A comparison of 2 extrafine hydrofluoroalkane-134a-beclomethasone formulations on methacholine hyperresponsiveness.

BACKGROUND: Small airways inflammation is a recognized pathologic component of asthma, and it is postulated that the observed airway-wall remodeling in small airways could be due to uncontrolled inflammation in airways that are not penetrated by conventional inhaled corticosteroids. Thus, extrafine particle formulations of inhaled corticosteroids are of clinical interest. OBJECTIVE: To compare 2 extrafine solution hydrofluoroalkane-134a formulations of beclomethasone dipropionate (Beclate and Qvar). METHODS: Fifteen asthmatic patients (mean +/- SEM forced expiratory volume in 1 second [FEV1], 2.62 +/- 0.21 L; provocative concentration of methacholine causing a 20% decrease in FEV1 [PC20], 1.06 +/- 0.58) were randomized to completion in a placebo-controlled, double-blind, crossover manner to receive Beclate or Qvar at doses of 100 or 400 microg/d for 2 weeks, with a 1-week washout period before each randomized treatment. Methacholine hyperresponsiveness was the primary outcome measure. RESULTS: The 2 formulations were equivalent in terms of predefined equivalence limits of +/- 1 doubling dilution for PC20 at both doses: -0.25 (95% confidence interval [CI], -0.77 to 0.27) doubling dilution difference between the 100-microg doses and a 0.26 (95% CI, -0.29 to 0.82) doubling dilution difference between the 400-microg doses for the difference between Beclate and Qvar, respectively. Both formulations, at either dose, produced a statistically significant (P < .05) reduction in mean exhaled nitric oxide levels: 400 microg/d of Beclate, 14.1 ppb (95% CI, 5.6 to 22.6 ppb); and 400 microg/d of Qvar, 14.2 ppb (95% CI, 6.0 to 22.4 ppb). The higher doses produced a statistically significant (P < .05) reduction in early morning urinary cortisol-creatinine ratio (geometric mean fold suppression: Beclate, 1.48 [95% CI, 1.16 to 1.89]; and Qvar, 1.42 [95% CI, 1.12 to 1.79]). Both formulations significantly improved peak expiratory flow, FEV1, and forced expiratory flow between 25% and 75% of forced vital capacity at the higher doses (P < .05). CONCLUSIONS: Beclate and Qvar were equivalent for all primary and secondary outcome measures.     

A calibration service for biomedical instrumentation maintenance laboratories

An in-house calibration laboratory for the Biomedical Instrumentation Maintenance Services of the hospitals in the West of Scotland was established in 1993. This paper describes the development of this calibration service in the context of an overall quality system and also estimates its costs. Not only does the in-house service have many advantages but it is shown to be cost effective for workloads exceeding 260 items per annum.     

Assay of cell attachment and spreading factors

Summary Methods are presented for the quantitative assay of proteins influencing cell attachment and spreading. These include assays in which cell-substratum interactions are quantitated directly and a serum-free assay in which cell growth is dependent on attachment under substratum-limited conditions. Procedures are also presented for the identification of active sites of substratum molecules through the use of antibodies and synthetic peptides that are inhibitory for cell attachment.     

The interaction of conflicting retinal motion stimuli in oculomotor control

Summary Oculomotor response has been assessed in humans during the presentation of conflicting retinal motion stimuli. In the majority of experiments a background stimulus was made to move with a constant velocity ramp in one direction followed by rapid resets at regular intervals. In the absence of an adequate fixation target this ramp-reset stimulus induced a nystagmus with a slow-phase velocity and saccadic frequency which remained almost constant as reset frequency was increased from 2 to 5 Hz. Moreover, the induced eye velocity could be considerably increased if the subject attempted active matching of display velocity. During both active and passive responses eye velocity gain reached a peak when display velocity was between 2°/s and 5°/s. The presence of small stationary targets induced a suppression of the passive ramp-reset response which was modified by target eccentricity and by tachistoscopic target illumination. When subjects pursued a sinusoidally oscillating target against a stationary structured background, eye velocity gain was significantly less than for pursuit against a blank background. The degree of interaction between conflicting stimuli was found to be dependent on their relative size, peripheral location and velocity. However, it appears that the human observer is able selectively to enhance feedback gain from one particular source in order to dominate stimuli from other unwanted sources.     

Patterns of cytokine production by mycobacterium-reactive human T-cell clones.

To gain insight into the functional capacity of human T cells in the immune response against Mycobacterium tuberculosis, we evaluated the spectrum of cytokines produced by mycobacterium-reactive human T-cell clones. Nine of 11 T-cell clones bearing alpha beta or gamma delta T-cell receptors produced both Th1 and Th2 cytokines, a pattern resembling that of murine Th0 clones. The most frequent pattern was secretion of gamma interferon, tumor necrosis factor alpha (TNF), and interleukin-10 (IL-10), in combination with IL-2, IL-5, or both. Two clones produced only Th1 cytokines, and none produced exclusively Th2 cytokines. Although IL-4 was not detected in cell culture supernatants, IL-4 mRNA was detected by polymerase chain reaction amplification in two of six clones. There were no differences between the cytokine profiles of alpha beta and gamma delta T cells. A striking finding was the markedly elevated concentrations of TNF in clone supernatants, independent of the other cytokines produced. Supernatants from mycobacterium-stimulated T-cell clones, in combination with granulocyte-macrophage colony-stimulating factor, induced aggregation of bone-marrow-derived macrophages, and this effect was abrogated by antibodies to TNF. The addition of recombinant TNF to granulocyte-macrophage colony-stimulating factor markedly enhanced macrophage aggregation, indicating that TNF produced by T cells may be an important costimulus for the granulomatous host response to mycobacteria. The cytokines produced by T cells may exert immunoregulatory and immunopathologic effects and thus mediate some of the clinical manifestations of tuberculosis.     

Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression

Seventeen families with Emery-Dreifuss muscular dystrophy (EDMD) have been studied both by DNA sequencing and by emerin protein expression. Fourteen had mutations in the X-linked emerin gene, while three showed evidence of autosomal inheritance. Twelve of the 14 emerin mutations caused early termination of translation. An in-frame deletion of six amino acids from the C-terminal transmembrane helix caused almost complete absence of emerin from muscle with no localization to the nuclear membrane, although mRNA levels were normal. This shows that mutant emerin proteins are unstable if they are unable to integrate into a membrane. A 22 bp deletion in the promoter region was expected to result in reduced emerin production, but normal amounts of emerin of normal size were found in leucocytes and lymphoblastoid cell lines. This shows that DNA analysis is necessary to exclude emerin mutations in suspected X-linked EDMD. Emerin levels in female carriers often deviated from the expected 50% and this was due, in at least two families, to skewed emerin mRNA expression from the normal and mutated alleles. In one family with a novel deletion of the last three exons of the emerin gene, a carrier had a cardiomyopathy and very low emerin levels (<5% of normal) due to skewed X-inactivation. In the three autosomal cases of EDMD, emerin was normal on western blots of blood cells, which suggests that autosomal EDMD is not caused by indirect reduction of emerin levels.      

Anxiety during pregnancy and fetal attachment after in-vitro fertilization conception

The aim of this study was to compare 70 couples who had conceived by in- vitro fertilization (IVF) with 63 matched controls for the prevalence of anxiety and quality of attachment to the baby during pregnancy. Results for mothers showed no group differences using a global measure of anxiety, the Spielberger State-Trait Anxiety Inventory. However, pregnancy-specific measures revealed significantly higher levels of anxiety in IVF mothers about the survival and normality of their unborn babies, about damage to their babies during childbirth and about separating from their babies after birth. When IVF mothers were differentiated according to the number of treatment cycles, more differences in anxiety level were revealed, with most increases occurring in mothers who had experienced two or more treatment cycles. IVF fathers did not differ from controls on the global anxiety measure. No data on pregnancy-specific anxiety were available for fathers. Neither IVF mothers nor IVF fathers differed from controls on measures of attachment to the baby during pregnancy. Results are discussed in the context of the need for researchers to employ differentiated and issue-specific measures to identify concerns that may be unique to IVF couples. Clinical implications regarding the need for psychological support during pregnancy are also discussed.      

Regional mapping of the gene encoding dihydroorotate dehydrogenase,an enzyme involved in UMP synthesis,electron transport,and superoxide generation,to human chromosome region 16q22

De novo UMP synthesis is a critical metabolic pathway for nucleic acid synthesis and for a variety of metabolic pathways. The pathway is a target for many widely used cancer chemotherapy agents, several of which are pyrimidine analogs. Humans and cattle have been described with mutations in UMP synthesis that lead to serious inborn errors of metabolism. Dihydroorotate dehydrogenase (EC 1.3.3.1) (DHODH) carries out the fourth committed step in the pathway and may also be important for mitochondrial electron transport and oxygen radical metabolism. We report here that the gene encoding this enzyme in humans is located in the chromosomal region 16q22. With the mapping of DHODH, the mapping of all the steps of UMP synthesis is complete. All three genes involved map to different human chromosomes. This information is important in consideration of regulation of UMP synthesis in mammals, including humans.     

Anticipatory control of hand and eye movements in humans during oculo-manual tracking

Anticipatory activity of hand and eye has been examined during oculo-manual tracking of a constant velocity visual target with a hand cursor. Both target and cursor were presented briefly (< 480 ms), but repeatedly, at regular inter-stimulus intervals (ISI). In Expt 1, the build-up of hand and eye responses was examined for target velocities varying from 10–40 deg s⁻¹ with an ISI of 2.4 s. The velocity 100 ms after target onset (i.e. prior to visual feedback) for both hand and eye ( V ₁₀₀) progressively increased over the first four presentations but then attained a steady state (SS). SS V ₁₀₀ values for eye and hand increased in proportion to target velocity and were thus predictive of forthcoming movement. Hand velocity exceeded eye velocity but both exhibited similar anticipatory trajectories. In Expt 2, target velocity was constant (40 deg s⁻¹) but ISI varied from 0.48–3.74 s. Subjects made anticipatory eye movements for all ISIs but hand movements were often reactive at the longest ISI. If the target failed to appear as expected, subjects initiated predictive hand and eye responses with timing appropriate for the prevailing ISI. In Expt 3, predictive responses were compared with responses to randomised presentation. Peak hand velocity was greater in the randomised mode than in the predictive condition, whereas the converse was true for peak eye velocity. This difference is discussed in terms of the mechanisms of positional error correction in hand and eye. Results provide evidence of similar anticipatory mechanisms in hand and eye, using storage of velocity and timing to achieve rapid prediction of target motion.     

Cryptococcus neoformans var. gattii in the koala (Phascolarctos cinereus): serological evidence for subclinical cryptococcosis.

Cryptococcus neoformans var. gattii has been shown to have a strong association with eucalypts frequently used by koalas and, not surprisingly, it has been shown to colonize the nasal cavities of koalas. The progression from nasal colonization to tissue invasion is critical to understanding the pathogenesis of cryptococcosis in this species and provides a model for pathogenesis of cryptococcosis in other species. Cryptococcal antigenaemia was detected in twenty-eight healthy koalas from three different regions. This was interpreted as representing limited subclinical disease. One koala developed cryptococcal pneumonia 6 months after leaving the study, whereas another developed cryptococcal meningoencephalitis during the course of the study. Opportunistic necropsies on ten antigen-positive koalas resulted in discovery of small cryptococcal lesions in two (paranasal sinus and lung, respectively). Our data suggest that cryptococcal antigenaemia occurs commonly in koalas, especially in areas with a high environmental presence of C n. var. gattii. Subclinical disease appears most likely to manifest as a small focal lesion in the respiratory tract. Possible outcomes include elimination by an effective immune response, quiescence with possibility of later re-activation or direct progression to overt disease. Symptomatic and subclinical cases showed differences in levels of antigenaemia. The data presented have significant implications for koalas in captivity.