Trans-crustal structural control of CO2-rich extensional magmatic systems revealed at Mount Erebus Antarctica.

Erebus volcano, Antarctica, with its persistent phonolite lava lake, is a classic example of an evolved, CO2-rich rift volcano. Seismic studies provide limited images of the magmatic system. Here we show using magnetotelluric data that a steep, melt-related conduit of low electrical resistivity originating in the upper mantle undergoes pronounced lateral re-orientation in the deep crust before reaching shallower magmatic storage and the summit lava lake. The lateral turn represents a structural fault-valve controlling episodic flow of magma and CO2 vapour, which replenish and heat the high level phonolite differentiation zone. This magmatic valve lies within an inferred, east-west structural trend forming part of an accommodation zone across the southern termination of the Terror Rift, providing a dilatant magma pathway. Unlike H2O-rich subduction arc volcanoes, CO2-dominated Erebus geophysically shows continuous magmatic structure to shallow crustal depths of < 1 km, as the melt does not experience decompression-related volatile supersaturation and viscous stalling.

Modelled evaluation of multi-component meningococcal vaccine (Bexsero®) for the prevention of invasive meningococcal disease in infants and adolescents in the UK.

Neisseria meningitidis is the main cause of bacterial meningitis and sepsis in the UK, and can potentially be lethal or cause long-term sequelae. Bexsero® (4CMenB) is a new multi-component vaccine approved by the European Commission for use in individuals aged ⩾2 months. A theoretical transmission model was constructed to assess the long-term effectiveness of Bexsero compared to standard care. The model was populated with UK-specific demographic data and calibrated to ensure that the transmission dynamics of meningococcal disease in the UK were adequately simulated. The model showed the best strategy to be a routine vaccination programme at ages 2, 3, 4, 12 months and 14 years combined with a 5-year catch-up programme in toddlers aged 12-24 months and adolescents aged 15-18 years. This would lead to a 94% reduction in meningococcal cases or 150 000 cases and 15 000 deaths over a 100-year time-frame.

A randomized targeted amino acid therapy with behaviourally at-risk adopted children.

BACKGROUND: Increasing numbers of children are at-risk for behavioural and emotional disorders, a phenomenon contributing to increased use of pharmacological interventions for paediatric clients. Adverse side effects and other risks associated with pharmacological approaches have helped fuel interest in nutritional interventions for behaviourally at-risk children. METHODS: The current randomized clinical trial evaluates the efficacy of a neurochemical intervention involving the glutamine and glutamate analogue L-theanine and 5-hydroxytryptophan, the precursor for serotonin, with children adopted from traumatic backgrounds. RESULTS: Results include significant increases in urinary levels of the biomarkers for serotonin and gamma-aminobutyric acid, coupled with significant decreases in parent reports of the children's behaviour problems. CONCLUSIONS: While further research is needed, these initial findings are encouraging and are consistent with a growing number of studies indicating the efficacy of nutritional approaches to help behaviourally at-risk children.

Four-way test of mortality: a useful tool for cancer education.

The use of a four-way test for the study of adverse outcomes in cancer, such as mortality and relapse, is described. This test facilitates a rapid, structured examination of patients' records that has been useful for teaching about the actual and apparent causes of treatment failure, and thus useful for teaching about how to achieve the best possible outcome for every patient. In this test, four questions are asked about factors identified: Was there evidence of 1) understaging, and/or 2) undertreatment, and/or 3) other factors, and/or 4) other causes? The use of the four-way test is illustrated by a review of 41 consecutive patients with Stage I colorectal cancer, 18 of whom had died at the time the study was conducted. One or more findings that contributed to either actual or apparent treatment failure were readily identified with the four-way test in 17 of the 18 fatal cases.

UVA, pheomelanin and the carcinogenesis of melanoma.

Cloudman S91 mouse melanoma cells vary in constitutive and inducible melanin levels. Survival, mutation induction and DNA damage were quantitated after exposure to UVB, UVA and FS20 lamps. Assuming that the observed differences are related to melanin, induced pigment is photo-protective for survival and mutation after UVB and FS20 exposure, and is photosensitizing for survival after UVA exposure. No changes in pyrimidine dimers could be measured. DNA damage in pigmented mouse melanocytes (melan-a and melan-b) was greater than that in albino melanocytes (melan-c) after UVB and FS20, and the pigmented cells were more sensitive to killing. Pigment appears to be protective for killing by UVA in these melanocytes. Human melanocytes from different skin types vary in both melanin amount and composition (eu- and pheomelanin). Effects of pigmentation on UVB responses are unclear. In UVA, heavily pigmented cells have more DNA damage than lightly pigmented cells, but are resistant to killing. Increased pheomelanin photosensitizes DNA damage in lightly pigmented cells. Since eumelanin predominates in the mouse melanoma cells and melanocytes, they are less likely than human cells to provide a satisfactory model for human solar melanomagenesis. In order to understand the mechanism of photocarcinogenesis of melanoma, melanins in human melanocytes from different pigment types should be carefully quantitated and characterized. Mutations induced in them by solar wavelength-emitting lamps with well-characterized spectra should be measured, and mutant DNA should be sequenced to determine the nature of the solar-induced lesions. Research should focus on UVA and pheomelanin.

Therapeutic resistance: characterization and inactivation by specific antiserum of a putative protein family produced by tumour cells.

A multitherapy resistance (MTR) factor produced by Cloudman S91 mouse melanoma cells rescues a responsive cell line after gamma-irradiation, short wavelength ultraviolet light, mitomycin C, vinblastine and actinomycin D. A similar activity with respect to ionizing radiation is now shown to be produced by human melanoma cells and by both human and mouse breast cancer cells but not by five normal cell lines. In these studies, the factor produced in serum-free conditioned medium (SFCM) by Cloudman S91/I3 cells is further characterized. Its activity in a clonogenic assay using related Cloudman S91/amel cells is destroyed by trypsin but not by DNase and is stable for at least 8 days at a variety of temperatures including 37 degrees C. Molecules greater than 30 kDa from SFCM collected from S91/I3 cells were concentrated and separated by preparative zonal electrophoresis (PZE). Bioactivity was present in both the cathode- and the anode-running fractions. The active acidic (anode) fractions were analysed by preparative isoelectric focusing. Bioactivity was present between pI 3.5 and 4.2. These PZE fractions were also used to immunize two rabbits, both of which produced antiserum that abrogated the bioactivity of SFCM and of the PZE cathode fractions. Antiserum also decreased the survival of irradiated S91/I3 producer cells that do not respond to SFCM but nonetheless must require MTR proteins for the expression of radiation resistance. These studies present a model for the production of rescue factors by non-clonogenic tumour cells that may persist in some tumours for considerable periods of time.

Survival of Cloudman mouse melanoma cells after irradiation by solar wavelengths of light.

A number of variants of Cloudman S91 mouse melanoma cells that differ with respect to the amount of pigment produced are available for study. In this report, we compare the photobiological responses of S91/amel, which contains about 1 pg of melanin per cell, with S91/I3, which contains about 3 pg/cell. Earlier studies had shown that UVC induced more oxidative damage (in the form of thymine glycols) in cell line S91/I3 than in S91/amel and that cell line S91/amel was more resistant to killing by UVC than S91/I3. The present study finds that S91/amel cells are also relatively resistant to killing by near monochromatic UVB from a Philips TL01 fluorescent lamp and by near monochromatic UVA from a Philips HPW125 lamp. However, when the cells are irradiated with a Westinghouse FS20 polychromatic lamp, the S91/I3 cells are more resistant than the S91/amel cells. These findings cannot be explained on the basis of pigment induction because in S91/I3 this is about the same after UVB and FS20, although the maximum is reached earlier after UVB. Nor can our findings be explained on the basis of pyrimidine dimer formation, which is comparable in the two cell lines regardless of the type of irradiation. These results suggest that, with a pigment such as melanin, which absorbs light across the visible and ultraviolet ranges of the spectrum, cellular responses to monochromatic light do not necessarily predict responses to polychromatic mixtures.

Comparative action spectrum for ultraviolet light killing of mouse melanocytes from different genetic coat color backgrounds.

The photobiology of mouse melanocyte lines with different pigment genotypes was studied by measuring colony-forming ability after irradiation. The cell lines were wild-type black (melan-a) and the mutants brown (melan-b) and albino (melan-c). Four lamps emitting various UV wavelengths were used. These were germicidal (UVC, 200-280 nm), 82.3% output at 254 nm, TL01 (UVB, 280-320 nm), 64.2% at 310-311 nm, FS20, broadband with peak output at 312 nm and Alisun-S (UVA, 320-400 nm), broadband with peak output at 350-354 nm. Appropriate filtration reduced the contaminating UVC to nonlethal levels for the longer waverange lamps. Wild-type melan-a was resistant to UVC and UVA compared to the other two cell lines, but the differences were small. The melan-c cell line was more resistant to UVB and markedly more resistant to FS20 than the pigmented lines. With the exception of FS20 responses, melan-b was more sensitive than melan-a to killing by the various UV lamps. There were more pyrimidine dimers (cyclobutane dimers and 6-4 photoproducts) produced in melan-a than in melan-c cells by UVC, UVB and FS20 lamps. Unlike melan-c, melan-a and melan-b showed a strong free radical signal of melanin character with a detectable contribution of pheomelanin-like centers. The contribution of pheomelanin was higher in melan-b than in melan-a, while the total melanin content in these two cell lines was comparable. The abundant melanin granules of wild-type melan-a melanocytes were well melanized and ellipsoidal, whereas those of melan-b melanocytes tended to be spherical. In the albino line (melan-c) the melanocytes contained only early-stage melanosomes, all of which were devoid of melanin. The results indicate that pigment does not protect against direct effect DNA damage in the form of pyrimidine dimers nor does it necessarily protect against cell death. High pigment content is not very protective against killing by UVC and UVA, and it may photosensitize in UVB the very wavelength range that is of greatest concern with respect to the rising incidence in skin cancer, especially melanoma. It is clear from these studies that, in pigment cells, monochromatic results cannot predict polychromatic responses and that cell death from solar irradiations is a complex phenomenon that depends on more than DNA damage.

Breast cancer in the inner city: intensive efforts may be succeeding.

Breast cancer is a significant problem in a 518 bed government supported university hospital in New Jersey's largest city. The following records were reviewed: tumor registry abstracts of the 367 analytic breast cancer patients admitted from 1/1/91 to 12/31/92; the 455 participants in the Breast Cancer Detection Awareness Program (BCDAP) from 1987 to 1992; and the 460 breast biopsies performed from 1990 to 1992. Breast cancer is less common at this inner city hospital than in the U.S. in general; the stage is more advanced at presentation than in the U.S. overall; and the overall survival is only 54% at five years. Approximately 40% of the patients were African-American women from the inner city. Their median age was 53, seven years younger than the median age for diagnosis in the U.S. overall, and their five year survival was only 46%. Intensive efforts have recently produced improvement in the proportion of cases diagnosed at early stages (T0 and T1), but a decrease in mortality has not yet been seen.

Growth and pigmentation in genetically related Cloudman S91 melanoma cell lines treated with 3-isobutyl-1-methyl-xanthine and beta-melanocyte-stimulating hormone.

4 clonal sublines of Cloudman S91 melanoma cells, S91/mel, S91/I3, S91/6 and S91/amel, were evaluated for changes in growth, pigment content and plating efficiency during and after treatment with a cyclic-AMP phosphodiesterase inhibitor-melanin-stimulating agent, 3-isobutyl-1-methyl-xanthine (IBMX) plus beta-melanocyte stimulating hormone (beta-MSH) or IBMX alone. After combined treatment, increases in melanin content on day 3 were 48, 27, 11, and 2 pg/cell in the four cell lines respectively. In each case IBMX alone was less effective than IBMX plus beta-MSH. Doubling time increased and plating efficiency decreased with increased melanization. The increases in doubling time and decreases in plating efficiency were cell line dependent. The greatest rate of increase in doubling time and decrease in plating efficiency as a function of melanin content were seen in S91/amel, which produced the least pigment. The lowest rates of increase/decrease were seen in S91/mel, which produced the most pigment. Melanin pigment induced in the cells was classified as eumelanin by EPR determination. The differential response to induction of pigmentation makes these cell lines suitable models for comparative studies on the role of melanin in pigment cell biology.

A multitherapy resistance factor from melanoma reveals that killing by near UV is different from genotoxic agents.

A diffusible multitherapy resistance factor (MTRF) is produced by Cloudman S91 melanoma cells in vitro. The MTRF decreases sensitivity of the target cell line, S91/amel, to gamma-irradiation, UVC (200-280 nm) and mitomycin C (MMC). In the present study, we demonstrate that MTRF also increases the survival of S91/amel after exposure to actinomycin D (AMD) and vinblastine (VBL). The MTRF is thus effective when target cells have been exposed to five genotoxic agents that act by different mechanisms. It does not alter the response to the same five agents of the S91/I3 producer cells, which are presumably saturated with the factor. The factor has no effect on the survival of S91/amel cells that have been exposed to lethal doses of near monochromatic UVB (280-320 nm) or UVA (320-400 nm) or to polychromatic FS20 lamps. The lack of effectiveness of MTRF after cells have been exposed to near (300-400 nm) UV radiation indicates that in this wavelength range, S91 melanoma cells are killed by mechanisms that are different from the lethal effects of the five genotoxic agents (gamma-irradiation, UVC, MMC, AMD and VBL) to which the target cells demonstrate a response.

Professor Kaposi's original concepts of Kaposi's sarcoma.

Kaposi's sarcoma has been identified since 1981 as one of the original disorders that defined AIDS and the AIDS epidemic. The authors provide biographical information about Kaposi, followed by a new English translation of a description by Kaposi in German of the sarcoma that bears his name.

Inheritance law in an aging society.

An exploratory analysis of states' inheritance law changes between 1961 and 1990 was conducted in order to discern major trends and their implications for older families. Results suggested that states were modifying their laws in ways similar to suggestions of the law community's Uniform Probate Code, with about one third of the states adopting the Code itself. Consequently, inheritance law has become less traditional and paternalistic and more like "facilitative law," that is, flexible, accommodating, and supportive of family autonomy and decisionmaking authority. These changes and new laws that simplify procedures, protect the dependent and vulnerable, treat marital property more like community property, recognize variant family forms, and enable extrafamilial bequests, may serve to minimize family disruption, conserve resources, and allow families to tailor property divisions and procedures to particular needs and wishes. An impact study is proposed for disclosing the actual effects on inheritance law reforms. Also, while trends observed in this study were fairly evident, states' adoption of new laws was uneven and selective, inviting continuing trend analyses and further research into the reasons for interstate variation.

Influence of an autocrine multitherapy resistance factor on radiation responses of melanoma cells.

An autocrine multitherapy resistance factor (MTRF) produced by a radioresistant subclone of S91 mouse melanoma (S91/I3) causes an increase in radioresistance of a radiosensitive subclone (S91/amel). MTRF has no effect on the survival of S91/I3, which is already relatively resistant to gamma-irradiation. In this study, we examined the effect of MTRF in the form of S91/I3 conditioned medium or as S91/I3 heavily-irradiated cells (I3-HRCells) on cellular responses of S91/amel cells after exposure to gamma-rays. Target S91/amel cells retained more than half of their ability to respond to rescue by MTRF on day 4 after exposure to 3 Gy. Continuous presence of MTRF during colony formation was necessary for maximum plating efficiency. Although the extent of double strand DNA breakage and repair was the same in S91/amel and S91/I3, split-dose recovery experiments with MTRF revealed previously undetected repair of sublethal damage in S91/amel cells. MTRF did not alter the extent of potentially lethal damage repair (PLDR) in S91/I3 or S91/amel. S91/amel cells were more responsive to MTRF if they had been harvested from confluent dishes, while S91/I3 cells produced a more effective factor if they had been harvested in exponential phase. These findings demonstrate that MTRF has unique properties. It does not appear to be involved in genome repair since it does not alter the extent of PLDR and it is effective when added to cells after complete split-dose recovery has occurred.