Monocyte-associated tissue factor is suppressed by phorbol myristate acetate

The monocyte is the only normal circulating cell type capable of initiating blood coagulation through the expression of tissue factor. Recently isolated peripheral blood monocytes that contain no demonstrable tissue factor activity can be induced to express tissue factor activity by a number of stimulatory agents. Monocyte-associated tissue factor activity transiently increases in response to adherence to tissue culture plates and, consistent with other reports, markedly increases after the isolated monocytes are treated with endotoxin. Phorbol myristate acetate (PMA) induced an increase in tissue factor activity at low doses (10(-11) to 10(-12) mol/L). Conversely, concentrations of PMA that stimulate release of oxygen metabolites or that cause the cytosol-to-membrane translocation of protein kinase C (PKC) (10(-9) to 10(-7) mol/L) resulted in a rapid decrease in both adherence-induced and endotoxin-induced monocyte tissue factor activity. The effects of PMA on monocytes were time- and dose-dependent with respect to PKC translocation, release of oxygen metabolites, and changes in tissue factor activity. Immunofluorescent staining of monocytes with monoclonal antibody (MoAb) HTF1-7B8, directed against human tissue factor, revealed that tissue factor antigen was induced concurrently with tissue factor activity by adherence and endotoxin and that tissue factor antigen decreased after PMA stimulation.     

Short-term frovatriptan for the prevention of difficult-to-treat menstrual migraine attacks

The efficacy of a 6-day regimen of frovatriptan for menstrual migraine (MM; attacks starting on day −2 to +3 of menses) prevention in women with difficult-to-treat MM was assessed. Women with a documented inadequate response to triptans for acute MM treatment were included in this placebo-controlled, parallel-group trial. Women were randomized to double-blind treatment for three perimenstrual periods (PMPs) with either frovatriptan 2.5 mg (q.d. or b.i.d.) or placebo initiated 2 days before anticipated MM. The efficacy analysis included 410 women with 85% completing three double-blind PMPs. The mean number of headache-free PMPs was 0.92 with frovatriptan b.i.d., 0.69 with frovatriptan q.d. and 0.42 with placebo [ P  < 0.001 (b.i.d.) and P  < 0.02 (q.d.) vs. placebo]. When migraine occurred, severity was reduced with frovatriptan q.d. ( P  < 0.001) and b.i.d. ( P  < 0.001) vs. placebo. Both frovatriptan regimens were well tolerated. In women with difficult-to-treat MM, a 6-day regimen of frovatriptan significantly reduced MM incidence and severity.     

Hypofractionated irradiation for inoperable non-small cell lung cancer

A policy of palliative intent thoracic irradiation was prospectively evaluated in 38 consecutive patients referred for treatment of inoperable non-small cell lung cancer at a single institution. A target dose of 1700cGy in two fractions 1 week apart was delivered. Characteristics of the treatment group revealed most (87%; 33/38) to be of good-excellent performance status with minimal weight loss before irradiation. Although three patients (8%) had initial metastatic disease, ail had symptoms referable to the thorax with cough (71%), dyspnoea (55%), haemoptysis (39%), and chest wall pain (34%) being dominant. Following treatment, the relative risk of maintaining complete response with regard to each of these symptoms was 0.91, 0.40, 0.92 and 0.78, respectively. Overall 70% of patients maintained complete symptomatic response to time of death or last review. Uncorrected median survival was 35 weeks and was comparable to best international end-results for either palliative intent or curative intent radiation schedules. We conclude that the radiation regimen employed is safe, efficacious and eminently resource conscious. Recognition of patient groups who overwhelmingly derive no benefit from conventional fractionation schedules will streamline access to radiotherapy services of patients suitable for radical treatment.     

Methysergide

Methysergide is a semisynthetic ergot alkaloid ergometrine derivative, introduced in pharmacotherapy for migraine prophylaxis as a specific serotonin (5HT) receptor antagonist. Methysergide is not just a 5HT₂ antagonist, it is also a 5HT₁ agonist. Open and controlled studies attest to methysergide's efficacy. It may be more effective in resistant cases with a high attack frequency and may act synergistically with ergotamine and dihydroergotamine (DHE) for breakthrough attacks. Contraindications include pregnancy, peripheral vascular disorders, severe arteriosclerosis, coronary artery disease, severe hypertension, thrombophlebitis or cellulitis of the legs, peptic ulcer disease, fibrotic disorders, lung diseases, collagen disease, liver or renal function impairment, valvular heart disease, debilitation, or serious infection. Methysergide can induce retroperitoneal fibrosis and pleural and heart valve fibrosis with an estimated incidence of 1 in 5,000 treated patients. Therefore, it should be reserved for severe cases in which other migraine preventive drugs are not effective.     

Measuring and reporting glycemic control in clinical trials: building a path to consensus

Clinical trials over time have used a variety of approaches for both measuring tight glycemic control and reporting results. The review by Finfer and colleagues in this issue of Critical Care is a step toward consensus within the research community to standardize the way blood glucose is measured and reported in clinical trials. The authors propose using specific measures of central tendency and dispersion for reporting glucose, advocate the use of blood gas analyzers and elimination of point-of-care glucose monitors in the intensive care unit, and comment on performance of continuous glucose monitors. As we await the release of updated rules from the International Standards Organization and process the new rules from the Clinical Laboratory and Standards Institute to regulate glucose monitoring, these recommendations should trigger many more conversations within the field as we strive for uniformity. However, we need to be cautious in prematurely proposing and adopting standards of care that fail to account for newer technology and data in this rapidly growing area of research.Although whether to perform tight glycemic control (TGC) in the adult intensive care unit (ICU) continues to be debated among intensivists and endocrinologists worldwide, how to report and assess TGC took a constructive step forward with the publication of the consensus recommendations in this issue of Critical Care [1]. The authors, some of whom are the principal investigators from many of the major adult TGC trials in the field, present a compelling case for uniformity in assessment and reporting of future trials.The group discussed and made recommendations in five areas: (a) measurement of intermittent blood glucose (BG) and characterization of those measurements, (b) performance standards for BG measurement devices, (c) use of continuous glucose monitoring (CGM), (d) assessment of CGM, and (e) performance of CGM. Although they cited much of the relevant published literature over the last several years, their task was daunting, particularly with new and improved BG measurement technology just recently brought to the inpatient setting [2]. The authors ultimately produced consensus recommen dations, which are excellent first steps toward the laudable goal of uniform assessment and reporting.In considering adoption of new standards, one has to take into account the quality and quantity of evidence that supports them as well as the structure of the formal analysis of the data. Finfer and colleagues put forth many resolutions to open questions. If adopted by clinical researchers, these standards would allow the signal to be noticed above the noise. However, some of the ''noise'' that exists in the TGC literature represents reasonable variability in experimental approaches to performing and measuring TGC as well as in real-world implementation. For example, the authors acknowledge that protocols that increase BG sampling frequency as BG drops below a certain range will have a lower BG mean. However, the meeting consensus stipulates that the central tendency be reported as a median of patients'' individual means, which does not mitigate the acknowledged bias.When stipulating methods of measuring BG at the bedside in the ICU, the authors review performance of hospital meters from the prior generation of technology and rightly conclude that the meters are inadequate for ICU monitoring. But with a new generation of hospital BG meters on the market, new ICU evaluations are surely warranted [2]. Similarly, the cited International Standards Organization (ISO) and Clinical Laboratory and Standards Institute (CLSI) rules for BG meters are inappropriately generous for ICU use [3,4]; however, new rules have been developed by both organizations and are currently being rolled out [5,6]. Although blood gas analyzers are widely accepted to have outstanding precision and accuracy, they are not present in every ICU. Stipulation in a consensus document that glucose meters are unacceptable on the basis of prior generations of devices might discourage investigators from conducting clinical trials. In fact, the largest adult and pediatric trials published to date used this prior generation of devices with relatively low rates of severe hypoglycemia (7% and 3%), although the pediatric trial also used a computerized algorithm augmented with CGM [7,8]. The authors make similarly strong statements about the use of CGM in TGC, concluding that there are insufficient data about performance in the ICU.Finfer and colleagues provide a first attempt at addressing the major issues in the field of conducting TGC in a clinical trial. The authors take a definitive position on a host of challenges facing TGC investigators, allowing the field to move forward. The phrase ''the devil is in the details'' was not coined to describe clinical research, but those of us engaged in its conception and design know that it may as well have been. In trying to pin down many of those details, the authors are to be congratulated. However, it behooves all of us in the field to continue to advance and refine the conversation and to update our conclusions with the most recently available devices and data so that, ultimately, in both adult and pediatric critical care, we can discern which populations derive what benefit when a well-defined therapy is applied to their care.     

Exosomes from human saliva as a source of microRNA biomarkers

Objective:  The aim of this study was to examine the presence of microRNAs (miRNAs) within exosomes isolated from human saliva and to optimize and test methods for successful downstream applications.
Design:  Exosomes isolated from fresh and frozen glandular and whole human saliva were used as a source of miRNAs. The presence of miRNAs was validated with TaqMan quantitative PCR and miRNA microarrays.
Results:  We successfully isolated exosomes from human saliva from healthy controls and a patient with Sjögren's syndrome. microRNAs extracted from the exosomal fraction were sufficient for quantitative PCR and microarray profiling.
Conclusions:  The isolation of miRNAs from easily and non-invasively obtained salivary exosomes with subsequent characterization of the miRNA expression patterns is promising for the development of future biomarkers of the diagnosis and prognosis of various salivary gland pathologies.     

Lumbar fusion outcomes stratified by specific diagnostic indication

BACKGROUND: One of the primary difficulties in evaluating the effectiveness of lumbar fusion is that, with the exception of spondylolisthesis, specific diagnostic indications for surgery are poorly defined. Diagnostic specificity beyond the symptom of low back pain or the presence of lumbar degeneration needs to be delineated such that outcomes data can be effectively translated into clinical decision making or evidence-based guidelines. PURPOSE: The purpose of this study was to report on prospectively collected clinical outcome measures, stratified by diagnosis, among a series of patients with lumbar degenerative disease whose treatment included lumbar spine fusion. STUDY DESIGN: Demographics, diagnostic categorization, and clinical outcome measures were prospectively collected by six spine surgeons at a single tertiary spine center, as part of the surgeons' standard clinical practice. PATIENT SAMPLE: Four hundred and twenty-eight patients were enrolled in the study and complete 1- and 2-year Health-Related Quality of Life (HRQOL) data were available in 327 patients whose treatment included decompression and posterolateral lumbar fusion. OUTCOME MEASURES: The Oswestry Disability Index (ODI), Short Form-36 (SF-36), numeric rating scales for back pain and leg pain. METHODS: Preoperative diagnosis was classified, in the primary surgical cases, as disc pathology, spondylolisthesis, instability, stenosis, or scoliosis. In revision cases, the diagnosis was classified as nonunion, adjacent level degeneration, or postdiscectomy revision. Patient-reported outcomes at 1 and 2 years post-op were assessed based on diagnostic stratification. Statistical evaluation of clinical outcome was performed for both mean net change in outcome scores and the percentage of patients reaching a minimum clinically important difference (MCID) threshold for each outcome measure. RESULTS: Preoperative diagnosis was spondylolisthesis (n=80), scoliosis (n=17), disc pathology (n=33), instability (n=21), stenosis (n=46), postdiscectomy revision (n=67), adjacent level degeneration (n=40), or nonunion (n=23). Evaluation of 2-year post-op HRQOL measures by diagnostic subgroup revealed the most substantial improvement in ODI score for patients with spondylolisthesis (22.7 points) and scoliosis (21.2 points). Patients with the diagnosis of disc pathology (16.2 points), postdiscectomy revision (14.0 points), instability (12.7 points), stenosis (10.6 points), and adjacent level degeneration (9.5 points) demonstrated a progressively smaller magnitude of ODI improvement. The least ODI improvement at 2 years after surgery was seen in patients with nonunion of a prior fusion (5.5 points). The percentage of patients reaching MCID for ODI at 2 years post-op ranged from 71.0% in the spondylolisthesis subgroup to 34.8% in the nonunion subgroup. The greatest SF-36 physical component score improvement at 2-year follow-up was seen in patients with disc pathology (7.9 points) and spondylolisthesis (7.7 points), followed by scoliosis (6.6 points) and stenosis (6.5 points), instability (5.6 points), postdiscectomy revision (5.3 points) nonunion (3.1 points) and adjacent level degeneration (2.5 points). No significant changes from Year 1 to Year 2 were noted in any of the subgroups. For SF-36 physical component score, percentage of patients reaching MCID ranged from 63.6% in the disc pathology subgroup to 25% in the nonunion subgroup. CONCLUSIONS: This study supports the concept that added diagnostic specificity is a critical component in building an improved evidence base for lumbar fusion surgery. The magnitude of HRQOL improvement was not equal among diagnostic subgroups. The percentage of patients reaching an MCID level of improvement was also significantly influenced by diagnostic stratification. Without diagnostic specificity for entities beyond spondylolisthesis, the absence of well-defined study populations will continue to limit our ability to move toward evidence-based decision making.