Organic solvents and Multiple Sclerosis: the doubled risk dilemma.

BACKGROUND: Compensation for industrial disease in the UK may be obtained in two ways. A State scheme includes a list of accepted associations between occupations and diseases with evidence of a causative association. Epidemiological evidence of a doubled risk in the occupation concerned is usually required. This takes no account of variation of exposures within occupations, excluding many occupations where risk is less than doubled. In such cases, compensation for a perceived industrial illness may be obtained in Civil Courts, where excessive exposures can be considered. AIMS: To show that in the Civil Courts evidence of excessive exposure may lead to compensation for diseases which are not yet compensable as Industrial Injuries in the UK and to draw attention to the association of multiple sclerosis (MS) with solvent exposure. METHODS: We report the case of an industrial spray painter, who claimed his MS had been caused by high-level exposure to organic solvents, and our examination of the epidemiological evidence submitted. RESULTS: The painter received compensation by an out-of-court settlement, despite the overall epidemiological risk in relation to solvent exposure having been shown to be less than doubled. The evidence hinged on individual risk in relation to high exposure, genetic susceptibility and demonstration of a plausible mechanism. CONCLUSIONS: High organic solvent exposure may lead to the development of MS. Those giving evidence in Court need to be able to discuss the epidemiological and toxicological issues in relation to exposure in the individual case.

Shock Ignition Laser-Plasma Interactions in Ignition-Scale Plasmas.

We use a subignition scale laser, the 30 kJ Omega, and a novel shallow-cone target to study laser-plasma interactions at the ablation-plasma density scale lengths and laser intensities anticipated for direct drive shock-ignition implosions at National Ignition Facility scale. Our results show that, under these conditions, the dominant instability is convective stimulated Raman scatter with experimental evidence of two plasmon decay (TPD) only when the density scale length is reduced. Particle-in-cell simulations indicate this is due to TPD being shifted to lower densities, removing the experimental back-scatter signature and reducing the hot-electron temperature. The experimental laser energy-coupling to hot electrons was found to be 1%-2.5%, with electron temperatures between 35 and 45 keV. Radiation-hydrodynamics simulations employing these hot-electron characteristics indicate that they should not preheat the fuel in MJ-scale shock ignition experiments.

Breastfeeding and introduction of complementary foods during infancy in relation to the risk of asthma and atopic diseases up to 10 years.

BACKGROUND: It has been hypothesized that changes in diet during early life may have contributed to the increase in childhood asthma and atopy. The long-term effect of the timing and content of infant feeding on the incidence of asthma and atopic diseases in children is unclear. OBJECTIVE: To investigate the associations between duration of breastfeeding and the timing of introduction of complementary foods during the first 6 months and parental-reported asthma, wheeze and atopic eczema up to 10 years of age. METHODS: Infant feeding practices (breastfeeding and introduction of complementary foods) of 1924 singleton children participating in the Study of Eczema and Asthma To Observe the influence of Nutrition (SEATON) birth cohort were prospectively collected up to 6 months with outcomes (wheeze, atopic eczema and asthma) being assessed at 1, 2, 5 and 10 years. Data were analysed using generalized estimating equations and discrete hazards models with adjustment for confounders. RESULTS: By 6 months, 59% and 35% of mothers had stopped exclusive and total breastfeeding, respectively. Although formula feeding was adversely associated with wheeze in the past 12 months (adjusted OR for no formula feeding: 070, 95% CI 0.50-0.97), and the introduction of biscuits/bread after 5 months of age adversely associated with atopic eczema (adjusted OR 1.34, 95% CI 1.06-1.69), these results lost their statistical significance after adjustment for multiple testing. Stratification of the results by the presence of eczema by 6 months of age and family atopic history did not substantially differ from the results of the whole study population. CONCLUSION AND CLINICAL RELEVANCE: Our results suggest that the nature of infant feeding during the first 6 months seems not to substantially influence the long-term risk of asthma and atopic diseases in children, nor in children at high risk of atopic disease because of a family history of atopic disease.

Inhibition of constitutive and cxc-chemokine-induced NF-kappaB activity potentiates ansamycin-based HSP90-inhibitor cytotoxicity in castrate-resistant prostate cancer cells.

BACKGROUND: We determined how CXC-chemokine signalling and necrosis factor-kappaB (NF-kappaB) activity affected heat-shock protein 90 (Hsp90) inhibitor (geldanamycin (GA) and 17-allylamino-demethoxygeldanamycin (17-AAG)) cytotoxicity in castrate-resistant prostate cancer (CRPC). METHODS: Geldanamycin and 17-AAG toxicity, together with the CXCR2 antagonist AZ10397767 or NF-kappaB inhibitor BAY11-7082, was assessed by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay in two CRPC lines, DU145 and PC3. Flow cytometry quantified apoptotic or necrosis profiles. Necrosis factor-kappaB activity was determined by luciferase readouts or indirectly by quantitative PCR and ELISA-based determination of CXCL8 expression. RESULTS: Geldanamycin and 17-AAG reduced PC3 and DU145 cell viability, although PC3 cells were less sensitive. Addition of AZ10397767 increased GA (e.g., PC3 IC(20): from 1.67+/-0.4 to 0.18+/-0.2 nM) and 17-AAG (PC3 IC(20): 43.7+/-7.8 to 0.64+/-1.8 nM) potency in PC3 but not DU145 cells. Similarly, BAY11-7082 increased the potency of 17-AAG in PC3 but not in DU145 cells, correlating with the elevated constitutive NF-kappaB activity in PC3 cells. AZ10397767 increased 17-AAG-induced apoptosis and necrosis and decreased NF-kappaB activity/CXCL8 expression in 17-AAG-treated PC3 cells. CONCLUSION: Ansamycin cytotoxicity is enhanced by inhibiting NF-kappaB activity and/or CXC-chemokine signalling in CRPC cells. Detecting and/or inhibiting NF-kappaB activity may aid the selection and treatment response of CRPC patients to Hsp90 inhibitors.

Asbestos: scientific developments and implications for public policy.

Asbestos is a commercial term for a group of fibrous minerals often associated with the development of pulmonary interstitial fibrosis (asbestosis), lung cancer, and malignant mesothelioma in occupationally exposed individuals. The pathogenicity of different forms of asbestos varies--long, thin amphibole fibers are most pathogenic, particularly in the induction of mesothelioma. Available data do not support the concept that low-level exposure to asbestos is a health hazard in buildings and schools. The concentration of asbestos fibers in air, type of asbestos, and size of fibers must be considered in evaluation of potential health risks.

A panel study of air pollution in subjects with heart failure: negative results in treated patients.

OBJECTIVES: To investigate preclinical adverse effects of ambient particulate air pollution and nitrogen oxides in patients with heart failure. METHODS: A cohort of 132 non-smoking patients living in Aberdeen, Scotland, with stable chronic heart failure were enrolled in a repeated-measures panel study. Patients with atrial fibrillation or pacemakers were excluded. Participants were studied for 3 days every 2 months for up to 1 year with monitoring of pollutant exposure and concurrent measurements of pathophysiological responses. Measurements included daily area concentration of particulate matter with a median aerodynamic diameter of <10 micrometres (PM(10)), particle number concentration (PNC) and nitrogen oxides; daily estimated personal concentration of particulate matter with a median aerodynamic diameter of <2.5 micrometres (PM(2.5)) and PNC exposures; and 3-day cumulative personal nitrogen dioxide (NO(2)). Concurrent meteorological data were recorded. Blood was taken at the end of each 3-day block for assays of markers of endothelial activation, inflammation and coagulation. Cardiac rhythm was monitored by ambulatory Holter monitor during the final 24 h of each block. RESULTS: The average 24 h background ambient PM(10) ranged from 7.4 to 68 microg.m(-3) and PNC from 454 to 11 283 particles.cm(-3). No associations were demonstrated between the incidence of arrhythmias, heart rate variability or haematological/biochemical measures and any variations in pollutant exposures at any lags. CONCLUSION: Assuming that low-level pollution affects the parameters measured, these findings may suggest a beneficial effect of modern cardioprotective therapy, which may modify responses to external risk factors. Widespread use of such drugs in susceptible populations may in future reduce the adverse effects of air pollution on the heart.

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer.

We sought to characterise whether dexamethasone (DEX) may enhance tumour response to docetaxel in in vitro and in vivo models of metastatic prostate cancer (CaP). In vitro experiments conducted on PC3 and human bone marrow endothelial cells (hBMECs) determined that administration of DEX (10 nM) reduced constitutive nuclear factor-kappaB (NF-kappaB) activity, decreasing interleukin (IL)-8, CXCL1 and VEGF gene expression in PC3 cells. Dexamethasone also attenuated docetaxel-induced NF-kappaB and activator protein-1 transcription and reduced docetaxel-promoted expression/secretion of IL-8 and CXCL1 in PC3 and hBMECs. Although DEX failed to enhance docetaxel cytotoxicity on PC3 cells, DEX potentiated the antiangiogenic activity of docetaxel in vitro, further reducing vessel area and vessel length in developing endothelial tubes (P<0.05). Docetaxel had a potent antiangiogenic activity in the dorsal skin flap-implanted PC3 tumours in vivo. Small blood vessel formation was further suppressed in tumours co-treated with docetaxel and DEX, substantiated by an increased average vessel diameter and segment length and a decreased number of branch points in the residual tumour vasculature (P<0.001). Our data show that DEX potentiates the antiangiogenic activity of docetaxel, suggesting a putative mechanism for the palliative and survival benefits of these agents in metastatic CaP.

Mineral dust exposure in young Indian adults: an effect on lung growth?

BACKGROUND/OBJECTIVE: Long-term occupational exposure to mineral dusts including quartz is known to cause pneumoconiosis but little is known about the effects of such exposure during the period of lung development in childhood. The objective of this study was to investigate the effects on young people of exposure to mineral dusts. METHODS: We carried out a cross-sectional study of a group of 81 Indian stone crushers (average age 21) and a control group of 72 nearby slum dwellers (average age 21) in order to assess dust exposures, respiratory symptoms and lung function. RESULTS: Stone crushers' corrected 8-hour time weighted average concentrations of total inhalable dust, respirable dust and respirable crystalline silica were 143 mg/m(3), 39.7 mg/m(3) and 2.29 mg/m(3) respectively, which are 14, 10 and 23 times the UK workplace exposure limits, respectively. Both groups also had high exposures to outdoor and general domestic particulate matter. Compared to controls, stone crushers had significantly more symptoms, lower levels of forced vital capacity (FVC) and forced expiratory time (FET) and higher levels of forced expiratory volume in one second (FEV(1))/FVC ratio and mid-expiratory flow rate (MEF). There were no differences in FEV(1) levels. Symptoms and lung function were not associated with time lived on site or time spent in job. A selection of chest radiographs showed no silicosis by International Labour Office (ILO) criteria. CONCLUSION: Individuals exposed to mixed mineral dust in childhood and early adult life had excess symptoms and reduced vital capacity without airflow obstruction compared with control subjects. We interpret this as evidence of stunting of lung growth caused by exposure to respirable dust.

Exposure to particulate matter on an Indian stone-crushing site.

BACKGROUND/OBJECTIVES: A large number of labourers work in the stone-crushing industry in India. Many of these workers are also exposed to high levels of particulate matter in their homes from the use of biomass fuels. As part of our investigations to examine the health of these workers we characterised their exposure to respirable crystalline silica and a number of other particulate matter exposure metrics in both occupational and domestic settings. METHODS: We used a combination of direct reading and gravimetric sampling of respirable dust, total inhalable dust and particulate matter <2.5 mum in diameter (PM(2.5)) at work (n = 19), within the general environment (n = 6) and inside the home (n = 7). We used x-ray diffraction to quantify the level of crystalline silica in the respirable dust samples. RESULTS: After correcting for the length of the working week, the arithmetic mean 8-hour time-weighted average (TWA) total inhalable dust exposure for this group was 143 mg/m(3), the mean 8-hour TWA respirable dust exposure was 39.7 mg/m(3) and the 8-hour TWA crystalline silica exposure was 2.29 mg/m(3). Our real-time data showed peaks in exposure under certain environmental and/or working conditions. General environmental and domestic PM(2.5) exposures were also high. CONCLUSIONS: Particulate matter exposures experienced by this group of workers and their families are likely to produce impaired lung function within a short time-frame. There is a need to introduce simple measures to reduce particulate matter exposure from both occupational sources and the use of biomass fuels in homes on this and similar sites.

Lung mechanics and frequency dependence of compliance in coal miners.

The mechanical properties of the lungs were studied in two groups of coal miners. The first group consisted of miners with either simple or no pneumoconiosis and was divided into two subgroups (1A and 1B). The former (1A) consisted of 62 miners most of whom had simple pneumoconiosis but a few of whom had clear films. Although their spirometry was normal, all claimed to have respiratory symptoms. The other subgroup (1B) consisted of 25 working miners with definite radiographic evidence of simple pneumoconiosis but normal spirometric findings. The second major group consisted of 25 men with complicated pneumoconiosis. In subjects with simple pneumoconiosis, static compliance was mostly in the normal range, whereas it was often reduced in subjects with the complicated disease. The coefficient of retraction was normal or reduced in most subjects except those with advanced complicated disease, in several of whom it was elevated. So far as simple pneumoconiosis was concerned, abnormalities, when present, reflected "emphysema" rather than fibrosis. In severe complicated pneumoconiosis, changes suggesting fibrosis tended to predominate. In the 25 working miners (subgroup 1B) dynamic compliance was measured at different respiratory rates. 17 of the subjects in this subgroup demonstrated frequency dependence of their compliance, a finding unrelated to bronchitis and suggestive of increased resistance to flow in the smallest airways.

Environmental risk factors for Parkinson's disease and parkinsonism: the Geoparkinson study.

OBJECTIVE: To investigate the associations between Parkinson's disease and other degenerative parkinsonian syndromes and environmental factors in five European countries. METHODS: A case-control study of 959 prevalent cases of parkinsonism (767 with Parkinson's disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Cases were defined using the United Kingdom Parkinson's Disease Society Brain Bank criteria, and those with drug-induced or vascular parkinsonism or dementia were excluded. Subjects completed an interviewer-administered questionnaire about lifetime occupational and hobby exposure to solvents, pesticides, iron, copper and manganese. Lifetime and average annual exposures were estimated blind to disease status using a job-exposure matrix modified by subjective exposure modelling. Results were analysed using multiple logistic regression, adjusting for age, sex, country, tobacco use, ever knocked unconscious and family history of Parkinson's disease. RESULTS: Adjusted logistic regression analyses showed significantly increased odds ratios for Parkinson's disease/parkinsonism with an exposure-response relationship for pesticides (low vs no exposure, odds ratio (OR) = 1.13, 95% CI 0.82 to 1.57, high vs no exposure, OR = 1.41, 95% CI 1.06 to 1.88) and ever knocked unconscious (once vs never, OR = 1.35, 95% CI 1.09 to 1.68, more than once vs never, OR = 2.53, 95% CI 1.78 to 3.59). Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson's disease showed significantly increased odds ratios. Tobacco use was protective (OR = 0.50, 95% CI 0.42 to 0.60). Analyses confined to subjects with Parkinson's disease gave similar results. CONCLUSIONS: The association of pesticide exposure with Parkinson's disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk.

Gene-environment interactions in parkinsonism and Parkinson's disease: the Geoparkinson study.

OBJECTIVES: To investigate associations of Parkinson's disease (PD) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene-environment interaction effects that modify risk. METHODS: A case-control study of 959 prevalent cases of parkinsonism (767 with PD) and 1989 controls across five European centres. Occupational hygienists estimated the average annual intensity of exposure to solvents, pesticides and metals, (iron, copper, manganese), blind to disease status. CYP2D6, PON1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, CYP1B1, MAO-A, MAO-B, SOD 2, EPHX, DAT1, DRD2 and NAT2 were genotyped. Results were analysed using multiple logistic regression adjusting for key confounders. RESULTS: There was a modest but significant association between MAO-A polymorphism in males and disease risk (G vs T, OR 1.30, 95% CI 1.02 to 1.66, adjusted). The majority of gene-environment analyses did not show significant interaction effects. There were possible interaction effects between GSTM1 null genotype and solvent exposure (which were stronger when limited to PD cases only). CONCLUSIONS: Many small studies have reported associations between genetic polymorphisms and PD. Fewer have examined gene-environment interactions. This large study was sufficiently powered to examine these aspects. GSTM1 null subjects heavily exposed to solvents appear to be at increased risk of PD. There was insufficient evidence that the other gene-environment combinations investigated modified disease risk, suggesting they contribute little to the burden of PD.

Death in the New Town: Edinburgh's hidden story of stonemasons' silicosis.

The building of the Edinburgh New Town, from the mid-18th to the mid-19th centuries, was a major advance in harmonious and elegant town planning. However, there is anecdotal evidence that it led to the occurrence of an epidemic of silicosis/tuberculosis among the stonemasons. We have reviewed contemporary accounts of the episode and early records of the understanding of silicosis. We have also studied the lung of a contemporary stonemason, preserved in the museum of the Royal College of Surgeons of Edinburgh, and confirmed the presence of silico-tuberculosis in it. The evidence shows that a major epidemic did occur, caused by a combination of factors. The size of the undertaking attracted many stonemasons to Edinburgh over a period of almost 100 years, intensively cutting and dressing stone. The principal stone worked was a very high-quartz sandstone, derived from the local Craigleith quarry, having properties that made it desirable for prestige buildings. However, even before the construction of the New Town, Craigleith sandstone was notorious for its dustiness and the Edinburgh stonemasons worked the stone in unventilated sheds. Stonemasons appeared to be aware of the risk of their trade, but little was known about preventive measures. It appears it was assumed that the risks to stonemasons disappeared after the Craigleith quarry closed, the employers emphasising (without evidence) the lack of health risks in other quarries, and the tragic episode appears to have been forgotten. However, we point to the continuing occurrence of silicosis among stonemasons to the present day; the importance of remembering such episodes is stressed lest the lessons of the past be forgotten.

Transplantation to the diseased and damaged retina.

Retinas of Royal College of Surgeons (RCS) dystrophic rats undergo a dramatic loss of photoreceptor cells as a result of defective retinal pigment epithelial (RPE) cells. These retinas are therefore a valuable model in the investigation of the role of the RPE on photoreceptor-cell survival and development. Also, rat retinas damaged by excessive light serve as a suitable environment to study survival of transplanted photoreceptor cells. Even though photoreceptor cells are lost in these retinas, a normal inner retinal structure is retained. Both models have recently been used in successful RPE-cell and/or photoreceptor-cell transplantation studies designed to replace defective or lost cells due to retinal disease or damage. These new approaches in the field of retinal transplantation offer unique and novel opportunities for the development of possible therapeutic strategies in human eye disease, and for improving our understanding of the normal relationships between retinal cells.

The London Underground: dust and hazards to health.

AIMS: To assess hazards associated with exposure to dust in the London Underground railway and to provide an informed opinion on the risks to workers and the travelling public of exposure to tunnel dust. METHODS: Concentrations of dust, as mass (PM2.5) and particle number, were measured at different underground stations and in train cabs; its size and composition were analysed; likely maximal exposures of staff and passengers were estimated; and in vitro toxicological testing of sample dusts in comparison with other dusts was performed. RESULTS: Concentrations on station platforms were 270-480 microg/m3 PM2.5 and 14,000-29,000 particles/cm3. Cab concentrations over a shift averaged 130-200 microg/m3 and 17,000-23,000 particles/cm3. The dust comprised by mass approximately 67% iron oxide, 1-2% quartz, and traces of other metals, the residue being volatile matter. The finest particles are drawn underground from the surface while the coarser dust is generated by interaction of brakes, wheels, and rails. Taking account of durations of exposure, drivers and station staff would have maximum exposures of about 200 microg/m3 over eight hours; the occupational exposure standard for welding fume, as iron oxide, is 5 mg/m3 over an eight hour shift. Toxicology showed the dust to have cytotoxic and inflammatory potential at high doses, consistent with its composition largely of iron oxide. DISCUSSION: It is unjustifiable to compare PM2.5 exposure underground with that on the surface, since the adverse effects of iron oxide and combustion generated particles differ. Concentrations of ultrafine particles are lower and of coarser (PM2.5) particles higher underground than on the surface. The concentrations underground are well below allowable workplace concentrations for iron oxide and unlikely to represent a significant cumulative risk to the health of workers or commuters.

Can we reduce the risk of dementia?

Public health and therapeutic measures to reduce cardiac and stroke risk may already be reducing risks of dementia in populations. In routine clinical care, dementia risk could be further reduced by optimized management of delirium, depressive disorders, traumatic brain injury and stroke. These are opportunities to minimize risk of progression to dementia during acute care and subsequent rehabilitation. Although interventions to protect against progress to dementia may be of small effect in each clinical situation, awareness of dementia risk and appropriate steps to reduce that risk should contribute to an overall reduction in the incidence of dementia.

An application of the United Kingdom Working Party diagnostic criteria for atopic dermatitis in Scottish infants.

The United Kingdom Working Party diagnostic criteria for atopic dermatitis have been characterized in infants and children; however, the need for visual confirmation of flexural dermatitis by a trained investigator limits their use in large epidemiologic studies. We have administered the complete United Kingdom Working Party criteria in a postal questionnaire format to the mothers of year old infants and determined the concordance between mothers' and trained investigator's reports of visual flexural dermatitis. Based on mothers' responses to the questionnaire, 59 infants with atopic dermatitis and 59 controls were identified. In subsequent home interviews conducted by a trained investigator, the United Kingdom criteria questions were repeated and sites of current visible dermatitis were identified by mothers and the investigator as per United Kingdom Working Party protocol. Agreement between the mothers' postal and home interview responses was high: kappa= 0.75-0.94 for individual criteria; kappa= 0.93 for diagnosed atopic dermatitis. Agreement between the mothers' and investigator's observations of visible flexural dermatitis was high for all sites: kappa= 0.88-1.0. The results demonstrate that mothers are able to apply the United Kingdom criteria and accurately report visible flexural dermatitis in their year old infants. The postal application of the United Kingdom Working Party's diagnostic criteria for atopic dermatitis in year old infants appears to be a practical, reliable, epidemiologic tool in the investigation of atopic dermatitis with results comparable with formal application of the criteria by a trained investigator.

Mechanistic and anti-proliferative studies of two novel, biologically active bis-benzimidazoles.

We have previously synthesised a number of novel head-to-head bis-benzimidazole derivatives that are structurally related to the fluorochrome, Hoechst 33258, and which possess strong affinity for A:T sites in the minor groove of duplex DNA. Initial studies revealed these compounds to exhibit potent antiproliferative activity against a range of ovarian cell lines and to inhibit transcription in an in vitro setting. In this study, we have examined their cellular behaviour in detail and have shown that two of these compounds (ABA13 and ABA833) potently inhibit the proliferation of a range of human tumour cell lines, and show some specificity towards breast carcinoma cell lines. In most of the cell lines investigated, ABA833 was the more potent of the two compounds. Flow cytometric analysis revealed that ABA13 and ABA833 (50-500 nM) induced an S phase block and increased the pre-G1 population in MCF-7 and MDA 468 human breast cancer cells. An increase in the pre-G1 population of RKO colon carcinoma cells was seen only at 500 nM with ABA833, reflecting the reduced sensitivity of this cell line to the bis-benzimidazoles in comparison to the breast cancer cell lines. Mechanistic studies revealed that neither ABA13 or ABA833 act as topoisomerase I (topo I) or topoisomerase II (topo II) poisons in plasmid or kinetoplast DNA (kDNA) relaxation assays, but both compounds do inhibit the catalytic activity of these enzymes. Drug uptake studies showed that reduced sensitivity of MCF-7adr and RKO cells compared with MCF-7 to both ABA13 and ABA833 correlated with a markedly reduced intracellular drug accumulation.

Structural studies on bioactive compounds. 32. Oxidation of tyrphostin protein tyrosine kinase inhibitors with hypervalent iodine reagents.

Hydroxylated styrenes (tyrphostins) undergo oxidation by hypervalent iodine oxidants such as [(diacetoxy)iodo]benzene (DAIB) to give a range of products depending on the structure of the phenolic substrate, the solvent, the oxidant stoichiometry, and the purification strategy. Conditions have been developed to modify the phenolic component of the tyrphostin without affecting the appended substituted-vinyl moiety. Novel products include: unstable 2-acyloxy-2-methoxy-4-(substituted-vinyl)cyclohexadienones and their rearrangement products 2-acyloxy-4-hydroxy-3-methoxy-1-(substituted-vinyl)benzenes; phenyliodoniophenolates and their rearrangement products iodophenoxytyrphostins; and 3,3'-dialkoxy-2,2'-dihydroxy-5, 5'-di(substituted-vinyl)biphenyls. None of these oxidation products displayed enhanced activity in vitro in the NCI 60-cell line panel or in a panel of human breast cancer cell lines, compared to their tyrphostin precursors. The inhibitory activity of three representative tyrphostins (3e,n, 28) was not modulated by aerobic/anaerobic conditions in MCF-7 and MDA 468 cells and was independent of EGFR status in clones of ZR75B cells transfected with this receptor. Basal growth of MCF-7 cells was unaffected by co-administration of the growth factors EGF, TGF-alpha, IGF-I, and IGF-II, and the new agents did not inhibit EGFR and c-erbB2 autophosphorylation in cell lysates from MDA 468 or SkBr3 cells, respectively, suggesting that receptor tyrosine kinases are not targets for these compounds. Growth stimulation by the tyrphostin 3n in the ER(+) breast cell lines MCF-7, T47D, and ZR75-1 was abolished by 1 microM tamoxifen, suggesting that this compound has estrogen agonist activity.

RPE transplants stabilize retinal vasculature and prevent neovascularization in the RCS rat.

Previous reports indicate that in the Royal College of Surgeons (RCS) rat a decline in the retinal vessel density accompanies the loss of the normal architecture of the deep bed. This begins at about three months with neovascularization that originates in the deep vessel bed and develops in the direction of the retinal pigment epithelial (RPE) cells by four months. A surgical technique has been developed recently for the transplantation of healthy RPE cells into the subretinal space of the RCS rat, resulting in the rescue of photoreceptor cells. This permits evaluation of the possibility that such transplants also protect the retinal vessels. We report for the first time: (1) the stabilization of the normal retinal vasculature by maintenance of the density and architecture of the deep vessel bed; and (2) prevention of neovascularization of the RPE by the surgical transplantation of healthy RPE cells into the subretinal space of the RCS rat. More specifically, we show a maintenance of the deep vessel bed density under the transplant in contrast to a significant reduction in the vessel density that had taken place in corresponding areas in nongrafted and sham injected controls at four months of age. The vessel density in the transplanted group is statistically different from the nongrafted and the sham injected groups. We also report a significant decline in the number of neovascularization profiles around the transplant site of the RPE-grafted RCS retina. We also note that the pathological changes in the vasculature of the RCS rat occur in a predictable central to peripheral gradient.