A case-control study of drug risk factors for age-related macular degeneration.

OBJECTIVE: To investigate the association between age-related macular degeneration (AMD) and exposure to antacids, antithyroids, thyroid hormones, and thiazide diuretics. DESIGN: Matched case-control study. PARTICIPANTS: Population-based participants were selected from the United Kingdom General Practice Research Database. A total of 18,007 people with diagnosed AMD were compared with 86 169 controls matched for age, gender, and general practice. METHODS: Conditional logistic regression was used to determine the association between exposure to each drug group of interest and a diagnosis of AMD, adjusting for relevant confounding variables. MAIN OUTCOME MEASURES: The primary outcome was the odds ratio for the association between exposure to antacids, antithyroids, thyroid hormones, or thiazide diuretics and AMD. Secondary analyses were conducted to assess the effect of recent exposure to the drugs of interest, the total number of prescriptions received, and restricting the data set to participants with more than 2 years of observation time. RESULTS: The crude odds ratios for association between any record of drug exposure and AMD were as follows: 1.34 (95% confidence interval [CI], 1.29-1.39) for antacids; 1.15 (95% CI, 0.92-1.44) for antithyroids; 1.34 (95% CI, 1.29-1.39) for thyroid hormones; and 1.13 (95% CI, 1.08-1.17) for thiazide diuretics. After adjusting for consultation rate, observation time, diabetes, heart failure, hyperlipidemia, cardiovascular drug use, atherosclerosis, hypertension, aspirin use, hormone replacement therapy use, body mass index, alcohol consumption, and smoking, the odds ratios reduced to: 1.06 (95% CI, 1.02-1.10) for antacids, 0.98 (95% CI, 0.78-1.24) for antithyroids, 0.99 (95% CI, 0.92-1.06) for thyroid hormones, and 0.98 (95% CI, 0.94-1.02) for thiazides. Secondary analyses were consistent with these findings for all 4 drug categories. CONCLUSIONS: No association was detected between short- and medium-term use of antithyroids, thyroid hormones, and thiazide diuretics and the risk of AMD. Short- and medium-term use of antacids seems to be associated with a small increase in the risk of this disease. However, this increased risk is likely the result of residual confounding by smoking or uncontrolled confounding resulting from socioeconomic status. No conclusions could be drawn regarding longer-term use of each drug category

Incremental Semantic Evaluation for Interactive Systems: Inertia, Pre-emption, and Relations

Although schemes for incremental semantic evaluation have been explored and refined for more than two decades, the demands of user interaction continue to outstrip the capabilities of these schemes. The feedback produced by a semantic evaluator must support the user's programming activities: it must be structured in a way that provides the user with meaningful insight into the program (directly, or via other tools in the environment) and it must be timely. In this paper we extend an incremental attribute evaluation scheme with three techniques to better meet these demands within the context of a modeless editing system with a flexible tool integration paradigm. Efficient evaluation in the presence of syntax errors (which arise often under modeless editing) is supported by giving semantic attributes inertia: a tendency to not change unless necessary. Pre-emptive evaluation helps to reduce the delays associated with a sequence of edits, allowing an evaluator to "keep pace" with the user. Relations provide a general means to capture semantic structure (for the user, other tools, and as attributes within an evaluation) and are treated efficiently using a form of differential propagation. The combination of these three techniques meets the demands of user interaction; leaving out any one does not

First evidence of cryptotephra in palaeoenvironmental records associated with Norse occupation sites in Greenland

The Norse/Viking occupation of Greenland is part of a dispersal of communities across the North Atlantic coincident with the supposed Medieval Warm Period of the late 1st millennium AD. The abandonment of the Greenland settlements has been linked to climatic deterioration in the Little Ice Age as well as other possible explanations. There are significant dating uncertainties over the time of European abandonment of Greenland and the potential influence of climatic deterioration. Dating issues largely revolve around radiocarbon chronologies for Norse settlements and associated mire sequences close to settlement sites. Here we show the potential for moving this situation forward by a combination of palynological, radiocarbon and cryptotephra analyses of environmental records close to three ‘iconic’ Norse sites in the former Eastern Settlement of Greenland – Herjolfsnes, Hvalsey and Garðar (the modern Igaliku). While much work remains to be undertaken, our results show that palynological evidence can provide a useful marker for both the onset and end of Norse occupation in the region, while the radiocarbon chronologies for these sequences remain difficult. Significantly, we here demonstrate the potential for cryptotephra to become a useful tool in resolving the chronology of Norse occupation, when coupled with palynology. For the first time, we show that cryptotephra are present within palaeoenvironmental sequences located within or close to Norse settlement ruin-groups, with tephra horizons detected at all three sites. While shard concentrations were small at Herjolfsnes, concentrations sufficient for geochemical analyses were detected at Igaliku and Hvalsey. WDS-EPMA analyses of these tephra indicate that, unlike the predominantly Icelandic tephra sources reported in the Greenland ice core records, the tephra associated with the Norse sites correlate more closely with volcanic centres in the Aleutians and Cascades. Recent investigations of cryptotephra dispersal from North American centres, along with our new findings, point to the potential for cryptotephra to facilitate hypothesis testing, providing a key chronological tool for refining the timing of Norse activities in Greenland (e.g. abandonment) and of environmental contexts and drivers (e.g. climate forcing)

Concomitant medication use and clinical outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder.

BackgroundRepetitive Transcranial Magnetic Stimulation (rTMS) is commonly administered to Major Depressive Disorder (MDD) patients taking psychotropic medications, yet the effects on treatment outcomes remain unknown. We explored how concomitant medication use relates to clinical response to a standard course of rTMS.MethodsMedications were tabulated for 181 MDD patients who underwent a six-week rTMS treatment course. All patients received 10 Hz rTMS administered to left dorsolateral prefrontal cortex (DLPFC), with 1 Hz administered to right DLPFC in patients with inadequate response to and/or intolerance of left-sided stimulation. Primary outcomes were change in Inventory of Depressive Symptomatology Self Report (IDS-SR30) total score after 2, 4, and 6 weeks.ResultsUse of benzodiazepines was associated with less improvement at week 2, whereas use of psychostimulants was associated with greater improvement at week 2 and across 6 weeks. These effects were significant controlling for baseline variables including age, overall symptom severity, and severity of anxiety symptoms. Response rates at week 6 were lower in benzodiazepine users versus non-users (16.4% vs. 35.5%, p = 0.008), and higher in psychostimulant users versus non-users (39.2% vs. 22.0%, p = 0.02).ConclusionsConcomitant medication use may impact rTMS treatment outcome. While the differences reported here could be considered clinically significant, results were not corrected for multiple comparisons and findings should be replicated before clinicians incorporate the evidence into clinical practice. Prospective, hypothesis-based treatment studies will aid in determining causal relationships between medication treatments and outcome

Incremental Context-Sensitive Evaluation in Context

Although techniques for implementing or generating incremental semantic evaluators have been explored and refined for more than two decades, several pragmatic concerns still impede the use of such techniques in practical development environments. This report not only addresses some of these concerns, but furthermore demonstrates the need to consider the problem of incremental semantic evaluation in context. The practical concerns addressed here stem from both user interaction and architectural requirements. In particular an innovative preemptive evaluation scheme is presented which helps to reduce delays associated with semantic evaluation over a sequence of edits. Furthermore, a technique for assigning attributes to syntactically erroneous material (the introduction of which is inevitable in a syntax recognition editor) is described, as well as a novel approach to handling "long-distance" semantic effects using fine-grained incremental evaluation of relations

Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease

There is mounting evidence for a role of the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) in inflammatory disease, including arthritis. In the present study, we examined the effectiveness of treatment of collagen-induced arthritis (CIA) with a neutralizing mAb to GM-CSF. DBA/1 mice were immunized for the development of CIA and treated at different times, and with different doses, with neutralizing mAb to GM-CSF or isotype control mAb. Anti-GM-CSF mAb treatment prior to the onset of arthritis, at the time of antigen challenge, was effective at ameliorating the ensuing disease. Modulation of arthritis was seen predominantly as a reduction in overall disease severity, both in terms of the number of limbs affected per mouse and the clinical score of affected limbs. Importantly, anti-GM-CSF mAb treatment ameliorated existing disease, seen both as a reduction in the number of initially affected limbs progressing and lower numbers of additional limbs becoming affected. By histology, both inflammation and cartilage destruction were reduced in anti-GM-CSF-treated mice, and the levels of tumor necrosis factor-a and IL-1? were also reduced in joint tissue washouts of these mice. Neither humoral nor cellular immunity to type II collagen, however, was affected by anti-GM-CSF mAb treatment. These results suggest that the major effect of GM-CSF in CIA is on mediating the effector phase of the inflammatory reaction to type II collagen. The results also highlight the essential role of GM-CSF in the ongoing development of inflammation and arthritis in CIA, with possible therapeutic implications for rheumatoid arthritis

Rate-limiting transport of positively charged arginine residues through the Sec-machinery is integral to the mechanism of protein secretion

Transport of proteins across and into membranes is a fundamental biological process with the vast majority being conducted by the ubiquitous Sec machinery. In bacteria, this is usually achieved when the SecY-complex engages the cytosolic ATPase SecA (secretion) or translating ribosomes (insertion). Great strides have been made towards understanding the mechanism of protein translocation. Yet, important questions remain – notably, the nature of the individual steps that constitute transport, and how the proton-motive force (PMF) across the plasma membrane contributes. Here, we apply a recently developed high-resolution protein transport assay to explore these questions. We find that pre-protein transport is limited primarily by the diffusion of arginine residues across the membrane, particularly in the context of bulky hydrophobic sequences. This specific effect of arginine, caused by its positive charge, is mitigated for lysine which can be deprotonated and transported across the membrane in its neutral form. These observations have interesting implications for the mechanism of protein secretion, suggesting a simple mechanism through which the PMF can aid transport by enabling a 'proton ratchet', wherein re-protonation of exiting lysine residues prevents channel re-entry, biasing transport in the outward direction

Urban policy

The employment relationship – that between employer and employee – is at the heart of capitalism and a core issue for public policy. Governments create rules, policies and institutions within which employees, their representatives, employers and their representatives, operate. The interest to governments when creating policy includes the form that bargaining takes, wage and employment levels, the nature and effects of contracting and the rights of workers – much of this boiling down to issues of power. In recent decades, major policy issues have included the federal Labor government’s Prices and Incomes Accords in the 1980s and 1990s, the Coalition government’s ‘WorkChoices’ legislation, the shift to enterprise bargaining, and developments in such areas as minimum wages and pay equity. In this chapter we outline the matters at stake, the players, the policy processes and some of the key issues

Binary black hole evolutions of approximate puncture initial data

Approximate solutions to the Einstein field equations are a valuable tool to investigate gravitational phenomena. An important aspect of any approximation is to investigate and quantify its regime of validity. We present a study that evaluates the effects that approximate puncture initial data, based on "skeleton" solutions to the Einstein constraints as proposed by Faye et al. [PRD 69, 124029 (2004)], have on numerical evolutions. Using data analysis tools, we assess the effectiveness of these constraint-violating initial data and show that the matches of waveforms from skeleton data with the corresponding waveforms from constraint-satisfying initial data are > 0.97 when the total mass of the binary is > 40M(solar). In addition, we demonstrate that the differences between the skeleton and the constraint-satisfying initial data evolutions, and thus waveforms, are due to negative Hamiltonian constraint violations present in the skeleton initial data located in the vicinity of the punctures. During the evolution, the skeleton data develops both Hamiltonian and momentum constraint violations that decay with time, with the binary system relaxing to a constraint-satisfying solution with black holes of smaller mass and thus different dynamics