Alpha2 macroglobulin and the risk of Alzheimer's disease

BACKGROUND: alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56). METHODS: We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism. RESULTS: We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors. CONCLUSIONS: Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.     

Esophageal hypermotility associated with intramural pseudodiverticulosis. Primary esophageal disease or epiphenomena?

Esophageal intramural pseudodiverticulosis is a very rare disease of unclear etiology. The clinical picture is characterized by progressive dysphagia. Because of its frequent association with alcohol abuse and subsequent weight loss, it must be differentiated reliably from esophageal carcinoma. The diagnosis is established by the characteristic detection of multiple intramural contrast accumulations in the barium esophagogram. Additional endoscopic and endosonographic confirmation and histological examination are required to exclude a malignant tumor. Moreover, associated diseases are almost always present and should also be diagnosed by pH-metry, cytology, and esophageal manometry. Good and long-lasting therapeutic success can be achieved by bouginage of the stenosis with concomitant treatment of the associated esophageal diseases. Based on two case reports of patients with this disease, we discuss the unusual association with esophageal hypermotility as well as the symptoms, clinical course, therapy, and pathogenesis of the disease.     

Insulin-like growth factor binding protein 1 (IGFBP-1) in vaginal secretion as a marker of premature rupture of amniotic membranes

Diagnosis of premature rupture of amniotic membranes in premature pregnancy allows to estimate dangers which threaten foetus and pregnant woman and helps to put into practice the most accurate therapeutics procedures. The aim of this study was to prove the clinical usefulness of test detecting insulin-like growth factor binding protein-1 in vaginal secretion for diagnose of premature rupture of amniotic membranes and compare the sensiviteness and specificity the above test with Gram stained vaginal smears. We examined group of 50 pregnant women between 25 and 42 week of pregnancy treated in Department of Fertility and Obstetrics Medical University of Wroc?aw. Pregnant women were divided into 3 groups. In each of them both tests were performed to diagnose premature rupture of amniotic membranes. Achieved scores shows that Amni Check is specific and sensitive test detecting even insignificant premature rupture of amniotic membranes and has higher sensitivity comparing with common method used until now for detection of premature rupture of amniotic membranes based on Gramm stained vaginal secretion.     

Reliable discrimination of elderly depressed and demented patients by electroencephalographic sleep data

Using electroencephalographic sleep data from a sample of 235 elderly subjects, discriminant function analyses of sleep alterations in depression and dementia were performed. Overall, 80% of patients were correctly classified using a backward discriminant function analysis, and 81% with a general stepwise discriminant function analysis. Four measures contributed to the separation of depressed and demented patients: rapid eye movement (REM) sleep latency (lower in depressives); REM sleep percent (higher in depressives); indeterminate non-REM sleep percent (higher in demented patients, reflecting greater loss of spindles and K complexes); and early morning awakening (more marked in depressives). When both discriminant functions were subjected to cross-validation in independent subsamples, both procedures correctly identified 78% of patients. The classification functions derived from nondemented depressed and nondepressed demented patients were applied to a mixed-symptom group (n = 42). Overall, 27 patients (64%) with either depressive pseudodementia or dementia with depressive features were correctly classified using the same four predictor variables. These findings suggest that sleep physiological alterations of depression and dementia reflect between-group differences in sleep continuity, sleep architecture, and REM sleep temporal distribution, and that the differences are statistically reliable, in both diagnostically pure and mixed clinical presentations. These findings are discussed in the context of current hypotheses of sleep regulation and its mechanisms.     

Relationship between serum prolactin, lactation and changes in maternal blood B-cell (CD19+) percents during the first 8 months post-partum

Lactation is an immunologically unique state when immune factors are produced by the mother for the protection of the infant rather than the mother. While several studies have focused on the immunological composition of human milk, much less information is available on maternal immune status during lactation. Sixty-four lactating and 43 bottlefeeding women at 1–2 weeks, 1, 2, 4 or 8 months post-partum were studied in a cross-sectional design, with 14 nulliparous women as controls. Flow cytometry analysis of peripheral blood lymphocytes showed dynamic, post-partum changes in the B-cell subpopulation. Among lactating women, the relative percents of CD19+ B-cells were significantly lower (P < 0.05) than control levels at 1–2 weeks and 1 month post-partum, but showed a significant, polynomial-linear rise (P < 0.05) over time, reaching control values by 2–4 months post-partum. Bottle-feeding women had an earlier rise in the percentage of CD 19 + cells, with relative percents always significantly higher than their lactating counterparts. The differing patterns may be due to changes in serum prolactin concentrations because, among the post-partum women, relative percents of CD19+ cells were negatively correlated with baseline serum prolactin concentrations. These results have implications for maternal immunization programs designed to enhance maternal and/or infant well-being as well as other maternal health effects related to breastfeeding.     

Paclitaxel induces the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 through a Cdk1-dependent mechanism

Initial chemotherapeutic treatment triggers a stress-related response, which can lead to an increase in the expression of survival proteins. In this study we examine whether paclitaxel (PTX) alters the expression and/or phosphorylation of the translation initiation proteins, eukaryotic initiation factor 4E (eIF-4E) and 4E-binding protein (4E-BP1), a suppressor of eIF-4E in the dephosphorylated state. We found that PTX induced the hyperphosphorylation of 4E-BP1 in the breast cancer cell line, MDA MB 231, which reduced its association with eIF-4E, but did not alter the expression and phosphorylation of eIF-4E. The hyperphosphorylation of 4E-BP1 correlated with G2/M accumulation and with an increase in the phosphorylation of cdk1 substrates. Cotreatment with a histone deacetylase inhibitor (an indirect inhibitor of cdk activity), purvalanol A and roscovitine (direct cdk inhibitors), and the reduction of cyclin B expression using RNA interference decreased the hyperphosphorylation of 4E-BP1 in PTX treated cells. The hyperphosphorylation of 4E-BP1 by PTX increased the association of eIF-4E with eIF-4G, whereas cotreatment with purvalanol A inhibited the association of eIF-4E with eIF-4G in PTX treated cells. Taken together, our data suggest that PTX-increases the functional level of eIF-4E by promoting the hyperphosphorylation and release of 4E-BP1 through a cdk1-dependent mechanism.     

Increased systemic efficacy of aphidicolin encapsulated in liposomes

Aphidicolin, a tetracyclic diterpene antibiotic produced by Cephalosporium aphidicola, is under investigation as anti-cancer drug. Because of its poor solubility in water, it cannot be administered directly in vivo. Systemic application of aphidicolin glycinate or aphidicolin gamma-cyclodextrin complexes resulted in tumour growth inhibition but not in cures. To improve the pharmacokinetics, a liposomal preparation of aphidicolin was developed and tested in neuroblastoma-bearing (UKF-NB-3) mice. The loading capacity of these liposomes was limited. Therefore, 4.5 mg aphidicolin/kg body weight was the maximum aphidicolin dose that could be applied as liposomal preparation in this approach. Comparison of effects on tumour growth exhibited by aphidicolin liposomes (4.5 mg aphidicolin/kg) given for 15 consecutive days to those of gamma-cyclodextrin inclusion complexes (15 mg aphidicolin/kg) revealed comparable tumour growth inhibition, although aphidicolin concentrations were approximately 3-fold lower. This shows that liposomal encapsulation is a promising strategy for the improvement of systemic anti-cancer activity of aphidicolin.