Acute bacterial maxillary sinusitis: time to symptom resolution and return to normal activities with moxifloxacin.

OBJECTIVES: This prospective, single-arm, open-label, multicentre phase IV (postmarketing surveillance) study determined time to resolution of key symptoms and return to normal activities in adults with acute bacterial maxillary sinusitis treated with moxifloxacin 400 mg qd for 10 days. The study also assessed whether responses to the Sino-Nasal Outcome Test-16 (SNOT-16) questionnaire [not yet validated for acute bacterial sinusitis (ABS)] accurately reflect clinical findings in these patients. METHODS: Adults with a clinical diagnosis of acute bacterial maxillary sinusitis with signs/symptoms present for > or = 7 but < 28 days took part. Patients were evaluated bacteriologically and clinically on day 1 (pretherapy), days 2-4 and 10-13 (test of cure), for bacterial presence and improvement/resolution of the signs/symptoms of acute bacterial maxillary sinusitis. They completed SNOT-16 and Activity Impairment Assessment questionnaires daily, before receiving moxifloxacin, until day 10. RESULTS: In both the bacteriologically and clinically evaluable populations, over 85% of patients showed clinical improvement by day 2, rising to over 96% by day 4. Pretherapy, according to the SNOT-16 questionnaire, almost all of the bacteriologically evaluable patients reported facial pain/pressure but this proportion had fallen to below 50% by day 4. In the bacteriologically evaluable population, 32/42 (76%) patients reported an improvement in facial pain/pressure from the pretherapy visit to day 4. Of patients showing improvement, 50% improved from 'moderate-to-severe facial pain' at pretherapy to 'no problem' at day 4. At day 4, 45-50% of patients reported impairment of normal activities, compared with 79-88% pretherapy. CONCLUSIONS: Moxifloxacin rapidly improves the signs and symptoms of acute bacterial maxillary sinusitis and results in clinical cure in most patients. Responses to the SNOT-16 questionnaire accurately reflected clinical assessments, indicating that when fully validated the SNOT-16 questionnaire may be a valuable tool for the assessment of patient outcomes in ABS.

Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors.

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyses the rate limiting step in cholesterol biosynthesis and is markedly inhibited by the statin family of drugs. The effect of statins on lipid lowering is clearly defined, but the ability of the drugs to directly regulate inflammatory functions has not been well explored. In this report, we show that there are differences among the statins in their capacity to induce proinflammatory responses both in human monocytes in vitro, and in leukocytes in mice in vivo. Treatment of human monocytes with lipophilic statins alone stimulated the production of MCP-1, IL-8, TNF-alpha and IL-1 beta and markedly sensitized the cells to subsequent challenge with inflammatory agents. Lipophilic statins also increased the production of reactive oxygen species in monocytes. In contrast, pretreatment of cells with the hydrophilic pravastatin did not induce these heightened inflammatory responses. Furthermore, treatment of mice with lipophilic statins caused a markedly higher influx of leukocytes into the inflamed peritoneal cavity following challenge with thioglycollate. Overall, these results demonstrate that the lipophilic statins influence a regulatory pathway in monocytes that controls cytokine production and that the statins induce different pro-inflammatory responses both in vitro and in vivo.

The evaluation of novel mixed metal hydroxy-carbonates as phosphate binders: an in-vivo study in the rat.

A number of novel phosphate binders based on mixed metal hydroxide structures incorporating Fe and Ca, or Fe and Mg (classified as CT, Crosfield test compounds), were compared with the established phosphate binders Mg(OH)2, Al(OH)3, CaCO3 and a commercial hydrotalcite (Al- and Mg-based) using a rat model. The changes in urine and soluble faecal phosphate were used to evaluate efficacy of phosphate binding. The binders were mixed into a standard rat maintenance food at a concentration of 1% (w/w). Four rats were used for each binder study group and fed over 7 days. Urine and faeces were collected (in a metabolic cage) over the last 24-h study period and the phosphate content measured. The urinary phosphate was significantly reduced (P < 0.001) with CTFeCa (72+/-44 microm), CTFeMg (13+/-4 microm), CT100 (26+/-11 microm), and Mg(OH)2 (65+/-53 microm), compared with control (766+/-188 microm), Al(OH)3 (1,256+/-279 microm), and CaCO3 (857+/-25 microm). The soluble phosphate content of the faeces was significantly reduced (P < 0.05) by up to 60 % with CTFeCa, CTFeMg and Mg(OH)2, and up to 40% with CT100 and Al(OH)3, compared with 30% in controls and 10% with CaCO3. The new mixed metal hydroxy-carbonate compounds based on FeCa or FeMg are effective phosphate binders in-vivo and warrant further testing in patients.

The development and in-vitro evaluation of novel mixed metal hydroxy-carbonate compounds as phosphate binders.

The currently available phosphate binders are relatively inefficient and suffer from clinical side-effects of increased absorption of calcium and aluminium and the diarrhoea-inducing effects of magnesium. A new class of compounds based on mixed metal hydroxides has been developed and evaluated for their potential as phosphate binders. The mixed metal hydroxides were prepared using a standard procedure for hydrotalcite (Al2Mg6(OH)16.CO3.4H2O) by substituting Fe3+ for Al3+, with Mg2+ or Ca2+ as the divalent metal ion. Phosphate precipitation (binding) was examined at different pH values in aqueous solution and in various food mixtures in comparison with hydrotalcite, Al(OH)3, CaCO3 and Mg(OH)2 on the same weight-to-weight basis. A series of compounds with differing ratios of metal ions (Fe:Mg/Ca 1:2 or 1:3) gave analytically similar ratios to those predicted from the initial amounts added. CTFeCa bound > 90% phosphate in aqueous solution compared with 65% binding with CTFeMg, 85% binding with Mg(OH)2, and less than 30% binding for CaCO3 and Al(OH)3. The mixed metal compounds also bound up to 80% phosphate in various food matrices, which was relatively independent of changes in pH, compared with Mg(OH)2, where binding decreased from 85% at pH 3.0 to 25% at pH 8.0. Al(OH)3 and CaCO3 were relatively ineffective phosphate binders under all the conditions tested. The mixed metal hydroxides compounds show considerable promise as phosphate binders over those currently available and warrant further patient-based in-vivo testing.

A D-amino acid peptide inhibitor of NF-kappa B nuclear localization is efficacious in models of inflammatory disease.

The transcription factor NF-kappa B regulates many genes involved in proinflammatory and immune responses. The transport of NF-kappa B into the nucleus is essential for its biologic activity. We describe a novel, potent, and selective NF-kappa B inhibitor composed of a cell-permeable peptide carrying two nuclear localization sequences (NLS). This peptide blocks NF-kappa B nuclear localization, resulting in inhibition of cell surface protein expression, cytokine production, and T cell proliferation. The peptide is efficacious in vivo in a mouse septic shock model as well as a mouse model of inflammatory bowel disease, demonstrating that NF-kappa B nuclear import plays a role in these acute inflammatory disease models.

Human monocytic cells contain high levels of intracellular Fas ligand: rapid release following cellular activation.

Human monocytes express both Fas and Fas ligand (FasL) on the cell surface, and the interaction of these molecules induces spontaneous apoptosis. In this report we present a study of monocytic cells by FACS and confocal microscopy using anti-FasL Abs that reveals high levels of preformed FasL within the intracellular compartment. Further analysis by immunoblotting of cell cytoplasmic proteins confirmed the presence of a 37-kDa protein recognized by anti-FasL Abs. Stimulation of the monocytic cells with immune complexes, PHA, or superantigen gave rise to the rapid release of soluble FasL from within the cells. The presence of high levels of FasL within human monocytes suggests that, upon stimulation, the cells can rapidly translocate intracellular FasL to the cell surface and release it into the extracellular milieu. These findings indicate a novel mechanism for monocytes to respond rapidly to environmental changes, resulting in the release of active, soluble FasL.

Does dependency cause despondency? Welfare receipt and normative expectations among inner-city African-American youth.

This study attempts to isolate the effects of receipt of welfare on adolescents' expectations net of other coexisting factors such as family and household characteristics, neighborhood situational effects, and individual demographics. In addition, apart from the direct effect of these exogenous variables on expectations, mediating effects of peer association, maternal orientations, and academic attainment are also included in the analysis. The results indicate that time on welfare not only contributes directly to the non-normative expectations of adolescents but also indirectly by undermining mothers' expectations for the future well-being of their children. The results also indicate that family characteristics and neighborhood disadvantage have important implications for the prosocial development of youth.

Effect of nicotine on large bowel mucus thickness, eicosanoids and faecal proteinase in ferrets.

BACKGROUND: Following observations on the effect of subcutaneous nicotine on rectal mucosal eicosanoids and mucus in the rabbit we have repeated the work in ferrets which may be a more suitable animal model. AIMS AND METHODS: The effect of nicotine on mucosal eicosanoids, the adherent mucus layer, and faecal proteinases in the large bowel of ferrets was examined in forty animals randomly allocated to five groups, a control and four treatment groups. They were given subcutaneous saline or nicotine via an Alzet pump in doses of 0.3, 0.6, 1.2 and 2.0 mg/kg/day for 10 days and then sacrificed; measurements were made of serum nicotine and cotinine levels, rectal mucosal eicosanoids, adherent rectal and colonic mucus thickness, and faecal proteinases. RESULTS: No significant differences were observed for any measurements, except for serum nicotine and cotinine levels, which were raised consistent with the dose given. CONCLUSION: Nicotine had no effect on measurements, which may possibly be important in the relationship between smoking and ulcerative colitis.

Using pretreatment and posttreatment assessments to enhance and evaluate existing treatment packages.

Pretreatment assessment data were used to enhance an existing treatment package to reduce aggression and to increase positive social interactions between a young boy and his peers. Based on the results of pretreatment assessments, additional reinforcement (differential reinforcement of alternative behavior with adult attention) and punishment (performing a nonpreferred task during time-out) components were added to an existing nonresetting differential reinforcement of other behavior (access to peers unless aggression occurred) plus time-out procedure. A posttreatment component analysis of the additional treatment components indicated that the reinforcement component facilitated positive social interactions and the punishment component suppressed aggression towards peers.

Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes.

CD40 is a glycoprotein of about 50 kDa that plays a crucial role in B cell growth and differentiation. It is found on the surface of B cells, follicular dendritic cells, monocytes, and some endothelial, epithelial, and carcinoma cells. Engagement of CD40 with anti-CD40 mAbs, gp39 expressed on the cell surface or soluble forms of gp39, primes B cells to efficiently respond to subsequent stimulatory signals leading to B cell proliferation, differentiation, and isotype switching. Peripheral monocytes also express CD40 on the cell surface and expression in increased following treatment with IFN-gamma. Using a soluble murine CD8/human gp39 fusion protein (sgp39) we have found that CD40 plays a crucial role in the regulation of monocyte function. Stimulation of human peripheral monocytes with sgp39 induced homotypic aggregation and significantly increased the expression of several cell-surface proteins including CD54, MHC class II, CD86, and CD40. Soluble gp39 also dramatically enhanced monocyte survival, preventing the onset of apoptosis that normally occurs upon withdrawal of serum. Finally, in the absence of any costimulatory molecules, sgp39 stimulated monocytes to produce TNF-alpha, IL-1 beta, IL-6, and IL-8. These results suggest that ligation of CD40 on human monocytes induces phenotypic changes that would be expected to influence T cell activation by the monocyte and also to enhance or prolong inflammatory responses.

Immune complexes of LDL induce atherogenic responses in human monocytic cells.

The ability of immune complexes of LDL or acetylated LDL (acLDL), together with antibodies to LDL, to induce a proatherogenic phenotype in human monocytic cells has been explored. Treatment of THP-1 monocytic cells or peripheral human monocytes with LDL immune complexes containing intact anti-LDL markedly enhanced the ability of these cells to subsequently bind and take up LDL, whereas aggregated LDL or LDL immune complexes prepared with F(ab')2 fragments of anti-LDL had no significant effect. Activation of THP-1 cells with intact LDL immune complexes also stimulated mRNA expression for the scavenger receptor. Additionally, activation of THP-1 cells with insoluble immune complexes of LDL or LDL stimulated generation of reactive oxygen intermediates that, in turn, could oxidize exogenous LDL. These results indicate that the binding of lipoprotein immune complexes to Fc receptors on monocytic cells activates a series of responses that could accelerate the initiation or progression of atherosclerosis.

Effect of interferon-gamma on antigen processing in human monocytes.

The effect of interferon-gamma (IFN-gamma) on the ability of human monocytic cells to process exogenous (major histocompability complex class II) antigens was investigated. The processing (i.e. protein degradation) of antigens that were internalized via Fc gamma receptor (Fc gamma R) was followed for various times after treatment of cells with IFN-gamma. THP-1 cells that had been treated with IFN-gamma for 4 h degraded antigen, internalized as an immune complex, at an enhanced rate. After 24 h of IFN-gamma treatment the rate of processing was similar to untreated cells. Unexpectedly, in cells which had been treated for 48-72 h there was a significant decrease in the rate of processing of the exogenous antigen. These effects were not due to changes in the rate of internalization of immune complex. The inhibition of the rate of processing was independent of the type of antigen, was dependent on the dose of IFN-gamma, and also occurred with normal human peripheral monocytes. Analysis of the degraded peptides by high-pressure liquid chromatography indicated that some of the peptides generated in the IFN-gamma-treated cells were both quantitatively and qualitatively different from the peptides generated in untreated cells. These data suggest that IFN-gamma modulates the way in which antigens, internalized through Fc receptors as immune complexes, are processed. Additionally, the results imply that decreases in the rate of antigen processing may lead to more efficient antigen presentation.

Cross-linking of Fc gamma receptor to surface immunoglobulin on B cells provides an inhibitory signal that closes the plasma membrane calcium channel.

Stimulation of B lymphocytes by the cross-linking of surface Ig (sIg) with an F(ab')2 antibody fragment leads to the rapid activation of several tyrosine kinases. This gives rise to the activation of phospholipase C gamma (PLC gamma) and the generation of inositol phosphates. These, in turn, lead to a prolonged elevation of intracellular Ca2+ ([Ca2+]i) consisting of a rapid release of Ca2+ from intracellular stores and a sustained influx of extracellular Ca2+. In contrast, co-cross-linking sIg to Fc gamma receptor (Fc gamma RII) with intact anti-sIg induces a much more transient increase in [Ca2+]i. Stimulation of the murine B cell lymphoma, A20, with F(ab')2 anti-sIgG leads to the production of high levels of IL-2, while co-cross-linking of sIgG with Fc gamma RII blocks this response. In studies reported here, we show that co-cross-linking of Fc gamma RII with sIg prevents the influx of extracellular Ca2+ without significantly affecting the tyrosine phosphorylation of substrates including PLC gamma 1, PLC gamma 2, and Syk or the mobilization of Ca2+ from intracellular stores. In cells that had been previously activated with F(ab')2 anti-IgG, co-cross-linking of sIg to Fc gamma RII rapidly abrogated the influx of extracellular Ca2+ by closing the plasma membrane Ca2+ channel. Additionally, even 2-3 h after stimulation of the cells with F(ab')2 fragment, addition of intact anti-IgG to the cells, or removal of extracellular Ca2+, markedly inhibited (> 90%) IL-2 production. These results indicate that co-cross-linking sIg with Fc gamma RII both prevented the opening of and actively closed the Ca2+ channel, and, through this mechanism, Fc gamma RII was able to control production of IL-2. Overall, since influx of extracellular Ca2+ has been found to be necessary for the proliferation and differentiation of B cells, Fc gamma RII may play a critical role in controlling these responses by regulating the opening of the Ca2+ channel.

Cross-linking of Fc gamma receptor I (Fc gamma RI) and receptor II (Fc gamma RII) on monocytic cells activates a signal transduction pathway common to both Fc receptors that involves the stimulation of p72 Syk protein tyrosine kinase.

Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP, and a protein that co-precipitated with the Fc gamma receptors and migrated with a molecular weight of about 70,000. Co-cross-linking an F(ab')2 anti-CD45 monoclonal antibody together with monoclonal antibodies to either of the Fc gamma receptors inhibited phosphorylation of all these proteins. Analysis of the tyrosine kinases in the cells revealed that both receptors stimulated the phosphorylation and activation of a kinase recognized by antibodies to Syk. Furthermore, the Syk kinase became associated with the Fc gamma RII following receptor cross-linking. These data indicate that although the two Fc gamma receptors have different cytoplasmic tails, they are coupled to the same signal transduction cascade that is regulated by CD45 and involves the activation of Syk.

Gamma-probe-guided lymph node localization in malignant melanoma.

The initial draining lymph node (sentinel node) has been successfully localized using intraoperative vital dye mapping and reportedly is predictive of regional nodal metastases in Clinical- Stage 1 melanoma. In an animal model, we previously established the technique of gamma-probe-guided localization of the technetium-99 sulfur colloid labelled sentinel node and found its sensitivity equal to vital dye mapping. We now report our initial experience using gamma-probe-guided localization to identify and then surgically remove the first draining lymph node(s) in 10 malignant melanoma patients. Lymphoscintigraphy was used to confirm localization. We conclude that this technique: (a) reliably localizes the sentinel node draining the site of a primary melanoma, (b) allows the lymphatic bed to be checked intraoperatively verifying complete sentinel node biopsy, and (c) is relatively simple and can be performed under local anaesthesia.

Stimulation of tyrosine phosphorylation and calcium mobilization by Fc gamma receptor cross-linking. Regulation by the phosphotyrosine phosphatase CD45.

The binding and subsequent cross-linking of murine IgG2a or human IgG to the Fc gamma R on the monocytic cell line THP-1 induced a rapid, dose-dependent increase in tyrosine phosphorylation of several proteins (a doublet centered around 110 kDa, and bands at 80, 60, and 52 kDa) and smaller increases in other proteins. This phosphorylation was accompanied by an increase in intracellular free Ca2+. The signaling required the cross-linking of the IgG, either through a biotin-avidin complex or with a F(ab')2 second antibody. Cross-linking of an F(ab')2 fragment of mAb 32.2 to Fc gamma RI (CD64) or an Fab fragment of mAb IV.3 to Fc gamma RII (CDw32) gave similar results to those observed with intact murine IgG2a or human IgG. Cross-linking of a F(ab')2 fragment of mAb 3G8 to Fc gamma RIII (CD16) had very little effect. Increases in both tyrosine phosphorylation and intracellular free Ca2+ were significantly reduced in a dose-dependent manner upon treatment of THP-1 cells with the tyrosine kinase inhibitors herbimycin-A, genistein, or erbstatin. Additionally, there was a marked inhibition of both Ca2+ mobilization and tyrosine phosphorylation when a F(ab')2 fragment of a mAb (T191) to the protein tyrosine phosphatase CD45, was co-cross-linked with either Hu-IgG, Mu-IgG2a, F(ab')2 anti-Fc gamma RI, or Fab anti-Fc gamma RII. Taken together these results suggest that signaling through Fc gamma RI (CD64) and Fc gamma RII (CDw32) in the monocytic leukemia cell line THP-1 gives rise to rapid tyrosine phosphorylation of several proteins followed by an increase in intracellular calcium. In addition, CD45 is able to inhibit the intracellular signaling when it is brought into close proximity to the Fc gamma R. This suggests that this transmembrane tyrosine phosphatase may regulate the stimulation of the cells through the Fc gamma R.

Maternal performance of Hereford, Brangus, and reciprocal crossbred cows under semidesert conditions.

Maternal performance of 134 Hereford (H), Brangus (B), and reciprocal crossbred (H x B and B x H) cows from 2 to 7 yr of age was evaluated under semidesert conditions in this study. Calves produced by 2- and 3-yr-old cows were sired by Brangus and Hereford bulls. Calves produced by 4- to 7-yr-old cows were sired by Charolais bulls. Breed of sire and breed of dam of cow affected kilograms of weaning weight, 205-d weight, weaning weight as a percentage of cow weight, and 205-d weight as a percentage of cow weight produced annually. Brangus (either as sire or dam of cow) was superior to Hereford in all cases. Observed maternal heterosis on 2- to 3-yr-old cows was 23.0, 20.1, 30.0, 29.1, 23.9, and 23.0% for calf birth date, weaning percentage, weaning weight per year, 205-d weight per year, weaning weight as a percentage of cow weight per year, and 205-d weight as a percentage of cow weight per year, respectively (P less than .01). Observed maternal heterosis from mature cows was 19.8, 12.8, 21.0, 18.7, 17.4, and 15.4% for calf birth date, weaning percentage, weaning weight per year, 205-d weight per year, weaning weight as a percentage of cow weight per year, and 205-d weight as a percentage of cow weight per year, respectively (P less than .01). Results indicate large heterotic effects on annual cow productivity and an adaptive advantage for cows with Brangus sires and(or) dams under semidesert conditions.