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Prevention of cardiovascular disease (CVD) remains one of the largest public health challenges of our time. Identifying individuals at increased cardiovascular risk at an asymptomatic, sub-clinical stage is of paramount importance for minimizing disease progression as well as the substantial health and economic burden associated with overt CVD. Vascular ageing (VA) involves the deterioration in vascular structure and function over time and ultimately leads to damage in the heart, brain, kidney, and other organs. Vascular ageing encompasses the cumulative effect of all cardiovascular risk factors on the arterial wall over the life course and thus may help identify those at elevated cardiovascular risk, early in disease development. Although the concept of VA is gaining interest clinically, it is seldom measured in routine clinical practice due to lack of consensus on how to characterize VA as physiological vs. pathological and various practical issues. In this state-of-the-art review and as a network of scientists, clinicians, engineers, and industry partners with expertise in VA, we address six questions related to VA in an attempt to increase knowledge among the broader medical community and move the routine measurement of VA a little closer from bench towards bedside.

Sleep staging is an essential component in the diagnosis of sleep disorders and management of sleep health. Sleep is traditionally measured in a clinical setting and requires a labor-intensive labeling process. We hypothesize that it is possible to perform automated robust 4-class sleep staging using the raw photoplethysmography (PPG) time series and modern advances in deep learning (DL). We used two publicly available sleep databases that included raw PPG recordings, totalling 2,374 patients and 23,055 hours of continuous data. We developed SleepPPG-Net, a DL model for 4-class sleep staging from the raw PPG time series. SleepPPG-Net was trained end-to-end and consists of a residual convolutional network for automatic feature extraction and a temporal convolutional network to capture long-range contextual information. We benchmarked the performance of SleepPPG-Net against models based on the best-reported state-of-the-art (SOTA) algorithms. When benchmarked on a held-out test set, SleepPPG-Net obtained a median Cohen's Kappa ($\kappa$) score of 0.75 against 0.69 for the best SOTA approach. SleepPPG-Net showed good generalization performance to an external database, obtaining a $\kappa$ score of 0.74 after transfer learning. Overall, SleepPPG-Net provides new SOTA performance. In addition, performance is high enough to open the path to the development of wearables that meet the requirements for usage in clinical applications such as the diagnosis and monitoring of obstructive sleep apnea.

So, Indonesia's President Abdurrahman Wahid doesn't want to visit Australia. PETER CHARLTON asks: Who cares? WAHID' -- Time, July 3. 'Wahid Told to Shut Up' -- South China Morning Post, […]

The strength and growth of Australia's economic links with the nations of the European Union and its neighbours is demonstrated again by the latest Australian Export Awards. More than half [...]

Strong leadership by John Howard and Goh Chok Tong is crucial to South East Asia's economic recovery -- and peace in the region. Australian Prime Minister John Howard and his […]

Breathing rate (BR) is a key physiological parameter used in a range of clinical settings. Despite its diagnostic and prognostic value, it is still widely measured by counting breaths manually. A plethora of algorithms have been proposed to estimate BR from the electrocardiogram (ECG) and pulse oximetry (photoplethysmogram, PPG) signals. These BR algorithms provide opportunity for automated, electronic, and unobtrusive measurement of BR in both healthcare and fitness monitoring. This paper presents a review of the literature on BR estimation from the ECG and PPG. First, the structure of BR algorithms and the mathematical techniques used at each stage are described. Second, the experimental methodologies that have been used to assess the performance of BR algorithms are reviewed, and a methodological framework for the assessment of BR algorithms is presented. Third, we outline the most pressing directions for future research, including the steps required to use BR algorithms in wearable sensors, remote video monitoring, and clinical practice.

India meets Asia in major new economic forum Advisory council formed of leading Australian, Asian and Indian business leaders and companies. Australian publisher Peter Charlton the brainchild behind INDOPAC; former […]

IN A STELLAR ECONOMY, THE AUSTRALIAN financial services sector has experienced a stellar year in 2006. Our five largest banks all reported healthy results--with even the smallest, St.George, joining the [...]

July: The Angry Golfer, by John Hawkins I spent a weekend watching the best golfers in the world play to is-handicaps in the U.S. Open, all because of the need [...]

One thing is obvious from the recent spate of world crises, and that is the importance of calmed reasoned voices being heard above the hyperbole. Clearly many of these events […]

The article examines several vintage ordnances in Malawi which include the Guendolen, Nordenfeldt, and the Armstrong 7. It states that there are several cannons in Malawi, however there origins are not clear with the lack of a comprehensive written record. The role of the ordnances in Malawi's history are explored as well as the characteristics and features of the ordnances an their manufactures.

Singapore, one-time Venice of Asia, may not be able to retain its specialness and charm. The miracle Lee Kuan Yew wrought is in trouble, not only because neighboring economies have big problems, but also because of the change of attitude of the people in the last five years. Hotel, restaurant, airline and shop staffs, taxi drivers, and others who serve customers have an arrogance they once did not have, and that is not found in nearby countries that compete for tourists. They do not try to serve customers as they once did, having grown up in a genuinely synthetic environment.

MurG is an essential bacterial glycosyltransferase enzyme in Pseudomonas aeruginosa performing one of the key membrane steps of peptidoglycan synthesis catalyzing the transfer of N-acetyl glucosamine (GlcNAc) from its donor substrate, UDP-GlcNAc, to the acceptor substrate Lipid I. We have solved the crystal structure of the complex between Pseudomonas aeruginosa MurG and UDP-GlcNAc and compared it with the previously solved complex from E. coli. The structure reveals a large-scale conformational change in the relative orientations of the N- and C-terminal domains, which has the effect of widening the cofactor binding site and displacing the UDP-GlcNAc donor. These results suggest new opportunities to design potent inhibitors of peptidoglycan biosynthesis.

DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients.

The article provides details of the medals issued during the administration of President Hastings Kanuzu Banda in Malawi from 1963 to 1994. It provides a description of the medals, the manufacturer of the medals, and the recipients of the medals. Some of the medals discussed include the medals for the Order of the Lion, the Republic of Malawi Medal, and the Army Meritorious Service medal.

XR5118 [(3Z,6Z)-6-benzylidine-3-(5-(2-dimethylaminoethyl-thio-))-2-(thienyl)methylene-2,5-dipiperazinedione hydrochloride] can inactivate the anti-proteolytic activity of the serpin plasminogen activator inhibitor-1 (PAI-1), a potential therapeutic target in cancer and cardiovascular diseases. Serpins inhibit their target proteases by the P1 residue of their reactive centre loop (RCL) forming an ester bond with the active-site serine residue of the protease, followed by insertion of the RCL into the serpin's large central β-sheet A. In the present study, we show that the RCL of XR5118-inactivated PAI-1 is inert to reaction with its target proteases and has a decreased susceptibility to non-target proteases, in spite of a generally increased proteolytic susceptibility of specific peptide bonds elsewhere in PAI-1. The properties of XR5118-inactivated PAI-1 were different from those of the so-called latent form of PAI-1. Alanine substitution of several individual residues decreased the susceptibility of PAI-1 to XR5118. The localization of these residues in the three-dimensional structure of PAI-1 suggested that the XR5118-induced inactivating conformational change requires mobility of α-helix F, situated above β-sheet A, and is in agreement with the hypothesis that XR5118 binds laterally to β-sheet A. These results improve our understanding of the unique conformational flexibility of serpins and the biochemical basis for using PAI-1 as a therapeutic target.

The activity of the serine proteinase inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is controlled by the intramolecular incorporation of the reactive loop into β-sheet A with the generation of an inactive latent species. Other members of the serpin superfamily can be pathologically inactivated by intermolecular linkage between the reactive loop of one molecule and β-sheet A of a second to form chains of polymers associated with diverse diseases. It has long been believed that PAI-1 is unique among active serpins in that it does not form polymers. We show here that recombinant native and latent PAI-1 spontaneously form polymers in vitroat low pH although with distinctly different electrophoretic patterns of polymerization. The polymers of both the native and latent species differ from the typical loop-A-sheet polymers of other serpins in that they readily dissociate back to their original monomeric form. The findings with PAI-1 are compatible with different mechanisms of linkage, each involving β-strand addition of the reactive loop to s7A in native PAI-1 and to s1C in latent PAI-1. Glycosylated native and latent PAI-1 can also form polymers under similar conditions, which may be of in vivoimportance in the low pH environment of the platelet.

The kinetics and nature of equilibrium binding were used to characterize the molecular interaction of the anthranilic acid derivative [3H]‐XR9576 with the multidrug resistance P‐glycoprotein (P‐gp). XR9576 displayed specific high‐affinity binding to P‐gp (Bmax=275 pmol mg−1, Kd=5.1 nM). The transport substrates [3H]‐vinblastine and [3H]‐paclitaxel displayed 4 fold and 20 fold lower affinity respectively for P‐gp. The duration of action of XR9576 with P‐gp was increased in comparison to that of vinblastine which displayed a slower rate of association and a faster dissociation rate.The relative affinities of several modulators and transport substrates to interact with P‐gp were determined from displacement drug equilibrium binding assays. Vinblastine and paclitaxel could only fractionally displace [3H]‐XR9576 binding, displaying Kivalues significantly different from their measured Kdvalues. This suggests a non‐competitive interaction between XR9576 and the P‐gp substrates vinblastine and paclitaxel.XR9576 was shown to be a potent modulator of P‐gp mediated [3H]‐vinblastine and [3H]‐paclitaxel transport as it increased the steady‐state accumulation of these cytotoxics in CHrB30 cells to levels observed in non‐P‐gp‐expressing AuxB1 cells (EC50=487±50 nM). This inhibition of drug transport is not mediated through competition for transport since [3H]‐XR9576 accumulation was not influenced by P‐gp expression or function.These results demonstrate that the P‐gp modulator XR9576 exhibits greater selectivity, duration of inhibition and potency of interaction with this transporter than any other reported modulators. Several lines of evidence suggest that XR9576 inhibits P‐gp function by binding at a site which is distinct from the site of interaction of transport substrates. The two sites may be classified as serving modulatory or transport functions.

THIS study of actors and smoking examines the career exigencies and professional constraints which encourage high levels of smoking in a professional group. Ideologies of smoking are also analysed in relation to potential change in habits and conventions.

CONTENT analysis of 68 episodes of soap opera show higher frequencies of smoking in UK soaps compared with US dramas or sitcoms. In UK soaps the smoking characters tend to be portrayed as insecure or vil lainous. Preliminary results from a secondary school audience study show considerable interpenetration between the fictional presentation of smoking and children's perceptions.

A SURVEY of 861 children aged 11 to 15 plus was carried out in five schools in one educational auth ority using an anonymous questionnaire. It was found that children who had viewed the Master's Snooker Tournament sponsored by Benson and Hedges were more likely to recall the brand than non-viewers. This replication of previous findings was extended to include the effects of sponsored sport on smoking, after allowing for personality and social factors known to influence the frequency of smoking. Associations between recall, other adver tising variables and smoking were positive in all but one instance after allowing for the effects of controls.

Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of tissue-type plasminogen activator (tPA). An increase in the plasma concentration of PAI-1 has been proposed as a risk factor in thrombotic disease and elevated PAI-1 is associated with a poor prognosis in a variety of cancers. These observations have led to numerous studies addressing the physiological and pathophysiological role of PAI-1 and to the proposal that manipulation of PAI-1 activity presents a new therapeutic target. Recent experimental studies with anti-PAI-1 antibodies and low molecular weight inhibitors have demonstrated efficacy in both arterial and venous thrombosis models. These studies have confirmed the potential clinical benefit of reducing PAI-1 activity. As it is now possible to manipulate PAI-1 activity in vivo, future studies should be aimed at confirming the importance of PAI-1 as a major therapeutic target.

THIS paper collates a number of results relating to schoolgirls and smoking, particularly in relation to the mass media, and suggests a strategy for intervention.

A “datathon” model combines complementary knowledge and skills to formulate inquiries and drive research that addresses information gaps faced by clinicians.

Several letters to the editor are presented in response to articles in previous issues including Michael Billington goals for a theatre as stated in his book "State of the Nation," underpaid non-professionals performers due to tightening and cutting of entertainment budgets, and regarding Patrick Newly's recent collection of old representative actors.

In this article the readers of the journal comment on various topics including the cancellation of the play "Jane Wenham: The Witch of Walkern" by the Ipswich School for Girls in Ipswich, England, the poster of theatrical production "Photograph 51" and the death of stage director Tony Yates.

Prevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis.

A letter to the editor is presented in response to the article "Manufacturing Mayday" published in the January 2007 issue of Spectrum.

MK-0457 (VX-680) is a potent small molecule inhibitor of the Aurora-family of protein kinases that inhibits cell proliferation through aberrant mitosis and failed cytokinesis. Affected cells are subsequently deleted by apoptosis. Tumor regression and increased survival have been reported in multiple in-vivo models and in January 2005 MK-0457 entered Phase I clinical trials as the first in class Aurora inhibitor. Although MK-0457 demonstrates significant selectivity over the vast majority of kinases tested, it has been shown to potently inhibit Flt-3 and Abl, both of which are targets for anti-cancer therapies. Most notably MK-0457 potently inhibits a series of mutant Abl kinases including the multi-drug resistant T315I form that is commonly expressed in Gleevec refractory CML and ALL. We report here the first MK-0457 / Aurora co-complex crystal structure and show that it adopts a closed inactive conformation. By comparison with other reported kinase structures we provide a structural basis for the cross-reactivity with wild type and drug resistant mutants of the Abl kinase. We also show that MK-0457 blocks both Aurora and Abl cellular kinase activity and displays potent cytotoxic activity against a range of leukemic cell lines, including Gleevec resistant cells that are reliant on mutant Abl for growth and survival. Similar observations have recently been made in the clinic, where new data show that MK-0457 has activity in patients with BCR-ABL T315I mutant CML and Philadelphia positive ALL.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.