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Background This randomized, double-blinded, placebo-controlled study investigated the efficacy of patient-controlled regional analgesia using a sciatic perineural catheter in the popliteal fossa and a portable infusion pump for outpatients having moderately painful, lower extremity orthopedic surgery. Methods Preoperatively, patients (n = 30) received a sciatic nerve block and perineural catheter in the popliteal fossa. Postoperatively, patients were discharged with both oral opioids and a portable infusion pump delivering study solution (0.2% ropivacaine or 0.9% saline) via the catheter for 3 days. Investigators and patients were blinded to random group assignment. Daily end-points included pain scores, opioid use and side effects, sleep quality, and symptoms of catheter- or local anesthetic-related complications. Results Ropivacaine (n = 15) infusion significantly reduced pain compared with saline (n = 15) infusion ( < 0.001). For example, the average pain at rest (scale: 0-10) on postoperative day 1 (median, 25th -75th percentile) was 4.0 (3.5-5.5) for the saline group, versus 0.0 (0.0-0.0) for the ropivacaine group (P < 0.001). Oral opioid use and related side effects were significantly decreased in the ropivacaine group. For example, on postoperative day 1, median tablet consumption was 8.0 (5.0-10.0) and 0.0 (0.0-0.0) for the saline and ropivacaine groups, respectively (P < 0.001). Sleep disturbance scores were more than 10-fold greater for saline administration than for ropivacaine infusion (P < 0.001). Overall satisfaction was significantly greater in the ropivacaine group. Other than two inadvertent catheter dislodgements, no catheter- or local anesthetic-related complications occurred. Conclusions After moderately painful orthopedic surgery of the lower extremity, ropivacaine infusion using a portable mechanical pump and a popliteal sciatic perineural catheter at home decreased pain, opioid use and related side effects, sleep disturbances, and improved overall satisfaction.

SUMMARY Eosinophils and eosinophil granule proteins may play an important role in the pathogenesis of asthma. BALF from 40 patients with symptomatic asthma were analysed for cytokine activity by the eosinophil survival assay. BALF from 15 patients showed increased survival activity. Survival activities in BALF from four of these patients were almost completely blocked by anti-IL-5 MoAb, and the remaining activities were blocked by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF), anti-IL-3 antibody, or both. Surprisingly, BALF samples from the other 25 patients decreased eosinophil viabilities below the levels of medium control. The inhibitory factor in these BALF was of low molecular weight, was heat-stable, was largely overcome by excess exogenously added cytokines, and was positively correlated with the concentrations of lidocaine in the BALF. Lidocaine itself inhibited eosinophil survival at concentrations less than those present in the BALF. These findings indicate that lidocaine is an inhibitor of cytokines in the eosinophil survival assay, and they suggest the need for caution in analyses of BALF containing lidocaine or other local anaesthetics.

Background— β-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. Methods and Results— Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol ( r =−0.72, P <0.0001) and was the most significant multivariate predictor of change in LVEF ( P =0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687±333 versus 420±246 pg/mL, P <0.05) and greater decrease in plasma norepinephrine in response to bucindolol (−249±171 versus −35±277 pg/mL, P <0.05). Conclusions— This study suggests a direct relationship between contractile reserve and improvement in LVEF with β-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.

AbstractSummary: The trace metal copper is an essential cofactor for a number of biological processes, including mitochondrial oxidative phosphorylation, free‐radical eradication, neurotransmitter synthesis and maturation, and iron metabolism. Consequently, copper transport at the cell surface and the delivery of copper to intracellular proteins are critical events in normal cellular homeostasis. Four genes have been reported to influence the cellular uptake and the delivery of copper to specific cell compartments and proteins. These include hCTR1, which regulates cellular copper uptake; HAH1, which mediates the transfer of copper to the Menkes and Wilson disease transporters; CCS, which is related to the transfer of copper to superoxide dismutase; and hCOX17, which directs trafficking of copper to mitochondrial cytochrome‐c oxidase. At present, no genetic disorders have been associated with defects in these four copper transporter genes. In this study, we test the possibility that defective copper uptake or intracellular translocation represents the basic defect in three categories of candidate phenotypes among 22 patients: ethylmalonic encephalopathy; mitochondriopathies of unknown aetiology; and neurodevelopmental abnormalities with clinical and chemical evidence of copper deficiency. Mutation analyses of the copper uptake protein, hCTR1, and the three copper chaperones were performed by direct sequencing of the whole coding regions. No causative mutations were identified for the four copper transporter genes in 22 patients. A heterozygous polymorphism (847G>A) for CCS was detected in 7 patients. For the distinct disease entity ethylmalonic encephalopathy, we additionally show normal mRNA levels for each of the four genes. The negative results notwithstanding, we encourage ongoing study of additional patients with candidate phenotypes. Further, our results are consistent with the notion that other unknown copper‐related transporters could be involved in diseases.

Albuminuria increases the risk of cardiovascular events in patients with essential hypertension and diabetic subjects. The heritability (h 2 ) of albuminuria in multiplex hypertensive families is unknown. We calculated the familial aggregation of urine albumin:creatinine ratio (ACR) and performed a genome-wide scan to assess for loci contributing to ACR in participants enrolled in the Hyper tension G enetic E pidemiology N etwork (HyperGEN). To perform the genome scan, we analyzed genotype results from 2589 individuals from 805 families in the Family Blood Pressure Program. ACR and covariates were available in 1727 individuals (mean age, 57.1 years). Estimates of h 2 were obtained by using variance component methodology as implemented in the SOLAR software package. Linkage was tested between 387 markers spanning the genome at an average interval of 9.32 cM, using SOLAR multipoint analysis. The h 2 of log urine ACR was 0.49 ( P <1×10 −7 ) after controlling for significant main and interactive effects of age, gender, race, body mass index, blood pressure, and use of ACE inhibitors or angiotensin-2 receptor blockers. The genome-wide scan revealed a maximum LOD score of 2.73 on chromosome 19 (robust corrected LOD, 2.40; P =0.0009) at marker D19S591 and a LOD score of 2.0 on chromosome 12 (robust corrected LOD, 1.75; P =0.005) at marker PAH. These analyses demonstrate the marked heritability of urine ACR in families enriched for the presence of members with essential hypertension. They suggest that a gene(s) associated with urinary ACR may be present on human chromosomes 19 and 12.

Abstract Exercise-induced hypoxia is an index of the severity of interstitial lung disease. We hypothesized that desaturation during a 6-minute walk test would predict mortality for patients with usual interstitial pneumonia (n = 83) and nonspecific interstitial pneumonia (n = 22). Consecutive patients with biopsy-proven disease performed a 6-minute walk test between January 1996 and December 2001. Desaturation was defined as a fall in oxygen saturation to 88% or less during the 6-minute walk test. Desaturation was common (44 of 83 usual interstitial pneumonia and 8 of 22 nonspecific interstitial pneumonia; chi square, p = 0.39). Patients with usual interstitial pneumonia or nonspecific interstitial pneumonia who desaturated had a significantly higher mortality than patients who did not desaturate (respective log-rank tests, p = 0.0018, p = 0.0089). In patients with usual interstitial pneumonia, the presence of desaturation was associated with an increased hazard of death (hazard ratio, 4.2; 95% confidence interval, 1.40, 12.56; p = 0.01) after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, FVC, and resting saturation. We conclude that knowledge of desaturation during a 6-minute walk test adds prognostic information for patients with usual interstitial pneumonia and nonspecific interstitial pneumonia.

Abstract Macrophage inflammatory protein-1α (MIP-1α) is produced in high concentration by multiple myeloma (MM) cells in about 70% of patients, and MIP-1α levels correlate with their disease activity. Patients who have high levels of MIP-1α have a poor prognosis. Furthermore, blocking MIP-1α expression in an in vivo model of human MM profoundly decreases both tumor burden and bone destruction, suggesting that MIP-1α is an important mediator of MM bone disease. Therefore, to analyze the regulation of MIP-1α production in MM, we cloned the human MIP-1α promoter and characterized the transcription factor (TF) motifs that control MIP-1α expression in MM cells. The proximal region of MIP-1α promoter was composed of 2 sets of identical transcription regulatory regions consisting of GATA-2+ AML-1+ C/EBPα motifs. Since 2 alternatively spliced variants of the acute myeloid leukemia-1 (AML-1) class of TFs can bind the AML-1 region, AML-1A and AML-1B, the relationship between the expression levels of AML-1A or AML-1B in MM cells and their capacity to express MIP-1α was examined. AML-1A mRNA was relatively overexpressed compared with AML-1B in MM cell lines that produced high levels of MIP-1α (> 1 ng/mL per 106 cells per 72 hours), but AML-1A was not increased in MM cell lines that expressed less than 200 pg/mL MIP-1α. More importantly, the ratio of AML-1A to AML-1B mRNA levels was also increased in 3 of 3 highly purified myeloma cells from patients with MM who expressed increased amounts of MIP-1α. The ratio of AML-1A to AML-1B mRNA in patients with MM was 8-fold higher than in healthy controls. Transduction of AML-1B into the MM-derived MM.1S and ARH-77 cells totally blocked MIP-1α production, while AML-1A did not further increase the already high levels of MIP-1α produced by these cells. Taken together, these data demonstrate that in patients with MM who produce increased concentrations of MIP-1α, the relative level of AML-1B is significantly decreased compared with healthy controls. The data suggest that strategies that enhance AML-1B expression or decrease AML-1A in MM cells may be beneficial therapeutically.