hflB, a new Escherichia coli locus regulating lysogeny and the level of bacteriophage lambda cII protein.

The level of the viral cII protein has been proposed to be the crucial determinant in the lysis-lysogeny decision of bacteriophage lambda. A new Escherichia coli locus (hflB) has been identified in which a mutation (hflB29) leads to high frequency of lysogeny by lambda. A double mutant defective in both hflB and the previously identified hflA gene displays a more severe Hfl- phenotype than either single mutant. The hflB locus is at 69 minutes on the E. coli map, 85% co-transducible with argG. The hflB29 mutation results in increased stability of the phage cII protein (increasing its half-life twofold) and is recessive to hflB+. We conclude that the hflB+ locus is a negative regulator of cII, perhaps coding for or regulating a protease that acts on cII. In addition, we observe that the can1 mutation, an alteration of the cII gene that results in enhanced lysogenization, leads to increased stability of cII protein. These observations reinforce the view that the level of cII is a key factor in the lysis-lysogeny decision of lambda.

Effects of low and high doses of inhaled flunisolide and triamcinolone acetonide on basal and dynamic measures of adrenocortical activity in healthy volunteers.

The objective of this study was to evaluate the effects of inhaled flunisolide (FN) and triamcinolone acetonide (TAA) on basal and dynamic adrenocortical activity. A randomized cross-over design was used, comparing placebo (PL), low (L) and high (H) doses of FN (Aerobid; 250 microg/actuation; without spacer; L, 1000 microg; H, 2000 microg/day), and TAA (Azmacort; 100 microg/actuation; with integrated actuator/spacer; L, 800 microg; H, 1600 microg/day). Each dose was given at 0800 and 2200 h for 3 days, and treatments were separated by a 10-day washout. Twelve normal volunteers (mean +/- SE age, 24.2 +/- 2.4 yr) were studied. After 3 days of treatment, blood samples were taken before ACTH stimulation at 0800 h (10 h after the sixth dose) and after ACTH (0.5 microg) stimulation for determination of serum cortisol. Overnight (starting at 2200 h on the third day of treatment) and early morning urine collections were taken for measurements of urinary cortisol corrected for creatinine excretion. For serum cortisol (pre- and post-ACTH stimulation), there was no significant difference compared with placebo for either drug. Post-ACTH cortisol (nanomoles per L) values were: PL, 666.3; H FN, 617.0; H TAA, 591.4; L FN, 699.2; and L TAA, 686.0. For overnight corrected urinary cortisol/creatinine excretion (nanomoles per mmol) compared with PL (6.4), there was a significant suppression (P < 0.05) at the high dose of both drugs (H FN, 2.6; H TAA, 2.3) but not at the low dose (L FN, 4.2; L TAA, 4.5). Likewise, values for early morning corrected urinary cortisol/creatinine (nanomoles per mmol) showed significant suppression (P < 0.05) only with high doses of both drugs (PL, 39.0; H FN, 26.5; H TAA, 26.6; L FN, 37.2; L TAA, 36.5). The following conclusions were reached. 1) Overnight and early morning corrected urinary cortisol/creatinine excretion was more sensitive at detecting adrenocortical suppression than basal 0800 h serum cortisol or response to 0.5 microg ACTH stimulation. 2) There were no significant differences between inhaled FN (without spacer) and TAA (with integrated actuator/spacer), which only produced detectable adrenocortical suppression at the highest recommended doses and was not associated with impaired adrenal reserve. 3) Even at the high dose, the suppression observed with both drugs is unlikely to be of clinical relevance.

Paradoxical down-regulation and desensitization of beta2-adrenoceptors by exogenous progesterone in female asthmatics.

We have demonstrated previously that exogenous progesterone, but not estrogen, up-regulated lymphocyte beta2-adrenoceptors (beta2-AR) when given during the follicular phase in healthy women. Female asthmatics exhibit loss of the cyclical pattern of beta2-AR regulation seen in healthy women, in that there is no luteal phase rise in beta2-AR. It has been postulated that abnormal cyclical regulation of beta2-AR might be a possible mechanism for premenstrual asthma. In this study, we were interested to see how exogenous female sex-steroid hormones altered beta2-AR regulation in female asthmatics during the follicular phase, when endogenous hormone levels are normally low. Seven nonsmoking female subjects with mild asthma, with a mean (SEM) age of 26 (2) years and FEV1 of 94.7% (6.4) of predicted, completed this randomized, double-blind, crossover study. They were evaluated at two successive menstrual cycles, during the follicular phase (day 1 to 6). They were randomized to receive single oral doses of either ethinyl estradiol (ethinyloestradiol), 50 microg, or medroxyprogesterone, 10 mg. Lymphocyte beta2-AR parameters were evaluated at baseline (T0), 24 h (T24), and 72 h (T72) after ingestion. Baseline levels of progesterone and estradiol were comparable on both cycles. Receptor binding density (log Bmax; fmol/10(6) cells) decreased significantly after progesterone but not after estrogen at T24: amounting to a 1.34-fold mean difference (95% confidence interval [CI], 1.01 to 1.78) between T24 vs T0 with progesterone. Comparing Bmax for progesterone with estrogen at T24 amounted to a 1.25-fold significant difference (95% CI, 1.00 to 1.56). This was associated with a trend (p=0.06) toward a lower cyclic-adenosine monophosphate (AMP) response to isoproterenol hydrochloride (isoprenaline) 10(-4) M (Emax) at T24 vs T0 with progesterone. Receptor binding affinity (Kd) was not altered by either treatment. These results show that exogenous progesterone, but not estrogen, given during the follicular phase, decreased beta2-AR density and cyclic-AMP response in female asthmatics, in contrast to the previously observed up-regulating effect of progesterone seen in healthy women. This paradoxical effect of progesterone in female asthmatics suggests an abnormal regulation of beta2-AR and might be a possible mechanism for premenstrual asthma when progesterone levels are high during this period of the cycle.

Beta2-adrenoceptor regulation and function in female asthmatic patients receiving the oral combined contraceptive pill.

STUDY OBJECTIVES: Previously it has been shown that there is abnormal hormonal control of beta2-adrenoceptors in asthmatic women. Exogenous progesterone but not estradiol produces paradoxic downregulation and desensitization of beta2-adrenoceptors in asthmatic women when compared with nonasthmatic subjects. This study investigates the effect of the oral combined contraceptive pill (OCP) on beta2-adrenoceptor regulation and function in female asthmatic patients. PATIENTS: The study population was comprised of 11 women with stable mild to moderate asthma. The mean age was 25 years; the FEV1 was 89% of predicted, and the forced expiratory flow, mid-expiratory phase (FEF25-75%) was 69% of predicted. DESIGN: Patients were evaluated while on (day 20 to 21) and off (day 5 to 7) the OCP during a 28-day calendar period. MEASUREMENTS: Serum sex hormones, lymphocyte beta2-adrenoceptor parameters, and bronchodilator and systemic dose-response curves (DRCs) to albuterol (Salbutamol) (100 to 1,600 microg) were measured at both on and off periods. RESULTS: Serum levels of endogenous estradiol and progesterone were both suppressed by the OCP. Baseline FEV1 were not different while patients were on (2.70 L) and off (2.72 L) the OCP. There were no significant differences in lymphocyte beta2-adrenoceptor parameters between the two phases of the cycle. Receptor density (geometric mean Bmax) was 1.78 (on OCP) vs 1.86 (off OCP) fentomole/10(6) cells, maximal cyclic adenosine monophosphate response to isoprenaline was 6.60 (on OCP) vs 7.58 (off OCP) pmol/10(6) cells, and binding affinity was 14.0 (on OCP) and 13.6 (off OCP) pmol/L. Likewise, there were no significant differences in the bronchodilator and systemic DRCs constructed at both phases of the cycle as evaluated: area-under-curve (AUC) FEV1 was 0.53 (on OCP) vs 0.56 (off OCP) L.h; and AUC FEF25-75% was 3,130 (on OCP) vs 3,640 (off OCP) L. Potassium (K) and finger tremor responses were unaltered between the two periods: AUC K was 0.50 (on OCP) vs 0.44 (off OCP) mmol . h/L and AUC tremor was 0.72 (on OCP) vs 0.89 (off OCP) log units.h. CONCLUSION: The OCP did not alter beta2-adrenoceptor regulation and function in stable female asthmatic patients. Further studies are required in patients who have premenstrual asthma.

Concomitant administration of low-dose prednisolone protects against in vivo beta2-adrenoceptor subsensitivity induced by regular formoterol.

STUDY OBJECTIVES: To assess whether concomitant administration of low-dose prednisolone (PRED) with regular inhaled formoterol (FM) might prevent the occurrence of beta2-adrenoceptor (beta2-AR) tachyphylaxis. DESIGN: Eleven healthy male subjects (mean age, 29 years) were randomized to receive 1 week with either inhaled FM, 24 microg bid, and placebo tablets (PL), or inhaled FM, 24 microg bid, and oral PRED, 15 mg daily, in double-blind, crossover fashion, with a 2-week washout between treatments. A dose-response curve (DRC) for systemic beta2-responses to inhaled salbutamol (800 to 3,200 microg) was constructed before and after each treatment period (ie, FM + PL or FM + PRED). Lymphocyte beta2-AR density (Bmax) and maximal cyclic adenosine monophosphate response to isoproterenol (isoprenaline) (Emax) were evaluated ex vivo at each visit; 8 AM serum cortisol level was also evaluated as a marker of systemic glucocorticoid activity. Comparisons for DRC were made as peak responses and area under curve (AUC). RESULTS: There was significant (p < 0.05) subsensitivity of systemic beta2-AR responses (as AUC) following FM + PL: for heart rate (before vs after), 760 vs 340 beats (95% confidence interval [CI], 160 to 680), for tremor 0.39 vs 0.19 log units/h (95% CI, 0.01 to 0.41), and for potassium, -0.34 vs -0.19 mmol x h/L (95% CI, -0.04 to -0.28). With PRED, there was protection against subsensitivity induced by FM with no significant difference in values before vs after FM: heart rate, 740 vs 640; tremor, 0.35 vs 0.34; and potassium, -0.30 vs -0.25. FM + PL induced significant downregulation of lymphocyte beta2-AR density (log Bmax; fmol/10(6) cells) (before vs after): 0.25 vs 0.11 (95% CI, 0 to 0.22; p < 0.05) and this was not altered by PRED (before vs after): 0.21 vs 0.10 (95% CI, 0.01 to 0.27; p < 0.05). FM + PL also caused desensitization of Emax (pmol/10(6) cells) (before vs after): 6.21 vs 2.29 (95% CI, 1.19 to 6.64; p < 0.05) and this was attenuated by PRED with no significant difference between before and after values: 4.60 vs 3.28. CONCLUSIONS: Concomitant administration of a low dose of PRED produced protection against FM-induced subsensitivity of systemic beta2-AR, as assessed by the response to inhaled salbutamol. In contrast, prednisolone did not prevent ex vivo beta2-AR downregulation despite causing significant cortisol suppression. This, in turn, suggests that there is a dissociation in the dose of PRED required to protect against beta2-AR downregulation and subsensitivity, following continuous exposure to long-acting beta2-agonist.

Systemic bioactivity profiles of oral prednisolone and nebulized budesonide in adult asthmatics.

STUDY OBJECTIVE: Because nebulized budesonide may be used as an alternative to maintenance oral prednisolone in the treatment of severe chronic asthma, it is important to compare these two drugs to determine their relative systemic bioactivity profiles in terms of effects on adrenal, bone, and hematologic markers. DESIGN: Twelve asthmatic patients (mean age; 34.7 years; mean FEV1; 88.3% predicted; mean forced expiratory flow between 25% and 75% of FVC, 54.8% predicted) were studied in a double-blind, double-dummy, randomized crossover design to compare placebo, low, medium, and high doses of nebulized budesonide given bid (1, 2, and 4 mg/d, respectively), and oral prednisolone given qd (5, 10, and 20 mg/d). All treatments and both placebos were given for 4 days at each dose level with a 7-day washout period between each treatment block with budesonide or prednisolone. All measurements were made at 8 AM after the last dose of each dose increment for plasma cortisol, serum osteocalcin, and blood eosinophil count. RESULTS: Regression analysis showed significant dose-related suppression with prednisolone for 8 AM plasma cortisol (p<0.0001), osteocalcin (p<0.05), and blood eosinophil count (p<0.0005), but not with budesonide. Compared with placebo, there were significant differences only with prednisolone, at the medium- and high-dose levels for all three markers. CONCLUSIONS: For all three systemic bioactivity markers (8 AM plasma cortisol, serum osteocalcin, and blood eosinophils), there was significant dose-related suppression with prednisolone but not with budesonide. Further long-term studies are required in more severe asthmatics in order to evaluate the therapeutic index.

Effects of inhaled fluticasone propionate and oral prednisolone on lymphocyte beta 2-adrenoceptor function in asthmatic patients.

The aim of the study was to evaluate the facilitatory effects of inhaled corticosteroid on in vitro parameters of lymphocyte beta 2-adrenoceptor function in asthmatic patients. Serum cortisol level was also evaluated as a measure of systemic bioactivity. Ten (four female) asthmatic subjects were evaluated, mean (SEM) age was 28.6(2.0) years, and FEV1 was 79.9%(8.7) predicted. Single doses of inhaled placebo (PL), fluticasone propionate, 1,000 micrograms (F1000), fluticasone propionate, 2,000 micrograms(F2000), or oral prednisolone, 50 mg(PRED), were given at 10 PM the previous night and measurements were made 10 h later. Values for beta 2-receptor density (logBmax: fmol/10(6)cells) were significantly (p < 0.05) greater than PL with PRED but not with inhaled fluticasone (as means and 95% confidence interval [CI] for difference vs PL): PL, 0.27; F1000, 0.30; F2000, 0.32; and PRED, 0.48 (95% CI vs PL, 0.075 to 0.341). Maximal cyclic adenosine monophosphate (cAMP) responses to isoproterenol hydrochloride (isoprenaline (Emax; pmol/10(6)cells) mirrored those for Bmax: PL, 4.00; F1000, 4.68; F2000, 4.26; and PRED, 7.46 (95% CI vs PL, -0.01 to 6.91). Receptor affinity (Kd) was not significantly altered by any treatment. There was significant (p < 0.05) suppression of serum cortisol (nmol/L) with F2000 and PRED compared with PL: PL, 307.9; F1000, 323.2; F2000, 130.1 (95% CI vs PL, 69.76 to 285.8) and PRED, 51.8 (95% CI vs PL, 144.11 to 368.01). Thus, high-dose inhaled fluticasone propionate did not have any facilitatory effects on lymphocyte beta 2-adrenoceptor parameters as compared with oral prednisolone which upregulated beta 2-receptor density and increased cAMP response. In contrast, high-dose inhaled fluticasone (2,000 micrograms) significantly suppressed serum cortisol. In conclusion, there would appear to be a dissociation in systemic sensitivity between effects of inhaled corticosteroid on adrenal suppression and lymphocyte beta 2-adrenoceptor regulation.

Absconding: why patients leave.

Absconding by patients from acute psychiatric care poses a significant problem to professional staff, and can involve significant risks for patients and others. This paper describes the methodology of a major prospective study of absconding recently completed in the East End of London, and reports the findings on why patients abscond from hospital. Interviews with 52 patients who returned to their wards showed that they abscond because they are bored, frightened of other patients, feel trapped and confined, have household responsibilities they feel they must fulfil, feel cut off from relatives and friends, or are worried about the security of their home and property. Psychiatric symptoms also contribute to the decision to leave, but in nearly every case patients can give additional and rational reasons for their abscond. Some patients leave impulsively and in anger following unwelcome news about delayed permission for leave or discharge. Others leave specifically in order to carry out some activity outside the hospital. In order to reduce absconding and rejection of care, nurses may need to carefully consider the meaning admission has for patients, and the impact it can have upon their everyday lives.

Absconding: how and when patients leave the ward.

Information about how and when patients abscond from acute psychiatric wards may provide important clues to effective prevention strategies. This paper reports relevant findings from a large scale study of absconding conducted in the East End of London. In contrast to the findings in previous studies, the vast majority of absconders left from the ward directly, mostly via the front door. Some were known to be at risk of absconding, and although more than half had declared their intention to leave, they still succeeded in getting away. On some occasions they circumvented locked or guarded doors, or special nursing observation. Shift handovers were a peak time for absconds, possibly due to decreased nursing surveillance of the ward. Most absconds occur during the first few weeks of admission, and most absconders simply went home and engaged in normal, everyday activities. The findings indicate that physical security measures alone are not a sufficient answer to the problem of absconding, and nurses need to work harder to develop supportive alliances with patients.

Absconding: outcome and risk.

Absconding by patients from acute psychiatric wards is known to be linked to self harm and harm to others. Previous research has focused only on officially reported absconds, thus missing out many patients who although they abscond and pose a risk, are never officially processed. This paper reports the findings of a large prospective study of absconding in the East End of London using an objective definition of absconding not linked to official bureaucratic processes. Absconders are considered by staff to be high risk patients, and many have histories of violence and/or suicide attempts. Nevertheless nurses only request the aid of the police in returning patients on 47% of occasions. The actions of the police are very variable, and range from two policemen calling at the patient's house, to an entire team in riot gear appearing at the patient's door in the early hours of the morning. Most absconds result in no harm to anyone, and most absconders return by themselves. Relatives and carers also play a significant role in persuading the patient to return or bringing them back. Nurses should develop more sophisticated ways of working with the police and with relatives to maintain absconding patients' safety.

Absconding: nurses views and reactions.

Absconding from acute psychiatric wards is common. This paper reports the views of 25 staff nurses working on acute mental health wards in East London about absconding. Interviews explored how staff feel when a patient absconds, the complexities of risk assessment and observation policies, who is blamed when patients abscond and what might reduce absconding. The assessment of the level of risk which a patient posed varied considerably, with some wards using standard risk assessment tools and others talking about their own methods. There was some evidence of conflict with medical staff about what measures should be put in place to manage the risk (observation level, leave). The interviewees were aware of serious consequences of absconding, and this made them worry when patients absconded. Following an abscond most nurses look for an explanation, and this can lead to blame of other members of the team. A sizeable minority spoke of feeling unsupported by their managers, and that their jobs could be at risk following an abscond. The nurses felt that absconding could be reduced through a number of measures, principally raising staffing levels and reducing the reliance on agency nurses.

Novel PCR assay for determining the genetic sex of mice.

A number of studies require the determination of the genetic sex of mouse embryos before sexual differentiation and/or of mutant mice that display partial or complete sex reversal. The majority of current methods for sexing by PCR involve multiplexing of 2 primer pairs. We have developed a novel sexing PCR using a single primer pair that amplifies fragments from the X and the Y chromosome with a clear size difference between the respective amplicons. This assay provides a rapid and reliable method to identify the genetic sex of mice across different mouse strains.

Prospective follow-up of novel markers of bone turnover in persistent asthmatics exposed to low and high doses of inhaled ciclesonide over 12 months.

CONTEXT: In asthmatic patients receiving long-term inhaled corticosteroid therapy, there are concerns regarding the potential for developing systemic adverse effects on bone metabolism, possibly even in the absence of adrenal suppression. OBJECTIVE: The aim of this study was to investigate whether exposure to inhaled ciclesonide at high vs. low doses over 1 yr causes any significant systemic adverse effect on sensitive biomarkers of bone turnover in asthmatic patients. DESIGN: Post hoc analysis of stored samples was performed in a subgroup of patients from a prospective, randomized parallel group trial with 1 yr follow-up. SETTING: We conducted a primary care study in Tayside, Scotland. PARTICIPANTS: A total of 164 mild-moderate persistent asthmatics aged 18-65 yr with evidence of airway hyperresponsiveness using mannitol bronchial challenge were enrolled into the original study. Of the 119 completed patients per protocol, 100 participants had bone marker samples available for analysis. INTERVENTIONS: Ciclesonide was titrated to control persistent asthma against either mannitol bronchial challenge [airway hyperresponsiveness (AHR) strategy] or a control group (based on symptoms, reliever use, and pulmonary function) over 1 yr. OUTCOME MEASURES: We measured markers of bone formation [amino-terminal propeptide of type I collagen (PINP), amino-terminal propeptide of type III collagen (PIIINP)], resorption [carboxy-terminal telopeptide of type I collagen (ICTP), type I collagen cross-linked C-telopeptide (CTx)], and adrenal suppression (overnight urinary cortisol/creatinine ratio) at 0 and 12 months. RESULTS: Mean ciclesonide doses after 12 months were: AHR, 507 µg/d (n = 50); and controls, 202 µg/d (n = 50) (P < 0.00001). There were no significant differences between AHR and control groups either at baseline or after 12 months in PINP, PIIINP, ICTP, or CTx; or in ratios of bone turnover as PINP/ICTP, PIIINP/CTx, or overnight urinary cortisol/creatinine ratio. CONCLUSION: Higher doses of inhaled ciclesonide do not adversely affect sensitive markers of bone turnover in persistent asthmatics over 12 months.

Non-coding RNAs in mammalian sexual development.

The present decade is witnessing a paradigm shift in our understanding of gene regulation. RNA, once relegated to an intermediary between DNA and protein, has emerged as a key contributor in the coordination of complex developmental pathways. For sexually reproducing organisms, propagation of the species is accomplished via an elaborate sexual phenotype. In mammals this consists of a highly complex cell lineage that has the capacity for intricate self-differentiation whilst maintaining the potential to generate all cell types upon fertilization. In addition, mammals possess a diverse range of somatic reproductive tissues and organs that often undergo dynamic morphological changes in response to a variety of external and internal cues. Although the protein component required to mediate these processes continues to be vigorously investigated, it is becoming increasingly apparent that an understanding of the non-coding RNA (ncRNA) component is required to develop a comprehensive picture of mammalian sexual development.

Differential anti-inflammatory effects of large and small particle size inhaled corticosteroids in asthma.

BACKGROUND: Extra-fine particle formulations of hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) exhibit clinical effects comparable with conventional particle formulations of chlorofluorocarbon beclometasone dipropionate (CFC-BDP) at half the dose. There is little data comparing their effects on inflammation. We have evaluated the effects of HFA-BDP and CFC-BDP on pulmonary and systemic markers of asthmatic inflammation. METHODS: A double-blind randomized crossover trial was undertaken comparing the anti-inflammatory effects of HFA-BDP (100 and 400 microg/day) and CFC-BDP (200 and 800 microg/day). Treatment with montelukast was evaluated as add-on to the higher dose of BDP. RESULTS: Compared with baseline after withdrawal of usual asthma therapy, 100 microg of HFA-BDP significantly attenuated serum eosinophilic cationic protein levels (0.61-fold change, 95% CI 0.49-0.77; a 39% reduction, P < 0.001), but 200 microg of CFC-BDP did not (0.87-fold change, 95% CI 0.63-1.23; P = 1). A dose of 800 microg of CFC-BDP and 400 microg of HFA-BDP led to reductions in exhaled nitric oxide (0.57-fold change, 95% CI 0.44-0.73; a 43% reduction, P < 0.001 and 0.65-fold change, 95% CI 0.47-0.91; a 35% reduction, P = 0.008, respectively); and peripheral eosinophils (-74 cells/microl, 95% CI -146 to -2; P = 0.020 and -77 cells/microl, 95% CI -140 to -14; P = 0.012, respectively). Montelukast further reduced exhaled nitric oxide (0.81-fold change, 95% CI 0.66-0.98; P = 0.028) with 400 microg HFA-BDP and eosinophils (-44 cells/microl, 95% CI -80 to -8; P = 0.012) with 800 microg CFC-BDP, but not vice versa. CONCLUSION: Chlorofluorocarbon beclometasone dipropionate and HFA-BDP have differential effects on pulmonary and systemic inflammation, which dictate the additive effects of montelukast.

Effect of exogenous female sex-steroid hormones on beta 2-adrenoceptors in healthy males.

OBJECTIVE: We have previously demonstrated that exogenous progesterone, but not oestrogen, upregulated lymphocyte beta 2-adrenoceptors (beta 2-AR) when given during the follicular phase in healthy females. In the present study, we were interested to see whether this facilitatory effect of female sex-steroid hormones could be demonstrated in healthy males. METHODS: Nine healthy male volunteers with a mean age of 24 years completed this randomised, double-blind, placebo-controlled, cross-over study. They were randomised to receive either oral placebo, oestradiol valerate (4 mg) or medroxyprogesterone (40 mg). The study medication was given in two divided doses 12 h apart. Subjects attended the laboratory at baseline (T0 is baseline), 1 h after ingestion of the second dose of study medication (T1) and 24 h later (T24). At each visit, 60 ml of peripheral blood was withdrawn for measurement of serum oestradiol, progesterone and testosterone levels, and for lymphocyte beta 2-AR parameters; density (Bmax), binding affinity (Kd) and maximal cyclic AMP response to isoprenaline (Emax). RESULTS: Baseline levels of sex-steroid hormones were comparable for each of the treatment periods. Serum oestradiol levels increased significantly, twofold, 1 h after ingestion of oestradiol but there was no significant change in levels of serum progesterone and testosterone. Lymphocyte beta 2-AR parameters following treatment with oestradiol and progesterone did not change significantly from baseline and were not different from placebo. CONCLUSION: In contrast to previously reported effects in women, female sex-steroid hormones did not appear to have any significant facilitatory effects on lymphocyte beta 2-AR parameters when given exogenously to healthy males. This lack of effect may be due either to the absence of receptors for female sex hormones in beta 2-AR or to reduced efficacy of female hormone-receptor coupling in male lymphocytes.

Loss of normal cyclical beta 2 adrenoceptor regulation and increased premenstrual responsiveness to adenosine monophosphate in stable female asthmatic patients.

BACKGROUND: A study was undertaken to investigate the influence of the menstrual cycle on airway responsiveness and beta 2 adrenoceptor function in female asthmatic patients. It has previously been shown that normal women exhibit cyclical changes in beta 2 adrenoceptor function with an increase in beta 2 adrenoceptor density in the luteal phase during the premenstrual period. METHODS: Fifteen women with stable, well controlled asthma (mean forced expiratory volume in one second (FEV1) 2.971 (93.8% predicted)) were evaluated. Measurements were made at the follicular phase (days 1-6) and the luteal phase (days 21-24) of the menstrual cycle. Airway responsiveness was assessed using adenosine 5'-monophosphate (AMP) and expressed as PC20 AMP. Beta 2 adrenoceptor function was evaluated by measuring lymphocyte beta 2 adrenoceptor parameters and constructing dose-response curves to salbutamol (100-1600 micrograms). The levels of female sex hormones were also measured at both phases of the cycle. RESULTS: There were significant increases in serum levels of both oestradiol (2.2-fold, p < 0.001) and progesterone (7.2-fold, p < 0.05) between the follicular and luteal phases. Geometric mean PC20 AMP was 19.0 mg/ml and 7.6 mg/ml during the follicular and luteal phases, respectively (p < 0.05), a 2.51-fold difference (95% CI 1.19 to 5.30) amounting to 1.33 doubling doses of AMP. There was no change in lymphocyte beta 2 adrenoceptor parameters or in airway beta 2 adrenoceptor responses to salbutamol between the two phases. CONCLUSIONS: Despite an appropriate rise in female sex hormones during the luteal period, beta 2 adrenoceptor regulation in female asthmatic subjects shows a loss of the normal cyclical pattern. In addition, there were cyclical changes in airway responsiveness to AMP which was highest during the premenstrual period. Thus, drugs such as theophylline which block adenosine receptors warrant investigation in premenstrual asthma.

Modulation of airway reactivity and peak flow variability in asthmatics receiving the oral contraceptive pill.

Female sex-steroid hormones may play an important influence in asthma. The aim of this study was to compare airway reactivity to adenosine monophosphate (AMP) in female asthmatics with natural menstrual cycles and those taking the oral combined contraceptive pill (OCP). Eighteen asthmatic subjects were evaluated. Nine subjects, mean (SEM) age, 24 (6) years, FEV1 93% (10) predicted, with natural cycles (group 1) were compared with nine subjects, age 24 (6) years, FEV1 93% (9) predicted taking the OCP (group 2). Group 1 subjects were evaluated at the follicular (visit 1) and luteal (visit 2) phases; group 2 subjects were evaluated during the week off OCP (visit 1) and at the end of the OCP cycle (visit 2). At each visit, serum progesterone and estradiol were measured. Airway reactivity to AMP was evaluated and expressed as PC20 (FEV1; mg/ml). Morning and evening peak expiratory flow rates (PEFR) were monitored throughout the study. In group 1, there was a significant increase in serum progesterone (nmol/l) and estradiol (pmol/l). (Visit 1 vs. 2): 2.5 vs. 13.5 (95% CI 2.1 to 19.9; p = 0.02) and 152.3 vs. 358.1 (95% CI 113.0 to 298.5; p < 0.001), respectively. In group 2, however, there was no increase between visit 1 vs. 2 in hormones: 0.9 vs. 1.0 and 75.7 vs. 21.8 for progesterone and estradiol, respectively. There was a significant increase in airway reactivity in group 1 during the luteal phase. Geometric mean PC20 (mg/ml) was 18.8 and 4.7 at visit 1 and 2, respectively: a 4.0-fold difference (95% CI 1.25 to 13.03; p = 0.03) amounting to two doubling doses. In contrast, there was no change in PC20 in group 2. Geometric mean PC20 was 23.5 and 21.4: a 1.06-fold difference (95% CI 0.41 to 2.78; p = 0.83). In group 1, morning and evening PEFR (l/min) were significantly different at both visits: at visit 1 (A.M. PEFR vs. P.M. PEFR) 403 vs. 430 (95% CI 5 to 50; p < 0.001) and visit 2, 415 vs. 439 (95% CI 1 to 46; p < 0.001). In group 2, there was no significant difference in diurnal PEFR variability at both visits; 411 vs. 417 at visit 1 and 413 vs. 427 at visit 2. In conclusion, asthmatic patients receiving the OCP had attenuated cyclical change in airway reactivity as well as reduced diurnal PEFR variability, which was associated with suppression of the normal luteal phase rise in sex-hormones.

Dose-response effect for adrenal suppression with repeated twice daily inhaled fluticasone propionate and triamcinolone acetonide in adult asthmatics.

A single blind randomized crossover trial was performed comparing placebo (PL); low (L), medium (M) and high (H) doses of fluticasone propionate (FP) L: 330 microg, M: 770 microg, H: 1,540 microg per day and triamcinolone acetonide (TAA) L: 400 microg, M: 800 microg, H: 1,600 microg per day. Each drug was given twice daily over a total of 9 d, with 3 d for each dose level. Each 9-d drug sequence was preceded by a 3-d placebo, and was separated by a 12-d washout period. Twelve mild-to-moderate, stable adult asthmatics, mean (SEM) age, 34.3 (2.9) yr, mean FEV1: 82.1 (2.0) % predicted, and FEF25-75%: 53.6 (5.5) % predicted, receiving up to 400 microg of inhaled corticosteroid per day, were studied. After each 3-d treatment period, blood samples were taken for 8:00 A.M. serum cortisol. Ten-hour overnight urine collections were taken for measurement of urinary cortisol and corrected for creatinine excretion, starting at 10:00 P.M. following the sixth dose. For 8:00 A.M. serum cortisol compared with PL there was significant (p < 0.001) dose-related suppression with FP but not with TAA, which amounted to a 2.03-fold ratio for H FP versus H TAA. For corrected urinary cortisol/creatinine excretion, there was a significant (p < 0.005) dose-related suppression for FP but not for TAA. This amounted to a 1.9-fold ratio for H FP versus H TAA. For doses < 1,000 microg/d, the number of individual results with an abnormal low urinary cortisol value (< 10 nmol/10 h) were: 10/24 for FP versus 3/24 for TAA (p < 0.005). In conclusion, for 8:00 A.M. serum cortisol and overnight corrected urinary cortisol/creatinine excretion, there was significant dose-related suppression with FP but not with TAA. For both of these parameters at the highest dose of both drugs, this amounted to a two-fold ratio in suppression.