we documented causes, clinical characteristics, and recurrence of syncope while driving. Of 3877 patients identified, 381 (9.8%) had syncope while driving (driving group). Compared with the 3496 patients (90.2%) who did not have syncope while driving, the driving group was younger ( P =0.01) and had higher percentages of male patients ( P <0.001) and patients with a history of any cardiovascular disease ( P =0.01) and stroke ( P =0.02). Syncope while driving was commonly caused by neurally mediated syncope (37.3%) and cardiac arrhythmias (11.8%). Long-term survival in the driving group was comparable to that of an age- and sex-matched cohort from the Minnesota population ( P =0.15). Among the driving group, syncope recurred in 72 patients, 35 of whom (48.6%) had recurrence >6 months after the initial evaluation. Recurrences during driving happened in 10 patients in the driving group, 7 of which (70%) were >12 months after the initial evaluation. Conclusions— In our study, neurally mediated syncope was the most common type of syncope while driving. The causes of syncope, the late recurrences of syncope (during ≥6 months of follow-up), and the overall low incidence of recurrent syncope while driving provide useful information to supplement current recommendations on driving for these patients.