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Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood-brain barrier and the potential to antagonize the peripherally mediated effects of opioids. The effectiveness of methylnaltrexone in preventing morphine-induced changes in gastrointestinal motility and transit without affecting analgesia was evaluated in humans. Twelve healthy volunteers were given intravenous placebo, placebo plus 0.05 mg/kg morphine, or 0.45 mg/kg methylnaltrexone plus 0.05 mg/kg morphine. Oral-cecal transit time was assessed by the pulmonary hydrogen measurement technique, and analgesia was measured with use of the cold-pressor test. Morphine significantly increased oral-cecal transit time from 104.6 ± 31.1 minutes (mean ± SD) to 163.3 ± 39.8 minutes (p < 0.01). Methylnaltrexone prevented 97% of morphine-induced increase in oral-cecal transit time (106.3 ± 39.8 minutes; not significant compared with baseline; p < 0.01 compared with morphine alone). Methylnaltrexone did not affect the analgesic effect of morphine on both pain intensity and pain bothersomeness ratings. At a higher dose of morphine (0.1 mg/kg), our preliminary results indicated that 0.45 mg/kg methylnaltrexone also prevented the morphine-induced delay in oral-cecal transit time, with no effect on analgesia. Methylnaltrexone may be a useful adjunct to opioids for the relief of opioid-induced constipation. Clinical Pharmacology & Therapeutics (1996) 59, 469–475; doi

We studied 61 patients undergoing elective major non-cardiac surgery in a randomized, double-blind, placebo-control clinical trial to test the hypothesis that the addition of clonidine to a standardized general anesthetic could safely provide postoperative sympatholysis for patients with known or suspected coronary artery disease. Patients were allocated randomly to receive either placebo (n = 31) or clonidine (n = 30). The treatment group received premedication with a transdermal clonidine system (0.2 mg/d) the night prior to surgery, which was left in place for 72 h, and 0.3 mg oral clonidine 60-90 min before surgery. Clonidine reduced enflurane requirements, intraoperative tachycardia, and myocardial ischemia (1/28 clonidine patients vs 5/24 placebo, P = 0.05). However, clonidine decreased heart rates only during the first five postoperative hours; the incidence of postoperative myocardial ischemia (6/28 clonidine vs 5/26 placebo) did not differ between the two groups. Patients who experienced postoperative myocardial ischemia tended to have higher heart rates after surgery. Clonidine significantly reduced the plasma levels of epinephrine (P = 0.009) and norepinephrine (P = 0.026) measured on the first postoperative morning. There were no differences in the need for intravenous fluid therapy or antihypertensive therapy after surgery. The number of hours spent in an intensive care setting and the number of days spent in hospital were not different between the two groups. These results suggest that larger doses of clonidine should be investigated for their ability to decrease postoperative tachycardia and myocardial ischemia.

Various noninvasive tests have been proposed to stratify perioperative cardiovascular risk, including dipyridamole thallium scintigraphy (DTS), ejection fraction estimation by radionuclide ventriculography (RNV), ischemia monitoring by ambulatory electrocardiography (AECG), and dobutamine stress echocardiography (DSE). Which of these tests is most effective for predicting adverse perioperative cardiac outcome? To answer this question, and also to stimulate future studies, we evaluated 56 studies examining one or more of the four tests. We conducted meta-analysis on 20 studies that met the inclusion criteria. Outcome measures evaluated were cardiac death or myocardial infarction occurring during hospital stay or within 1 mo after surgery. Relative risk (RR), which is the probability of adverse cardiac outcome when the test is positive divided by the probability of adverse outcome when the test is negative, was used to combine evidence from different studies. An empirical Bayes procedure with a normal-normal hierarchic model was then used to obtain a meta-analytic confidence interval for the overall median of the relative risks. The between-study variance was estimated using the method of moments approach described by DerSimonian and Laird (Controlled Clin Trials 1986; 7:177–88). Combined (median) RR [95% confidence interval (CI)] and the number of studies included in our meta-analysis for different evaluative tests were as follows: DTS 4.6 (2.1–10.4) (n = 6); RNV 3.7 (1.6–8.3) (n = 5); AECG 2.7 (1.4–5.1) (n = 6), and DSE 6.2 (1.7–22.8) (n = 3). We conclude that while DTS, RNV, AECG, and DSE are effective (the 95% CIs are greater than 1.0) in predicting the cardiac outcome after vascular surgery, the data are not definitive in determining the optimal test (95% CIs for RR overlap). Future studies should include DSE, as this test shows great promise for predicting adverse cardiac events after vascular surgery.

The NF-kappa b/Rel and I kappa B proteins are important regulators of lymphocyte activation and gene expression. We have identified a rearrangement of the NFKB-2 gene in the HUT 78 human cutaneous T-cell leukemia (CTCL) line, cDNA and genomic DNA sequence predicted the presence of a truncated 80 kD NFKB-2 precursor protein (p80HT), instead of the normal p100 protein. No wild-type allele was identified. Elevated levels of two aberrantly sized RNAs were detected, and high levels of p80HT and processed p52 protein were present in HUT 78 cell nuclei. The p52 protein bound to a palindromic kappa B DNA motif, however p80HT did not. Rearrangement of the NFKB-2 gene was also detected in DNA from two patients with CTCL. Rearrangement and overexpression of the NFKB-2 gene may contribute to the genesis of a subset of T-cell malignancies.

This paper describes in some detail the procedures used by the Bureau of Economic Analysis to estimate the change in business inventories in the U.S. national accounts. The main underlying approach has not changed in several decades but relatively recent improvements in basic data, supplied chiefly by the Census Bureau, plus computerization, have made possible more refined estimates.

The operating principle, and proof-of-concept data, for a physical device (the mass loading monitor) to alert plant operators when airborne dust approaches the minimum explosive concentration (MEC) level are presented. The MEC, stated as g m−3, is dependent upon the material and environmental factors. Values as low as 30 g m−3 must be evaluated. The measurement strategy, a temporal integration of the piston face pressure as the air-plus-dust charge is impulsively expelled from a cylinder compared with the same integral for an air-only sample, is shown to yield the mass loading (xx g m−3) of the airborne dust. This measurement strategy is demonstrated using a dedicated test apparatus. This demonstration establishes the proof of concept.

Visual analog scales (VAS) ranging from 0 cm (no pain) to 10 cm (worst imaginable pain) are used widely for pain measurement, but various investigators have not treated these data consistently. Conventional statistical tests of such data, although evaluating the "statistical significance" may obscure the clinical value of a treatment. On the other hand, confidence intervals (CIs) can illuminate both statistical and clinical importance. CIs give a range of values based on the observed data which contain, with a specified probability, a true but unknown variable typifying a population. We reviewed 112 articles published recently in anesthesia journals for statistical reporting of VAS data. Of the 112 articles, only two used CIs to report mean pain scores and one used CIs to report differences in median pain scores between the study groups. Only two articles presented 95% CI for the mean pain scores graphically. Analgesic techniques that produce VAS values in the range of 0-3 have been reported to represent adequate analgesia. A graphical method using CIs is proposed that allows ready interpretation of VAS data. With this approach, one evaluates whether the 95% CI for the mean pain score in a group during a particular period lies entirely within the zone defined as "analgesic success" (0-3). Such an analysis allows a visual assessment of whether a particular technique would produce clinically important effects in the population at large. This approach seems to provide more information than the use of conventional hypothesis testing in the interpretation of VAS data for pain measurement.

Prefatory Note Acknowledgments Introduction Murray F. Foss Marilyn E. Manser Allan H. Young I. High-Tech Products: Computers 1. Constant-Quality Price Change, Depreciation, And Retirement Of Mainframe Computers Stephen D. Oliner 2. Price Indexes For Microcomputers: An Exploratory Study Ernst R. Berndt Zvi Griliches Comment (On 1 & 2): Rosanne Cole II. High-Tech Products: Semiconductors 3. Sources Of Price Decline In Computer Processors: Selected Electronic Components Ellen R. Dulberger 4. Cost Function Estimation Of Quality Change In Semiconductors John R. Norsworthy Show-Ling Jang 5. Measurement Of Dram Prices: Technology And Market Structure Kenneth Flamm Comment ( On 3, 4, & 5): Jack E. Triplett III. Quality-Change Issues In Consumer Prices 6. Adjusting Apparel Indexes In The Cpi For Quality Differences Paul R. Liegey Jr. 7. The Effect Of Outlet Price Differentials On The U.S. Consumer Price Index Marshall Reinsdorf Comment (On 6 & 7): Joel Popkin IV. Transaction Prices 8. The Problem Of List Prices In The Producer Price Index: The Steel Mill Products Case Thomas Betsock Irwin B. Gerduk 9. Does Government Regulation Inhibit The Reporting Of Transactions Prices By Business? Murray F. Foss Comment (On 8 & 9): Robert W. Crandall V. Price Indexes For Defense And International Trade 10. The Deflation Of Military Aircraft Richard C. Ziemer Pamela A. Kelly Comment: Arthur J. Alexander VI. Implications Of Bea's Treatment Of Computer Prices For Productivity Measurement 11. Panel Discussion: Implications Of Bea's Treatment Of Computer Prices And Productivity Measurement Chair: Frank De Leeuw Statements: Edward F. Denison, Zvi Griliches, Charles R. Hulten, And Thomas K. Rymes Comments: Arthur J. Alexander, Edwin R. Dean, Reni Durand, And Michael Harper

An oscillating inverted D shaped obstruction has been used to provide a well defined vortex street at Reynolds number (U0d/v) equal to 23,000. U0 and d are defined in Fig i which also presents a schematic of the flow based upon phase averaged results.

Background: Belinostat (PXD101) is a hydroxamate pan-histone deacetylase inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. Phase I studies have shown that belinostat is well-tolerated. Methods: This Phase II trial evaluated the activity of belinostat in patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥ 1 prior systemic therapy. Belinostat (1000 mg/m2) was administered as a 30-min IV infusion on Days 1–5 of a 3-wk cycle. The primary endpoint was objective response (OR) rate analyzed separately for PTCL and CTCL using the Cheson criteria and Severity Weighted Assessment Tool (SWAT), respectively. For each arm, a Simon 2-stage design was used based on target OR rate of 25%, with expansion to 34 pts if ≥ 2/13 OR were observed. Results: In the PTCL arm, 12 pts (9 with stage III/IV disease) were enrolled; (7 PTCL-unspecified (PTCL-U), 2 anaplastic large cell lymphoma (ALCL), 2 angioimmunoblastic T-cell lymphoma and 1 NK-T-cell lymphoma), treated for a median of 2 cycles (range 1–8). Of 11 evaluable pts, 2 achieved a CR and 5 pts had SD. The two CR (11+ and 15+ wks) were both in pts with PTCL-U. A third pt with PTCL-U had SD lasting 14 wks and discontinued treatment due to an adverse event (AE). Both pts with ALCL had durable SD (20+ and 14 wks). In the CTCL arm, 16 pts were enrolled (9 Mycosis Fungoides (MF), 5 Sezary Syndrome (SS), 2 primary cutaneous ALCL) and treated for a median of 2 cycles (range 1–6). Four ORs were observed (25%): 1 CR (ALCL) and 3 PR (MF/SS). The median duration of the OR was 10 wks (range 7 to 39+ wks). Four additional pts had a 25 – 50% decrease in SWAT. Improvement in pruritus score by ≥ 3 on a visual analog scale was reported in 5/6 patients with significant pruritus at baseline. Overall in both study arms the drug was well-tolerated and most AE were grade 1/2 (nausea, fatigue, constipation, diarrhea, and vomiting). Grade 3 AE attributed to the study drug was reported in 7 pts and included peripheral edema, apraxia, adynamic ileus, pruritus, rash, and infections. Only 1 treatment related Grade 4 AE was noted (thrombocytopenia). One patient with progressive PTCL died 6 days after last belinostat dose with ventricular fibrillation and drug causality could not be excluded. Conclusions: Belinostat (PXD101) is generally well tolerated and demonstrates encouraging clinical activity in recurrent or refractory PTCL and CTCL. The objective response rate in both arms has met the pre-defined criteria for study expansion to stage II of enrollment.

6713 Background: CTCL comprises a spectrum of diseases of mature CD4+ T-lymphocytes. While a number of therapies, including cytokines, retinoids, and IL-2 receptor targeted agents, have demonstrate...

ContextConstipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient.ObjectiveTo evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation.DesignDouble-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998.SettingClinical research center of a university hospital.ParticipantsTwenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation.Main Outcome MeasuresLaxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups.ResultsThe 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P

To the Editor. —Although we found the article by Dr Phillips and colleagues1 interesting, we have several questions regarding their assumptions. First of all, were the correct costs for false-positive testing included? If one assumes the sensitivity and specificity of the tests cited in the article (99% and 99.9% for two of three enzyme-linked immunosorbent assay tests and a Western blot for confirmation), for every 100 000 surgeons tested (assuming a prevalence of 0.06%; data cited in the article), 59.4 true positives and 99 false positives would be detected. Thus, two thirds of the surgeons detected by even this careful scheme of testing would not have human immunodeficiency virus (HIV) infection. Alternatively, if a prevalence rate of 0.4% is assumed, 396 surgeons would be true positives and 99.6 surgeons (20% of the surgeons tested positive) would be false positives.Our analysis indicates that this article may have underestimated the

Methylnaltrexone (MNTX) is a quaternary derivative of naltrexone. It does not cross the blood-brain barrier and, thus, it reverses peripherally mediated effects of morphine without blocking its centrally located analgesic effects. The effects of MNTX on morphine-induced depression of hypoxic ventilatory response are unknown. We evaluated the efficacy of MNTX, compared with naloxone, in reversing this effect. On three sessions separated by a week, 10 healthy male volunteers received morphine, 0.125 mg/kg, as a bolus at 20 min after completing a control hypoxic ventilatory challenge. At 60 min, naloxone, 5 micrograms/kg, MNTX, 0.3 mg/kg, or placebo was administered in a randomized double-blind order. Four isocapnic hypoxic ventilatory challenges were conducted: 0 min (control), 40 min (postmorphine), and 80 and 120 min (postreversal) and the hypoxic respiratory responses were recorded. Morphine administration was associated with a significant depression in hypoxic responses: The slope of the response (L/min/Spo2) and the predicted ventilation at 80% O2 saturation (VE80) (L/min) decreased significantly in the three sessions (P < 0.05). Naloxone injection reversed the respiratory depression at 80 min (85% of the control value of the slope and 89% of VE80), whereas MNTX and placebo did not. At 120 min, the slope (69%) and VE80 (80%) after naloxone administration were not significantly different from control. MNTX slope (69%) was not statistically different from the control, whereas VE80 (70%) was still depressed (P < 0.05). Placebo slope and VE80, at 120 min, remained lower than the control (P < 0.05). These data show that MNTX is not as effective as naloxone for reversal of morphine-mediated depression of respiration during acute hypoxia.

(1960). Placement Bureau Data and Teaching Success. The Journal of Educational Research: Vol. 53, No. 7, pp. 276-278.

Peritoneal macrophages and peripheral blood monocytes were collected from healthy women undergoing laparoscopic tubal clipping. Monolayers of adherent cells were examined for protein content, intracellular levels of lysosomal enzymes, and antimicrobial capacity. Compared to blood monocytes, peritoneal macrophages were larger and less glass-adherent and were less capable of intracellular killing of Salmonella typhimurium. Acid hydrolase content, however, was increased in peritoneal macrophages. These data suggest that resting human tissue macrophages may be less active in certain respects than their blood precursors. One should then question whether the enhanced functions observed after long-term in vitro culture of blood monocytes-macrophages accurately reflect the in vivo status of their more differentiated descendants.

Acquired resistance to multiple natural products in vitro is mediated by P-glycoprotein (Pgp). Expression of this protein has been demonstrated in some normal tissues and in tumor samples obtained from both untreated and treated patients. In situ hybridizations with RNA probes have demonstrated higher levels of expression of mdr-1/Pgp in well-differentiated tumors and in well-differentiated areas in tumors with mixed histologies. Expression of mdr-1/Pgp in human colon carcinoma cell lines was increased by the differentiating agents sodium butyrate, dimethyl sulfoxide, and dimethylformamide. In the SW-620 cell line addition of sodium butyrate resulted in a rapid induction of mdr-1/Pgp mRNA that was sustained for the duration of the exposure. The levels of P-glycoprotein were measured by immunoblotting and were also increased. Similar results were obtained in three other cell lines including the HCT-15 line. This induction occurred without alterations in nuclease sensitivity. Discontinuation of sodium butyrate was followed by a rapid fall in the levels of mRNA. The levels of P-glycoprotein returned to normal with a half-life of about 24 h. In spite of a 20-25-fold increase in the level of mdr-1/Pgp mRNA and P-glycoprotein, the SW-620 cell line did not demonstrate increased resistance to doxorubicin and vinblastine or decreased accumulation of vinblastine. In contrast, in the HCT-15 cell line, a 5-fold increase of mdr-1/Pgp was accompanied by a comparable fall in vinblastine accumulation which was reversed by verapamil. In the SW-620 cell line, the induced protein could be photolabeled using [3H]azidopine. Expression of mdr-1/Pgp appears to correlate with the degree of differentiation. However, its induction is not always accompanied by expression of the multidrug-resistance phenotype.

Cancer of the colon disguised as appendicitis occurs more frequently than is generally realized and will probably be seen more often as the elderly population increases. In all patients over 40 years of age presenting with acute appendicitis, further diagnostic testing (ie, double contrast enema or colonoscopy) should be done to rule out occult cancer.

Opioids administered to produce analgesia cause unwanted emesis in patients (incidence 20%-30%, depending on situation). Tests in animals show that quaternary narcotic antagonists like methylnaltrexone (MNTX) do not affect the analgesic potency of morphine, but such compounds have not been examined for their potential to antagonize morphine-induced emesis. To determine the effects of MNTX on emetic response, we assigned 85 dogs to one of 11 groups challenged with morphine alone or morphine and various doses of MNTX IM or i.v. Antagonism of the emetic response was dose related: MNTX, 0.25 mg/kg IM or 0.2 mg/kg i.v., completely blocked the emetic effect of morphine in dogs for approximately 60 minutes. If morphine-induced emesis is mediated by receptors available to a quaternary antagonist (perhaps on the peripheral side of the blood-brain barrier), MNTX may prevent opioid-induced emesis. These data indicate that opioid-induced emesis might be prevented without affecting analgesia.