Targeted lung cancer screening selects individuals at high risk of cardiovascular disease.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in populations eligible for lung cancer screening. The aim of this study was to determine whether a brief CV risk assessment, delivered as part of a targeted community-based lung cancer screening programme, was effective in identifying individuals at high risk who might benefit from primary prevention. METHODS: The Manchester Lung Screening Pilot consisted of annual low dose CT (LDCT) over 2 screening rounds, targeted at individuals in deprived areas at high risk of lung cancer (age 55-74 and 6-year risk ≥1.51%, using PLCOM2012 risk model). All participants of the second screening round were eligible to take part in the study. Ten-year CV risk was estimated using QRISK2 in participants without CVD and compared to age (±5 years) and sex matched Health Survey for England (HSE) controls; high risk was defined as QRISK2 score ≥10%. Coronary artery calcification (CAC) was assessed on LDCT scans and compared to QRISK2 score. RESULTS: Seventy-seven percent (n=920/1,194) of screening attendees were included in the analysis; mean age 65.6 ± 5.4 and 50.4% female. QRISK2 and lung cancer risk (PLCOM2012) scores were correlated (r = 0.26, p < 0.001). Median QRISK2 score was 21.1% (IQR 14.9-29.6) in those without established CVD (77.6%, n = 714/920), double that of HSE controls (10.3%, IQR 6.6-16.2; n = 714) (p < 0.001). QRISK2 score was significantly higher in those with CAC (p < 0.001). Screening attendees were 10-fold more likely to be classified high risk (OR 10.2 [95% CI 7.3-14.0]). One third (33.7%, n = 310/920) of all study participants were high risk but not receiving statin therapy for primary CVD prevention. DISCUSSION: Opportunistic CVD risk assessment within a targeted lung cancer screening programme is feasible and is likely to identify a very large number of individuals suitable for primary prevention.

Differences by age and sex in general dental practitioners' knowledge, attitudes and behaviours in delivering prevention.

PURPOSE: To assess sex and age differences in NHS dentists' knowledge, attitudes and behaviours in providing preventive care. MATERIALS AND METHODS: A cross-sectional questionnaire survey was conducted with dentists working in North London, UK. RESULTS: The sample displayed limited knowledge in certain key aspects of prevention, but expressed generally positive attitudes towards preventive care. More female and younger dentists reported that a child should attend the dentist before the age of 3 years (p = 0.03 and p = 0.04, respectively). No other differences in knowledge or attitudes were found by age and sex. The majority of the sample reported routinely providing oral hygiene (95.7%), diet (85.4%) and smoking cessation advice (76.7%), but provision of alcohol advice was much less common (38%). A significantly higher proportion of younger dentists were more likely to give diet advice (p = 0.03) and smoking cessation support (p = 0.009) than their older colleagues. Female dentists were more likely to provide fissure sealants (p = 0.04), diet advice (p = 0.02) and smoking cessation support (p = 0.03). The main perceived barriers were related to organisational factors including insufficient remuneration (86.3%), lack of time (84%) and poor patient compliance (66%). There were no significant differences in perceived barriers by sex, but younger dentists were significantly more likely to identify poor patient compliance as a barrier (p = 0.02). CONCLUSION: Although dentists in this study may lack some core preventive knowledge, many expressed very positive attitudes towards prevention and reported to be routinely offering a range of preventive measures. Younger and female dentists tended to engage more frequently in preventive activities.

An overview of the prison population and the general health status of prisoners.

This article is the first in a series of four, which explore the oral and dental health of male prisoners in the United Kingdom. The series comprises: an overview of the general and oral health status of male prisoners, a discussion on how multi-disciplinary team working can be used to benefit the care of patients in prison environments and a description of the future planning of dental services for male prisoners. The oral health of prisoners is linked to their general health status, due in part to the presence of common risk factors such as smoking, drinking alcohol and in some cases use of recreational drugs, poor dietary and poor oral hygiene habits. Barriers to healthcare services can all have an effect on oral disease in this group. This paper highlights some of the common medical problems that oral healthcare providers face when treating prisoners in male UK prison establishments.

Local excision of rectal cancer followed by radical surgery because of poor prognostic features does not compromise the long term oncologic outcome.

AIM: The outcome of patients undergoing full-thickness local excision (LE) of rectal cancers may be compromised if poor prognostic features are found in the LE specimen. Our aim was to evaluate the long-term results of radical surgery performed after LE because poor prognostic factors are identified. METHOD: Patients with biopsy-proven rectal cancer who had undergone full-thickness LE followed by radical surgery because of a positive margin, T stage ≥3, lymphovascular invasion, poor differentiation or mucinous histology were identified from a prospective database. Their records were retrospectively reviewed and follow up was updated. RESULTS: Between 1995 and 2003, 17 patients underwent LE followed by radical surgery because of poor prognostic features. Combined chemotherapy and radiotherapy was given to 11 (65%) patients before radical surgery. Patients underwent radical surgery after a median of 14 (range: 0-40) weeks from LE. Nine underwent a low anterior resection and eight an abdominoperineal resection. At the time of radical surgery, residual disease was found in six (35%) patients (in lymph nodes in three; intramural in two; and both lymph nodes and intramural in one). Four of the patients with residual disease had undergone neoadjuvant therapy before radical surgery. The mean follow up was 110 (95% CI: 92-129) months. Recurrence-free survival at 10 years was 88%. There was no case of local recurrence, and two patients died of metastatic disease. CONCLUSION: In this series patients who underwent early radical surgery because of poor prognostic features found at LE had good overall and cancer-specific long-term survival. Even after neoadjuvant therapy, more than a third of patients had residual disease at the time of radical surgery. We therefore recommend radical surgery with neoadjuvant therapy when poor prognostic features are found at LE.

d-Cycloserine administration does not affect neurocognition in concurrent cocaine- and nicotine-dependent volunteers.

Neurocognitive impairment is a well-documented consequence of long-term, repeated cocaine exposure and has been identified as an important target of treatment. Thus, this study sought to determine whether the N-methyl-d-aspartate (NMDA) partial agonist, d-cycloserine could improve neurocognitive performance in a sample of 27 long-term, high dose cocaine dependent individuals who were not seeking treatment at the time of enrollment in the study. This double-blind, placebo-controlled study evaluated whether a single dose of 0 or 50mg of d-cycloserine would enhance performance on measures of attention/information processing speed, episodic memory, and executive/frontal lobe functioning relative to test performance at baseline. The results revealed that d-cycloserine did not modulate neurocognition in this cohort, though there are a number of factors that may have mitigated the effects of d-cycloserine in this particular study. The negative findings notwithstanding, the current study serves as a springboard for future investigations that will examine whether other medications that can modulate neurocognition in cocaine-dependent study participants.

An assessment of oral health promotion programmes in the United Kingdom.

BACKGROUND: Improving oral health and reducing tooth decay is a key area for action, both in the United Kingdom (UK) and overseas. The World Health Organization (WHO) has highlighted the unique advantage schools have in promoting oral health. AIM: We summarise current oral health promotion strategies in the United Kingdom and estimate the spread of their use as well as their impact on oral health and influence on the oral health-related knowledge and behaviour in a patient population. METHODS: A structured overview of published papers, government publications, official government websites and policy reports. A cross-sectional study of patients referred for a tooth extraction in one dental surgery in south-east London. Statistical methods consisted of logistic and ordinal regressions to model the likelihood of exposure to oral health promotion and of obtaining higher levels of knowledge of oral health issues, respectively. Linear regression was used to model the level of oral health and knowledge of oral health issues. RESULTS: We found three main promotion programmes, namely, National Healthy Schools (NHS), Sure Start and Brushing for life plus a small number of local initiatives. Sure Start targets disadvantaged areas, but is limited. In our observational study, 34% of the patients reported exposure to a settings-based oral health education programme: Sure Start (5%), NHS (7%) and other (22%). This exposure was not influenced by age or gender, but an association with education was detected. Although oral health promotion was not found to influence the actual knowledge of oral health issues, it was found to influence some oral health-related attitudes and perceptions. CONCLUSIONS: Participation in an oral health promotion programme was found to be significantly associated with the patients' education, their belief that they can prevent oral disease and the subjective perception of their own oral health. The WHO principles need to be embedded across all schools to achieve a true national oral health promotion programme for the United Kingdom. The National Healthy Schools programme provides the perfect platform.

Ten year performance evaluation of a field-scale zero-valent iron permeable reactive barrier installed to remediate trichloroethene contaminated groundwater.

The Monkstown zero-valent iron permeable reactive barrier (ZVI PRB), Europe's oldest commercially-installed ZVI PRB, had been treating trichloroethene (TCE) contaminated groundwater for about 10 years on the Nortel Network site in Northern Ireland when cores from the reactive zone were collected in December, 2006. Groundwater data from 2001-2006 indicated that TCE is still being remediated to below detection limits as the contaminated groundwater flows through the PRB. Ca and Fe carbonates, crystalline and amorphous Fe sulfides, and Fe (hydr)oxides have precipitated in the granular ZVI material in the PRB. The greatest variety of minerals is associated with a approximately 1-2 cm thick, slightly cemented crust on top (up-gradient influent entrance) of the ZVI section of the PRB and also with the discontinuous cemented ZVI material ( approximately 23 cm thick) directly below it. The greatest presence of microbial communities also occurred in the up-gradient influent portion of the PRB compared to its down-gradient effluent section, with the latter possibly due to less favorable conditions (i.e., high pH, low oxygen) for microbial growth. The ZVI filings in the down-gradient effluent section of the PRB have a projected life span of >10 years compared with ZVI filings from the continuous to discontinuous cemented up-gradient ZVI section (upper approximately 25 cm) of the PRB, which may have a life span of only approximately 2-5 more years. Supporting Information from applied, multi-tracer testing indicated that restricted groundwater flow is occurring in the upper approximately 25 cm of the ZVI section and preferential pathways have also formed in this PRB over its 10 years of operation.

Assembly and structure of alpha-helical peptide films on hydrophobic fluorocarbon surfaces.

The structure, orientation, and formation of amphiphilic alpha-helix model peptide films on fluorocarbon surfaces has been monitored with sum frequency generation (SFG) vibrational spectroscopy, near-edge x-ray absorption fine structure (NEXAFS) spectroscopy, and x-ray photoelectron spectroscopy (XPS). The alpha-helix peptide is a 14-mer of hydrophilic lysine and hydrophobic leucine residues with a hydrophobic periodicity of 3.5. This periodicity yields a rigid amphiphilic peptide with leucine and lysine side chains located on opposite sides. XPS composition analysis confirms the formation of a peptide film that covers about 75% of the surface. NEXAFS data are consistent with chemically intact adsorption of the peptides. A weak linear dichroism of the amide pi( *) is likely due to the broad distribution of amide bond orientations inherent to the alpha-helical secondary structure. SFG spectra exhibit strong peaks near 2865 and 2935 cm(-1) related to aligned leucine side chains interacting with the hydrophobic surface. Water modes near 3200 and 3400 cm(-1) indicate ordering of water molecules in the adsorbed-peptide fluorocarbon surface interfacial region. Amide I peaks observed near 1655 cm(-1) confirm that the secondary structure is preserved in the adsorbed peptide. A kinetic study of the film formation process using XPS and SFG showed rapid adsorption of the peptides followed by a longer assembly process. Peptide SFG spectra taken at the air-buffer interface showed features related to well-ordered peptide films. Moving samples through the buffer surface led to the transfer of ordered peptide films onto the substrates.

Genome-wide scan identifies novel modifier loci of acromegalic phenotypes for isolated familial somatotropinoma.

Isolated familial somatotropinoma (IFS) accounts for 18% of familial isolated pituitary adenoma (FIPA) cases. Recently, germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have been found in families with pituitary adenoma predisposition, FIPA, and IFS. In this study, we investigate the AIP mutation status and perform a genome-wide scan to search for the modifier regions of acromegalic phenotypes in an IFS family of 31 aborigines from Borneo. Complete endocrine diagnosis and data could not be collected due to logistical and cultural reasons. AIP mutation screening was carried out by direct sequencing and the genome-wide scan was performed using 400 microsatellites. Non-parametric linkage analysis was performed to obtain the logarithm of odds (LOD) scores. A novel AIP frameshift mutation in exon 4 (c.500delC) (p.P167HfsX3) was identified in all members with acromegalic features, as well as in 15 members without acromegalic features, revealing incomplete penetrance of AIP. The data showed that patients with the same mutation may express acromegalic features of differing severity, suggesting the existence of modifier genes. The highest LOD score of 2.2 was obtained near D19S571 (19q13.41). We also found weak linkages on chromosomes 3q28, 8q12.1, and 21q22.13, with LOD scores of 1.1, 1.8, and 1.4 respectively. Our results show the first genome-wide scan that identifies novel modifier loci for acromegalic phenotypes in an IFS family. Identification of modifier loci may provide further insight into the disease mechanism and explain the clinical variability observed in its patients.

Who is referred for sedation for dentistry and why?

OBJECTIVE: To assess referrals to sedation, examining dental anxiety and background of patients, and compare these characteristics to those referred to a restorative dentistry clinic. DESIGN: Descriptive, cross sectional survey. SUBJECTS AND METHODS: Subjects were 100 consecutive new patients in sedation and special care and 50 new patients in restorative dentistry at Guy's and St Thomas NHS Foundation Trust. A questionnaire included demographics, self-reported oral health and dental attendance, and dental fear. Information from the patients records was taken: ASA classification, previous sedation or general anaesthesia, alcohol and tobacco use, and medications. RESULTS: The best predictors of referral were dental anxiety level and an irregular attendance. The most important fears were seeing, hearing and feeling the vibrations of the dental drill, and the perception of an accelerated heart rate. Other factors such as general, mental and dental health and alcohol use were related to referral but less important. CONCLUSIONS: Referral is consistent with the goal of the sedation clinic to see anxious patients. Referring general practitioners are able to identify these patients.

Genotype by environment interaction for 450-day weight of Nelore cattle analyzed by reaction norm models

Genotype by environment interactions (GEI) have attracted increasing attention in tropical breeding programs because of the variety of production systems involved. In this work, we assessed GEI in 450-day adjusted weight (W450) Nelore cattle from 366 Brazilian herds by comparing traditional univariate single-environment model analysis (UM) and random regression first order reaction norm models for six environmental variables: standard deviations of herd-year (RRMw) and herd-year-season-management (RRMw-m) groups for mean W450, standard deviations of herd-year (RRMg) and herd-year-season-management (RRMg-m) groups adjusted for 365-450 days weight gain (G450) averages, and two iterative algorithms using herd-year-season-management group solution estimates from a first RRMw-m and RRMg-m analysis (RRMITw-m and RRMITg-m, respectively). The RRM results showed similar tendencies in the variance components and heritability estimates along environmental gradient. Some of the variation among RRM estimates may have been related to the precision of the predictor and to correlations between environmental variables and the likely components of the weight trait. GEI, which was assessed by estimating the genetic correlation surfaces, had values < 0.5 between extreme environments in all models. Regression analyses showed that the correlation between the expected progeny differences for UM and the corresponding differences estimated by RRM was higher in intermediate and favorable environments than in unfavorable environments (p < 0.0001).

Comprehensive characterization of the effect of tissue storage conditions on tissue-adhesive interaction.

In the evaluation of tissue adhesives, freshly harvested tissues are the most relevant to clinical application; however, it is difficult to obtain and test experimental samples immediately following surgery. The aim of the present investigation is to elucidate the effect of storage conditions on the ability of preserved tissue samples to mimic freshly harvested tissue. Porcine small intestine was used as a model tissue for the experiments. The treatment conditions were freshly harvested, 24-h aged in phosphate-buffered saline at 5 degrees C and formalin-fixed tissue. Adhesive performance of cyanoacrylate and a newly synthesized tissue adhesive on the three substrates was characterized by T-peel testing. Regardless of the adhesive used, the fresh tissue samples had the weakest bond strength. The 1-day aged tissue produced a bond that was approximately twice as strong, and the formalin-fixed intestine substrate had intermediate bond strength. Comprehensive tissue characterization using attenuated total reflection infrared (ATR-IR) spectroscopy, captive-bubble contact angle, Raman spectroscopy, bulk tissue water content measurement and histology were employed. The results from the different characterization techniques show that storage of tissue samples causes interfacial and chemical changes, limiting their ability to mimic freshly harvested tissue. In particular, the results show the importance of water detected by ATR-IR in mediating adhesion to the tissue samples.

Interprofessional education in undergraduate healthcare programmes: the reaction of student dietitians.

BACKGROUND: Interprofessional education (IPE) is a novel teaching and learning initiative where students of more than one health profession learn interactively together. However, despite its potential for improving interprofessional relationships, there is little information regarding the participation of student dietitians in IPE. The aim of this paper was to consider the reaction of student dietitians to an IPE course in order to stimulate debate between dietitians regarding the issues relating to IPE. METHODS: Student dietitians participated in an IPE course consisting of seven sessions on communication and ethics in health care together with students of medicine and nursing. Student dietitians completed an evaluation questionnaire following each session that surveyed their reaction to the session using both a Likert scale and free-text comments. RESULTS: Twenty-six student dietitians completed the IPE course. All sessions were rated positively for interest value (P < or = 0.14), learning experience (P < or = 0.036) and value for clinical practice (P < or = 0.05). The limited number of free-text comments indicated some positive experiences regarding interprofessional learning, teaching content and teaching strategy. CONCLUSIONS: This is one of very few evaluations to describe the reaction of student dietitians to IPE. Student dietitians had largely positive reactions to the IPE course. Further research is required to evaluate whether these positive reactions were a direct consequence of the inclusion of students from other health professions and whether these translate into positive effects on learning, behaviour and results. The opportunities for the dietetic profession posed by students' involvement in IPE are discussed.

Monocyte activation on polyelectrolyte multilayers.

The adherence and activation of primary human monocytes was investigated on a polyelectrolyte multilayer film containing hyaluronic acid (HA) and poly-L-lysine (PLL). The sequential layer-by-layer deposition of the multilayer film was characterized by surface plasmon resonance. Eight alternating bilayers displayed an effective thickness of 16.15 nm with a total polymer coverage of 2.10 microg/cm2. For cell studies, HA-PLL multilayers were constructed on tissue culture polystyrene (TCPS) substrates and characterized by time of flight second ion mass spectrometry (ToF-SIMS) analysis. Principal component analysis of the ToF-SIMS spectra resolved no significant difference in surface chemistry between PLL-terminated and HA-terminated multilayer surfaces. Monocyte adhesion on PLL- and HA-terminated surfaces was measured by the lactate dehydrogenase assay and showed a significant decrease in cell adhesion after 24 h incubation. Cell viability measured by Live/Dead fluorescent staining showed significant cell death in the adherent cell population over these 24 h. Tumor necrosis factor-alpha (TNF-alpha) production, a measure of monocyte activation, was quantified by ELISA and normalized to the number of adherent monocytes. The activation of monocytes on PLL-terminated and HA-terminated surfaces was nearly identical, and both surfaces had TNF-alpha levels that were 8-fold higher than TCPS. These results demonstrate that sufficient PLL had diffused into the surface layer to direct monocyte adherence and to induce cytokine activation and cell death on the HA-terminated multilayer films. The diffusion of the second multilayer component to the coating surface should, thus, be taken into account in the design of polyelectrolyte-based biomaterial coating strategies.

The rare phakomatoses.

This article outlines the clinical, central nervous system, and neuropathologic features,pathogenesis, genetics, molecular biology, and neuroimaging characteristics of the rare vascular phakomatoses, melanophakomatoses, and organoid phakomatoses.

Tumour necrosis factor and PI3-kinase control oestrogen receptor alpha protein level and its transrepression function.

Oestrogen receptor alpha (ERalpha) is an oestrogen-activated transcription factor, which regulates proliferation and differentiation of mammary epithelial cells by activating or repressing gene expression. ERalpha is a critical prognostic indicator and a therapeutic target for breast cancer. Patients with tumours that express higher level of ERalpha have better prognosis than patients with tumours that are ERalpha negative or express lower level of ERalpha. Better prognosis in ERalpha-positive patients is believed to be due to repression of proinvasive gene expression by ERalpha. Oestrogen receptor alpha represses gene expression by transrepressing the activity of the transcription factors such as nuclear factor-kappaB or by inducing the expression of transcriptional suppressors such as MTA3. In this report, we show that ERalpha transrepresses the expression of the proinvasive gene interleukin 6 (IL-6) in ERalpha-negative MDA-MB-231 breast cancer cells stably overexpressing ERalpha. Using these cells as well as ERalpha-positive MCF-7 and ZR-75-1 cells, we show that tumour necrosis factor alpha (TNFalpha) and the phosphatidylinositol-3-kinase (PI3-kinase) modulate transrepression function of ERalpha by reducing its stability. From these results, we propose that TNFalpha expression or PI3-kinase activation lead to reduced levels of ERalpha protein in cancer cells and corresponding loss of transrepression function and acquisition of an invasive phenotype.

Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide.

The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-kappaB remains sequestered in an inactive state by cytoplasmic inhibitor-of-kappaB (IkappaB) proteins. NF-kappaB translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines. We and others have shown previously that NF-kappaB is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-kappaB leads to overexpression of the anti-apoptotic genes c-inhibitor of apoptosis 2 (c-IAP2) and manganese superoxide dismutase (Mn-SOD) in breast cancer cells. Furthermore, expression of the anti-apoptotic tumor necrosis factor receptor associated factor 1 (TRAF1) and defender-against cell death (DAD-1) is regulated by NF-kappaB in certain breast cancer cells. We also demonstrate that NF-kappaB-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modified to overexpress IkappaBalpha required lower concentrations of paclitaxel to arrest at the G2/M phase of the cell cycle and undergo apoptosis when compared to parental cells. The effect of NF-kappaB on paclitaxel-sensitivity appears to be specific to cancer cells because normal fibroblasts derived from embryos lacking p65 subunit of NF-kappaB and wild type littermate embryos were insensitive to paclitaxel-induced G2/M cell cycle arrest. Parthenolide, an active ingredient of herbal remedies such as feverfew (tanacetum parthenium), mimicked the effects of IkappaBalpha by inhibiting NF-kappaB DNA binding activity and Mn-SOD expression, and increasing paclitaxel-induced apoptosis of breast cancer cells. These results suggest that active ingredients of herbs with anti-inflammatory properties may be useful in increasing the sensitivity of cancers with constitutively active NF-kappaB to chemotherapeutic drugs. Oncogene (2000) 19, 4159 - 4169

Negative regulation of transactivation function but not DNA binding of NF-kappaB and AP-1 by IkappaBbeta1 in breast cancer cells.

The transcription factor NF-kappaB regulates the expression of genes involved in cancer cell invasion, metastasis, angiogenesis, and resistance to chemotherapy. In normal cells NF-kappaB is maintained in the cytoplasm by protein-protein interaction with inhibitor IkappaBs. In contrast, in cancer cells a substantial amount of NF-kappaB is in the nucleus and constitutively activates target genes. To understand the mechanisms of constitutive NF-kappaB activation, we have analyzed the function of IkappaBalpha and IkappaBbeta in breast cancer cells. In most cases, constitutive NF-kappaB DNA binding correlated with reduced levels of either IkappaBalpha or IkappaBbeta isoforms. Overexpression of IkappaBalpha but not IkappaBbeta1 resulted in reduced constitutive DNA binding of NF-kappaB in MDA-MB-231 cells. Unexpectedly, IkappaBbeta1 overexpression moderately increased 12-O-tetradecanoylphorbol-13-acetate- and interleukin-1-inducible NF-kappaB DNA binding. 12-O-Tetradecanoylphorbol-13-acetate- and interleukin-1-induced transactivation by NF-kappaB, however, was lower in IkappaBbeta1-overexpressing cells. Mutants of IkappaBbeta1 lacking the C-terminal casein kinase II phosphorylation sites, which form a stable complex with DNA bound NF-kappaB without inhibiting its transactivation in other cell types, repressed the transactivation by NF-kappaB in MDA-MB-231 cells. Consistent with the results of transient transfections, the expression of urokinase plasminogen activator, an NF-kappaB target gene, was reduced in IkappaBbeta1-overexpressing cells. These results suggest that depending on the cell type, IkappaBbeta1 represses the expression of NF-kappaB-regulated genes by inhibiting either DNA binding or transactivation function of NF-kappaB.

Cocaine enhances monocyte migration across the blood-brain barrier. Cocaine's connection to AIDS dementia and vasculitis?

Cocaine has wide-ranging effects on the immune and neuroendocrine systems (Fiala et al., 1996) resembling an inflammatory "stress" response with upregulation of pro-inflammatory cytokines and stimulation of the HPA axis (Gan et al., 1997). Cocaine abuse has also been associated with vascular pathology, including vasculitis, vasospasm and hemorrhage. These effects suggest that cocaine could perturb the function of endothelial cells, including the blood-brain barrier, and influence the progression to AIDS in HIV-infected individuals (Shapshak et al., 1997; Goodkin et al., 1997). In order to understand clinical consequences of cocaine abuse, it is important to gain insight into molecular and cellular basis of cocaine's effects on immune and endothelial cells. Cocaine's in vitro effects on (a) permeability, (b) immune cell migration, (c) adhesion molecules, and (d) cytokine expression were investigated in a blood-brain barrier model constructed with brain microvascular endothelial cells and fetal astrocytes with the following results: (a) cocaine and tumor necrosis factor-alpha (TNF-alpha) increased the model's permeability to inulin similarly in a dose-responsive fashion; (b) cocaine (10(-4) to 10(-8_ M) enhanced monocyte migration across the barrier with the maximum increase, approximately 100%, by 10(-5) M cocaine; (c) cocaine treatment also increased the expression of endothelial adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecules-1 (VCAM-1) and platelet/endothelial cell adhesion molecule-1 (PECAM-1); (d) although the cocaine in vitro effects on cytokine production by mononuclear cells have been difficult to assess due to a heterogeneity in the degree of responsiveness between individuals, the data suggest that mononuclear cells from cocaine addicts are sensitized to in vitro cocaine challenge with hypersecretion of inflammatory cytokines. Cocaine's in vivo manifestations are compatible with these in vitro effects: (A) chronic cocaine treatment of rats significantly increased rolling white blood cell flux, leukocyte-endothelium adhesion, and ICAM-1 expression in the mesentery (House et al., 1996); (B) cocaine injection to cocaine-dependent subjects tipped the balance of cytokine secretion by mononuclear cells to Th1-type (Gan et al., 1997), and (C) cocaine injection stimulated the hypothalamic-pituitary axis (HPA) to increase both anti- and pro-inflammatory hormonal secretion. Collectively, these results suggest that the immune effects of cocaine on endothelial, immune and neuroendocrine cells impair the function of the blood-brain, barrier, increase cell emigration from the blood vessels, in particular into the brain, and may cause vasculitis. These effects could also increase importation of HIV-1 into the brain.

NF-kappaB activation and interleukin 6 production in fibroblasts by estrogen receptor-negative breast cancer cell-derived interleukin 1alpha.

Several angiogenic factors and extracellular matrix-degrading enzymes that promote invasion and metastasis of cancer are produced by stromal fibroblasts that surround cancer cells. The expression of genes that code for some of these proteins is regulated by the transcription factor NF-kappaB. In this report, we demonstrate that conditioned medium (CM) from estrogen receptor (ER)-negative but not ER-positive breast cancer cells induces NF-kappaB in fibroblasts. In contrast, CM from both ER-positive and ER-negative breast cancer cells induces NF-kappaB in macrophages and endothelial cells. NF-kappaB activation in fibroblasts was accompanied by induction of interleukin 6 (IL-6) and urokinase plasminogen activator (uPA), both of which promote angiogenesis and metastasis. A survey of cytokines known for their ability to induce NF-kappaB identified IL-1alpha as the factor responsible for NF-kappaB activation in fibroblasts. Analysis of primary breast carcinomas revealed the presence of IL-1alpha transcripts in majority of lymph node-positive breast cancers. These results along with the known role of IL-1alpha and IL-6 in osteoclast formation provide insight into the mechanism of metastasis and hypercalcemia in advanced breast cancers.