PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress.

The accumulation of unfolded proteins elicits a cellular response that triggers both pro-survival and pro-apoptotic signaling events. PERK-dependent activation of NF-E2-related factor-2 (Nrf2) is critical for survival signaling during this response; however, the mechanism whereby Nrf2 confers a protective advantage to stressed cells remains to be defined. We now demonstrate that Nrf2 activation contributes to the maintenance of glutathione levels, which in turn functions as a buffer for the accumulation of reactive oxygen species during the unfolded protein response.

Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells.

Aging is associated with a rise in intracellular reactive oxygen species (ROS) and a loss of telomerase reverse transcriptase activity. Incubation with H2O2 induced the nuclear export of telomerase reverse transcriptase (TERT) into the cytosol in a Src-family kinase-dependent manner. Therefore, we investigated the hypothesis that age-related increase in reactive oxygen species (ROS) may induce the nuclear export of TERT and contribute to endothelial cell senescence.

The cyclin D3 knockout: a pound of redundancy with a dash of tissue specificity.

Progression through each phase of the cell division cycle is driven by specific cyclin/CDK holoenzymes complexes, each complex having a discrete subset of critical substrates. Phosphorylation of these substrates by the appropriate cyclin/CDK complex in turn directs regulated cell cycle progression. Based on this notion, a reasonable assumption is that elimination of any one of these complexes would be catastrophic with regard to cellular and organismal development.

[Mild cognitive disorder. Questions of definition, diagnosis, prognosis and therapy].

The syndrome of mild cognitive impairment (MCI) is heterogeneous in terms of aetiology, psychopathology, and prognosis. It is characterised by cognitive deterioration significantly exceeding the decline attributable to aging but not reaching the severity of dementia. The prevalence of MCI is estimated to be 17% in the population over 65 years old.

Organization of porcine platelet-activating factor receptor gene.

Four exons of porcine platelet-activating factor receptor (PAFr) gene expressing transcript 1 and transcript 2 were determined previously. In this study, we cloned and sequenced a new exon, which also initiates transcript 2, and determined the order of 5 exons in the PAFr gene. In addition, two other variants of transcript 2 were found, but no additional variants of transcript 1 were found.

An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene.

Glycogen synthase kinase-3beta-dependent phosphorylation of cyclin D1 at a conserved COOH-terminal residue, Thr-286, promotes CRM1-dependent cyclin D1 nuclear export at the G(1)-S boundary. Mutations that perturb the phosphorylation of cyclin D1 at Thr-286 contribute to cell transformation, although to date, no such mutations have been found in human cancers. Cyclin D1 (CCND1) undergoes alternative splicing leading to the production of an mRNA predicted to encode a unique cyclin D1 isoform, cyclin D1b, which lacks Thr-286.

Human epicardial adipose tissue is a source of inflammatory mediators.

Background: Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD.

Cell cycle progression without cyclin E/CDK2: breaking down the walls of dogma.

G1 is the phase of the cell cycle wherein the cell is responsive to growth factor-dependent signals. As such, G1 regulation is frequently disrupted in cancer through deregulation of cyclin/CDK activity; deregulation of G1 phase provides tumorigenic cells with a growth advantage. Cyclin E, the regulatory cyclin for CDK2, is considered a requisite regulator of G1 progression.

Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival.

Activation of PERK following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) promotes translation inhibition and cell cycle arrest. PERK function is essential for cell survival following exposure of cells to ER stress, but the mechanisms whereby PERK signaling promotes cell survival are not thoroughly understood. We have identified the Nrf2 transcription factor as a novel PERK substrate.

[Frontotemporal dementia. Results from "Frontotemporal Demential and Pick's Disease Conference"].

At the Frontotemporal Dementia and Pick's Disease Conference, recent data concerning the epidemiology, diagnosis, and therapy of frontotemporal dementia were presented. Topics included clinical manifestations, differential diagnosis, pathologic and genetic bases of the disease, therapy, and specific problems facing patients and care givers. A consensus in the terminology of this condition was sought.

[Features of frontotemporal dementia from the perspective of a special family support group].

Eight spouses of patients diagnosed with frontotemporal dementia (FTD) participated in a special support group. Seven weekly sessions of 90-min duration were held. This pilot project provided the opportunity to learn more about FTD and the specific problems and needs of caregivers.

Assessment of resting energy expenditure in mechanically ventilated patients.

Background: Usual equations for predicting resting energy expenditure (REE) are not appropriate for critically ill patients, and indirect calorimetry criteria render its routine use difficult.

Objective: Variables that might influence the REE of mechanically ventilated patients were evaluated to establish a predictive relation between these variables and REE.

Design: The REE of 70 metabolically stable, mechanically ventilated patients was prospectively measured by indirect calorimetry and calculated with the use of standard predictive models (Harris and Benedict's equations corrected for hypermetabolism factors).

GATA-1-mediated proliferation arrest during erythroid maturation.

Transcription factor GATA-1 is essential for erythroid and megakaryocytic maturation. GATA-1 mutations are associated with hematopoietic precursor proliferation and leukemogenesis, suggesting a role in cell cycle control. While numerous GATA-1 target genes specifying mature hematopoietic phenotypes have been identified, how GATA-1 regulates proliferation remains unknown.

Clinically significant gastrointestinal bleeding in critically ill patients with and without stress-ulcer prophylaxis.

Objective: To compare the rates of clinically significant gastrointestinal bleeding and the number of blood units and endoscopies required for gastrointestinal hemorrhage between patients receiving or not receiving stress-ulcer prophylaxis.

Design: Historical observational study comparing two consecutive periods: with (phase 1) and without stress-ulcer prophylaxis (phase 2).

Design And Setting: A 17-bed intensive care unit in a university teaching hospital.

[German-speaking memory clinics: state of the art and practical recommendations].

The 7th annual meeting of the memory clinics of Germany, Switzerland and Austria in March 2002 in Göttingen, Germany was an optimal opportunity to make an inventory about the state of the art in diagnostic and therapy of dementia and mild cognitive impairment in German-speaking memory clinics. Several problems were discussed including difficulties in 1) diagnosis of patients with aphasia or foreign patients, 2) handling of demented patients without a caregiver, 3) psychological support for patients, who have been diagnosed in a very early stage, 4) misunderstandings between general practitioners, neurologists and psychiatrists in private practice on the one hand and the memory clinics on the other hand, 5) recommendations for prevention of dementia, 6) recommendations concerning dementia and car driving and 7) questions of genetic counselling. The following paper is a summary of the results of a workshop in Göttingen and gives practical recommendations based on the experiences of the memory clinics.

Helium/oxygen mixture reduces the work of breathing at the end of the weaning process in patients with severe chronic obstructive pulmonary disease.

Objective: To test the hypothesis that helium/oxygen mixture can reduce the work of breathing at the end of the weaning process in patients with chronic obstructive pulmonary disease.

Design: Prospective, randomized, crossover study.

Setting: Two medical intensive care units at two university tertiary care centers.

Lack of association between a single nucleotide polymorphism within the choline acetyltransferase gene and patients with Alzheimer's disease.

Alterations of the cholinergic system may account for typical clinical and pathophysiological disturbances of Alzheimer's disease (AD). In particular, a marked decline of choline acetyltransferase activity (CHAT) and as a consequence of acetylcholine during the course of the disease has been described. Due to the chromosomal localization of CHAT at 10q11.

Osteoporosis disease management in a rural health care population: hip fracture reduction and reduced costs in postmenopausal women after 5 years.

A 5 year observational study is reported which reviews the implementation of the Geisinger Health System Osteoporosis Disease Management Program. This program includes Osteoporosis Clinical Practice Guidelines, physician and allied health care provider education, community education, and a bone density testing program. All women over the age of 55 years enrolled in the Geisinger Health Plan (GHP) from 1996 to 2000 were included in this analysis.

Effectiveness of non-invasive positive pressure ventilation differs between decompensated chronic restrictive and obstructive pulmonary disease patients.

Objective: To compare the efficiency of non-invasive positive pressure ventilation (NPPV) in decompensated patients with either chronic obstructive pulmonary disease (COPD) or chronic restrictive pulmonary disease.

Design: Retrospective study.

Setting: A 17-bed intensive care unit in a university teaching hospital.

Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase.

The cyclin D-dependent kinase is a critical mediator of mitogen-dependent G1 phase progression in mammalian cells. Given the high incidence of cyclin D1 overexpression in human neoplasias, the nature and complexity of cyclin D complexes in vivo have been subjects of intense interest. Besides its catalytic partner, the nature and complexity of cyclin D complexes in vivo remain ambiguous.

The cyclin D1-dependent kinase associates with the pre-replication complex and modulates RB.MCM7 binding.

The capacity of the cyclin D-dependent kinase to promote G(1) progression through modulation of RB.E2F is well documented. We now demonstrate that the cyclin D1/CDK4 kinase binds to components of the MCM complex.

Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment.

Context: Cerebrospinal fluid tau protein and beta-amyloid 42 (Abeta42) protein are altered even in very mild Alzheimer disease (AD). So far, few data exist for subjects with mild cognitive impairment (MCI).

Objective: To investigate the potential of cerebrospinal fluid tau and Abeta42 for predicting progression from MCI to AD in a longitudinal study of 28 patients with MCI who received follow-up for 18 months.

Cycling to cancer with cyclin D1.

Genetic aberrations in the regulatory circuits that govern transit through the G(1) phase of the cell cycle occur frequently in human cancer and overexpression of the G(1) phase cyclin, cyclin D1, is one of the most commonly observed alterations. Cyclin D1 accumulates and activates its cognate CDK (CDK4/6) in response to mitogenic growth factors in early to mid G(1) phase. The resulting cyclin D1-dependent kinase initiates the phosphorylation-dependent inactivation of the retinoblastoma tumor suppressor protein.