Interaction of Tau with Fe65 links tau to APP

The beta-amyloid precursor protein APP and the microtubule-associated protein Tau play a crucial role in the pathogenesis of Alzheimer's disease (AD). However, the possible molecular events linking these two proteins are still unknown. Here, we show that Fe65, one of the ligands of the APP cytodomain, is associated with Tau in vivo and in vitro, as demonstrated by co-immunoprecipitation, co-localization, and FRET experiments. Deletion studies indicated that the N-terminal domain of Tau and the PTB1 domain of Fe65 are required for this association. This interaction is regulated by the phosphorylation of Tau at selected sites, by glycogen synthase kinase-3beta (GSK3beta) and cyclin-dependent kinase 5 (Cdk5), and requires an intact microtubule network. Furthermore, laser scanner microscopy and co-immunoprecipitation experiments provide preliminary evidence of possible complex(es) involving Tau, Fe65, APP. These findings open new perspectives for the study of the possible crosstalk between these proteins in the pathogenesis of AD.     

Preliminary evidence for an association between aggressive and hostile behaviour and 3alpha,5alpha-tetrahydroprogesterone plasma levels in schizophrenia

OBJECTIVE: Because it has been suggested that agents acting on the gamma-aminobutyric acid-A (GABA(A)) receptor complex, such as the neuroactive steroid 3!#!alpha;,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), may be biologic modulators of aggression, we aimed to measure 3alpha,5alpha-THP plasma concentrations in subjects with schizophrenia in order to investigate a possible relation with aggressive and hostile behaviour. METHODS: Eight outpatients with schizophrenia diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), were included. Aggression and hostility were assessed using the Modified Overt Aggression Scale and the paranoid/belligerence symptom cluster of the Positive and Negative Syndrome Scale. Plasma samples were obtained 1 hour before psychometric assessment and were quantified for 3alpha,5alpha-THP using a highly sensitive and specific combined analysis by gas chromatography-mass spectrometry. RESULTS: Increased aggressiveness and hostility were associated with increased 3alpha,5alpha-THP plasma levels (Pearson r = 0.72, p = 0.043 and Pearson r = 0.72, p = 0.041, respectively). CONCLUSIONS: These preliminary results suggest that the neuroactive steroid 3alpha,5alpha-THP may affect aggression and hostility in humans.     

Nicergoline, a drug used for age-dependent cognitive impairment, protects cultured neurons against beta-amyloid toxicity

Nicergoline, a drug used for the treatment of Alzheimer's disease and other types of dementia, was tested for its ability to protect neurons against beta-amyloid toxicity. Pure cultures of rat cortical neurons were challenged with a toxic fragment of beta-amyloid peptide (betaAP(25-35)) and toxicity was assessed after 24 h. Micromolar concentrations of nicergoline or its metabolite, MDL, attenuated betaAP(25-35)-induced neuronal death, whereas MMDL (another metabolite of nicergoline), the alpha1-adrenergic receptor antagonist, prazosin, or the serotonin 5HT-2 receptor antagonist, methysergide, were inactive. Nicergoline increased the basal levels of Bcl-2 and reduced the increase in Bax levels induced by beta-amyloid, indicating that the drug inhibits the execution of an apoptotic program in cortical neurons. In mixed cultures of rat cortical cells containing both neurons and astrocytes, nicergoline and MDL were more efficacious than in pure neuronal cultures in reducing beta-amyloid neurotoxicity. Experiments carried out in pure cultures of astrocytes showed that a component of neuroprotection was mediated by a mechanism of glial-neuronal interaction. The conditioned medium of cultured astrocytes treated with nicergoline or MDL for 72-96 h (collected 24 h after drug withdrawal) was neuroprotective when transferred to pure neuronal cultures challenged with beta-amyloid. In cultured astrocytes, nicergoline increased the intracellular levels of transforming-growth factor-beta and glial-derived neurotrophic factor, two trophic factors that are known to protect neurons against beta-amyloid toxicity. These results raise the possibility that nicergoline reduces neurodegeneration in the Alzheimer's brain.     

Plant Origin of Green Propolis: Bee Behavior, Plant Anatomy and Chemistry

Propolis, a honeybee product, has gained popularity as a food and alternative medicine. Its constituents have been shown to exert pharmacological effects, such as anti-microbial, anti-inflammatory and anticancer. Shoot apices of Baccharis dracunculifolia (alecrim plant, Asteraceae) have been pointed out as sources of resin for green propolis. The present work aimed (i) to observe the collecting behavior of bees, (ii) to test the efficacy of histological analysis in studies of propolis botanical origin and (iii) to compare the chemistries of alecrim apices, resin masses and green propolis. Bee behavior was observed, and resin and propolis were microscopically analyzed by inclusion in methacrylate. Ethanol extracts of shoot apices, resin and propolis were analyzed by gas chromatography/mass spectroscopy. Bees cut small fragments from alecrim apices, manipulate and place the resulting mass in the corbiculae. Fragments were detected in propolis and identified as alecrim vestiges by detection of alecrim structures. Prenylated and non-prenylated phenylpropanoids, terpenoids and compounds from other classes were identified. Compounds so far unreported for propolis were identified, including anthracene derivatives. Some compounds were found in propolis and resin mass, but not in shoot apices. Differences were detected between male and female apices and, among apices, resin and propolis. Alecrim apices are resin sources for green propolis. Chemical composition of alecrim apices seems to vary independently of season and phenology. Probably, green propolis composition is more complex and unpredictable than previously assumed.     

Origin and Chemical Variation of Brazilian Propolis

Propolis is a hive product containing chiefly beeswax and plant-derivedsubstances such as resin and volatile compounds. Propolis hasbeen used as an antiseptic and wound healer since ancient timesand interest for the product has increased recently. Probablyfew plant species contribute as major resin sources. Green propolisderives mainly from vegetative apices of Baccharis dracunculifolia(alecrim plants). However, wide variation detected in the chemicalcomposition suggests contributions from alternative resin plantsources. Predominant components of the resin of green propolisare cinnamic acids, chiefly compounds bearing prenyl groups.Terpenoid compounds, such as sesqui, di and pentacyclic triterpenoids,have been detected in many, but not all, samples investigated.Propolis research has uncovered potentialities of substancespreviously isolated from plants and has detected constituentsof plant origin that would hardly be known otherwise.     

P-cadherin expression and survival rate in oral squamous cell carcinoma:an immunohistochemical study

Background  

P-cadherin (P-cad) is a transmembrane molecule involved in the cell-cell adhesion and similar to E-cadherin (E-cad), but less investigated in oncology, especially in in vivo studies. Aims of the present study were to assess the prevalence of P-cad expression in oral squamous cell carcinoma (OSCC) and to verify whether P-cad can be considered a marker of prognosis in patients with OSCC.     

Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors

Cdk9 is a member of the Cdc2-like family of kinases. Its cyclin partners are members of the family of cyclin T (T1, T2a and T2b) and cyclin K. The Cdk9/Cyclin T complex appears to be involved in regulating several physiological processes. Recently, Cdk9 has been identified as a regulator of the differentiation program of several cell types, such as muscle cells, monocytes and lymphocytes, suggesting that it may have a function in controlling specific differentiative pathways. We analyzed whether Cdk9 and Cyclin T1 may be involved in the regulation of neuron and astrocyte differentiation. Cdk9 and Cyclin T1 expression levels were monitored during the differentiation program of neuroblastoma and astrocytoma cell lines. Our results suggest that Cdk9/Cyclin T1 complex may be required for neuron differentiation induced by retinoic acid, because the expression level of the complex varies during differentiation, but no significant changes were observed in its expression in the astrocytoma cell line. In addition, the expression of Cdk9 and Cyclin T1 was evaluated by immunohistochemistry in samples of neuroblastoma, PNET (Primary Neuroectodermal Tumor) and astrocytoma tumors of different grades, in order to assess whether there was a correlation between Cdk9 expression and tumor grading. Our results show that in neuroblastoma and PNET tumor samples Cdk9 is more expressed the more differentiated the tumor is. Conversely, no significant alteration of Cdk9 expression was observed in astrocytoma tumor samples of different grades, thus confirming the results obtained for the cell lines.     

The role of interleukin-6 and of its soluble receptors in the biocompatibility of dialysis treatment

Proinflammatory cytokines, in addition to their role in host defence, may be considered mediators of disease; a reduction of cytokine synthesis or effects is, therefore, becoming a target of many diseases. IL-6 is a pro-inflammatory cytokine that may play a role in several clinical problems related to dialysis treatment. An enhanced spontaneous production of IL-6 by Peripheral Blood Mononuclear Cells (PBMC) harvested from ESRD patients dialyzed with a poor biocompatible membrane has been first demonstrated by our group. These results were also obtained in patients undergoing continuous peritoneal dialysis, in absence of peritonitis. We have also demonstrated that IL-6 release was inversely correlated with serum albumin changes. Biological activities of IL-6 may be modulated by two soluble circulating receptors, namely sIL-6R and sgp130. sIL-6R may enhance the inflammatory effects of IL-6 and is, therefore, an "agonistically" acting molecule. We have recently studied sIL-6R production in ESRD patients dialyzed with different membranes; the conclusion was that poor biocompatible membranes, via the sIL-6R, might further increase the inflammatory effects of IL-6. On the contrary, sgp130 can efficiently bind the IL-6/sIL-6R complex with "antagonistic" effects. We have evaluated plasma levels of sgp130 in 18 ESRD patients regularly dialyzed with hemophan membranes (HE) and in 15 patients dialyzed with more biocompatible synthetic membranes (BIO). Our results demonstrate that plasma levels of sgp130 in HE are 33% higher than in both healthy controls and BIO. Circulating levels of sgp130 were correlated positively with C-reactive protein (r: 0.338, p<0.05) and negatively with serum albumin (r: -0.334, p<0.05). These results suggest that higher circulating levels of sgp130 are likely associated with higher IL-6 levels. These higher amounts are probably insufficient to control the activity of IL-6 and may be considered only as a marker of PBMC activation.     

Assessment of working conditions in health care workers

OBJECTIVE: Validation and first use of a self-completed questionnaire to assess opinion on working conditions in health professionals. METHODS: The questionnaire consisted of 40 items. It was developed via review of the literature and two focus groups. A reliability test-retest study was performed on 45 health professionals with different roles. Factorial validity and internal consistency of each derived subscale were evaluated on a wide sample of 514 professionals. In addition, the opinion of the health care professionals was evaluated and possible relationships were tested between total and subscale scores and the following variables: age, sex, professional role and years in the job. RESULTS: Weighted kappa was higher than 0.60 for 95% of the items, higher than 0.70 for 43% and higher than 0.80 for 20%. Factor analysis revealed that six factors--work content and organisation, physical fatigue, relationships, mental stress, hours of work, and physical environment--explained 57% of total variance. Cronbach's alpha coefficient of the subscales ranged from 0.70 to 0.91. Low levels of satisfaction in dfferent job aspects were found among general hospital staff. They were particularly dissatisfied with personal growth and development, fairness in incentives, dissemination of information, environment, support of new ideas and skills, career opportunities. In particular, satisfaction differed among the various professional roles. DISCUSSION: The questionnaire was found reliable and had a coherent factor structure, with six factors or subscales that showed good internal consistency. This questionnaire may be useful to assess satisfaction with work in health care staff. The preliminary results of its use suggest that satisfaction with different aspects of work is low.     

Latex allergy in children with urological malformation and chronic renal failure

PURPOSE: Children with spina bifida, bladder exstrophy and anorectal anomalies are at risk for latex allergy. Severe intraoperative anaphylaxis in a boy treated with kidney transplantation prompted this study to evaluate the prevalence of latex allergy in a cohort of children with chronic renal failure (CRF). MATERIALS AND METHODS: Between 1996 and 2002, 57 boys and 28 girls were investigated at a median age of 10.5 years (range 1.3 to 22.9). Urological malformations were the underlying cause of CRF in 33 patients (39%). Of the patients 39 were on conservative treatment, 20 were on dialysis and 26 had a functioning renal graft. Latex reaction was assessed by a careful history, specific serum latex IgE and skin prick test. RESULTS: A total of 19 patients (22%) showed latex reaction, of whom 8 had allergy (clinical symptoms included severe intraoperative anaphylaxis in 1) and 11 had sensitivity (positive IgE or prick test without symptoms). Of these 19 patients 11 had urological malformations. The number of surgical procedures, young age at operation and atopy were significant risk factors. When operations were analyzed separately, ie urological vs nonurological surgery, only urological surgery was significantly associated with latex reaction. A significant correlation was also found between the overall number of operations and latex radioallergosorbent class. CONCLUSIONS: All children with CRF who undergo early and multiple urological surgery are at high risk for latex reaction. Primary latex prevention, ie the routine use of latex-free gloves, tubes and catheters, should be implemented in all children with complex urological malformations.