Metastatic pathways in patients with cutaneous melanoma

Metastasis represents the end product of an elaborate biological process, which is determined by a complex interplay between metastatic tumour cells, host factors and homoeostatic mechanisms. Cutaneous melanoma can metastasize haematogenously or lymphogenously. The three predominant models that endeavour to explain the patterns of melanoma progression are the stepwise spread model, the simultaneous spread model and the model of differential spread. The time course to the development of metastases differs between the different metastatic routes. There are several clinical and histopathological risk factors for the different metastatic pathways. In particular, patient sex and the anatomical location of the primary tumour influence patterns of disease progression. There is limited existing evidence regarding the relationship between tumour mutation status, other diagnostic and prognostic biomarkers and the metastatic pathways of primary cutaneous melanoma. This knowledge gap needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies.     

Neuropsychiatric symptoms in patients with aortic aneurysms

Background

Emerging evidence suggests that vascular disease confers vulnerability to a late-onset of depressive illness and the impairment of specific cognitive functions, most notably in the domains of memory storage and retrieval. Lower limb athero-thrombosis and abdominal aortic aneurysm (AAA) have both been previously associated with neuropsychiatric symptoms possibly due to associated intracerebral vascular disease or systemic inflammation, hence suggesting that these illnesses may be regarded as models to investigate the vascular genesis of neuropsychiatric symptoms. The aim of this study was to compare neuropsychiatric symptoms such as depression, anxiety and a variety of cognitive domains in patients who had symptoms of peripheral athero-thrombosis (intermittent claudication) and those who had an asymptomatic abdominal aortic aneurysm AAA.

Methodology/Principal Findings

In a cross-sectional study, 26 participants with either intermittent claudication or AAA were assessed using a detailed neuropsychiatric assessment battery for various cognitive domains and depression and anxiety symptoms (Hamilton Depression and Anxiety Scales). Student t test and linear regression analyses were applied to compare neuropsychiatric symptoms between patient groups. AAA participants showed greater levels of cognitive impairment in the domains of immediate and delayed memory as compared to patients who had intermittent claudication. Cognitive dysfunction was best predicted by increasing aortic diameter. CRP was positively related to AAA diameter, but not to cognitive function. AAA and aortic diameter in particular were associated with cognitive dysfunction in this study.

Conclusions/Significance

AAA patients are at a higher risk for cognitive impairment than intermittent claudication patients. Validation of this finding is required in a larger study, but if confirmed could suggest that systemic factors peculiar to AAA may impact on cognitive function.     

Association of common health symptoms with bullying in primary school children.

OBJECTIVE--To estimate the prevalence of bullying in primary school children and to examine its association with common symptoms in childhood. DESIGN--Semistructured health interview conducted by school nurses as part of a school medical. SETTING--Newham, east London. SUBJECTS--All children in year 4 of school during the academic year 1992-93. MAIN OUTCOME MEASURES--Reported bullying and common health symptoms. RESULTS--2962 children (93.1% of those on the school roll) were interviewed (ages 7.6 to 10.0 years). Information about bullying was not recorded for 114 children, 22.4% (95% confidence interval 20.9 to 24.0) of children for whom information was available reported that they had been bullied. There was an association between children reporting being bullied sometimes or more often and reporting not sleeping well (odds ratio 3.6, 2.5 to 5.2), bed wetting (1.7, 1.3 to 2.4), feeling sad (3.6, 1.9 to 6.8), and experiencing more than occasional headaches (2.4, 1.8 to 3.4) and tummy aches (2.4, 1.8 to 3.3). A significant trend for increasing risk of symptoms with increased frequency of bullying was shown for all reported health symptoms (P < 0.001). CONCLUSIONS--Health professionals seeing primary schoolchildren who present with headaches, tummy ache, feeling sad or very sad, bed wetting, and sleeping difficulties should consider bullying as a possible contributory factor.     

Differentiation pathways of primary erythroid cells in chickens

Proliferation and differentiation processes of chick embryo primary erythroid cells (PEC) were studied. A novel differentiation pathway was discovered by which cells of proerythroblastic and erythroblastic stages are blocked in G1 or G2 phases, to develop then directly into reticulocytes, i.e. terminally differentiated non-dividing cells with high hemoglobin contents differing in shape from erythrocytes. These cells appear in blood two days earlier than erythrocytes, then they co-exist with the latter and are eliminated in parallel with them. This pathway leads to a rapid enrichment of PEC with hemoglobin. A fraction of PEC forms accessory nuclei, which, as it is shown here, contain an extra quantity of DNA. Compared to the diploid ones, such cells reveal increased hemoglobin contents which enabled us to assume that they may have amplified the globin genes. The above-mentioned pecularities of cytodifferentiation may be presumably an adaptation to oxygen supply of growing embryos which are known to stay in hypoxia. A comparison of these results with results of our earlier study on experimental anemia makes it possible to suppose that pecularities of these two types of cytodifferentiation may be based on similar or, perhaps, analogous mechanisms of regulation.     

Detecting psychogeriatric problems in primary care: factors related to psychiatric symptoms in older community patients

Objective The aim was to determine the relationship and influence of different variables on the psychiatric symptomatology of older people who reside in the community, as detected by family practitioners.Design A cross-sectional and multi-centre study.Setting Twenty-eight general practices and two psychiatric practices in Huesca, Spain, from 19 primary care health centres.Subjects A sample of 324 patients aged over 65 years, representative of the older people who reside in the community in the province of Huesca.Main outcome measures Symptoms of depression (Yesavage GDS), cognitive impairment (MMSE), anxiety (GADS), psychotic symptoms, obsessive symptoms and hypochondriacal ideas (GMS) were measured by family practitioner and were detected following specific questions from the Geriatric Mental State (GMS-B) examination, following DSM-IV criteria, being defined as 'concern and fear of suffering, or the idea of having a serious disease based on the interpretation of somatic symptoms'. Sociodemographic, physical and somatic, functional and social data were evaluated. Analysis was carried out in three phases: univariate, bivariate and multivariate with logistic regression.Results At the time of the study, 46.1% of the older people studied suffered from some psychiatric symptom; 16.4% had cognitive impairment, 15.7% anxiety, 14.3% depression, 6.1% hallucinations and delusions, 7.2% hypochondriacal ideas and 4.4% obsessive symptoms. Female gender was significantly associated with depression (prevalence ration (PR) 3.3) and anxiety (PR 3.9). Age was a factor associated with cognitive impairment (PR 4.4). Depression was significantly related to severity of the physical illness (PR 61.7 in extremely severe impairment). Isolation (PR 16.3) and being single (PR 13.4) were factors which were strongly associated with anxiety; living in a nursing home was associated with psychotic symptoms (PR 7.6).Conclusions Severity of physical illness, isolation, living in a nursing home and female gender, among others, are related to psychiatric symptoms in community-residing older people identified in primary healthcare centres.     

Multiple pathways of apolipoprotein E signaling in primary neurons

Apolipoprotein E is a genetic risk factor for Alzheimer's disease, and the apoE protein is associated with beta-amyloid deposits in Alzheimer's disease brain. We examined signaling pathways stimulated by apoE in primary neurons in culture. ApoE and an apoE-derived peptide activated several intracellular kinases, including prominently extracellular signal-regulated kinase 1/2 (ERK1/2). ERK1/2 activation by apoE was blocked by an inhibitor of the low-density lipoprotein receptor family, the specific NMDA glutamate receptor antagonist MK 801 and other calcium channel blockers. Activation of apoE receptors also induced tyrosine phosphorylation of Dab1, an adaptor protein of apoE receptors, but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for ERK activation. In contrast, apoE treatment of primary neurons decreased activation of c-Jun N-terminal kinase, a kinase that interacts with another apoE receptor adaptor protein, c-Jun N-terminal kinase-interacting protein. This change also depended on interactions with the low-density lipoprotein receptor family but was independent of calcium channels. c-Jun N-terminal kinase deactivation by apoE was blocked by gamma-secretase inhibitors and pertussis toxin. These results demonstrate that apoE affects several signaling cascades in neurons: increased disabled phosphorylation, activation of the ERK1/2 pathway (dependent on calcium influx via the NMDA receptor) and inhibition of the c-Jun N-terminal kinase 1/2 pathway (dependent on gamma-secretase and G proteins).     

Engineering primary metabolic pathways of industrial micro-organisms

Metabolic engineering is a powerful tool for the optimisation and the introduction of new cellular processes. This is mostly done by genetic engineering. Since the introduction of this multidisciplinary approach, the success stories keep accumulating. The primary metabolism of industrial micro-organisms has been studied for long time and most biochemical pathways and reaction networks have been elucidated. This large pool of biochemical information, together with data from proteomics, metabolomics and genomics underpins the strategies for design of experiments and choice of targets for manipulation by metabolic engineers. These targets are often located in the primary metabolic pathways, such as glycolysis, pentose phosphate pathway, the TCA cycle and amino acid biosynthesis and mostly at major branch points within these pathways. This paper describes approaches taken for metabolic engineering of these pathways in bacteria, yeast and filamentous fungi.     

Cortical connectivity in schizophrenic patients with positive and negative symptoms

The paper is dedicated to the problem of disturbed "connectivity" between different cortical areas in schizophrenic patients with the dominance of "negative" and "positive" symptoms. The architecture of cortical connections in high-frequency range of the beta rhythm (beta 2, 20-40 Hz) was studied in three groups of right-handed men: healthy control group (16 subjects) and schizophrenic patients with the dominance of positive (16 subjects) and negative (22 subjects) symptoms assessed by the SAPS and SANS scales. Two versions of the Intracortical Interaction Mapping (IIM) technique of examination of cortical connections were used. In the 1st version, mean connection frequencies in the beta 2-rhythm for each group were analyzed. In the 2nd version, the most typical for a given group connection frequencies were studied. Additionally, since the IIM technique is rather new, coherence function in the beta 2-rhythm calculated by the standard way was also taken into account. The obtained results made it possible to reveal the derangements in the system of cortical interactions in schizophrenic patients.     

Chromosomal aberrations in patients with primary biliary cirrhosis

Summary Chromosomal aberrations in untreated lymphocyte cultures, bleomycin (BLM)-induced aberrations and sister chromatid exchanges (SCE) in the peripheral blood lymphocytes of 11 patients suffering from primary biliary cirrhosis (PBC) and 14 matched control individuals were analysed. The lymphocytes of the PBC patients had on average a lower mitotic index (2.3) compared with controls (3.5) in the untreated cultures. The mean baseline rate of aberrations of the cultured lymphocytes of the patients was 5.3 aberrations per 100 metaphases (%); this was significantly different (P=0.0291) from that of the controls with a mean of 2.3%. In lymphocytes of the patients and controls, most of the aberrations observed took the form of gaps; there was an almost equal breakage rate in both groups (0.5% and 0.4%, respectively). The average number of mitoses with aberrations in the PBC patients studied was double that of the controls (4.9% and 2.3% respectively, P=0.0323). The mean number of the BLM-induced aberrations was 54.0% and 27.7% for the lymphocytes of the patients and controls, respectively. The mean number of the aberrant mitoses in the BLM cultures was 6 times higher than that of the untreated cultures for both groups, 25.7% and 14.6% respectively (P=0.018). The chromosomal distribution of baseline and induced aberrations was not random. The PBC patients had a mean number of 8.7 SCE per mitosis, which was significantly higher than the SCEs in the controls (6.3 SCE per mitosis; P=0.0156). The evidence suggests that the chromosomes of the lymphocytes of PBC patients may be less stable than those of the control individuals in this study.     

Cellular immunity in patients with multiple primary tumors

Summary Immunological studies for evaluation of cellular immunity were carried out on 22 patients who had two primary malignant tumors and who had no evidence of active disease. The tests performed were for skin reactivity to 3 recall antigens, PPD, Candidine, and Streptokinase and in vitro lymphocyte stimulation by PHA. Of these, 6 patients were anergic to all three recall antigens and 5 other patients to two out of three antigens. A depression of the in vitro reactivity was encountered in 11 patients. The immune incompetence was more evident in patients with simultaneous tumors than in those with metachroneous tumors. The longer the interval between the appearance of the primary and the secondary tumors, the less immunosuppression was seen.Presented at the 24th Israel Medical Association Conference on Immunological Aspects of Cancer, Tel-Aviv, December 26, 1974This work was supported in part by the Office of the Administrator General, Ministry of Justice and the Medical Research Fund under the Sponsorship of the Ministry of Health     

Rho kinase signaling pathways during stretch in primary alveolar epithelia

Alveolar epithelial cells (AECs) maintain integrity of the blood-gas barrier with actin-anchored intercellular tight junctions. Stretched type I-like AECs undergo magnitude- and frequency-dependent actin cytoskeletal remodeling into perijunctional actin rings. On the basis of published studies in human pulmonary artery endothelial cells (HPAECs), we hypothesize that RhoA activity, Rho kinase (ROCK) activity, and phosphorylation of myosin light chain II (MLC2) increase in stretched type I-like AECs in a manner that is dependent on stretch magnitude, and that RhoA, ROCK, or MLC2 activity inhibition will attenuate stretch-induced actin remodeling and preserve barrier properties. Primary type I-like AEC monolayers were stretched biaxially to create a change in surface area (ΔSA) of 12%, 25%, or 37% in a cyclic manner at 0.25 Hz for up to 60 min or left unstretched. Type I-like AECs were also treated with Rho pathway inhibitors (ML-7, Y-27632, or blebbistatin) and stained for F-actin or treated with the myosin phosphatase inhibitor calyculin-A and quantified for monolayer permeability. Counter to our hypothesis, ROCK activity and MLC2 phosphorylation decreased in type I-like AECs stretched to 25% and 37% ΔSA and did not change in monolayers stretched to 12% ΔSA. Furthermore, RhoA activity decreased in type I-like AECs stretched to 37% ΔSA. In contrast, MLC2 phosphorylation in HPAECs increased when HPAECs were stretched to 12% ΔSA but then decreased when they were stretched to 37% ΔSA, similar to type I-like AECs. Perijunctional actin rings were observed in unstretched type I-like AECs treated with the Rho pathway inhibitor blebbistatin. Myosin phosphatase inhibition increased MLC2 phosphorylation in stretched type I-like AECs but had no effect on monolayer permeability. In summary, stretch alters RhoA activity, ROCK activity, and MLC2 phosphorylation in a manner dependent on stretch magnitude and cell type.