The experience of anger (i.e. trait anger) and anger management style (i.e. anger-in, anger-out) are related to sensitivity to acute and chronic pain stimuli, although underlying mechanisms are unknown. This study tested whether anger variables are associated with impaired endogenous opioid antinociceptive activity, and whether these relationships differed between chronic pain patients and healthy normals. Forty-three chronic low back pain (LBP) sufferers and 45 pain-free normals received opioid blockade (8 mg naloxone i.v.) or placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each session, subjects participated in a 1-min finger pressure pain task followed by an ischemic forearm pain task (maximum duration 5 min), providing pain intensity ratings during and immediately following each task. As a measure of opioid antinociceptive function, drug effects were derived by subtracting placebo from blockade condition pain ratings. Multivariate general linear model analyses indicated that anger-out, but not anger-in, had significant main effects on both finger pressure drug effects (P < 0.05) and ischemic task drug effects (P < 0.05). As hypothesized, high anger-out scores were associated with an absence of opioid analgesia during the acute pain tasks; low anger-out scores were associated with effective opioid analgesia. A similar non-significant trend was noted for trait anger on finger pressure drug effects (P < 0.06). Anger-out x LBP/normal interactions were non-significant, suggesting that links between anger-out and drug effects were similar for patients and normals. Controlling for depression did not eliminate the significant relationship between anger-out and drug effects. Findings suggest that anger-in and anger-out affect pain sensitivity through different mechanisms: only the effects of anger-out may be mediated by endogenous opioid dysfunction.

Resting blood pressure is inversely correlated with acute pain sensitivity in healthy normotensives. This study tested: (1) whether endogenous opioid activity is necessary for this adaptive relationship to occur, (2) whether this relationship is altered in chronic low back pain (LBP), and (3) whether endogenous opioid dysfunction underlies any such alterations. Fifty-one pain-free normotensives and 44 normotensive chronic LBP sufferers received opioid blockade (8 mg naloxone i.v.) or placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each session, subjects participated in a 1-min finger pressure (FP) pain task followed by an ischemic (ISC) forearm pain task. Among pain-free normotensives, elevated resting systolic (SBP) and diastolic (DBP) blood pressure were associated with significantly higher ISC pain thresholds (P values <0.05). Elevated SBP was also associated with significantly lower FP pain ratings (P<0.05). Opioid blockade had no significant effect on the BP-pain relationships detected (P values >0.10). In combined groups analyses, a significant subject typexSBP interaction (P<0.005) was found on ISC pain threshold: elevated SBP was associated with higher pain threshold in pain-free controls, but with lower pain threshold in LBP subjects. Although subject typexBP interactions on FP and ISC pain ratings were not significant, inclusion of LBP subjects in these analyses resulted in the overall relationship between BP and pain sensitivity becoming positive (P values <0.05). Opioid blockade exerted no significant main or interaction effects in these combined groups analyses (p values >0.10). Higher DBP was associated with greater clinical pain intensity among the LBP subjects (P<0.001). Overall, these results suggest: (1) endogenous opioids do not mediate the inverse relationship between resting blood pressure and acute pain sensitivity in pain-free normotensives; (2) the BP-pain sensitivity relationship is altered in chronic pain, suggesting dysfunction in pain regulatory systems, and (3) these alterations are not related to opioid dysfunction.

Cancer cell detachment in three distinct and critical parts of the metastatic cascade is discussed. The detachment of cancer cells from their parent tumors is an initial early event in metastasis. The site of detachment with respect to proximity to blood vessels may determine the initial dissemination route. Many factors affect cell detachment; we specifically consider the effects of growth-rate, necrosis, enzyme activity, and stress on cell release in terms of metastasis-promoting mechanisms. Detachment is also discussed in relation to active cancer cell locomotion, where localized detachment from the substratum is a prerequisite for translatory movement. The importance of active cell movement in tissue invasion has only recently been assessed, and, in the case of at least some human malignant melanomas, a zone of actively moving cancer cells is believed to precede the growing body of the tumor. The secondary release of cancer cells from temporary arrest sites at the vascular endothelium consequent upon intravascular dissemination is also a major area of investigation. Circulating cancer cells arrest at vascular endothelium or are impacted in small vessels, however, most are released into the circulation and subsequently perish. The blood stream is a hostile environment, and it is probable that cancer cells are sufficiently damaged in translocation by hemodynamic trauma and humoral factors such that they easily detach or are 'sheared-off' the vascular endothelium by blood flow. Another possibility is that in some cases they are processed by 'first organ encounters' and perish before or shortly after arriving in a second organ. Animal studies have shown that, following intravenous injection, 60-100% of the injected dose of viable cancer cells are initially arrested in the lungs, but very few remain after 24 hr. As it is only those retained cells which produce tumors, the mechanisms involved in this secondary release, which occurs in all organs so far examined, are critical to any understanding of the metastatic cascade and metastatic inefficiency. The arrest of cancer cells at the vascular endothelium and their subsequent release have been associated with the presence of platelets, and the deposition of fibrin and manipulation of platelet-aggregating mechanisms and fibrinolysis are discussed in terms of their antimetastatic effects. The role of the reticuloendothelial system, natural killer cells, and polymorphs is discussed in relation to cancer cell clearance from blood vessels and also to inherent cancer cell properties which may act to inhibit their metastasis. Although detachment of cancer cells from a primary tumor may be regarded as metastasis promoting, secondary release of cancer cells may be associated with inhibition of metastasis.

Oral phosphodiesterase (PDE) 4 inhibitors such as roflumilast have established the potential of PDE4 inhibition for the treatment of respiratory diseases. However, PDE4 inhibitor efficacy is limited by mechanism-related side effects such as emesis and nausea. Delivering the inhibitor by the inhaled route may improve therapeutic index, and we describe 6-, an exceptionally high-affinity inhibitor of PDE4 designed for inhaled administration. GSK256066 is a slow and tight binding inhibitor of PDE4B (apparent IC 50 3.2 pM; steady-state IC 50 Ͻ0.5 pM), which is more potent than any previously documented compound, for example, roflumilast (IC 50 390 pM), tofimilast (IC 50 1.6 nM), and cilomilast (IC 50 74 nM). Consistent with this, GSK256066 inhibited tumor necrosis factor ␣ production by lipopolysaccharide (LPS)-stimulated human peripheral blood monocytes with 0.01 nM IC 50 (compared with IC 50 values of 5, 22, and 389 nM for roflumilast, tofimilast, and cilomilast, respectively) and by LPS-stimulated whole blood with 126 pM IC 50 . GSK256066 was highly selective for PDE4 (Ͼ380,000-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and Ͼ2500-fold against PDE7), inhibited PDE4 isoforms A-D with equal affinity, and had a substantial high-affinity rolipram binding site ratio (Ͼ17). When administered intratracheally to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia with ED 50 values of 1.1 g/kg (aqueous suspension) and 2.9 g/kg (dry powder formulation) and was more potent than an aqueous suspension of the corticosteroid fluticasone propionate (ED 50 9.3 g/kg). Thus, GSK256066 has been demonstrated to have exceptional potency in vitro and in vivo and is being clinically investigated as a treatment for chronic obstructive pulmonary disease.

T-cell large granular lymphocyte (T-LGL) leukemia is clinically indolent, but is associated with severe neutropenia in approximately 50% of cases. The pathogenesis of the neutropenia is unclear. We report reversal of severe neutropenia associated with T-LGL leukemia in five patients treated with cyclosporine (CSA). All five had persistent neutrophil counts below 0.5 × 109/L, two had agranulocytosis, and four had recurrent infections. Increased populations of LGL were present in blood and marrow, with a T-LGL immunophenotype (CD3+CD8+CD16±CD56±CD57+) shown by multiparameter flow cytometry, and clonal T-cell receptor (TCR) gene rearrangements in two of two pretreatment blood samples studied. CSA was initiated at doses of 1 to 1.5 mg/kg orally every 12 hours, with subsequent dose adjustments based on trough serum levels. Four patients attained normal neutrophil counts with CSA alone; one required addition of low-dose granulocyte-macrophage colony-stimulating factor. Time to attainment of 1.5 × 109/L neutrophils ranged from 21 to 75 days. Attempts to taper and withdraw CSA resulted in recurrent neutropenia. Three patients have maintained normal neutrophil counts on continued CSA therapy for 2, 8, and 8.5 years. Two patients died 1.7 and 4.6 years after initiation of CSA despite normal neutrophil counts—one of metastatic melanoma and one of complications after aortofemoral bypass surgery. Despite resolution of neutropenia, increased populations of T-LGL cells have persisted in all patients during CSA therapy, as shown by morphology and flow cytometry and by the presence of clonal TCR gene rearrangements in four patients' posttreatment blood samples. We conclude that CSA is an effective therapy for neutropenia associated with T-LGL leukemia, and that resolution of neutropenia despite persistence of abnormal cells implies that CSA may inhibit T-LGL secretion of yet unidentified mediators of neutropenia.

The neurotoxin conotoxin GI from Conus geographus has been synthesised by a solid-phase method using fluorenylmethoxycarbonylamino acids and a polar, poly(dimethylacry1amide)-based support. The two disulphide bridges were formed selectively by differential protection of cysteine residues using Sacetamidomethyl and S-t-butylsulphenyl groups.Our attention was first drawn to the series of highly potent peptide neurotoxins from Conus sea snails when Dr W. Gray of the University of Utah visited our Laboratory in 1977. He brought with him the newly determined amino acid sequence (1) for conotoxin G1 from Conus geographus. The four cysteine residues in (1) were thought to be linked in pairs forming two intramolecular disulphide bonds in a bicyclic tridecapeptide amide structure of type a, b, or c. These structures were of interest to us because of their biological significance and novelty, and because total synthesis would provide a severe test for the new polyamide-based solid-phase methods which we were developing at that time.' Conotoxin GI includes in its tridecapeptide amide sequence both arginine and histidine as well as the four cysteine residues; all three are recognised as difficult amino acids in peptide synthesis. Accordingly, synthetic studies were carried out on two (b, c) of the three possible disulphide isomers of (l), the third possibility (a) being considered less likely. These studies were apparently successful; the synthetic bicyclic tridecapeptide amides obtained were very similar to natural conotoxin in physical properties, but both were biologically inactive. We know now that the amino acid sequence (1) was incorrect. Details of this early work have been published el~ewhere,~ together with later synthetic and other studies establishing the correct disulphide pairing in conotoxin Gl as type b.

Facklamia species are a rarely reported etiology of clinical infection with few cases described in literature. However, the prevalence of infection may be underestimated due to challenges in species identification. We describe 3 cases of Facklamia species bacteremia and the unique microbiologic aspects inherent to this genus that make it particularly challenging to identify. In addition, given the unique susceptibility profile of Facklamia species, we discuss the importance of fully identifying this organism when it is a suspected as a pathogen, to optimize therapy based on its distinct antibiotic resistance profile.

An examination of the frequency distributions most commonly used to estimate mean coliform densities in flowing water compares their reliability in describing coliform data obtained from sample tests.