Blinding decreased recruitment in a prevention trial of postmenopausal hormone therapy

PURPOSE: To compare the effect of blind design (active drug and placebo) and nonblind design (active drug and no treatment) on recruitment. SETTING: A primary prevention trial with postmenopausal hormone therapy in Estonia. METHODS: Women who were eligible and willing to participate on the basis of the questionnaire survey were randomized into blind and nonblind groups. Recruitment rates are based on record keeping, and reasons for participating were requested in the first-year follow-up. RESULTS: The recruitment was 30% higher in the nonblind group: of the 4,295 women invited, 37% (95% confidence interval CI=35-39%) in the blind group and 48% (95% CI=46-49%) in the nonblind group were recruited. In both groups, once randomized, most of the losses were women who did not attend the first clinical examination: 49% (blind; 95% CI=47-51%) and 40% (nonblind; 95% CI=38-42%). The rest were found ineligible or lost their interest during clinical examinations. The reasons for joining the trial were relatively similar in the two groups. CONCLUSIONS: Blinding decreased women's interest in joining a long-term preventive trial. Women's reasons for joining the trial were not influenced by blinding.     

Transglutaminase-mediated cross-linking of a peptic fraction of omega-5 gliadin enhances IgE reactivity in wheat-dependent,exercise-induced anaphylaxis

BACKGROUND: Patients with wheat-dependent, exercise-induced anaphylaxis (WDEIA) experience recurrent anaphylactic reactions when exercising after ingestion of wheat products. We have identified omega-5 gliadin (Tri a 19) as a major allergen in WDEIA, but the role of exercise in eliciting the symptoms remains obscure. OBJECTIVE: The aim was to examine whether tissue transglutaminase (tTG)-mediated cross-linking could be involved in modulating the IgE-binding ability and in vivo reactivity of digested omega-5 gliadin peptides in WDEIA. METHODS: Purified omega-5 gliadin was digested with pepsin or with pepsin and trypsin and treated with tTG. The binding of IgE antibodies in pooled sera from 10 patients with WDEIA was studied by means of immunoblotting before and after tTG treatment of the digested peptides. The peptides derived from pepsin digestion were separated by means of gel-filtration chromatography, and IgE reactivity of 4 different peptide fractions was studied by immunoblotting before and after tTG treatment. The fraction showing the greatest degree of cross-linking by tTG was further studied by means of IgE ELISA, ELISA inhibition, and skin prick testing. RESULTS: The IgE-binding ability of omega-5 gliadin was retained after pepsin and pepsin-trypsin digestion. tTG treatment of the whole peptic digest formed large peptide complexes, with molecular weights ranging from 40 to greater than 200 kd. These cross-linked aggregates bound IgE antibodies in immunoblotting more intensely than untreated, pepsin-digested, or pepsin-trypsin-digested omega-5 gliadin. A gel-filtration fraction of the whole peptic digest corresponding to the highest peak of the chromatogram and showing the greatest degree of tTG-mediated cross-linking showed an increase in serum IgE reactivity in ELISA after tTG treatment, as well as a shift of reactivity to cross-linked complexes. In the 20 patients with WDEIA, the mean skin prick test wheal elicited by this tTG-treated peptic fraction was 77% larger (P <.001) than that elicited by the untreated peptic fraction and 56% larger (P <.01) than that elicited by intact omega-5 gliadin. CONCLUSIONS: Omega-5 gliadin-derived peptides are cross-linked by tTG, which causes a marked increase in IgE binding both in vitro and in vivo. Activation of tTG during exercise in the intestinal mucosa of patients with WDEIA could lead to the formation of large allergen complexes capable of eliciting anaphylactic reactions.     

Update on female pubertal development

PURPOSE OF REVIEW: To elucidate recent findings regarding female puberty. The successful completion of puberty is a prerequisite for reproduction. Many later disorders of fertility and metabolism may develop during puberty. New more sensitive and specific assays provided us with possibilities for a better understanding of the process of puberty, and the discovery of new factors such as leptin evoked the hope of finding key regulators of the onset of puberty. RECENT FINDINGS: The secular trend towards earlier menarche appears now to have come to an end, but discussions about changes in the age of pubertal onset still continue. In a few detected cases of leptin mutations puberty has not occurred spontaneously. The intact secretion of leptin seems to be a necessary prerequisite for the onset of puberty. Apart from that, recent research has indicated that leptin levels mainly reflect body composition. Leptin as well as gonadotropins, steroids and growth hormone shows specific circadian patterns. The 24 h pattern of leptin is similar before and after puberty, but the 24 h pattern of the other hormones changes. The serum concentration of inhibin B increases in the years preceding puberty and in early puberty, whereas inhibin A increases in mid to late puberty. SUMMARY: The biological significance of the changing circadian patterns remains to be determined. Inhibin B serum concentrations together with follicle-stimulating hormone may indicate remaining potential ovarian activity during childhood in, for example, patients with Turner syndrome, but more information and other possible markers are needed.     

Reactions of N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil) with 2'-deoxyadenosine

N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil, 1; 0.6 mM) was allowed to react with 2'-deoxyadenosine (16.1 mM) at physiological pH (cacodylic acid, 50% base), and the reactions were followed by HPLC-MS and HPLC-MS/MS techniques. Although the predominant reaction observed was chlorambucil hydrolysis, ca. 7% of 1 reacted with various heteroatoms of the nucleoside. The principal site of alkylation was N1. Several other adducts were also detected. The N1, N6, N3, and N7 derivatives were characterized by means of MS/MS, UV, and (1)H NMR. The N6 adduct is derived directly from alkylation of N6 of 2'-dAdo. Dimroth rearrangement of the N1 adduct to the N6 adduct was very slow under the reaction conditions employed. Minor adducts such as a carbohydrate derivative were tentatively characterized by MS/MS. No cross-links were detected. The role of chlorambucil-2'-deoxyadenosine adducts in the cytotoxicity and mutagenicity of 1 is also discussed.     

New prolyl oligopeptidase inhibitors developed from dicarboxylic acid bis(l-prolyl-pyrrolidine) amides

Isophthalic acid bis(l-prolyl-pyrrolidine) amide is a very potent prolyl oligopeptidase inhibitor, but it has a log P value of -0.2, which is very low for a compound targeted to the brain. Therefore, these types of compounds were further modified to improve the structure-activity relationships, with the focus on increasing the log P value. The inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. The most promising compounds resulted from replacing the pyrrolidinyl group at the P5 site by cycloalkyl groups, such as cyclopentyl and cyclohexyl groups, and by a phenyl group. These compounds are slightly more potent, and they have a significantly higher log P value. The potency of these compounds was further increased by replacing the pyrrolidinyl group at the P1 site by 2(S)-cyanopyrrolidinyl and 2(S)-(hydroxyacetyl)pyrrolidinyl groups.     

Multidisciplinary biopsychosocial rehabilitation for neck and shoulder pain among working age adults: a systematic review within the framework of the Cochrane Collaboration Back Review Group

STUDY DESIGN: A systematic review of randomized controlled trials. OBJECTIVES: To evaluate the effectiveness of multidisciplinary biopsychosocial rehabilitation for neck and shoulder pain among working age adults. SUMMARY OF BACKGROUND DATA: Multidisciplinary biopsychosocial rehabilitation programs for neck and shoulder pain require substantial staff and financial resources. They are widely used, despite questionable evidence of their effectiveness. METHODS: The reviewed randomized controlled and controlled trials appraising the effectiveness of biopsychosocial rehabilitation for working age patients with neck and shoulder pain were identified by searching electronic bibliographic databases, checking references, and consulting experts in the rehabilitation field. Four blinded reviewers selected the trials. Two specialists on rehabilitation evaluated the clinical relevance. Two other blinded reviewers extracted the data and assessed the main results and the methodologic quality of the studies. A qualitative analysis was performed to evaluate the level of scientific evidence. RESULTS: After 1808 abstracts and the references of 65 reviews were screened, only two relevant studies were found that satisfied the criteria. One of these was considered a methodologically low-quality randomized controlled trial, and the other was a methodologically low-quality controlled clinical trial. The clinical relevance of included studies was satisfactory. The level of scientific evidence for the effectiveness of multidisciplinary biopsychosocial rehabilitation for neck and shoulder pain was limited. CONCLUSIONS: There appears to be little scientific evidence for the effectiveness on neck and shoulder pain of multidisciplinary biopsychosocial rehabilitation compared with other rehabilitation methods. There is an urgent need for high-quality trials in this field.     

In vitro activity of rilopirox against fluconazole-susceptible and fluconazole-resistant Candida isolates from patients with HIV infection

The in vitro antifungal activity of the new hydroxypyridone antimycotic rilopirox has been evaluated against 38 fluconazole-susceptible and -resistant clinical isolates of Candida albicans together with other Candida species isolated from patients with human immunodeficiency virus (HIV) infection and oropharyngeal candidosis. Minimum inhibitory concentrations (MICs) of both rilopirox and fluconazole were measured by a microdilution method using high-resolution medium supplemented with asparagine and glucose at pH 7.0. In comparison, an agar dilution technique was carried out for susceptibility testing of the antifungal agents. Rilopirox was found to be able to inhibit growth of all clinical yeast isolates. The rilopirox MICs at which 50% and 90% of strains were inhibited (MIC50 and MIC90 respectively), as determined by the microdilution method, were 4 and 8 micrograms ml-1 respectively. The highest MIC values for rilopirox using microdilution and the agar dilution method were 32 or 25 micrograms ml-1 respectively. On the other hand, for fluconazole, the MIC50 and MIC90 achieved were 0.5 and 128 micrograms ml-1, respectively, which means that the MIC90 value of fluconazole was 16-fold higher than that of rilopirox. Using the agar dilution technique, the MIC values of rilopirox were in the range 0.006-25 micrograms ml-1 with a median of 3.12 micrograms ml-1. For fluconazole, the MIC90 value was four-fold higher than that for rilopirox, indicating a considerable proportion of yeast strains with high MICs of 100 micrograms ml-1, suggesting in vitro resistance to this azole antifungal. All strains with diminished fluconazole susceptibility were susceptible to rilopirox. Even Candida krusei and Candida glabrata exhibited good in vitro susceptibility to rilopirox. Therefore, this new antifungal agent may be used as an alternative not only in the treatment of vaginal candidosis, but also in oropharyngeal Candida infections, e.g. in AIDS patients.     

Variability of Heidelberg Retina Tomograph parameters during exercise

Purpose: The purpose of this study was to determine whether exercise affects the stereometric parameters representing optic nerve head (ONH) topography. Methods: ONH topography, intraocular pressure (IOP) and blood pressure of 30 healthy volunteers were monitored before, during and after dynamic exercise raising systolic blood pressure by a minimum of 30 mmHg. Change in the stereometric ONH parameters was calculated. Results: IOP decreased and blood pressure increased during exercise, resulting in an increase in mean ocular perfusion pressure. Exercise was associated with an increase in variance in 17 of the 18 stereometric ONH parameters. The increase in variance was statistically significant in eight parameters, including rim area, cup/disc area ratio and cup shape measure. There was no statistically significant change in image quality. The absolute change from baseline in rim area, cup area, cup/disc area ratio, rim/disc area ratio and rim volume showed a statistically significant (p < 0.05) correlation with change in mean ocular perfusion pressure. Conclusions: Exercise increases variability in stereometric ONH parameters. To avoid increased variance in the stereometric parameters, ONH imaging should be performed after allowing sufficient time to rest.     

Dyspnoea associated with anxiety��symptomatic therapy with opioids in combination with lorazepam and its effect on ventilation in palliative care patients

Purpose  

Opioids are used for symptomatic therapy of dyspnoea, and benzodiazepines if dyspnoea is associated with anxiety. When given at the same time, the risk of respiratory depression will increase. The aim of this study was to assess the safety of this treatment regimen in palliative care patients.