The contribution of major depression to the global burden of ischemic heart disease : a comparative risk assessment

Background Cardiovascular disease and mental health both hold enormous public health importance, both ranking highly in results of the recent Global Burden of Disease Study 2010 (GBD 2010). For the first time, the GBD 2010 has systematically and quantitatively assessed major depression as an independent risk factor for the development of ischemic heart disease (IHD) using comparative risk assessment methodology. Methods A pooled relative risk (RR) was calculated from studies identified through a systematic review with strict inclusion criteria designed to provide evidence of independent risk factor status. Accepted case definitions of depression include diagnosis by a clinician or by non-clinician raters adhering to Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) classifications. We therefore refer to the exposure in this paper as major depression as opposed to the DSM-IV category of major depressive disorder (MDD). The population attributable fraction (PAF) was calculated using the pooled RR estimate. Attributable burden was calculated by multiplying the PAF by the underlying burden of IHD estimated as part of GBD 2010. Results The pooled relative risk of developing IHD in those with major depression was 1.56 (95% CI 1.30 to 1.87). Globally there were almost 4 million estimated IHD disability-adjusted life years (DALYs), which can be attributed to major depression in 2010; 3.5 million years of life lost and 250,000 years of life lived with a disability. These findings highlight a previously underestimated mortality component of the burden of major depression. As a proportion of overall IHD burden, 2.95% (95% CI 1.48 to 4.46%) of IHD DALYs were estimated to be attributable to MDD in 2010. Eastern Europe and North Africa/Middle East demonstrate the highest proportion with Asia Pacific, high income representing the lowest. Conclusions The present work comprises the most robust systematic review of its kind to date. The key finding that major depression may be responsible for approximately 3% of global IHD DALYs warrants assessment for depression in patients at high risk of developing IHD or at risk of a repeat IHD event.

The empire of cancer: Gene patents and cancer voices

In his book, The Emperor of All Maladies, Siddhartha Mukherjee writes a history of cancer — "It is a chronicle of an ancient disease — once a clandestine, 'whispered-about' illness — that has metamorphosed into a lethal shape-shifting entity imbued with such penetrating metaphorical, medical, scientific, and political potency that cancer is often described as the defining plague of our generation." Increasingly, an important theme in the history of cancer is the role of law, particularly in the field of intellectual property law. It is striking that a number of contemporary policy debates over intellectual property and public health have concerned cancer research, diagnosis, and treatment. In the area of access to essential medicines, there has been much debate over Novartis’ patent application in respect of Glivec, a treatment for leukaemia. India’s Supreme Court held that the Swiss company’s patent application violated a safeguard provision in India’s patent law designed to stop evergreening. In the field of tobacco control, the Australian Government introduced plain packaging for tobacco products in order to address the health burdens associated with the tobacco epidemic. This regime was successfully defended in the High Court of Australia. In the area of intellectual property and biotechnology, there have been significant disputes over the Utah biotechnology company Myriad Genetics and its patents in respect of genetic testing for BRCA1 and BRCA2, which are related to breast cancer and ovarian cancer. The Federal Court of Australia handed down a decision on the validity of Myriad Genetics’ patent in respect of genetic testing for BRCA1 in February 2013. The Supreme Court of the United States heard a challenge to the validity of Myriad Genetics’ patents in this area in April 2013, and handed down a judgment in July 2013. Such disputes have involved tensions between intellectual property rights, and public health. This article focuses upon one of these important test cases involving intellectual property, public health, and cancer research. In June 2010, Cancer Voices Australia and Yvonne D’Arcy brought an action in the Federal Court of Australia against the validity of a BRCA1 patent — held by Myriad Genetics Inc, the Centre de Recherche du Chul, the Cancer Institute of Japan and Genetic Technologies Limited. Yvonne D’Arcy — a Brisbane woman who has had treatment for breast cancer — maintained: "I believe that what they are doing is morally and ethically corrupt and that big companies should not control any parts of the human body." She observed: "For my daughter, I've had her have [sic] mammograms, etc, because of me but I would still like her to be able to have the test to see if the mutation gene is in there from me." The applicants made the following arguments: "Genes and the information represented by human gene sequences are products of nature universally present in each individual, and the information content of a human gene sequence is fixed. Genetic variations or mutations are products of nature. The isolation of the BRCA1 gene mutation from the human body constitutes no more than a medical or scientific discovery of a naturally occurring phenomenon and does not give rise to a patentable invention." The applicants also argued that "the alleged invention is not a patentable invention in that, so far as claimed in claims 1–3, it is not a manner of manufacture within the meaning of s 6 of the Statute of Monopolies". The applicants suggested that "the alleged invention is a mere discovery". Moreover, the applicants contended that "the alleged invention of each of claims 1-3 is not a patentable invention because they are claims for biological processes for the generation of human beings". The applicants, though, later dropped the argument that the patent claims related to biological processes for the generation of human beings. In February 2013, Nicholas J of the Federal Court of Australia considered the case brought by Cancer Voices Australia and Yvonne D’Arcy against Myriad Genetics. The judge presented the issues in the case, as follows: "The issue that arises in this case is of considerable importance. It relates to the patentability of genes, or gene sequences, and the practice of 'gene patenting'. Briefly stated, the issue to be decided is whether under the Patents Act 1990 (Cth) a valid patent may be granted for a claim that covers naturally occurring nucleic acid — either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) — that has been 'isolated'". In this context, the word "isolated" implies that naturally occurring nucleic acid found in the cells of the human body, whether it be DNA or RNA, has been removed from the cellular environment in which it naturally exists and separated from other cellular components also found there. The genes found in the human body are made of nucleic acid. The particular gene with which the patent in suit is concerned (BRCA1) is a human breast and ovarian cancer disposing gene. Various mutations that may be present in this gene have been linked to various forms of cancer including breast cancer and ovarian cancer.' The judge held in this particular case that Myriad Genetics’ patent claims were a "manner of manufacture" under s 6 of the Statute of Monopolies and s 18(1)(a) of the Patents Act 1990 (Cth). The matter is currently under appeal in the Full Court of the Federal Court of Australia. This article interprets the dispute over Myriad Genetics in light of the scholarly work of Nobel Laureate Professor Joseph Stiglitz on inequality. Such work has significant explanatory power in the context of intellectual property and biotechnology. First, Stiglitz has contended that "societal inequality was a result not just of the laws of economics, but also of how we shape the economy — through politics, including through almost every aspect of our legal system". Stiglitz is concerned that "our intellectual property regime … contributes needlessly to the gravest form of inequality." He maintains: "The right to life should not be contingent on the ability to pay." Second, Stiglitz worries that "some of the most iniquitous aspects of inequality creation within our economic system are a result of 'rent-seeking': profits, and inequality, generated by manipulating social or political conditions to get a larger share of the economic pie, rather than increasing the size of that pie". He observes that "the most iniquitous aspect of this wealth appropriation arises when the wealth that goes to the top comes at the expense of the bottom." Third, Stiglitz comments: "When the legal regime governing intellectual property rights is designed poorly, it facilitates rent-seeking" and "the result is that there is actually less innovation and more inequality." He is concerned that intellectual property regimes "create monopoly rents that impede access to health both create inequality and hamper growth more generally." Finally, Stiglitz has recommended: "Government-financed research, foundations, and the prize system … are alternatives, with major advantages, and without the inequality-increasing disadvantages of the current intellectual property rights system.’" This article provides a critical analysis of the Australian litigation and debate surrounding Myriad Genetics’ patents in respect of genetic testing for BRCA1. First, it considers the ruling of Nicholas J in the Federal Court of Australia that Myriad Genetics’ patent was a manner of manufacture as it related to an artificially created state of affairs, and not mere products of nature. Second, it examines the policy debate over gene patents in Australia, and its relevance to the litigation involving Myriad Genetics. Third, it examines comparative law, and contrasts the ruling by Nicholas J in the Federal Court of Australia with developments in the United States, Canada, and the European Union. Fourth, this piece considers the reaction to the decision of Nicholas at first instance in Australia. Fifth, the article assesses the prospects of an appeal to the Full Federal Court of Australia over the Myriad Genetics’ patents. Finally, this article observes that, whatever happens in respect of litigation against Myriad Genetics, there remains controversy over Genetic Technologies Limited. The Melbourne firm has been aggressively licensing and enforcing its related patents on non-coding DNA and genomic mapping.

A rapid and efficient two-step gel electrophoresis method for the purification of major rye grass pollen allergens

Purified proteins are mandatory for molecular, immunological and cellular studies. However, purification of proteins from complex mixtures requires specialised chromatography methods (i.e., gel filtration, ion exchange, etc.) using fast protein liquid chromatography (FPLC) or high-performance liquid chromatography (HPLC) systems. Such systems are expensive and certain proteins require two or more different steps for sufficient purity and generally result in low recovery. The aim of this study was to develop a rapid, inexpensive and efficient gel-electrophoresis-based protein purification method using basic and readily available laboratory equipment. We have used crude rye grass pollen extract to purify the major allergens Lol p 1 and Lol p 5 as the model protein candidates. Total proteins were resolved on large primary gel and Coomassie Brilliant Blue (CBB)-stained Lol p 1/5 allergens were excised and purified on a secondary "mini"-gel. Purified proteins were extracted from unstained separating gels and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot analyses. Silver-stained SDS-PAGE gels resolved pure proteins (i.e., 875 μg of Lol p 1 recovered from a 8 mg crude starting material) while immunoblot analysis confirmed immunological reactivity of the purified proteins. Such a purification method is rapid, inexpensive, and efficient in generating proteins of sufficient purity for use in monoclonal antibody (mAb) production, protein sequencing and general molecular, immunological, and cellular studies.

Monoclonal antibody screening of a phage-displayed random peptide library reveals mimotopes of chemokine receptor CCR5: Implications for the tertiary structure of the receptor and for an n-terminal binding site for HIV-1 gp120

The chemokine receptor CCR5 contains seven transmembrane-spanning domains. It binds chemokines and acts as co-receptor for macrophage (m)-tropic (or R5) strains of HIV-1. Monoclonal antibodies (mAb) to CCR5, 3A9 and 5C7, were used for biopanning a nonapeptide cysteine (C)-constrained phage-displayed random peptide library to ascertain contact residues and define tertiary structures of possible epitopes on CCR5. Reactivity of antibodies with phagotopes was established by enzyme-linked immunosorbent assay (ELISA). mAb 3A9 identified a phagotope C-HASIYDFGS-C (3A9/1), and 5C7 most frequently identified C-PHWLRDLRV-C (5C7/1). Corresponding peptides were synthesized. Phagotopes and synthetic peptides reacted in ELISA with corresponding antibodies and synthetic peptides inhibited antibody binding to the phagotopes. Reactivity by immunofluorescence of 3A9 with CCR5 was strongly inhibited by the corresponding peptide. Both mAb 3A9 and 5C7 reacted similarly with phagotopes and the corresponding peptide selected by the alternative mAb. The sequences of peptide inserts of phagotopes could be aligned as mimotopes of the sequence of CCR5. For phage 3A9/1, the motif SIYD aligned to residues at the N terminus and FG to residues on the first extracellular loop; for 5C7/1, residues at the N terminus, first extracellular loop, and possibly the third extracellular loop could be aligned and so would contribute to the mimotope. The synthetic peptides corresponding to the isolated phagotopes showed a CD4-dependent reactivity with gp120 of a primary, m-tropic HIV-1 isolate. Thus reactivity of antibodies raised to CCR5 against phage-displayed peptides defined mimotopes that reflect binding sites for these antibodies and reveal a part of the gp120 binding sites on CCR5.

Neuropsychological studies of late onset and subthreshold diagnoses of adult Attention-Deficit/Hyperactivity Disorder

Background Diagnosing attention-deficit/hyperactivity disorder (ADHD) in adults is difficult when the diagnostician cannot establish an onset prior to the DSM-IV criterion of age 7 or if the number of symptoms recalled does not achieve the DSM-IV threshold for diagnosis. Because neuropsychological deficits are associated with ADHD, we addressed the validity of the DSM-IV age at onset and symptom threshold criteria by using neuropsychological test scores as external validators. Methods We compared four groups of adults: 1) full ADHD subjects met all DSM-IV criteria for childhood-onset ADHD; 2) late-onset ADHD subjects met all criteria except the age at onset criterion; 3) subthreshold ADHD subjects did not meet full symptom criteria; and 4) non-ADHD subjects did not meet any of the above criteria. Results Late-onset and full ADHD subjects had similar patterns of neuropsychological dysfunction. By comparison, subthreshold ADHD subjects showed few neuropsychological differences with non-ADHD subjects. Conclusions Our results showing similar neuropsychological underpinning in subjects with late-onset ADHD suggest that the DSM-IV age at onset criterion may be too stringent. Our data also suggest that ADHD subjects who failed to ever meet the DSM-IV threshold for diagnosis have a milder form of the disorder.

Crystal structures and hydrogen bonding in the morpholinium salts of four phenoxyacetic acid analogues

The anhydrous salts morpholinium (tetrahydro-2-H-1,4-oxazine) phenxyacetate, C4H10NO+ C8H7O3- (I), (4-fluorophenoxy)acetate, C4H10NO+ C8H6FO3- (II) and isomeric morpholinium (3,5-dichlorophenoxy)acetate (3,5-D) (III) and morpholinium (2,4-dichlorophenoxy)acetate (2,4-D), C4H10NO+ C8H5Cl2O3- (IV), have been determined and their hydrogen-bonded structures are described. In the crystals of (I), (III) and (IV), one of the the aminium H atoms is involved in a three-centre asymmetric cation-anion N-H...O,O' R2/1(4) hydrogen-bonding interaction with the two carboxyl O-atom acceptors of the anion. With the structure of (II), the primary N---H...O interaction is linear. In the structures of (I), (II) and (III), the second N-H...O(carboxyl) hydrogen bond generates one-dimensional chain structures extending in all cases along [100]. With (IV), the ion pairs are linked though inversion-related N-H...O hydrogen bonds [graph set R2/4(8)], giving a cyclic heterotetrameric structure.

Structural and Sequence Characteristics of Long alpha Helices in Globular Proteins

Elucidation of the detailed structural features and sequence requirements for iv helices of various lengths could be very important in understanding secondary structure formation in proteins and, hence. in the protein folding mechanism. An algorithm to characterize the geometry of an alpha helix from its C-alpha coordinates has been developed and used to analyze the structures of long cu helices (number of residues greater than or equal to 25) found in globular proteins, the crystal structure coordinates of which are available from the Brookhaven Protein Data Bank, Ail long a helices can be unambiguously characterized as belonging to one of three classes: linear, curved, or kinked, with a majority being curved. Analysis of the sequences of these helices reveals that the long alpha helices have unique sequence characteristics that distinguish them from the short alpha helices in globular proteins, The distribution and statistical propensities of individual amino acids to occur in long alpha heices are different from those found in short alpha helices, with amino acids having longer side chains and/or having a greater number of functional groups occurring more frequently in these helices, The sequences of the long alpha helices can be correlated with their gross structural features, i.e., whether they are curved, linear, or kinked, and in case of the curved helices, with their curvature.

Oxovanadium(IV)-based near-IR PDT agents: design to biological evaluation

An oxovanadium(IV) complex of dipyridophenazine, as a potent metal-based PDT agent, shows efficient DNA photocleavage activity at near-IR region and high photocytotoxicity in both UV-A and visible light in HeLa cells.

Karl Josef Scheuermann Collection 1981-1986

Photocopies of correspondence between Scheuermann, Ernst Cramer, Cardinal Ratzinger, Reuben Hecht on Pope John XXIII and his alleged repentance prayer.

Memoirs : Heida Hermanns Holde /

The author's mother Alice Goldschmidt was a gifted piano player, who studied with Carl Maria Breithaupt and became his most talented student. Childhood recollections. Early musical awakening. Outbreak of World War One. Recollections of air raids and scarceness of food. Inflation and political instability in post-war Germany. Piano lessons by her mother from an early age. Heida made her debut at age fourteen with the Wiesbaden Symphony under the conductor Carl Schuricht, who became a close mentor and friend. Close relationship to her mother, who had a great influence on her professional career. Heida had a number of outstanding teachers, among them Artur Schnabel, Karl Leimer and Egon Petri. Heida was accepted as a student of Petri at the "Hochschule fuer Musik" in Berlin, where she studied between 1922-1925. Salon at her aunt's house with guests such as the playwright Georg Kaiser and Siegfried Wagner. Her sister Elsie received her Ph.D. in economics and moved to Berlin as well. Heida graduated from the "Hochschule" in 1925. Soon after she won an international piano competition in Berlin. Engagements with various conductors such as Max Fiedler and Otto Klemperer. Private lessons with Arthur Schnabel and Carl Friedberg, the co-founder of Juilliard. Due to occasional experiences of antisemitism during her music career Heida decided to change her name from Goldschmidt to Hermanns. Position at the "Hoch Conservatory" in Frankfurt. Encounter with the music critic Artur Holde, Heida's future-husband. Engagement and wedding in 1932. Move to Berlin.

[Childhood memories of Berlin, Rhineland, Holland] 1933-1945

Childhood memories of Berlin, Rhineland, Holland; emigration to United States in 1936; impressions of New York; life in Paso Robles, California; memories of his mother; reflections on life of mother.

Topochemically controlled hydrogen reduction of scheelite-related rare-earth metal molybdates

Scheelite-related -Ln2Mo3O12(Ln = La, Pr, Nd, Sm, Gd, Tb, or Dy) oxides are reduced by hydrogen at 780–870 K yielding molybdenum (IV) oxides of formula Ln2Mo3O9. The latter crystallize in a tetragonal scheelite (ABO4) type structure where one third of the A sites and a quarter of the anion sites are vacant: Ln2/3(cat)1/3MoO3(an). The reaction Ln2Mo3O12+ 3H2 Ln2Mo3O9(an)3+ 3H2O may be regarded as topochemically controlled, since both the parent and the product phases have scheelite-related structures. Infrared spectra and electrical and magnetic properties of these metastable defect scheelite phases are reported.

The profile of psychiatric symptoms exacerbated by methamphetamine use

Background Methamphetamine use can produce symptoms almost indistinguishable from schizophrenia. Distinguishing between the two conditions has been hampered by the lack of a validated symptom profile for methamphetamine-induced psychiatric symptoms. We use data from a longitudinal cohort study to examine the profile of psychiatric symptoms that are acutely exacerbated by methamphetamine use. Methods 164 methamphetamine users, who did not meet DSM-IV criteria for a lifetime primary psychotic disorder, were followed monthly for one year to assess the relationship between days of methamphetamine use and symptom severity on the 24-item Brief Psychiatric Rating Scale. Exacerbation of psychiatric symptoms with methamphetamine use was quantified using random coefficient models. The dimensions of symptom exacerbation were examined using principal axis factoring and a latent profile analysis. Results Symptoms exacerbated by methamphetamine loaded on three factors: positive psychotic symptoms (suspiciousness, unusual thought content, hallucinations, bizarre behavior); affective symptoms (depression, suicidality, guilt, hostility, somatic concern, self-neglect); and psychomotor symptoms (tension, excitement, distractibility, motor hyperactivity). Methamphetamine use did not significantly increase negative symptoms. Vulnerability to positive psychotic and affective symptom exacerbation was shared by 28% of participants, and this vulnerability aligned with a past year DSM-IV diagnosis of substance-induced psychosis (38% vs. 22%, _2 (df1) = 3.66, p = 0.056). Conclusion Methamphetamine use produced a symptom profile comprised of positive psychotic and affective symptoms, which aligned with a diagnosis of substance-induced psychosis, with no evidence of a negative syndrome.

Intraday Dynamics of International Equity Markets

The increased availability of high frequency data sets have led to important new insights in understanding of financial markets. The use of high frequency data is interesting and persuasive, since it can reveal new information that cannot be seen in lower data aggregation. This dissertation explores some of the many important issues connected with the use, analysis and application of high frequency data. These include the effects of intraday seasonal, the behaviour of time varying volatility, the information content of various market data, and the issue of inter market linkages utilizing high frequency 5 minute observations from major European and the U.S stock indices, namely DAX30 of Germany, CAC40 of France, SMI of Switzerland, FTSE100 of the UK and SP500 of the U.S. The first essay in the dissertation shows that there are remarkable similarities in the intraday behaviour of conditional volatility across European equity markets. Moreover, the U.S macroeconomic news announcements have significant cross border effect on both, European equity returns and volatilities. The second essay reports substantial intraday return and volatility linkages across European stock indices of the UK and Germany. This relationship appears virtually unchanged by the presence or absence of the U.S stock market. However, the return correlation among the U.K and German markets rises significantly following the U.S stock market opening, which could largely be described as a contemporaneous effect. The third essay sheds light on market microstructure issues in which traders and market makers learn from watching market data, and it is this learning process that leads to price adjustments. This study concludes that trading volume plays an important role in explaining international return and volatility transmissions. The examination concerning asymmetry reveals that the impact of the positive volume changes is larger on foreign stock market volatility than the negative changes. The fourth and the final essay documents number of regularities in the pattern of intraday return volatility, trading volume and bid-ask spreads. This study also reports a contemporaneous and positive relationship between the intraday return volatility, bid ask spread and unexpected trading volume. These results verify the role of trading volume and bid ask quotes as proxies for information arrival in producing contemporaneous and subsequent intraday return volatility. Moreover, asymmetric effect of trading volume on conditional volatility is also confirmed. Overall, this dissertation explores the role of information in explaining the intraday return and volatility dynamics in international stock markets. The process through which the information is incorporated in stock prices is central to all information-based models. The intraday data facilitates the investigation that how information gets incorporated into security prices as a result of the trading behavior of informed and uninformed traders. Thus high frequency data appears critical in enhancing our understanding of intraday behavior of various stock markets’ variables as it has important implications for market participants, regulators and academic researchers.

Bridging East and West : The Establishment of the International Institute for Applied Systems Analysis (IIASA) in the United States Foreign Policy of Bridge Building, 1964-1972.

The dissertation examines the foreign policies of the United States through the prism of science and technology. In the focal point of scrutiny is the policy establishing the International Institute for Applied Systems Analysis (IIASA) and the development of the multilateral part of bridge building in American foreign policy during the 1960s and early 1970s. After a long and arduous negotiation process, the institute was finally established by twelve national member organizations from the following countries: Bulgaria, Canada, Czechoslovakia, Federal Republic of Germany (FRG), France, German Democratic Republic (GDR), Great Britain, Italy, Japan, Poland, Soviet Union and United States; a few years later Sweden, Finland and the Netherlands also joined. It is said that the goal of the institute was to bring together researchers from East and West to solve pertinent problems caused by the modernization process experienced in industrialized world. It originates from President Lyndon B. Johnson s bridge building policies that were launched in 1964, and was set in a well-contested and crowded domain of other international organizations of environmental and social planning. Since the distinct need for yet another organization was not evident, the process of negotiations in this multinational environment enlightens the foreign policy ambitions of the United States on the road to the Cold War détente. The study places this project within its political era, and juxtaposes it with other international organizations, especially that of the OECD, ECE and NATO. Conventionally, Lyndon Johnson s bridge building policies have been seen as a means to normalize its international relations bilaterally with different East European countries, and the multilateral dimension of the policy has been ignored. This is why IIASA s establishment process in this multilateral environment brings forth new information on US foreign policy goals, the means to achieve these goals, as well as its relations to other advanced industrialized societies before the time of détente, during the 1960s and early 1970s. Furthermore, the substance of the institute applied systems analysis illuminates the differences between European and American methodological thinking in social planning. Systems analysis is closely associated with (American) science and technology policies of the 1960s, especially in its military administrative applications, thus analysis within the foreign policy environment of the United States proved particularly fruitful. In the 1960s the institutional structures of European continent with faltering, and the growing tendencies of integration were in flux. One example of this was the long, drawn-out process of British membership in the EEC, another is de Gaulle s withdrawal from NATO s military-political cooperation. On the other hand, however, economic cooperation in Europe between East and West, and especially with the Soviet Union was expanding rapidly. This American initiative to form a new institutional actor has to be seen in that structural context, showing that bridge building was needed not only to the East, but also to the West. The narrative amounts to an analysis of how the United States managed both cooperation and conflict in its hegemonic aspirations in the emerging modern world, and how it used its special relationship with the United Kingdom to achieve its goals. The research is based on the archives of the United States, Great Britain, Sweden, Finland, and IIASA. The primary sources have been complemented with both contemporary and present day research literature, periodicals, and interviews.