Life or death by NFκB, Losartan promotes survival in dy2J/dy2J mouse of MDC1A.

Inflammation and fibrosis are well-defined mechanisms involved in the pathogenesis of the incurable Laminin α2-deficient congenital muscular dystrophy (MDC1A), while apoptosis mechanism is barely discussed. Our previous study showed treatment with Losartan, an angiotensin II type I receptor antagonist, improved muscle strength and reduced fibrosis through transforming growth factor beta (TGF-ß) and mitogen-activated protein kinases (MAPK) signaling inhibition in the dy(2J)/dy(2J) mouse model of MDC1A. Here we show for the first time that Losartan treatment up-regulates and shifts the nuclear factor kappa B (NFκB) signaling pathway to favor survival versus apoptosis/damage in this animal model. Losartan treatment was associated with significantly increased serum tumor necrosis factor alpha (TNF-α) level, p65 nuclei accumulation, and decreased muscle IκB-ß protein level, indicating NFκB activation. Moreover, NFκB anti-apoptotic target genes TNF receptor-associated factor 1 (TRAF1), TNF receptor-associated factor 2 (TRAF2), cellular inhibitor of apoptosis (cIAP2), and Ferritin heavy chain (FTH1) were increased following Losartan treatment. Losartan induced protein expression toward a pro-survival profile as BCL-2 expression levels were increased and Caspase-3 expression levels were decreased. Muscle apoptosis reduction was further confirmed using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay. Thus, along with TGF-ß and MAPK signaling, NFκB serves as an important regulatory pathway which following Losartan treatment promotes survival in the dy(2J)/dy(2J) mouse model of MDC1A.

Maintenance of inspiratory muscle training in COPD patients: one year follow-up.

In most chronic obstructive pulmonary disease (COPD) patients, dyspnoea and functional exercise capacity may improve as a result of inspiratory muscle training (IMT). However, the long-term benefits of IMT have been investigated to a much lesser extent. The present study investigated the short-term and long-term benefits of IMT on inspiratory muscle performance (strength and endurance), exercise capacity and the perception of dyspnoea. Thirty-eight patients with significant COPD had 3 months of basic IMT and were then randomised into a group that received maintenance IMT for the next year, and a group that got training with very low load. Following the basic training there was a statistically significant increase in inspiratory muscle performance, 6-min walk test (6MWT), and a decrease in the dyspnoea. During the second stage of the study, the training group continued to maintain the improvement in all parameters, while there was already deterioration in the inspiratory muscle performance, exercise capacity and dyspnoea in the low intensity group during the 6-12 month period. The present study concludes that, in patients with significant chronic obstructive pulmonary disease, inspiratory muscle training results in improvement in performance, exercise capacity and in the sensation of dyspnoea. The benefits of 12-weeks of inspiratory muscle training decline gradually over 1 yr of follow-up if maintenance training is not performed.

Long-acting bronchodilators in premenstrual exacerbation of asthma.

Premenstrual exacerbation (PME) of asthma occurs during the 5-10 days leading up to the menses and can be demonstrated in about 40% of asthmatic females. Peak expiratory flow rate (PEFR) and beta2-agonist consumption were recorded during three menstrual cycles in 67 females with mild-severe asthma. All were treated with inhaled glucocorticosteroids (IGC) and beta2-agonists, as required. Following, the patients with a premenstrual reduction in PEFR > 20%, received either salmeterol, 50 microg x 2 day(-1) or placebo, in the 10 days leading up to the menses, in a randomized, double-blind, cross-over design. Thirteen patients (19.4%) showed PME (mean +/- SEM decrease in PEFR 27 +/- 2.2%) in association with a significant increase in the mean daily beta2-agonist consumption. Following administration of salmeterol, there was a complete ablation of the PME in seven patients, a partial ablation in two patients and no effect in the remaining four patients. Only one patient showed a partial ablation of the PME following placebo. There was also a significant decrease in the beta2-agonists consumption in the responders. About 20% of the women with asthma, under chronic IGC treatment, had PME of asthma. In 54% of them, it could be prevented by the use of long-acting bronchodilators (LABD) during the 10 days leading up to the menses, and partially prevented in another 15%.

Hypercalcaemia in systemic lupus erythematosus.

Hypercalcaemia is a common electrolyte abnormality. The vast majority of patients will be shown to have either hyperparathyroidism or malignancy. In less than 10% of patients other, less common causes of hypercalcaemia will be present. Systemic lupus erythematosus is a very rare cause of hypercalcaemia. It may be associated with lymphadenopathy and pleuritis to constitute a distinct clinical entity described as 'hypercalcaemia-lymphoedema syndrome'. In these cases the pathophysiology of the hypercalcaemia is not completely understood. In some cases it is associated with elevated levels of parathyroid-related peptide (PTHrP). In others the level of PTHrP is normal, and it has been suggested that autoantibodies may cause hypercalcaemia by activating the PTH receptor. We describe a case of a woman who presented with severe hypercalcaemia, developed the hypercalcaemia-lymphodema syndrome and fulfilled the diagnostic criteria of systemic lupus erythematosus.

The cumulative effect of long-acting bronchodilators, exercise, and inspiratory muscle training on the perception of dyspnea in patients with advanced COPD.

BACKGROUND: Dyspnea is a common complaint during daily activities in patients with advanced COPD. The mechanisms underlying dyspnea and the appropriate treatment strategies to relieve it are still not totally understood. We hypothesized that the perception of dyspnea (POD) may be modified by the accumulative effect of bronchodilator therapy, exercise, and inspiratory muscle training (IMT). METHODS: Spirometry, submaximal exercise performance, inspiratory muscle strength and endurance, and the POD were assessed before and following three consecutive 6-week periods of therapy with a long-acting bronchodilator (LABD), the LABD plus exercise, and the LABD plus exercise plus IMT in 30 patients with moderate-to-severe COPD. RESULTS: There was a small, statistically insignificant, increase in FEV(1) in the study group (mean [+/- SEM] increase, 1.42+/-0.3 to 1.49+/-0.4 L) following the LABD therapy period, and no additional increase following the two other periods of therapy. There was a significant increase (p<0.05) in the 6-min walk distance following the therapy period with the LABD plus exercise (mean increase, 252+/-41 to 294+/-47 m) and an additional small increase following the therapy period with the LABD plus exercise plus IMT period (mean increase, 252+/-41 to 302+/-49 m). The decrease in the POD was small and statistically not significant following the therapy periods with the LABD and the LABD plus exercise. The major and statistically significant decrease in the POD was noted following the therapy period with the LABD plus exercise plus IMT. CONCLUSIONS: In patients with moderate-to-severe COPD, following sequential periods of therapy with the LABD, the LABD plus exercise, and the LABD plus exercise plus IMT, there is a cumulative benefit in the POD. The most significant improvement was associated with IMT and not with the LABD and exercise training. The FEV(1) was moderately increased following the therapy period with the LABD, and the addition of exercise has most affected the 6-min walk distance.

The perception of dyspnoea in patients with asthma, before and following treatment with inhaled glucocorticosteroids.

This study was designed in order to establish the perception of breathlessness during rest and while breathing against resistance, in patients with asthma, before and after 8 weeks of inhaled glucocorticoids (IGC) treatment and to compare these parameters in patients with and without improvement in FEV1. Sixty-seven asthmatic patients, with moderate asthma, attending the asthma clinic, and 20 normal subjects were studied. After a 2-week run-in period, in which the subjects were asked to use exclusively beta2-agonists as needed, the asthmatic patients were randomized to receive either treatment with IGC, 250 microg of fluticasone propionate (FP) twice a day, via a diskhaler (47 patients), or to receive placebo (20 patients) and to serve as a control group, for 8 weeks. Spirometry and measurements for the sensation of dyspnoea were performed before and at the end of the treatment period. The mean dyspnoea score during breathing against resistance was significantly lower (P<0.05) in the patients with asthma than in normal subjects, before entering the study. Following 8 weeks of inhaled FP, there was a significant improvement in the mean dyspnoea score during breathing against resistance in the asthmatics receiving IGCs but not in the control group (P<005). In the study group 32 patients had an improved FEV1 > 15% and 15 patients did not. There was a statistically significant difference in perception of dyspnoea (P<0.01), between the group of patients with a improved FEV1 and the group of patients that were under IGC treatment without improvement in their FEV1. There was also a difference in the mean beta2-agonists consumption between the two groups (P<0.01). Asthmatic patients have a significantly lower perception of dyspnoea compared to normal subjects. IGC treatment was associated with increased perception of dyspnoea. However, this improvement was noted only in patients with improved FEV1, while the patients without improvement remained with an equal degree of dyspnoea perception and beta2-agonists consumption.

Specific inspiratory muscle training in patients with mild asthma with high consumption of inhaled beta(2)-agonists.

BACKGROUND: It has been known for many years that there are variations between asthmatic patients in terms of their perception of breathlessness during airway obstruction. STUDY OBJECTIVE: To investigate the relationship between beta(2)-agonist consumption and the score of perception of dyspnea, in mild asthmatics, and the relationship between the effect of specific inspiratory muscle training (SIMT) on the score of perception of dyspnea and beta(2)-agonist consumption in "high perceivers." METHODS: Daily beta(2)-agonist consumption was assessed during a 4-week run-in period in 82 patients with mild asthma. Patients with a mean beta(2)-agonist consumption of > 1 puff/d ("high consumers") then were randomized into two groups: one group of patients received SIMT for 3 months; the other group of patients was assigned as a control group and received sham training. Inspiratory muscle strength and perception of dyspnea were assessed before patients entered the study, following the 4-week run-in period, and after completing the training period. RESULTS: Following the 4-week run-in period, 23 high-consumer patients (mean [+/- SEM] beta(2)-agonist consumption, 2.7 +/- 0.4 puffs/d) were detected. The mean Borg score during breathing against resistance was significantly higher (p < 0.05) in the patients with high beta(2)-agonist consumption than in the subjects with low mean beta(2)-agonist consumption. Following SIMT, the mean maximal inspiratory pressure increased significantly from 94.1 +/- 5.1 to 109.7 +/- 5.2 cm H(2)O (p < 0.005) in the training group. The increase in inspiratory muscle strength was associated with a statistically significant decrease in the mean Borg score during breathing against resistance (p < 0.05) as well as in the mean daily beta(2)-agonist consumption. CONCLUSIONS: We have shown that patients with mild asthma, who have a high beta(2)-agonist consumption, have a higher perception of dyspnea than those with normal consumption. In addition, SIMT was associated with a decrease in perception of dyspnea and a decrease in beta(2)-agonist consumption.

The effect of specific inspiratory muscle training on the sensation of dyspnea and exercise tolerance in patients with congestive heart failure.

BACKGROUND: It has been previously shown that the inspiratory muscles of patients with congestive heart failure (CHF) are weaker than those of normal persons. This weakness may contribute to the dyspnea and limit exercise capacity in these patients. The respiratory muscles can be trained for both strength and endurance. HYPOTHESIS: The present study was designed to evaluate the effect of specific inspiratory muscle training (SIMT) on inspiratory muscle performance, lung function, dyspnea, and exercise capacity in patients with moderate heart failure. METHODS: Twenty patients with CHF (NYHA functional class II-III) were recruited for the study. The subjects were randomized into two groups: 10 patients were included in the study group and received SIMT and 10 patients were assigned to the control group and received sham training. Subjects in both groups trained daily, 6 times/week, for one-half h, for 3 months. The subjects started breathing at a resistance equal to 15% of their PImax for 1 week and the resistance was then increased incrementally to 60%. Spirometry, inspiratory muscle strength (assessed by measuring the PImax at residual volume), and endurance (expressed by the relationship between PmPeak and PImax), the 12-min walk test, and peak VO2 were performed before the beginning and at the end of the training period. RESULTS: All patients in the training group showed an increase in the inspiratory muscle strength [mean (+/- standard error of the mean) PImax increased from 46.5 +/- 4.7 to 63.6 +/- 4.0 cm H2O, p < 0.005], and endurance (mean PmPeak/PImax from 47.8 +/- 3.6 to 67.7 +/- 1.7%, p < 0.05), while they remained unchanged in the control group. This was associated in the training group with a small but significant increase in forced vital capacity, a significant increase in the distance walked (458 +/- 29 to 562 +/- 32 m, p < 0.01), and an improvement in the dyspnea index score. No statistically significant change in the mean peak VO2 was noted in either group. CONCLUSIONS: Specific inspiratory muscle training resulted in increased inspiratory muscle strength and endurance. This increase was associated with decreased dyspnea, increase in submaximal exercise capacity, and no change in maximal exercise capacity. This training may probe to be a complementary therapy in patients with congestive heart failure.

Nocturnal cortisol secretion in asthmatic patients after inhalation of fluticasone propionate.

OBJECTIVES: This study was designed to assess the relationship between the degree of airflow obstruction and the suppression of the hypothalamic-pituitary-adrenal axis after inhalation of fluticasone propionate (FP) in asthmatic patients with varying degrees of airway obstruction. STUDY DESIGN: The nocturnal cortisol production (from 10:00 PM to 6:00 AM), defined as the integrated area under the curve of nocturnal plasma cortisol, was measured following inhalation of a placebo or a single dose of 500 microg FP at 8:00 PM in 28 patients with mild to moderate asthma, in a single, blind, 2-night study. RESULTS: The mean morning rise of cortisol decreased significantly following a single dose of inhaled FP. When the total nocturnal cortisol production after the second night (when the FP was inhaled) was compared to that after the first night (when the placebo was administered), it was found to have decreased by 29.4%. There was a statistically significant correlation between the FEV(1) and the fall in cortisol production just before the inhalation of FP (p < 0. 001). There was no correlation between baseline cortisol production and the fall in cortisol production. CONCLUSIONS: Our findings suggest that the degree of airway obstruction affects the systemic bioavailability of FP. FP is likely to induce a more severe decrease in nocturnal cortisol secretion in less obstructed patients. In order to reduce the risk for systemic side effects, the patient's degree of airway obstruction should be considered when planning inhaled FP treatment.

[Effect of specific inspiratory muscle training on dyspnea and exercise tolerance in congestive heart failure].

It has been shown that the inspiratory muscles of patients with congestive heart failure (CHF) are weaker than normal. This weakness may contribute to dyspnea and limit exercise capacity. But respiratory muscles can be trained for increase in both strength and endurance. This study was designed to evaluate the effect of specific inspiratory muscle training (SIMT) on muscular performance, lung function, dyspnea and exercise capacity in moderate heart failure. 10 patients with CHF (NYHA functional class II-III) received 1/2 hour of SIMT daily, 6 times/week, for 3 months. They started breathing at a resistance 15% of their Pimax for 1 week and the resistance was then increased incrementally to 60%. Spirometry, inspiratory muscle strength and endurance, and the 12-minute walk test were performed before and after the training period. All showed an increase in inspiratory muscle strength and endurance. This was associated with a small but significant increase in FVC, a significant increase in the distance walked (458 +/- 29 to 562 +/- 32 m, p < 0.01), and improvement in the dyspnea index score. SIMT resulted in increased inspiratory muscle strength and endurance. This increase was associated with decreased dyspnea and an increase in submaximal exercise capacity. SIMT may prove to be useful complementary therapy in CHF.

Double transfer of embryos in in vitro fertilization, or is there a delayed receptivity of the endometrium?

Sixty-seven in vitro fertilization (IVF) patients who underwent ultrasonically guided oocyte pickup (OPU) after induction of superovulation with human menopausal gonadotropins were submitted to two different protocols of embryo transfer. In the first group of 33 patients, four to five embryos were transferred to the uterus 48 hr after OPU. In the second group of 34 patients two to three embryos were transferred at 48 hr after OPU and two other embryos were transferred after freezing and thawing 48 hr later (96 hr after OPU). The pregnancy rate achieved in the double embryo transfer (ET) protocol was significantly higher than in the single-ET protocol (32.4 vs. 18.2%, respectively; P less than 0.05).