ER stress is involved in Abeta-induced GSK-3beta activation and tau phosphorylation

Intracellular neurofibrillary tangles, one of the characteristic hallmarks of Alzheimer's disease (AD), are mainly composed of hyperphosphorylated tau. The abnormal tau phosphorylation seems to be related to altered activity of kinases such as glycogen synthase kinase-3beta (GSK-3beta). Tau pathology is thought to be a later event during the progression of the disease, and it seems to occur as a consequence of amyloid-beta (Abeta) peptide accumulation. The aim of this work was to investigate whether soluble Abeta1-42, particularly oligomers that correspond to the neurotoxic species involved early in the development of AD, triggers tau phosphorylation by a mechanism involving activation of tau-kinase GSK-3beta. Several studies suggest that GSK-3beta plays a central role in signaling the downstream effects of endoplasmic reticulum (ER) stress. Therefore, the involvement of ER Ca(2+) release in GSK-3beta activation and tau phosphorylation induced by Abeta1-42 oligomers was evaluated using dantrolene, an inhibitor of Ca(2+) release through channels associated with ER ryanodine receptors. We observed that Abeta1-42 oligomers increase tau phosphorylation and compromises cell survival through a mechanism mediated by GSK-3beta activation. We also demonstrated that oligomeric Abeta1-42 induces ER stress and that ER Ca(2+) release is involved in oligomer-induced GSK-3beta activation and tau phosphorylation. This work suggests that GSK-3beta can be a promising target for therapeutic intervention in AD.     

Adaptive visual memory reorganization in right medial temporal lobe epilepsy

Purpose: We investigated functional reorganization mechanisms of the human medial temporal lobe (MTL) for episodic memory, in patients suffering from medial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS).
Methods: We used functional magnetic resonance imaging (fMRI) to measure brain activity changes during matched episodic encoding tasks of abstract words (Verbal) and line drawings (Visual), in patients with unilateral right MTLE undergoing presurgical evaluation and healthy controls.
Results: As expected, a significant interaction between material type and the side of MTL activity was present in the control group, with preferential involvement of the left hippocampus in verbal encoding and the right parahippocampal region in visual encoding. When compared with controls, right MTLE patients with intact performance activated a region in the left hippocampus more during visual encoding, which resulted in an interaction between group and hemisphere. Importantly, an effect of memory performance on visual encoding activity was observed in the patients, with greater engagement of the left MTL being associated with higher recognition scores. Interestingly, activity in the left MTL also depended on the epileptic seizure frequency, suggesting a role for this clinical parameter in the recruitment of contralateral regions.
Discussion: Taken together, these results indicate functional reorganization of the MTLs in right HS, through transfer of function from the right to the left hemisphere, and strongly suggest an adaptive role for such reorganization mechanism in supporting preserved visual memory.     

Clinical course of nonvisceral soft tissue leiomyosarcoma in 225 patients from the Scandinavian Sarcoma Group

BACKGROUND: Leiomyosarcoma of nonvisceral soft tissues is an uncommon malignant tumor; thus, only small numbers of cases have been reported. This study was based on a large series of patients from the Scandinavian Sarcoma Group Register acquired during a 15-year period (from 1986 to 2001). Follow-up information was available for all patients. METHODS: The authors analyzed the clinical features of 225 patients with cutaneous, subcutaneous, or deep-seated leiomyosarcoma of the extremities, trunk wall, and superficial parts of the head and neck region to determine the natural course of the disease. Only patients who received their treatment at a specialist sarcoma center were included. Re-evaluation of histopathology was performed. RESULTS: The age of the patients (121 women and 104 men) ranged from 20 years to 98 years (median, 70 years), and the tumors ranged in size from 0.6 cm to 35 cm (median, 4.0 cm). Eighty-two percent of the tumors were classified as high grade. The median follow-up for survivors was 5.5 years. The local treatment was adequate in 154 of 206 patients (75%) who were without metastasis at presentation. At 10 years, 84% of the 206 patients with localized disease at presentation were free from local recurrence, 66% remained metastasis free, and 49% were alive. Multivariate analysis showed that higher malignancy grade (P = .006), larger tumor size (P = .003), and deeper tumor location (P = .002) were correlated significantly with decreased metastasis-free survival, inadequate local treatment was correlated with local recurrence (P = .007), and high malignancy grade was correlated with decreased overall survival (P = .007). CONCLUSIONS: The long-term prognosis for patients with subcutaneous and deep-seated soft tissue leiomyosarcoma remains poor despite the ability to achieve adequate local control through nonmutilating surgery with or without radiotherapy.     

Airborne exposures and risk of gastric cancer: a prospective cohort study

There is an unexplained male predominance among patients with gastric cancer, and many carcinogens are found in male-dominated dusty occupations. However, the relation between occupational exposures and risk of gastric cancer remains unclear. To investigate whether airborne occupational exposures might influence the risk of noncardia gastric cancer, we used a large, prospective cohort study of male Swedish construction workers. These workers were, during the period 1971-1993, regularly invited to health examinations by a nationwide occupational health service organization. Data on job titles and other variables were collected through self-administered questionnaires and forms completed by the health organization's staff. Industrial hygienists assessed 12 specific airborne occupational exposures for 200 job titles. Gastric cancer, death or emigration occurring during follow-up in 1971-2002 were identified by linkage to the Swedish registers of Cancer, Causes of Death and Total Population, respectively. Incidence rate ratios (IRR) and 95% confidence intervals (CI), adjusted for attained age, tobacco smoking, calendar period and body mass, were derived from Cox regression. Among 256,357 cohort members, contributing 5,378,012 person-years at risk, 948 noncardia gastric cancers were identified. Increased risk of this tumor was found among workers exposed to cement dust (IRR 1.5 [95% CI 1.1-2.1]), quartz dust (IRR 1.3 [95% CI 1.0-1.7]) and diesel exhaust (IRR 1.4 [95% CI 1.1-1.9]). Dose-response relations were observed for these exposures. No consistent positive associations were found regarding exposure to asbestos, asphalt fumes, concrete dust, epoxy resins, isocyanates, metal fumes, mineral fibers, organic solvents or wood dust. In conclusion, this study provides some support to the hypothesis that specific airborne exposures increase the risk of noncardia gastric cancer.     

Lesão tumoral gigante na aurícula esquerda: um caso incomum de sarcoma cardíaco indiferenciado

Primary cardiac tumors are rare, with an incidence ranging from 0.0001% to 0.030%; 80% are benign, while sarcomas account for 95% of malignant tumors.The authors report the case of a 75-year-old patient with a giant mass in the left atrium. The final diagnosis was of an undifferentiated cardiac sarcoma. This tumor represents a real challenge not only for timely diagnosis, but especially the therapeutic approach to adopt.     

Acidianus filamentous virus 1 coat proteins display a helical fold spanning the filamentous archaeal viruses lineage

Acidianus filamentous virus 1 (AFV1), a member of the Lipothrixviridae family, infects the hyperthermophilic, acidophilic crenarchaeaon Acidianus hospitalis. The virion, covered with a lipidic outer shell, is 9,100-Å long and contains a 20.8-kb linear dsDNA genome. We have identified the two major coat proteins of the virion (MCPs; 132 and 140 amino acids). They bind DNA and form filaments when incubated with linear dsDNA. A C-terminal domain is identified in their crystal structure with a four-helix-bundle fold. In the topological model of the virion filament core, the genomic dsDNA superhelix wraps around the AFV1–132 basic protein, and the AFV1–140 basic N terminus binds genomic DNA, while its lipophilic C-terminal domain is imbedded in the lipidic outer shell. The four-helix bundle fold of the MCPs from AFV1 is identical to that of the coat protein (CP) of Sulfolobus islandicus rod-shaped virus (SIRV), a member of the Rudiviridae family. Despite low sequence identity between these proteins, their high degree of structural similarity suggests that they could have derived from a common ancestor and could thus define an yet undescribed viral lineage.     

PLAG1 gene alterations in salivary gland pleomorphic adenoma and carcinoma ex-pleomorphic adenoma: a combined study using chromosome banding, in situ hybridization and immunocytochemistry.

Pleomorphic adenoma is the most common benign tumor of the salivary glands. It has marked histological diversity with epithelial, myoepithelial and mesenchymal-type cells arranged in a variety of architectural and differentiation patterns. Pleomorphic adenoma gene 1 (PLAG1), shown to be consistently rearranged in pleomorphic adenomas, is activated by chromosomal translocations involving 8q12, the chromosome region that is most frequently affected in these tumors. In this study, we evaluated PLAG1 involvement in salivary gland tumorigenesis by determining the frequency of its alterations in a selected group of 20 salivary gland tumors: 16 pleomorphic adenomas and four carcinomas ex-pleomorphic adenoma, having in common the presence of karyotypic chromosome 8 deviations, either structural, with 8q12 rearrangements, or numerical, with gain of chromosome 8. PLAG1 status was analyzed using in situ hybridization techniques, on metaphase cells, by fluorescence detection and/or interphase cells in paraffin sections, by chromogenic detection. Except for one pleomorphic adenoma case (5%) that lacked PLAG1 involvement, 17 tumors (85%), (14 pleomorphic adenomas and three carcinomas ex-pleomorphic adenoma) showed intragenic rearrangements of PLAG1 and the remaining two cases (10%), (one pleomorphic adenoma and one carcinoma ex-pleomorphic adenoma), had chromosome trisomy 8 only. To further investigate the role of PLAG1 on pleomorphic adenomas tumorigenesis, as well as the putative morphogenesis mechanism, we attempted to identify the cell types (epithelial vs myoepithelial) carrying 8q12/PLAG1 abnormalities by a combined phenotypic/genotypic analysis in four cases (three pleomorphic adenoma and one carcinoma ex-pleomorphic adenoma) characterized by 8q12 translocations and PLAG1 rearrangement. In these cases, both cells populations carried PLAG1 rearrangements. This finding further supports the pluripotent single-cell theory, which postulates that the tumor-initiated, modified myoepithelial cell, evolves into the varied somatic cell phenotypes present in pleomorphic adenoma, and reinforces the role of PLAG1 on the tumorigenesis of benign and malignant pleomorphic adenoma.     

Thermoregulation and aging.

Worldwide climate changes, bringing long-lasting higher and lower extremes of temperature, are leading to an increased mortality rate in elderly people due to cardiocirculatory dysfunction. The ability of young adults to make physiological adjustments when exposed to low or high temperatures decreases with age. The purpose of this literature review is to assess the dysfunctions occurring in the elderly as a result of their reduced responsiveness to thermal stress. Physiological responses to cold environment induce a reversible plasma water shift from the intravascular to the interstitial and intracellular level due to peripheral vasoconstriction. This phenomenon occurs on exposure to cold water or air and even during facial cooling by a cold wind. Above-normal temperatures induce a reduction in intravascular water due to sweating. Older people are less able to cope with the increased viscosity of blood and are thus more liable to suffer a cardiocirculatory accident.     

Antiplatelet therapy and cardiovascular primary prevention: influence of gender, age and other risk factors.

Intervention for cardiovascular primary prevention has shown promising results in several trials. Studies performed up to 2002 showed a significant effect of aspirin in primary prevention of ischemic heart disease, with a significant reduction in non-fatal acute myocardial infarction, especially in men. Since then, new evidence has demonstrated the potential effect of antiplatelet therapy in cardiovascular primary prevention, particularly in less represented subgroups. In this article, we review the main studies on antiplatelet therapy and cardiovascular primary prevention, highlighting the results for these subgroups in terms of gender, age and presence of diabetes, chronic renal failure or atrial fibrillation, and then propose some clinical guidelines.     

OPPORTUNITIES AND BURDENS FOR NURSE-MIDWIVES WORKING IN PRIMARY HEALTH CARE: An Example From Population-Based Cervical Cancer Screening in Urban Sweden

In Sweden, nurse-midwives in primary health care are responsible for taking Papanicolaou smears in population-based cervical cancer screening programs. This article discusses the manner in which a group of nurse-midwives, working with the cervical cancer screening program, view both opportunities and burdens inherent in their work. Semistructured interviews were conducted with 21 nurse-midwives engaged in screening at seven antenatal health care centers in demographically different parts of Stockholm, using a team approach to collect and inductively analyze the interviews. Results indicate discrepancies between ideals guiding the midwives and their practice. Positive aspects described by the midwives appear to be related to an ideology of care, whereas perceived burdens include the midwives' sense of powerlessness, lack of congruence between midwives' ideology and screening organization, and lack of professional familiarity with cancer. Several of these features can be related to issues that are challenges for many health care practitioners today, even in other settings. Our conclusion is that the screening program has latent potential for further development of the role of the nurse-midwife as an advocate for women throughout the lifespan and in a variety of situations.