Activation of protein kinase C and nicotinamide adenine dinucleotide phosphate oxidase in leukocytes of spontaneously hypertensive rats.

The involvement of oxidative stress in polymorphonuclear leukocytes (PMN) in the pathogenesis of hypertension remains to be elucidated. We analyzed the generation of reactive oxygen species (ROS) by the circulating and peritoneally infiltrating PMN from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Flow cytometric analysis revealed that ROS generation by PMN from SHR was higher than that from WKY before (at 6 weeks of age) and after (at 16 weeks of age) the onset of hypertension. In vivo, ROS generation by PMN from SHR, but not that by PMN from WKY, was significantly suppressed by 10-week treatment with 50 mg/kg/day carvedilol, and this treatment did not affect blood pressure. Western blotting analysis revealed that protein kinase C alpha (PKCalpha), but not PKCbetaI or betaII, was activated more strongly in PMN from SHR than in PMN from WKY. Furthermore, expression of p47phox of nicotinamide adenine dinucleotide phosphate oxidase, but not of p67phox, in PMN from SHR was higher than that in PMN from WKY. These results suggest that ROS generation by PMN is principally enhanced in SHR through activation of PKCalpha and p47phox.     

Safety and efficacy of botulinum toxin type A following long-term use

Botulinum toxin serotype A (BoNT-A) has long heritage of use leading to confidence in its safety and efficacy. The application of BoNT-A does not lead to persistent histological changes in the nerve terminal or the target muscle. Clinical trials defined the safety and tolerability profile of BoNT-A across common therapeutic indications and showed an incidence of adverse events of approximately 25% in the BoNT-A-treated group compared with 15% in the control group. Focal weakness was the only adverse event to occur more often following BoNT-A treatment. Long-term BoNT-A administration has been assessed in various treatment settings, with the level and duration of BoNT-A efficacy response being maintained over repeated rounds of injection with no major safety concerns. The treatment of children with cerebral palsy often require long-term, repeated, multimuscle BoNT-A injections that lead to the administration of comparably higher toxin doses. Despite the high total body doses used, their distribution over multiple muscles and injection sites means that systemic side effects are rare. Recent formulation changes have reduced the incidence of antibody development following treatment with BOTOX^®. These findings show long-term BoNT-A treatment to be both safe and efficacious for a wide variety of indications.     

Localized Kaposi''s sarcoma in a patient with pemphigus vulgaris

We report the case of a patient with a 13-year history of pemphigus vulgaris (PV) treated with immunosuppressive agents, prednisone and mycophenolate mofetil who had developed lesions of Kaposi's sarcoma (KS) on a sole plaque of PV that had been previously treated with intralesional injections of steroids. The lesions were surgically removed and polymerase chain reaction (PCR) demonstrated human herpesvirus-8 (HHV-8) DNA. There were neither recurrences nor later dissemination of KS following gradual decrease of the immunosuppressive therapy. We suggest that the treatment with intralesional steroids may have influenced the local reactivation of a latent infection of the virus, determining the appearance of this localized KS.     

Treatment of dysfunctional uterine bleeding in the perimenopause: the effects of adding combined estradiol/norethisterone acetate therapy to goserelin acetate treatment--a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To assess the effects of adding combined estradiol/norethisterone acetate therapy (CENT) to goserelin acetate treatment (GA) of dysfunctional uterine bleeding (DUB) in perimenopausal women. METHODS: In a randomized, placebo-controlled, double-blind trial followed by an open follow-up study, 31 perimenopausal women with DUB were recruited from gynecological outpatient departments of two Dutch hospitals and randomized for treatment with either GA/placebo or GA/CENT for 6 months followed by 18 months of GA/CENT for all. The main outcome measures were abdominal pain, number of bleeding days, double-layer endometrial thickness (DET), Greene climacteric score (GCS), visual analog scale for well-being, bone mineral density (BMD) and mammographic density (BI-RAD score). RESULTS: Abdominal pain, number of bleeding days and DET decreased in both groups, the between-group difference in decrease not being statistically significant. GCS initially showed significant improvement in the GA/CENT group. BMD decreased significantly in the GA/placebo group (-4.1%) compared with the GA/CENT group (-0.3%). Another 18 months of GA/CENT did not result in a lasting difference in BMD between groups. BI-RAD scores did not differ significantly between or within the two groups. CONCLUSIONS: Adding CENT to GA treatment for DUB in perimenopausal women initially prevented BMD loss and improved climacteric complaints, while having no negative impact on vaginal bleeding, abdominal pain or BI-RAD scores. However, prolonged treatment did not result in a lasting prevention of bone loss.     

European Committee on Antimicrobial Susceptibility Testing (EUCAST) Technical Notes on antimicrobial susceptibility testing

The main objectives of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are to harmonise breakpoints for antimicrobial agents in Europe, and to act as the breakpoint committee for the European Medicines Agency (EMEA) during the registration of new antimicrobial agents. Detailed EUCAST procedures for harmonising and setting breakpoints for antimicrobial agents are available on the EUCAST website. Beginning with the current issue, a series of EUCAST Technical Notes will be published in CMI, based on the rationale documents produced by EUCAST for each of the antimicrobial agents studied, with the aim of highlighting important background information underlying decisions on breakpoints made by EUCAST.     

Hood versus mask nebulization in infants with evolving bronchopulmonary dysplasia in the neonatal intensive care unit.

OBJECTIVE: To compare infants' discomfort, nursing-time and caregiver preference, and assess the clinical efficiency (as a secondary outcome) of hood versus facemask nebulization in infants with evolving bronchopulmonary dysplasia (BPD) in the neonatal intensive care unit. STUDY DESIGN: A prospective, open, randomized, controlled crossover clinical trial. In total, 10 infants with BPD who were on inhaled beta-agonist bronchodilators and corticosteroids were randomly assigned to receive their nebulized treatments either by a facemask, or by a hood for 2-3 days, and then crossover to receive the same treatments with the other technique for another 2-3 days. Infants' discomfort, nursing-time, caregiver preference and clinical efficiency were compared. RESULTS: At baseline there was no significant clinical difference between the groups. Nurse-time required for administering the hood nebulization (mean+/-s.e.m.: 1.9+/-0.1 min) was significantly shorter than the time for mask nebulization (12.0+/-0.6 min, P<0.0001). Infants' discomfort score was significantly lower (0.1+/-0.04) for hood versus mask nebulization (2.5+/-0.2, P<0.0001). Nurses and parents unequivocally preferred the hood treatment. During both mask and hood nebulization therapies (2-3 days) clinical efficiency was comparable. While both methods caused an immediate (20 min post) clinical improvement, the immediate respiratory assessment change score was significantly greater for the hood versus the mask nebulization (0.62+/-0.27 versus 0.13+/-0.14, P<0.05). CONCLUSIONS: Nebulization of aerosolized medications in infants with evolving BPD by hood was less time-consuming for caregivers and was much better tolerated by the infants while being at least as effective as the conventional facemask nebulization.     

1,25(OH)2Vitamin D3 induces elevated expression of the cell cycle inhibitor p18 in a squamous cell carcinoma cell line of the head and neck

BACKGROUND: 1Alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2) Vitamin D(3)] induces growth inhibition in squamous cell carcinoma (SCC) cell lines of the head and neck by arresting the cells in the G0/G1 phase of the cell cycle, probably due to an enhanced expression of p21, which could be demonstrated in other cell lines (JPPA, SCC9) before. In SCC25, a SCC cell line isolated from tongue, growth inhibition but no overexpression of p21 was detected. The retinoblastoma gene, as a direct target of G1 cyclin-CDK complexes, showed an obvious shift from the hyperphosphorylated to the hypophosphorylated form under 1,25(OH)(2)Vitamin D(3), which indicates that the growth inhibition takes place in the G0/G1 phase. To explore the possible pathway of growth inhibition in SCC25 we investigated other cell cycle inhibitors (p18, p19, p27). METHODS: Synchronized cells were treated with 1,25(OH)(2)Vitamin D(3) over 96 h. The cell cycle status and expression of cell cycle-regulating proteins was determined by fluorescence-activated cell sorting (FACS) and Western blotting. An overexpression of p18 in 1,25(OH)(2)Vitamin D(3) vs. ethanol-treated cells was determined until 30 h in SCC25. No influence was detectable on the expression of p27 and p19. CONCLUSION: One mechanism by which 1,25(OH)(2)Vitamin D(3) controls cell growth might be the upregulation of p21. As p21 was unsusceptible to 1,25(OH)(2)Vitamin D(3) in SCC25, other inhibiting proteins were necessary to be tested. The proven upregulation of p18 seems to be the responsible step for growth inhibition of 1,25(OH)(2)Vitamin D(3) in SCC25.