Skin Cancer Excision Is More Efficient and Cost Effectivein a Specialist Secondary Care Service.

Aim To compare the relative efficiencies of skin excisions in primary and secondary care. Methods We compared the benign: malignant ratio for specimens referred by General Practice, General Surgery and the Skin Cancer Service to the regional pathology laboratory over one month. We used cost minimization analysis to compare the relative efficiencies of the services. Results 620 excisions were received: 139 from General Practice, 118 from General Surgery and 363 from the Skin Cancer Service. The number (%) of malignant lesions was 13 (9.4%) from General Practice, 18 (15.2%) from General Surgery and 137 (37.7%) from the Skin Cancer Service. Excision was cheaper in General Practice at €84.58 as compared to €97.49 in the hospital day surgical unit. However, the cost per malignant lesion excised was €1779.80 in general practice versus €381.78 in the Skin Cancer Service. Conclusion Our results indicate that moving skin cancer treatment to General Practice may result in an excess of benign excisions and therefore be both less efficient and less cost effective.

Duration of action of hypertonic saline on mucociliary clearance in the normal lung.

Inhalation of hypertonic saline (HS) acutely enhances mucociliary clearance (MC) in both health and disease. In patients with cystic fibrosis (CF), repeated use of HS causes a sustained improvement in MC as well as clinical benefit. The pharmacodynamic duration of activity on MC may be an important determinant of its therapeutic potential in other airways diseases. Before moving toward testing the clinical benefits of HS for non-CF indications, we sought to assess the duration of pharmacodynamic effects of HS in healthy subjects by performing radiotracer clearance studies at baseline, 30-min post-HS administration, and 4-h post-HS administration. Indeed, acceleration of MC was observed when measured 30 min after HS inhalation. This acceleration was most pronounced in the first 30 min after inhaling the radiotracer in the central lung region (mean Ave30Clr = 15.5 vs. 8.6% for 30-min post-HS treatment vs. mean baseline, respectively, P < 0.005), suggesting that acute HS effects were greatest in the larger bronchial airways. In contrast, when MC was measured 4 h after HS administration, all indices of central lung region MC were slower than at baseline: Ave30Clr = 5.9% vs. 8.6% (P = 0.10); Ave90Clr = 12.4% vs. 16.8% (P < 0.05); clearance through 3 h = 29.4 vs. 43.7% (P < 0.002); and clearance through 6 h = 39.4 vs. 50.2% (P < 0.02). This apparent slowing of MC in healthy subjects 4-h post-HS administration may reflect depletion of airway mucus following acute HS administration.

Respiratory medical societies and the threat of bioterrorism.

Respiratory medical societies throughout the world have an important role in helping governments to develop public policy to counter the threat of bioterrorism.

Elevated tissue kallikrein activity in airway secretions from patients with tracheobronchitis associated with prolonged mechanical ventilation.

The clinical course of patients undergoing prolonged mechanical ventilation is often complicated by the development of purulent tracheobronchitis. The purpose of this study was to assess whether ventilator-associated hypersecretion is associated with elevated levels of tissue kallikrein (TK) activity. TK can induce marked bronchial inflammation in animal models and TK activity is increased in the airway secretions of symptomatic asthmatics. It has not been studied in conditions with predominantly neutrophilic bronchial secretions, although animal data indicate that neutrophil elastase may stimulate TK activity. We measured TK activity in airway secretions of patients undergoing mechanical ventilation for more than 4 weeks (PMV group) and in two comparator groups: patients with cystic fibrosis, who were colonized with Pseudomonas aeruginosa (CF group) and patients undergoing mechanical ventilation for less than one week who did not have clinical evidence of purulent airway secretions (acute mechanical ventilation, AMV group). We also compared the level of neutrophil elastase (NE) activity, an index of neutrophil activation, in the three patient groups. TK and NE activity in the sol phase were measured by the degradation of chromogenic substrates (DL Val-Leu-Arg pNA and N-Methoxy Succinyl Ala-Ala-Pro-Val pNA, respectively). Intergroup differences in cell counts were not significant. However, TK activity was significantly less in the AMV group than in the PMV and cystic fibrosis patients (Kruskal-Wallis ANOVA, p < 0.05). Elastase activity was significantly greater in the CF group (p < 0.05) than in the other two groups. Compared to patients undergoing short-term mechanical ventilation (AMV group), TK activity was elevated in patients with purulent tracheobronchitis associated with prolonged mechanical ventilation (PMV group). The elevation in TK activity in these patients is comparable to levels in sputum from patients with cystic fibrosis (CF group), although the latter had a significantly higher level of NE activity. The observation of increased TK activity in patients with neutrophilic airway inflammation suggests that TK may play a role in modulating inflammation in ventilator-associated tracheobronchitis and may be worthy of further study to determine its source and significance.

Effects of unilateral bronchoconstriction on distribution of aerosols in ovine airways.

The purpose of the study was to assess the effect of unilateral bronchoconstriction on the deposition patterns of aerosolized particles in a sheep model. Unilateral bronchoconstriction was induced in intubated conscious sheep by placing a protective, obstructing balloon catheter in either main bronchus, prior to administration of aerosolized carbachol at a dose that increased pulmonary resistance by 200-400% above baseline. The catheter was then removed and the animals were positioned under a gamma camera. An equilibrium image was obtained with xenon (133Xe), to determine a lung outline that was used to calculate the proportion of counts in each lung. Aerosols, labeled with technetium (99mTc) and generated by two jet nebulizers, were inhaled tidally by the sheep in serial experiments. (For nebulizer A, mass median aerodynamic diameter [MMAD] = 0.39 microm; for nebulizer B, MMAD = 1.1 microm.) For nebulizer A, percentage deposition in the treated and untreated lungs was not significantly different (50.8% versus 49.2%, respectively), while for nebulizer B, the median deposition in the carbachol treated lung was significantly greater than in the untreated lung (55.8% versus 44.2% respectively; p = 0.005). There was a more central pattern of deposition in the treated lung than in the untreated lung for both nebulizers, but the degree of central deposition was significantly greater with nebulizer B. The findings of the present study suggest that regional obstruction does not preclude the delivery of therapeutic aerosols to the airways in such a region, and may, depending on the size of the aerosol, result in enhanced airway deposition relative to less obstructed regions.

Monofunctional derivatives of coproporphyrins for phosphorescent labeling of proteins and binding assays.

p-Isothiocyanatophenyl derivatives of Pt(II)- and Pd(II)-coproporphyrin I are described as stable monofunctional reagents which enable simple covalent labeling of proteins and other biomolecules under mild conditions in aqueous solutions. Labeling procedure was optimized for antibodies, avidin, and neutravidin. Photophysical properties of resulting conjugates important for their use in binding assays based on time-resolved phosphorescence detection were studied. The functional activity and long-term storage stability of antibody conjugates were assessed in comparison with unmodified proteins. The new labels and their conjugates were evaluated in the solid-phase immunoassays using commercial time-resolved phosphorescence readers Victor(2) and Arcus-1230 (Wallac). Potential applications of these reagents in in vitro diagnostics are discussed.

Inhaled antimicrobial therapy: from cystic fibrosis to the flu.

Recent controlled clinical trials have confirmed the usefulness of aerosolized tobramycin in cystic fibrosis and have emphasized the importance of ensuring adequate lung delivery of inhaled antimicrobials. For purulent tracheobronchitis associated with prolonged mechanical ventilation it has recently been established that it is possible to deliver substantial and measurable doses of medications to the airway via aerosolization, but controlled studies are needed to determine the efficacy and safety of inhaled antibiotic therapy in this setting. However, prophylactic aerosolized antibiotic therapy in an intensive care unit setting may be counterproductive. Aerosolized pentamidine continues to provide prophylaxis against PCP in a substantial minority of subjects with human immunodeficiency virus infection who are intolerant of oral agents. The effectiveness of aerosolized amphotericin B as prophylaxis against aspergillosis in neutropenic patients needs to be evaluated in a large clinical trial. Zanamivir, an inhibitor of neuraminidase, delivered via inhalation, shows promise in the treatment of uncomplicated influenza infection, but more data are needed on its effectiveness and safety in patients with preexisting respiratory disease. The development of new chemical entities, more efficient delivery systems, and more precise measurement of dose-response and regional pulmonary drug distribution of inhaled antimicrobials suggest that this somewhat neglected topic in therapeutics may be about to receive an increased degree of attention.

Phosphorescent porphyrin probes in biosensors and sensitive bioassays.

Platinum(II) and palladium(II) complexes of porphyrins and related tetrapyrrolic pigments emit strong phosphorescence at room temperatures, which is characterized by long lifetimes falling into the sub-millisecond range and long-wave spectral characteristics. These features make the dyes useful as probes for a number of bioanalytical applications, particularly those employing time-resolved fluorescent detection. They can provide high sensitivity and selectivity, together with rather simple instrumental set-up. A number of analytical systems are now under development that are based on the use of phosphorescent porphyrin probes. Experimental results are presented on the following systems: (i) fibre-optic phosphorescence lifetime-based oxygen sensor on the basis of hydrophobic platinum-porphyrins and development of advanced sensing materials and prototype instrumentation; (ii) practical applications of the optical oxygen sensor, including a sensitive immunosensor that employs glucose oxidase labels, a rapid screening method for cell viability in microtitre-plate format, non-destructive measurement of oxygen in packaged foods and reagentless biosensors for metabolites (glucose, lactate); and (iii) the use of water-soluble platinum- and palladium-porphyrins as labels for ultra-sensitive time-resolved phosphorescence immunoassays.

Behavioural and physiological responses of sheep to 16 h transport and a novel environment post-transport.

The effect of a novel lairage environment on the ability of sheep to recover from 16 h of transport was investigated. Sheep were transported from grass paddocks to either novel outside paddocks or inside pens, and housed groups were transported to either familiar or novel inside pens. During transport, sheep from outside paddocks lay down less than those from inside pens. In sheep transported to inside pens, those from outside paddocks spent more time lying and spent less time eating; hay and water intakes during the first 12 h post-transport were lower than those previously kept inside. There was no obvious effect of a novel environment post-transport on blood biochemistry, suggesting that the lower post-transport feed and water intakes in a novel environment did not have a significant effect on the ability of the sheep to recover from the feed and water deprivation associated with transport.

A cell viability assay based on monitoring respiration by optical oxygen sensing.

A cell viability assay based on monitoring of the metabolic activity of living cells via their consumption of dissolved oxygen has been developed. It uses a microwell plate format and disposable phosphorescent sensor inserts incorporated into each sample. The wells are subsequently sealed from ambient oxygen using a layer of mineral oil, and periodically scanned from underneath with a simple fiber-optic phosphorescent phase detector. Thus, dissolved oxygen levels and time profiles of cell respiration can be determined noninvasively and compared to each other. The system was tested by monitoring the viability of the fission yeast Schizosaccharomyces pombe. In comparison with the conventional cell densitometry assay, the optical oxygen sensor method could reliably monitor lower numbers of cells (10(4)-10(5) vs 10(6)-10(7) cells/ml for densitometry), and accurately determine culture viability within 1 h. The assay was then applied to determine the viability of samples treated with toxic agents such as azide and in response to expression of a physiological inducer of cell death, the Bcl-2 family member Bak. The results obtained confirm that measurement of cell respiration by this assay can serve as a predictable, reliable, and fast method for high-throughput determination of cell viability and growth.

A 1-year study of salmeterol powder on pulmonary function and hyperresponsiveness to methacholine.

BACKGROUND: Long-acting beta(2)-sympathomimetic agonists such as salmeterol have been proved safe and effective for the treatment of asthma. However, controversy still exists as to the appropriateness of scheduled long-term therapy with these agents. OBJECTIVE: This study assessed the degree of bronchodilation provided by treatment with salmeterol for a period of 52 weeks and evaluated bronchial hyperresponsiveness to methacholine during and after the treatment period. METHODS: Three hundred fifty-two patients with mild to moderate asthma were assessed by 12-hour serial spirometry and serial methacholine challenge tests. RESULTS: The mean area under the FEV(1) curve above baseline over 12 hours after drug at day 1 was significantly greater with salmeterol powder compared with placebo (5.06 liter hours vs 0.77 L/h) and did not change significantly over 1 year. The mean increase in the log(2) of the provocative cumulative methacholine dose producing a 20% decrease in FEV(1) (PD(20)FEV(1)) during treatment was significantly higher in the salmeterol-treated patients than in the placebo group (1.02 doubling doses vs 0.43 doubling doses at week 4, 1.06 doubling doses vs 0.41 doubling doses at week 24). At week 52 the increase from baseline in log(2)PD(20)FEV(1) was not significantly different between salmeterol and placebo (1.08 vs 0.69 doubling doses). Seven days after treatment the log(2)PD(20)FEV(1) was -0.60 doubling doses lower than baseline for salmeterol compared with 0.10 doubling doses for placebo (P =.031). Long-term salmeterol use was not associated with a deleterious effect on asthma control during and after treatment. CONCLUSION: This study demonstrates that the bronchodilator properties of salmeterol are sustained over 52 weeks and that bronchial hyperresponsiveness to methacholine is decreased to a modest degree during treatment. Clinically significant increases in hyperresponsiveness did not develop after discontinuation of salmeterol treatment.

Aerosolization of P2Y(2)-receptor agonists enhances mucociliary clearance in sheep.

The purpose of this study was to determine whether aerosolized INS316 (UTP) stimulates lung mucociliary clearance (MCC) in sheep and, if so, to compare its effects with INS365, a novel P2Y(2)-receptor agonist. In the first series of studies, we used a previously described roentgenographic technique to measure tracheal mucus velocity (TMV), an index of MCC, before and for 4 h after aerosolization of INS316 (10(-1) M and 10(-2) M) and INS365 (10(-1) M and 10(-2) M), or normal saline in a randomized crossover fashion (n = 6). In a second series of studies, we compared the ability of these agents to enhance total lung clearance. For these tests, the clearance of inhaled technetium-labeled human serum albumin was measured serially over a 2-h period after aerosolization of 10(-1) M concentration of each agent (n = 7). Aerosolization of both P2Y(2)-receptor agonists induced significant dose-related increases in TMV (P < 0.05) compared with saline. The greatest increase in TMV was observed between 15 and 30 min after drug treatment. The highest dose (10(-1) M) of INS316 produced a greater overall stimulation of TMV than did INS365 (10(-1) M). Both compounds, compared with saline, induced a significant increase in MCC (P < 0.05) within 20 min of treatment. This enhancement in MCC began to plateau at 60 min. Although the response to INS316 started earlier, there was no significant difference between the clearance curves for the two compounds. We conclude that inhaled P2Y(2)-receptor agonists can increase lung MCC in sheep and that for P2Y(2)-receptor stimulation TMV accurately reflects changes in whole lung MCC.

Inhaled antimicrobial therapy.

Although antimicrobial therapy has been administered through the inhaled route for decades, it has always been controversial. There are relatively few accepted indications for this mode of administration. Well-controlled studies of aerosolized antibiotics in cystic fibrosis demonstrate that tobramycin on a cyclical basis may reduce sputum volume, bacterial counts, and improve pulmonary function. Preliminary data indicate that inhaled antibiotic therapy of ventilator-associated tracheobronchitis may reduce sputum volume, but the clinical significance of this finding remains to be determined. Inhaled pentamidine is used for prophylaxis of Pneumocystis carinii in patients with human immunodeficiency virus infection who are intolerant of oral prophylactic agents. Ribavirin has been used for 30 years to treat respiratory syncytial virus. The role, if any, of inhaled antifungal therapy with amphotericin B remains undetermined.

Bench testing of nebulizers: a comparison of three methods.

Although nebulizers can vary widely in performance, there is no uniformly accepted method for bench testing these devices. In the present study, we compared three bench methods of measuring the performance of three commercial jet nebulizers (Whisper Jet [WJ; Marquest Medical, Englewood, CO], Sidestream [SS; Marquest Medical], and Vixone [VO; Westmed, Tucson, AZ] to assess the impact of the method of testing on reported nebulizer performance. Each nebulizer was charged with 3 mL of albuterol mixed with a radiotracer (technetium [99mTc]), and the radioactivity captured on a paper filter was expressed as a percentage of the nebulizer charge (% delivered). The nebulizers were tested with and without duplication of spontaneous respiration by a piston pump (spontaneous respiration and standing cloud methods, respectively). The nebulizers were also tested using a model of mechanical ventilation (mechanical ventilation method). For all three devices, the addition of the standardized breathing pattern significantly reduced the % delivered with all three nebulizers compared with the standing cloud method. For the standing cloud method, the presence of the T-piece/mouth-piece significantly reduced the % delivered with the WJ but not with the other two devices. The mechanical ventilation method had the lowest % delivered for all three devices. The magnitude of the differences between nebulizers varied with duration of treatment. The findings of this study emphasize the importance of bench testing that duplicates intended clinical usage, because significant differences in nebulizer performance may be manifested under certain clinical conditions but not under others.

An immunosensor based on the glucose oxidase label and optical oxygen detection.

A novel optical immunosensor setup is described which uses glucose oxidase enzyme as a label in conjunction with a luminescence lifetime-based oxygen sensor and phase measurements. The oxygen sensor membranes prepared on microporous filters were used as a solid phase on which the immunoassay was carried out. These sensing materials in combination with a new measurement setup provided high sensitivity for the detection of oxidase enzymes, being at nanogram per milliliter level, i.e., 10(-11)-10(-12) M, with respect to glucose oxidase and its conjugates. Experimental data on the sensitivity were validated using theoretical equations and calculations. Using the new measurement setup and IgG-anti-IgG as a model, a number of different sensing materials were studied aimed to optimize the immunosensor and evaluate its performance. This approach was then applied to a practical system for the detection of human lactate dehydrogenase isoenzymes. It provided similar sensitivity of approximately 1 ng/mL, which is comparable to that of standard ELISA. The attributes of the new immunosensor approach are discussed with respect to performance and versitility.

Secretory leukocyte protease inhibitor prevents allergen-induced pulmonary responses in animal models of asthma.

Secretory leukocyte protease inhibitor (SLPI) is a naturally occurring protein of human airways that exhibits broad spectrum inhibitory activity against mast cell and leukocyte serine proteases implicated in asthma pathology. To assess the potential therapeutic utility of SLPI in this disorder, its effects on antigen-induced pulmonary responses were evaluated. In Ascaris-sensitized sheep, SLPI (3 mg) administered by aerosol daily for 4 days, with the final dose 0.5 h before antigen challenge, reduced the areas under the curve for early- and late-phase bronchoconstriction (73 and 95%, respectively; p <.05 versus control responses). SLPI also inhibited the development of airway hyperresponsiveness to carbachol (84%, p <. 05 versus control response) measured 24 h after antigen challenge. In ovalbumin-sensitized guinea pigs, intratracheal administration of SLPI daily for 3 days, with the final dose 1 h before antigen challenge, inhibited the development of airway hyperresponsiveness to histamine with an ED50 of <0.05 mg/kg. Prolonged pharmacodynamic activity of SLPI was observed in both species. In a murine model of atopic asthma, SLPI inhibited leukocyte influx into the airways after chronic allergen challenge. SLPI administered to sheep by the predosing protocol described above also prevented the antigen-induced decrease of tracheal mucus velocity (p <.05). In addition, a single aerosol administration of SLPI (30 mg) to sheep 1 h after antigen challenge inhibited the subsequent late-phase bronchoconstriction and development of hyperresponsiveness and reversed the stimulated decrease in tracheal mucus velocity. These results suggest that SLPI may provide therapeutic intervention against the pathophysiology of asthma and its underlying pathology.

Simultaneous analysis of individual and aggregate responses in psychometric data using multilevel modeling.

Psychometric data on risk perceptions are often collected using the method developed by Slovic, Fischhoff, and Lichtenstein, where an array of risk issues are evaluated with respect to a number of risk characteristics, such as how dreadful, catastrophic or involuntary exposure to each risk is. The analysis of these data has often been carried out at an aggregate level, where mean scores for all respondents are compared between risk issues. However, this approach may conceal important variation between individuals, and individual analyses have also been performed for single risk issues. This paper presents a new methodological approach using a technique called multilevel modelling for analysing individual and aggregated responses simultaneously, to produce unconditional and unbiased results at both individual and aggregate levels of the data. Two examples are given using previously published data sets on risk perceptions collected by the authors, and results between the traditional and new approaches compared. The discussion focuses on the implications of and possibilities provided by the new methodology.

A quantitative test of the cultural theory of risk perceptions: comparison with the psychometric paradigm.

This paper seeks to compare two frameworks which have been proposed to explain risk perceptions, namely, cultural theory and the psychometric paradigm. A structured questionnaire which incorporated elements from both approaches was administered to 129 residents of Norwich, England. The qualitative risk characteristics generated by the psychometric paradigm explained a far greater proportion of the variance in risk perceptions than cultural biases, though it should be borne in mind that the qualitative characteristics refer directly to risks whereas cultural biases are much more distant variables. Correlations between cultural biases and risk perceptions were very low, but the key point was that each cultural bias was associated with concern about distinct types of risks and that the pattern of responses was compatible with that predicted by cultural theory. The cultural approach also provided indicators for underlying beliefs regarding trust and the environment; beliefs which were consistent within each world view but divergent between them. An important drawback, however, was that the psychometric questionnaire could only allocate 32% of the respondents unequivocally to one of the four cultural types. The rest of the sample expressed several cultural biases simultaneously, or none at all. Cultural biases are therefore probably best interpreted as four extreme world views, and a mixture of qualitative and quantitative research methodologies would generate better insights into who might defend these views in what circumstances, whether there are only four mutually exclusive world views or not, and how these views are related to patterns of social solidarity, and judgments on institutional trust.