Tumor necrosis factor-alpha in whole blood cultures of preeclamptic patients and healthy pregnant and nonpregnant women.

OBJECTIVES: Tumor necrosis factor-alpha (TNF-alpha) is recognized as a likely mediator of the excessive endothelial activation and injury that is a key pathogenetic mechanism of preeclampsia. We used whole blood cell cultures from 12 patients with severe preeclampsia and from 12 healthy pregnant and nonpregnant women to determine the release of TNF-alpha by unstimulated leukocytes as a measure of their state of activation, and their response to stimulation with lipopolysaccharide (LPS) as an indicator of their state of priming. METHODS: Blood was cultivated without and with LPS, and TNF-alpha release was measured after six and 24 hours of cultivation by enzyme-linked immunoassays. Differential leukocyte counts were performed, and TNF-alpha values calculated per 10(5) monocytes. RESULTS: In unstimulated whole blood cultures, TNF-alpha release after six hours of cultivation was similar in all three groups; but after 24 hours, TNF-alpha concentrations in culture supernatants from preeclamptic patients were significantly higher than were values obtained in blood from normotensive pregnant women. In LPS-stimulated blood cultures with a maximum of TNF-alpha release at six hours cultivation time, TNF-alpha concentrations were significantly lower in preeclamptic women than they were in both control groups. We showed in an additional experiment that a strong LPS challenge following preactivation with high doses of LPS resulted in reduced release of TNF-alpha compared with release of TNF-alpha following preactivation with low doses of LPS. CONCLUSIONS: The observed high capacity for spontaneous TNF-alpha release by leukocytes in preeclampsia indicates activation of TNF-alpha producing leukocytes by the disease process. Preactivation and exhaustion of leukocytes by leakage of TNF-alpha could lead to the reduced response to TNF-alpha inducer LPS as observed in blood cultures from preeclamptic patients.     

Effectiveness of a Multidisciplinary Education Protocol in Children with Asthma (0-4 Years) in Primary Health Care

This paper describes the results of an asthma self-management protocol delivered to parents of children aged 0-4 years. The protocol was delivered by general practitioners (GPs), community nurses, asthma nurses, and doctors in child health centers. It consisted of 16 educational modules developed after an initial needs assessment of parents and a task analysis of primary care practitioners. The program was evaluated by means of an experimental design. Parents participating in the program had significantly more knowledge, a more favorable attitude toward asthma, and a higher self-efficacy score with respect to performing asthma self-management behaviors. Also, they reported performing self-management behaviors more frequently than parents in the control group. One-year follow-up results, which were collected for parents in the treatment group only, showed that the described changes were sustained. Further, the treatment group was found to have decreased its emergency and nonemergency use of the physician's office and to have a reduction in (reported) asthma severity. Process evaluation indicated that most modules were provided by the GPs to nearly all parents. After parents had read the modules at home, almost all the information was discussed in the next contact. GPs seldom referred patients to the community nurses, although this was suggested in the protocol.     

Probiotics as flourishing benefactors for the human body.

This article provides a comprehensive review of the beneficial effects of various strains of probiotics in preventing and treating certain diseases. Currently, changed lifestyles as well as the increased use of antibiotics are significant factors challenging the preservation of a healthy intestinal microflora. The concept of probiotics is to restore and uphold a microflora advantageous for the human body. Probiotics are found in a number of fermented dairy products, infant formula, and dietary supplements. In the presence of prebiotics, which are nondigestible food ingredients favorable for probiotic growth, their survival in the intestine is ameliorated.     

The effect of the interferon-gamma-inducible processing machinery on the generation of a naturally tumor-associated human cytotoxic T lymphocyte epitope within a wild-type and mutant p53 sequence context

The human wild-type (wt) p53.264-272 peptide is a universal tumor antigen and recognized by HLA-A*0201 (A2.1)-restricted CTL. Generation of this epitope by constitutive 20S proteasomes is prevented by a p53 R to H hotspot mutation at the C-terminal flanking residue 273. We report on the impact of the interferon-gamma (IFN-gamma)-inducible proteasomal activator PA28 (11S regulator) and the immunoproteasome on the in vitro and cellular processing of wt and mutant (mut) p53 substrates. We found that production of the antigenic 264-272 peptide from wt p53 by constitutive as well as immunoproteasomes is accelerated and amplified by the PA28 activator. PA28 and (immuno)proteasomes were not capable to reconvert the resistance of epitope release from mut p53. Maximum and accelerated antigen production in vitro and on the cellular level required the IFN-gamma-inducible interaction of immunoproteasomes and PA28. We conclude that efficient processing of p53.264272 from wt p53 is governed by the proteasome/PA28 complex. These studies have important implications for p53-specific cancer immunotherapy and demonstrate that the effects of the immunoproteasome and PA28 are influenced by the individual epitope and its flanking sequence context.     

Deletion of the ferric uptake regulator Fur impairs the in vitro growth and virulence of Actinobacillus pleuropneumoniae

In order to investigate the role of the ferric uptake regulator Fur in the porcine lung pathogen Actinobacillus pleuropneumoniae, we constructed an isogenic in-frame deletion mutant, A. pleuropneumoniae Deltafur. This mutant showed constitutive expression of transferrin-binding proteins, growth deficiencies in vitro, and reduced virulence in an aerosol infection model.     

Alprazolam and amitriptyline in the treatment of major depressive disorder: a double-blind clinical and sleep EEG study

This study was designed to compare the antidepressant effects of alprazolam and amitriptyline in a group of 30 inpatients suffering from a severe major endogenous depression, diagnosed by Research Diagnostic Criteria and the Newcastle Rating scale, and to examine the effects of alprazolam and amitriptyline on two biological markers of depression, the dexamethasone suppression test and sleep EEG parameters. The 6-week study was double-blind with a random allocation of treatment. Patients were treated with flexible doses of 4-9 mg of alprazolam and 100-225 mg of amitriptyline. After 4 weeks of treatment the antidepressant effects of amitriptyline significantly exceeded those of alprazolam, as measured on the Hamilton Rating Scale for Depression. There was a high drop-out rate in the alprazolam group because of ineffectiveness of treatment. Alprazolam showed similar effects on sleep parameters as amitriptyline: lengthening of the REM latency and a tendency to shorten stages 3 and 4 and stage REM. These negative clinical results should be interpreted with caution, because of the severity of our selection criteria, and should not be extended to all depressive disorders.     

Overrepresentation of genetic variation in the AnkyrinG interactome is related to a range of neurodevelopmental disorders

Upon the discovery of numerous genes involved in the pathogenesis of neurodevelopmental disorders, several studies showed that a significant proportion of these genes converge on common pathways and protein networks. Here, we used a reversed approach, by screening the AnkyrinG protein-protein interaction network for genetic variation in a large cohort of 1009 cases with neurodevelopmental disorders. We identified a significant enrichment of de novo potentially disease-causing variants in this network, confirming that this protein network plays an important role in the emergence of several neurodevelopmental disorders.Subject terms: Genetics research, Neurological disorders     

Differences of E-cadherin expression levels and patterns in primary and metastatic human lung cancer

Normal lung epithelium and 52 lung carcinomas obtained at surgical resection were examined by immunofluorescence for their expression levels and patterns of the calcium-dependent intercellular adhesion molecule E-cadherin. In dysplastic lung tissue and in well-differentiated squamous cell and adenocarcinomas, expression of E-cadherin was confined to the lateral cell border, similar to the expression level and pattern of normal lung tissue. The E-cadherin level was reduced and expression pattern was spotty or diffuse in moderately and poorly differentiated squamous cell and in small cell carcinomas of the lung. Most metastases resected also had a reduced level and an altered pattern of E-cadherin expression. In contrast, no such correlation was found in adenocarcinomas of the lung. This indicates that different cellular mechanisms are responsible in the progression of squamous cell carcinomas and adenocarcinomas of the lung.