Physiological and ecological performance differs in four coral taxa at a volcanic carbon dioxide seep.

Around volcanic carbon dioxide (CO2) seeps in Papua New Guinea, partial pressures of CO2 (pCO2) approximate those as predicted for the end of this century, and coral communities have low diversity and low structural complexity. To assess the mechanisms for such community shifts in response to ocean acidification, we examined the physiological performance of two hard corals that occur with increased or unaltered abundance at a seep site (mean pHTotal=7.8, pCO2=862 µatm) compared to a control site (mean pHTotal=8.1, pCO2=323 µatm), namely massive Porites spp. and Pocillopora damicornis, and two species with reduced abundance, Acropora millepora and Seriatopora hystrix. Oxygen fluxes, calcification, and skeletal densities were analyzed in corals originating from the seep and control site. Net photosynthesis rates increased considerably in Porites spp. and A. millepora and slightly in P. damicornis at increased pCO2, but remained unaltered in S. hystrix. Dark respiration rates remained constant in all corals investigated from both sites. Rates of light calcification declined in S. hystrix at high pCO2, but were unaffected by pCO2 in the other three coral taxa. Dark and net calcification rates remained unchanged in massive Porites and P. damicornis, but were drastically reduced at high pCO2 in A. millepora and S. hystrix. However, skeletal densities were similar at both seep and control sites in all coral taxa investigated. Our data suggest that the pCO2-tolerant corals were characterized by an increased ability to acclimatize to ocean acidification, e.g. by maintaining net calcification. Thus, robust corals, such as Porites spp. and P. damicornis, are more likely to persist for longer in a future high pCO2 world than those unable to acclimatize.

Ecological effects of ocean acidification and habitat complexity on reef-associated macroinvertebrate communities.

The ecological effects of ocean acidification (OA) from rising atmospheric carbon dioxide (CO2) on benthic marine communities are largely unknown. We investigated in situ the consequences of long-term exposure to high CO2 on coral-reef-associated macroinvertebrate communities around three shallow volcanic CO2 seeps in Papua New Guinea. The densities of many groups and the number of taxa (classes and phyla) of macroinvertebrates were significantly reduced at elevated CO2 (425-1100 µatm) compared with control sites. However, sensitivities of some groups, including decapod crustaceans, ascidians and several echinoderms, contrasted with predictions of their physiological CO2 tolerances derived from laboratory experiments. High CO2 reduced the availability of structurally complex corals that are essential refugia for many reef-associated macroinvertebrates. This loss of habitat complexity was also associated with losses in many macroinvertebrate groups, especially predation-prone mobile taxa, including crustaceans and crinoids. The transition from living to dead coral as substratum and habitat further altered macroinvertebrate communities, with far more taxa losing than gaining in numbers. Our study shows that indirect ecological effects of OA (reduced habitat complexity) will complement its direct physiological effects and together with the loss of coral cover through climate change will severely affect macroinvertebrate communities in coral reefs.

Immobilisation in Australian paediatric medical imaging: A pilot study.

AIMS: The primary aim of this study is to document the use of paediatric immobilisation techniques in medical imaging. Secondary aims are to investigate differences between current practice of paediatric and non-paediatric facilities and radiographer gender and to investigate immobilisation protocols. METHODS: A SurveyMonkey link was distributed through the Australian Society of Medical Imaging and Radiation Therapy (ASMIRT) newsletter. Radiographer members of ASMIRT were invited to participate. Frequency percentage analysis was undertaken; as the 'frequency of immobilisation' response was on a Likert scale and the ages categorical, a Fisher's exact test could determine dependency. RESULTS: The use of paediatric immobilisation techniques was determined to be related to age. The most commonly used technique in general X-ray was "other people"; in computed tomography, Velcro, verbal reminders and distraction techniques; and in magnetic resonance imaging, sedation and Velcro. A comparison of immobilisation techniques demonstrated that Velcro use in X-ray was dependent on facility (p = 0.017) with paediatric facilities using it up to 17 years. Immobilisation frequency was dependent in 13-17 years (p = 0.035) with paediatric facilities rarely immobilising and non-paediatric facilities never. No dependencies resulted upon comparing genders. Immobilisation frequency was not dependent between protocols or current practice. CONCLUSION: The use of paediatric immobilisation technique is related to age with "other people", sedation, Velcro, verbal reminders and distraction techniques being regularly used. The dependency of Velcro use and immobilisation frequency in 13-17 years is for unknown reasons and further investigation is required. A larger study should be carried out to validate these findings.

Host-associated coral reef microbes respond to the cumulative pressures of ocean warming and ocean acidification.

Key calcifying reef taxa are currently threatened by thermal stress associated with elevated sea surface temperatures (SST) and reduced calcification linked to ocean acidification (OA). Here we undertook an 8 week experimental exposure to near-future climate change conditions and explored the microbiome response of the corals Acropora millepora and Seriatopora hystrix, the crustose coralline algae Hydrolithon onkodes, the foraminifera Marginopora vertebralis and Heterostegina depressa and the sea urchin Echinometra sp. Microbial communities of all taxa were tolerant of elevated pCO2/reduced pH, exhibiting stable microbial communities between pH 8.1 (pCO2 479-499 µatm) and pH 7.9 (pCO2 738-835 µatm). In contrast, microbial communities of the CCA and foraminifera were sensitive to elevated seawater temperature, with a significant microbial shift involving loss of specific taxa and appearance of novel microbial groups occurring between 28 and 31 °C. An interactive effect between stressors was also identified, with distinct communities developing under different pCO2 conditions only evident at 31 °C. Microbiome analysis of key calcifying coral reef species under near-future climate conditions highlights the importance of assessing impacts from both increased SST and OA, as combinations of these global stressors can amplify microbial shifts which may have concomitant impacts for coral reef structure and function.

Relationship of anatomic disease to appropriateness ratings of coronary angiography.

BACKGROUND: At Harvard Community Health Plan (HCHP), Brookline, Mass, a mixed-model health maintenance organization (HMO), coronary angiography is performed at numerous community and tertiary-level teaching hospitals. OBJECTIVE: To determine the appropriateness of coronary angiography within HCHP according to RAND (1992) criteria and to examine the relationship between the appropriateness rating and (1) the clinical indication for catheterization and (2) the extent of anatomic disease. METHOD: A retrospective, randomized hospital medical record review of 292 patients enrolled in HCHP who underwent coronary angiography in 1992, stratified by four distinct HCHP subgroups. RESULTS: Of the coronary angiographies reviewed, 78% were rated appropriate, 16% uncertain, and only 6% inappropriate across the entire sample. Ratings were comparable in all subdivisions of HCHP despite an incidence rate of catheterization in one of the three HMO divisions that was 60% and 40% higher than in the other two divisions. The lowest appropriateness ratings were for Asymptomatic patients (43%) and those with Chest Pain of Uncertain Origin (35%) (capital letters refer to the RAND clinical indication criteria mentioned above). A rating of necessity was not a better discriminator of anatomic disease than a rating of appropriateness alone: 82% and 84%, respectively, were found to have disease by angiography. CONCLUSION: The low HCHP rate of inappropriateness for coronary angiography is comparable with the RAND 1992 New York State data. This finding, coupled with marked differences in the incidence rate of this procedure among the HCHP divisions, is consistent with either major differences in the sickness of the HMO's sub-populations or, more likely, a lack of specificity of the RAND criteria for coronary angiography.

Nintedanib, a novel triple angiokinase inhibitor for the treatment of non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Recent advances involving targeted therapies are promising, but most patients do not have an "oncogene addicted" disease. A platinum doublet chemotherapy regimen has been the mainstay of therapy since 1997. The addition of antiangiogenic agents to traditional chemotherapy has improved survival in patients with non-small cell lung cancer. However, these agents are limited by serious adverse events such as thromboembolism, bowel perforation and hemorrhage and by the development of resistance. Nintedanib is a novel, orally available triple angiokinase inhibitor that targets three important pathways involved in the initiation and propagation of angiogenesis in tumors, the VEGF, FGF and PDGFR pathways. Phase I and II trials have identified the maximum tolerated dose in monotherapy and in combination with traditional chemotherapy. The toxicity profile is tolerable and reversible, dominated by transaminitis and gastrointestinal side effects. The phase III LUME-lung 1 study (NCT00805194) compared docetaxel, a standard treatment in the second line, with docetaxel in combination with nintedanib. Progression-free survival was 3.4 months in the combination group compared to 2.7 months in the docetaxel group, (HR 0.79, 95% CI 0.68-0.92, P = 0.0019). There was a significant improvement in overall survival in adenocarcinoma patients, 12.6 vs. 10.3 months (HR 0.83, 95% CI 0.7-0.99, P = 0.036). Based on the results of this study, nintedanib has been approved by the EMA in Europe, as a second-line treatment in patients with adenocarcinoma. It is a promising, well-tolerated therapy that is currently being investigated in multiple different tumor types.

Alectinib for the treatment of ALK-positive stage IV non-small cell lung cancer.

Our increased understanding of the molecular subsets of non-small cell lung cancer (NSCLC) has led to the development of highly effective targeted therapies. In particular, the outcomes of patients with advanced NSCLC driven by the EML4-ALK fusion protein, which comprise 3-5% of cases, have remarkably improved with the use of crizotinib, an oral multi-tyrosine kinase inhibitor that targets ALK. However, patients inevitably develop progression while on crizotinib due to various mechanisms of resistance. Alectinib is a novel oral small molecule that inhibits ALK with high potency and selectivity, and demonstrates promising antitumor effects in NSCLC. Preclinical studies have shown that it is also active against several mutant forms of ALK that confer resistance to crizotinib, including the gatekeeper mutation L1196M. Moreover, an objective response rate of over 90% was observed in a phase I trial. Due to the impressive results of early phase studies, alectinib was approved for the treatment of advanced ALK-positive NSCLC in Japan, while it has been granted a breakthrough therapy designation by the FDA. A phase III trial is currently ongoing. This review will describe the biology and significance of ALK rearrangements in NSCLC, ALK inhibition by crizotinib and mechanisms of resistance, as well as the preclinical and clinical evidence for the novel ALK inhibitor alectinib.

In situ changes of tropical crustose coralline algae along carbon dioxide gradients.

Crustose coralline algae (CCA) fulfill important ecosystem functions in coral reefs, including reef framework stabilization and induction of larval settlement. To investigate in situ the effects of high carbon dioxide on CCA communities, we deployed settlement tiles at three tropical volcanic CO2 seeps in Papua New Guinea along gradients spanning from 8.1 to 7.4 pH. After 5 and 13 months deployment, there was a steep transition from CCA presence to absence around pH 7.8 (660 µatm pCO2): 98% of tiles had CCA at pH > 7.8, whereas only 20% of tiles had CCA at pH ≤ 7.8. As pH declined from 8.0 to 7.8, the least and most sensitive CCA species lost 43% and 85% of cover, respectively. Communities on upward facing surfaces exposed to high light and high grazing pressure showed less steep losses than those on shaded surfaces with low grazing. Direct CO2 effects on early life stages were the main mechanisms determining CCA cover, rather than competitive interactions with other benthic groups. Importantly, declines were steepest at near-ambient pH, suggesting that CCA may have already declined in abundance due to the recent seawater pH decline of 0.1 units, and that future severe losses are likely with increasing ocean acidification.

Transduction of normal and malignant oral epithelium by particle bombardment.

Although genetic approaches to the treatment and prevention of oral cancer are being developed, there are no suitable methods of transduction of the oral mucosa or early cancers. We therefore tested the technique of particle bombardment for its ability to transduce oral cancer cells in vitro and normal epithelium of the hamster cheek pouch in vivo. A gene gun was used to transfer a plasmid that encoded a marker/suicide fusion gene, beta-galactosidase-thymidine kinase (GAL-TEK), under control of a CMV promoter. For comparison we used the method of lipofection and an adenovirus vector. Particle bombardment transduced up to 13% of cells in culture, resulting in a 24.3% reduction in growth in the presence of ganciclovir. The efficiency of transduction was similar to that of lipofection but was much less than that of the adenovirus vector, which transduced 54% of cells and completely inhibited their growth in the presence of ganciclovir. Transduction of the hamster cheek pouch by particle bombardment produced expression of beta-galactosidase as judged by macroscopic staining, for up to 5 days. However, histological examination showed that the transduced cells were rare and superficial, and that administration of systemic ganciclovir did not lead to any changes in the tissue. Improvements in efficiency are necessary before the gene gun can be used in the management of oral cancer.

Lymphocyte ultrastructure in two cases of neuronal ceroid-lipofuscinosis.

Circulating blood lymphocytes from two patients with neuronal ceroid-lipofuscinosis (NCL) were investigated by transmission electronmicroscopy. Ultrastructural examination showed two forms of intracytoplasmic single membrane-limited inclusions. Contents of the first inclusion form were arranged in five distinct patterns: (1) granules, (2) membranous formations, (3) paracrystalline forms, (4) alternating electron-dense/electron-lucent arrangements, and (5) admixtures of these components. These molecular morphologies suggest the usefulness of lymphocyte fine structure as a diagnostic tool in NCL. The second inclusion form contained cylinder-like structures. These structures are not specific for NCL and have been identified in other diseases.

Retinoic acid induction of the tissue transglutaminase promoter is mediated by a novel response element.

We recently cloned and sequenced two kilobases of the upstream flanking region of the mouse tissue transglutaminase gene. Transfection experiments showed that this region of the transglutaminase flanking sequence was sufficient to mediate a 4-fold induction in reporter gene expression by retinoic acid. The goal of these studies was to identify retinoid receptor binding sites within this proximal 2 kilobase sequence and then to determine if these binding sites had ligand-dependent enhancer activity. To accomplish this we first employed a competitive band-shift assay using PCR-synthesized genomic DNA fragments as probes. This assay identified a receptor binding site located 1.7 Kb upstream from the transcription start site that contained three consensus hexanucleotide 'half sites' separated by 7 and 5 bp, respectively. This tripartite response element was shown to mediate retinoic acid activation of a heterologous promoter in transient transfection assays in RAW264.7 cells. Our results suggest that this novel retinoid response element is responsible for the retinoic acid induction of mouse tissue transglutaminase gene expression observed in numerous cells.

Strength and specificity of different gene promoters in oral cancer cells.

Gene therapy of oral cancer will require expression of genes by promoters that are both powerful and relatively tumor specific. We compared the level of expression of a reporter gene from promoters of human cytomegalovirus (CMV), SV40 virus, mouse mammary tumor virus (MMTV), human papillomaviruses (HPV) types 16 and 18, and the human multi-drug-resistance gene (mdr1), in several lines of oral cancer cells. In the oral cancer cell line 686LN the rank order of expression levels was: CMV > SV40 > HPV > mdr1 > MMTV. Unlike in previous reports the mdr1 promoter was no more active in two cancer cell lines with mutations in the p53 gene than in two other lines with wild-type p53, and its expression level could not be increased by either doxorubicin or taxol. On the other hand, expression from the MMTV promoter was increased over 10-fold by the presence of 1 microM dexamethasone. Thus, by an appropriate choice of promoter and inducer a wide variety of expression levels, over a 3-log range, could be attained in 686LN cells. The oral cancer-specificity of each promoter was judged by comparing expression in the neuroblastoma line IMR32. The most specific promoters were those from papillomaviruses, which were up to 45 times more active in the oral cancer cells, and the least specific was the CMV promoter. In order to find if an HPV-derived promoter was sufficient to produce expression of a suicide phenotype the 686 promoter was cloned adjacent to the thymidine kinase gene of herpes simplex and the construct was expressed from an adenovirus vector. The vector reduced the growth of 686LN cells over a 5-day period by up to 32% when optimal concentrations of virus and ganciclovir were used. These data will be valuable in the design of new constructs for gene therapy of oral cancer.

Ultrastructural observations of cytoplasmic inclusions in Tay-Sachs lymphocytes.

Our preliminary study on the circulating leukocytes from two children with Tay-Sachs disease and six heterozygotes from four different families is reported at the levels of both light and transmission electron microscopy. Ultrastructural investigation revealed two types of cytoplasmic inclusions in the lymphocytes of the Tay-Sachs homozygotes. The heterozygotes demonstrated only one of the inclusion forms within the cytoplasm of their circulating lymphocytes. These fine structural observations have not been described previously in Tay-Sachs disease and they may suggest new functional implications for the involvement of the lymphocyte in this storage disorder.

Novel in vitro functional assays for the determination of anthrax toxin components.

The characterisation and evaluation of the UK licensed human anthrax vaccine depends on several in vivo tests that determine its safety and potency. Assays for the determination of functionally active and/or immunoreactive toxin components and S-layer proteins have been developed and applied to the characterisation of anthrax vaccine. These technologies may support production of consistent and effective vaccines, and may ultimately reduce the requirements for in vivo testing.

Women and headache pain. Breaking the cycle.

Hormone-related migraines correspond with a woman's reproductive life cycle. Migraines first occur as a girl enters puberty and are rare after menopause. Is there medical relief available for this pain?

Taking action on arthritis.

The statistics regarding arthritis are mind boggling: one out of every six Americans have arthritis. In New Jersey, more than one million people are affected by arthritis diseases. The condition costs the U.S. economy $65 billion annually in medical care and lost wages. The Centers for Disease Control and Prevention (CDC) projects that in the year 2020, one in five Americans will have arthritis--an estimated 59.4 million people. Increasing awareness of this disease among physicians is a necessity.

Sickle cell patients find a brand New World.

As recently as the 1970s, sickle cell anemia patients had little hope of living past their teen years and little relief from painful crises. With the 1980s came the use of prophylactic penicillin to significantly reduce morbidity and mortality from infection in sickle cell youngsters. One of the sickle cell breakthroughs of the 1990s is the use of hydroxyurea for sickle cell treatment in adult patients. In the future, gene therapy may be the answer to the complex problems sickle cell anemia presents.

A prescription for trouble.

An elderly arthritis patient repeatedly asks her doctor to prescribe a weight-loss drug for her, and repeatedly, he refuses. But during one visit the harried doctor, intending to write a prescription for Feldene, an arthritis agent, wrote one for Fastin. The script caught the attention of the dispensing pharmacist, who called the physician to confirm the order, and with that telephone call, a medication error was caught before any damage was done.

Physician assistants come of age in New Jersey.

Until recently, New Jerseyans' exposure to physician assistants (PAs) was through television programs such as "E.R." But with the 1992 legislation enabling PAs to work in New Jersey and a growing acceptance among physicians, patients are seeing more of these health care providers in the examining room.

Kids having kids: the teen birth rate.

PIP: This article focuses on adolescent pregnancy and birth issues in the US. Although the birth rate among adolescents aged 10-19 years in New Jersey declined to 9609 infants per year in 1994, a decline of 7% from 1990, there remain concerns about the welfare of the mother and fetal development. Adolescent birth rates in New Jersey are higher for Black youths compared to White youths (100/1000 births vs. 25.4/1000). During 1990-94, births to girls aged 10-14 years increased from 241 to 284. There are many reasons for teenage pregnancy: abuse or coercion, peer pressure, misinformation, defiant behavior, person whims, and need for success through pregnancy. Pregnant teens frequently do not receive adequate prenatal care, maintain good nutrition, and/or refrain from unhealthy habits such as cigarette smoking, alcohol drinking, and/or drug use. The lack of prenatal care until late pregnancy may be due to lack of health insurance coverage or money for transportation. Teenagers have higher rates of premature births. Fetal development may be impaired due to lack of a proper maternal diet with a sufficient amount of folic acid, iron and protein, or food intake. Teenagers have twice the rate of spina bifida. Girls need to know the facts about the risk of premature birth and low birth weight associated with their cigarette smoking during pregnancy. Girls should be asked to reduce smoking to 3-5 cigarettes per week by the next visit and to stop entirely by the following visit. Teenagers need reinforcement in adopting the right eating patterns and curbing undesirable habits. Prenatal care should be comprehensive. The evidence suggests that fetal development is hampered by the competition for resources between the mother and fetus. Health care professionals must provide contraceptives and education; most hope that the repetitive cycle of repeat pregnancy and poverty does not continue.^ieng