A brilliant breakthrough in OI type V

Interferon-induced transmembrane protein 5 or bone-restricted i ifitm-like gene (Bril) was first identified as a bone gene in 2008, although no in vivo role was identified at that time. A role in human bone has now been demonstrated with a number of recent studies identifying a single point mutation in Bril as the causative mutation in osteogenesis imperfecta type V (OI type V). Such a discovery suggests a key role for Bril in skeletal regulation, and the completely novel nature of the gene raises the possibility of a new regulatory pathway in bone. Furthermore, the phenotype of OI type V has unique and quite divergent features compared with other forms of OI involving defects in collagen biology. Currently it appears that the underlying genetic defect in OI type V may be unrelated to collagen regulation, which also raises interesting questions about the classification of this form of OI. This review will discuss current knowledge of OI type V, the function of Bril, and the implications of this recent discovery.

Reverie I

Reverie I is a large-scale public art work commissioned by the Brisbane City Council for permanent installation on the Gardens Point Road Plinth adjacent to QUT Gardens Point campus in Brisbane. The work forms part of the artist's ongoing exploration of the methodology of self-portraiture and amorphous form. In this work, sculpted curls of hair have been assembled according to contours of its constituent cast panels - their capacity to nest with one another determined the final form of the work. The resulting mass of curls resembles both an oversized wig, a withered mulberry and a leaden cloud to invoke notions of movement, reflection and temporality. From the didactic panel: "The curls of Reverie I are derived from 18th century sculptural portraiture. The twisting forms of the highly styled wig known as a periwig were abstracted and inventive, while also bestowing an air of intellectual authority. Curls also evoke two aspects of this particular site: the erratic movement of water associated with the complex tidal movements of Brisbane River, and a state of mental reflection relevant to both the nearby university grounds (where intellectual work takes place) and the riverside pathway (a site for daydreaming)."

Novel 3-dimensional sixfold interpenetrating diamondoid networks of copper(I) coordination polymers of polypyridyl ligands - Syntheses,characterization and crystal structures

Two new coordination polymers [Cu(L-1)(2)](n)(ClO4)(n)center dot 2nH(2)O (1), [Cu(L-2)(2)](n)(ClO4)(n)center dot 2nH(2)O (2) of polydentate imine/pyridyl ligands, L-1 and L-2 with Cu(I) ion have been synthesized and characterized by single crystal X-ray diffraction studies, elemental analyses, IR' UV-vis and NMR spectroscopy. They represent 3-dimensional, sixfold interpenetrating diamondoid network structures having large pores of dimension, 35 x 21 angstrom(2) in 1 and 38 x 19 angstrom(2) in 2, respectively.

Mediastinitis after cardiac surgery

Mediastinitis as a complication after cardiac surgery is rare but disastrous increasing the hospital stay, hospital costs, morbidity and mortality. It occurs in 1-3 % of patients after median sternotomy. The purpose of this study was to find out the risk factors and also to investigate new ways to prevent mediastinitis. First, we assessed operating room air contamination monitoring by comparing the bacteriological technique with continuous particle counting in low level contamination achieved by ultra clean garment options in 66 coronary artery bypass grafting operations. Second, we examined surgical glove perforations and the changes in bacterial flora of surgeons' fingertips in 116 open-heart operations. Third, the effect of gentamicin-collagen sponge on preventing surgical site infections (SSI) was studied in randomized controlled study with 557 participants. Finally, incidence, outcome, and risk factors of mediastinitis were studied in over 10,000 patients. With the alternative garment and textile system (cotton group and clean air suit group), the air counts fell from 25 to 7 colony-forming units/m3 (P<0.01). The contamination of the sternal wound was reduced by 46% and that of the leg wound by >90%. In only 17% operations both gloves were found unpunctured. Frequency of glove perforations and bacteria counts of hands were found to increase with operation time. With local gentamicin prophylaxis slightly less SSIs (4.0 vs. 5.9%) and mediastinitis (1.1 vs. 1.9%) occurred. We identified 120/10713 cases of postoperative mediastinitis (1.1%). During the study period, the patient population grew significantly older, the proportion of women and patients with ASA score >3 increased significantly. In multivariate logistic regression analysis, the only significant predictor for mediastinitis was obesity. Continuous particle monitoring is a good intraoperative method to control the air contamination related to the theatre staff behavior during individual operation. When a glove puncture is detected, both gloves are to be changed. Before donning a new pair of gloves, the renewed disinfection of hands will help to keep their bacterial counts lower even towards the end of long operation. Gentamicin-collagen sponge may have beneficial effects on the prevention of SSI, but further research is needed. Mediastinitis is not diminishing. Larger populations at risk, for example proportions of overweight patients, reinforce the importance of surveillance and pose a challenge in focusing preventive measures.

Prevalence and determinants of respiratory symptoms, asthma, chronic bronchitis and allergic sensitization in Helsinki : A comparison between Finland, Sweden and Estonia. The FinEsS studies - Helsinki I

Objectives: To assess the prevalence and risk factor profiles of respiratory symptoms, asthma and chronic bronchitis in Helsinki, and to compare these results with those for Sweden and Estonia. Other important aims were to evaluate the prevalence and determinants of type 1 sensitization in Helsinki. Materials and methods: This presentation is a part of a large epidemiological study in Finland, Estonia and Sweden (FinEsS). The first part of the study consisted of a postal questionnaire in 1995-1996 distributed to subjects in eight study centres. The study population in each centre was a population-based random sample designed to be representative of the general population. The original study sample in Helsinki consisted of 8000 subjects aged 20-69 years, 6062 (76%) of whom participated. Comparisons between countries were based on a narrower age group, 20-64 years, since 64 years was the upper age limit used in the original study in Estonia. Thus, altogether 58 661 subjects aged 20-64 years were invited to participate in Finland, Sweden and Estonia, and 44 483 (76%) did so. The second part of the study was a clinical study with a structured interview, lung function measurements and skin-prick tests with 15 common allergens. This thesis reports only the results of the prick tests in Helsinki. Of the 1200 subjects invited to participate in Helsinki, 643 (54%) consented. Skin-prick tests were performed on subjects ≤ 60 years of age; thus, a total of 498 tests were done. Results: In Helsinki, the prevalence of physician-diagnosed asthma was 6.6% and of physician-diagnosed chronic bronchitis 3.7% among subjects aged 20-69 years. Comparison of the results between Finland, Sweden and Estonia in subjects 20-64 years of age revealed the highest prevalence of physician-diagnosed asthma in Sweden, 7.8%, while the prevalence in Finland was 5.9% and in Estonia 2.0% (p<0.001). The prevalence of physician-diagnosed asthma among those aged 20-29 years was 7.9% in Stockholm, 6.3% in Helsinki and 2.8% in Tallinn. Asthma-related symptoms were most common in Estonia, and among those with typical asthma symptoms the diagnosis of asthma was least likely in Estonia. Physician-diagnosed chronic bronchitis was reported to be 10.7% in Estonia, 3.1% in Sweden and 2.9% in Finland among subjects aged 20-64 years (p<0.001). Among those aged 20-29 years, 7.6% in Tallinn reported physician-diagnosed chronic bronchitis, while the prevalence estimates were 1.4% in Stockholm and 1.3% in Helsinki. The prevalence of smoking was similar for women in all three countries, around 30%, but large differences in smoking habits were present among men; 60% of Estonian, 39% of Finnish and 28% of Swedish men smoked. Skin-prick tests in Helsinki revealed a high prevalence of sensitization, 46.9%. For subjects aged 26-39 years, the prevalence was highest, 56.8%, and 23.7% were sensitized to at least four allergens. The most common sensitizing allergen was the dog. Sensitization to multiple allergens was associated with a high prevalence of asthma and allergic rhinitis. Conclusions: Compared with earlier Finnish studies, a higher prevalence of asthma and a lower prevalence of chronic bronchitis were found in Helsinki. The prevalence of physician-diagnosed chronic bronchitis was low in Helsinki, with only one-fifth of subjects fulfilling the symptom criteria for chronic bronchitis reporting having a diagnosis of chronic bronchitis. The prevalences of asthma and chronic bronchitis were similar in Finland and Sweden, but in Estonia physician-diagnosed asthma was less common and physician-diagnosed chronic bronchitis more common, particularly among young subjects. Further analyses revealed that the diagnosis of asthma was favoured in Finland and Sweden, while the diagnosis of chronic bronchitis was more likely in Estonia for subjects with the same symptoms. Allergic sensitization was common in Helsinki. Our findings of multiple sensitization also speak in favour of evaluating the degree of sensitization when assessing allergies.

Ligand Specificity of Group I Biotin Protein Ligase of Mycobacterium tuberculosis

Background: Fatty acids are indispensable constituents of mycolic acids that impart toughness & permeability barrier to the cell envelope of M. tuberculosis. Biotin is an essential co-factor for acetyl-CoA carboxylase (ACC) the enzyme involved in the synthesis of malonyl-CoA, a committed precursor, needed for fatty acid synthesis. Biotin carboxyl carrier protein (BCCP) provides the co-factor for catalytic activity of ACC. Methodology/Principal Findings: BPL/BirA (Biotin Protein Ligase), and its substrate, biotin carboxyl carrier protein (BCCP) of Mycobacterium tuberculosis (Mt) were cloned and expressed in E. coli BL21. In contrast to EcBirA and PhBPL, the similar to 29.5 kDa MtBPL exists as a monomer in native, biotin and bio-5'AMP liganded forms. This was confirmed by molecular weigt profiling by gel filtration on Superdex S-200 and Dynamic Light Scattering (DLS). Computational docking of biotin and bio-5'AMP to MtBPL show that adenylation alters the contact residues for biotin. MtBPL forms 11 H-bonds with biotin, relative to 35 with bio-5'AMP. Docking simulations also suggest that bio-5'AMP hydrogen bonds to the conserved `GRGRRG' sequence but not biotin. The enzyme catalyzed transfer of biotin to BCCP was confirmed by incorporation of radioactive biotin and by Avidin blot. The K-m for BCCP was similar to 5.2 mu M and similar to 420 nM for biotin. MtBPL has low affinity (K-b = 1.06 x 10(-6) M) for biotin relative to EcBirA but their K-m are almost comparable suggesting that while the major function of MtBPL is biotinylation of BCCP, tight binding of biotin/bio-5'AMP by EcBirA is channeled for its repressor activity. Conclusions/Significance: These studies thus open up avenues for understanding the unique features of MtBPL and the role it plays in biotin utilization in M. tuberculosis.

Cutaneous porphyrias : Clinical and histopathological study

The prevalence of variegate porphyria (VP) (2.1:100 000, in 2006 n=108) was higher in Finland than elsewhere in European countries due to a founder effect (R152C). The incidence of VP was estimated at 0.2:1 000 000 based on the number of new symptomatic patients yearly. The prevalence of porphyria cutanea tarda (PCT) was 1.2:100 000 (in 2006 n=63), which is only one fourth of the numbers reported from other European countries. The estimated incidence of PCT was 0.5:1 000 000. Based on measurements of the uroporphyrinogen decarboxylase activity in erythrocytes, the proportion of familial PCT was 49% of the cases. The prevalence of erythropoietic protoporphyria (EPP) was at 0.8:100 000 (in 2006 n=39) including asymptomatic carriers of a mutation in the ferrochelatase (FECH) gene. The incidence of EPP was estimated at 0.1:1 000 000. After 1980 the penetrance was 37% among patients with VP. Of the mutation carriers (n=57) 30% manifested with skin symptoms. Frequency of skin symptom as only clinical sign was stable before or after 1980 (22% vs. 21%), but acute attacks became infrequent (29% vs. 7%). Of the symptomatic patients 30% had both acute attacks and skin symptoms and 80% had skin symptoms. Fragility (95%) and blistering (46%) of the skin in the backs of the hands were the most common skin symptoms. Transient correction of porphyrin metabolism using eight haem arginate infusions within five weeks had no effect on the skin symptoms in three of four patients with VP. In one case skin symptoms disappeared transiently. One patient with homozygous VP had severe photosensitivity since birth. Sensory polyneuropathy, glaucoma and renal failure developed during the 25-year follow-up without the presence of acute attacks. The I12T mutation was detected in both of his alleles in the protoporphyrinogen oxidase gene. Lack of skin symptoms and infrequency of acute attacks (1/9) in the patients with I12T mutation at the heterozygous stage indicate a mild phenotype (the penetrance 11%). Four mutations (751delGAGAA, 1122delT, C286T, C343T) in the FECH gene were characterised in four of 15 families with EPP. Burning pain (96%) and swelling (92%) of the sun-exposed skin were the major skin symptoms. Hepatopathy appeared in one of 25 symptomatic patients (4%). Clinical manifestations and associated factors of PCT were similar in the sporadic and familial types of PCT. The majority of the patients with PCT had one to three precipitating factors: alcohol intake (78%), mutations in hemochromatosis associated gene (50%), use of oestrogen (25% of women) and hepatitis B or C infections (25 %). Fatty liver disease (67%) and siderosis (67%) were commonly found in their liver biopsies. The major histopathological change of the sun-exposed skin in the patients with VP (n=20), EPP (n=8) and PCT (n=5) was thickening of the vessel walls of the upper dermis suggesting that the vessel wall is the primary site of the phototoxic reaction in each type of porphyria. The fine structure of the vessel walls was similar in VP, EPP and PCT consisting of the multilayered basement membrane and excess of finely granular substance between the layers which were surrounded by the band of homogenous material. EPP was characterised by amorphous perivascular deposits extending also to the extravascular space. In direct immunofluorescence study homogenous IgG deposits in the vessel walls of the upper dermis of the sun-exposed skin were demonstrated in each type of porphyria. In EPP the excess material around vessel walls consisted of other proteins such as serum amyloid protein, and kappa and lambda light chains in addition to the basement membrane constituents such as collagen IV and laminin. These results suggest that the alterations of the vessel walls are a consequence of the repeated damage and the repairing process in the vessel wall. The microscopic alterations could be demonstrated even in the normal looking but sun-exposed skin of the patients with EPP during the symptom-free phase suggesting that vascular change can be chronic. The stability of vascular changes in the patients with PCT after treatment indicates that circulating porphyrins are not important for the maintenance of the changes.

I build my dwelling

'I build my dwelling' was an exhibition of works including ‘Muscle flex’, ‘Language is, Language is not’, ‘S.O.S’ and the ‘Studio Remix’, held at Metro Arts Galleries, Brisbane in 2012. This body of work pursues a feminist engagement with art history and philosophy, engaging with pictorial, literary and vernacular quotations in order to replay and reveal the complexities of gender politics, representation and language.

The dynamics of magnetically trapped fluids. I - Implications for umbral dots and penumbral grains

A study of the magnetohydrodynamic system in which a nonmagnetized fluid in a gravitational field is surrounded by a fluid carrying a vertical magnetic field is presented. It is pointed out that this study can throw some light on the fine-structural features of a sunspot. The equilibrium configuration of the field-free fluid is a tapering column ending at an apex. The regions away form the apex can be studied by the slender flux tube approximation. A scheme developed to treat the apex indicates that, just below the apex, the radius of the tapering column opens up with a 3/2 power dependence on the depth below the apex. If the internal pressure of the field-free fluid is increased, the apex rises, and a static equilibrium may not be possible beyond a limit if the magnetic pressure drops quickly above a certain height. The nature of steady-flow solutions beyond this limit is investigated. Under conditions inside a sunspot, a column of field-free gas is found to rise with a velocity of about 100 km/hr. If umbral dots and penumbral grains are interpreted as regions where the field-free gas ultimately emerges, a very natural explanation of most of their observed properties is obtained.

Recognition, comorbidity, and outcome of DSM-IV bipolar I and II disorders in psychiatric care

This study is part of an ongoing collaborative bipolar research project, the Jorvi Bipolar Study (JoBS). The JoBS is run by the Department of Mental Health and Alcohol Research of the National Public Health Institute, Helsinki, and the Department of Psychiatry, Jorvi Hospital, Helsinki University Central Hospital (HUCH), Espoo, Finland. It is a prospective, naturalistic cohort study of secondary level care psychiatric in- and outpatients with a new episode of bipolar disorder (BD). The second report also included 269 major depressive disorder (MDD) patients from the Vantaa Depression Study (VDS). The VDS was carried out in collaboration with the Department of Psychiatry of the Peijas Medical Care District. Using the Mood Disorder Questionnaire (MDQ), all in- and outpatients at the Department of Psychiatry at Jorvi Hospital who currently had a possible new phase of DSM-IV BD were sought. Altogether, 1630 psychiatric patients were screened, and 490 were interviewed using a semistructured interview (SCID-I/P). The patients included in the cohort (n=191) had at intake a current phase of BD. The patients were evaluated at intake and at 6- and 18-month interviews. Based on this study, BD is poorly recognized even in psychiatric settings. Of the BD patients with acute worsening of illness, 39% had never been correctly diagnosed. The classic presentations of BD with hospitalizations, manic episodes, and psychotic symptoms lead clinicians to correct diagnosis of BD I in psychiatric care. Time of follow-up elapsed in psychiatric care, but none of the clinical features, seemed to explain correct diagnosis of BD II, suggesting reliance on cross- sectional presentation of illness. Even though BD II was clearly less often correctly diagnosed than BD I, few other differences between the two types of BD were detected. BD I and II patients appeared to differ little in terms of clinical picture or comorbidity, and the prevalence of psychiatric comorbidity was strongly related to the current illness phase in both types. At the same time, the difference in outcome was clear. BD II patients spent about 40% more time depressed than BD I patients. Patterns of psychiatric comorbidity of BD and MDD differed somewhat qualitatively. Overall, MDD patients were likely to have more anxiety disorders and cluster A personality disorders, and bipolar patients to have more cluster B personality disorders. The adverse consequences of missing or delayed diagnosis are potentially serious. Thus, these findings strongly support the value of screening for BD in psychiatric settings, especially among the major depressive patients. Nevertheless, the diagnosis must be based on a clinical interview and follow-up of mood. Comorbidity, present in 59% of bipolar patients in a current phase, needs concomitant evaluation, follow-up, and treatment. To improve outcome in BD, treatment of bipolar depression is a major challenge for clinicians.

Pathobiological Aspects of Nonreheumatic Aortic Valve Stenosis

Aortic valve stenosis (AS) is an active disease process akin to atherosclerosis, with chronic inflammation, lipid accumulation, extracellular matrix remodeling, fibrosis, and extensive calcification of the valves being characteristic features of the disease. The detailed mechanisms and pathogenesis of AS are still incompletely understood, however, and pharmacological treatments targeted toward components of the disease are not currently available. In this thesis project, my coworkers and I studied stenotic aortic valves obtained from 86 patients undergoing valve replacement for clinically significant AS. Non-stenotic control valves (n=17) were obtained from patients undergoing cardiac transplantation or from organ donors without cardiac disease. We identified a novel inflammatory factor, namely mast cell, in stenotic aortic valves and present evidence showing that this multipotent inflammatory cell may participate in the pathogenesis of AS. Using immunohistochemistry and double immunofluorescence stainings, we found that a considerable number of mast cells accumulate in stenotic valves and, in contrast to normal valves, the mast cells in diseased valves were in an activated state. Moreover, valvular mast cells contained two effective proteases, chymase and cathepsin G, which may participate in adverse remodeling of the valves either by inducing fibrosis (chymase and cathepsin G) or by degrading elastin fibers in the valves (cathepsin G). As chymase and cathepsin G are both capable of generating the profibrotic peptide angiotensin II, we also studied the expression and activity of angiotensin-converting enzyme (ACE) in the valves. Using RT-PCR, imunohistochemistry, and autoradiography, we observed a significant increase in the expression and activity of ACE in stenotic valves. Besides mast cell-derived cathepsin G, aortic valves contained other elastolytic cathepsins (S, K, and V). Using immunohistochemistry, RT-PCR, and fluorometric microassay, we showed that the expression and activity of these cathepsins were augmented in stenotic valves. Furthermore, in stenotic but not in normal valves, we observed a distinctive pattern of elastin fiber degradation and disorganization. Importantly, this characteristic elastin degradation observed in diseased valves could be mimicked by adding exogenous cathepsins to control valves, which initially contained intact elastin fibers. In stenotic leaflets, the collagen/elastin ratio was increased and correlated positively with smoking, a potent AS-accelerating factor. Indeed, cigarette smoke could also directly activate cultured mast cells and fibroblasts. Next, we analyzed the expression and activity of neutral endopeptidase (NEP), which parallels the actions of ACE in degrading bradykinin (BK) and thus inactivates antifibrotic mechanisms in tissues. Real-time RT-PCR and autoradiography revealed NEP expression and activity to be enhanced in stenotic valves compared to controls. Furthermore, both BK receptors (1 and 2) were present in aortic valves and upregulated in stenotic leaflets. Isolated valve myofibroblasts expressed NEP and BK receptors, and their upregulation occurred in response to inflammation. Finally, we observed that the complement system, a source of several proinflammatory mediators and also a potential activator of valvular mast cells, was activated in stenotic valves. Moreover, receptors for the complement-derived effectors C3a and C5a were expressed in aortic valves and in cultured aortic valve myofibroblasts, in which their expression was induced by inflammation as well as by cigarette smoke. In conclusion, our findings revealed several novel mechanisms of inflammation (mast cells and mast cell-derived mediators, complement activation), fibrosis (ACE, chymase, cathepsin G, NEP), and elastin fiber degradation (cathepsins) in stenotic aortic valves and highlighted these effectors as possible pathogenic contributors to AS. These results support the notion of AS as an active process with inflammation and extracellular matrix remodeling as its key features and identify possible new targets for medical therapy in AS.

Tacrolimus ointment for long-term treatment of atopic dermatitis

Atopic dermatitis (AD) or atopic eczema is characterised by a superficial skin inflammation with an overall Th2 cell dominance and impaired function of the epidermal barrier. Patients also are at an increased risk for asthma and allergic rhinitis. Treatment with tacrolimus ointment inhibits T cell activation and blocks the production of several inflammatory cytokines in the skin, without suppressing collagen synthesis. The aims of this thesis were to determine: (1) long-term efficacy, safety, and effects on cell-mediated immunity and serum IgE levels in patients with moderate-to-severe AD treated for 1 year with tacrolimus ointment or a corticosteroid regimen, (2) the 10-year outcome of eczema, respiratory symptoms, and serum IgE levels in AD patients initially treated long-term with tacrolimus ointment, and (3) pharmacokinetics and long-term safety and efficacy of 0.03% tacrolimus ointment in infants under age 2 with AD. Cell-mediated immunity, reflecting Th1 cell reactivity, was measured by recall antigens and was at baseline lower in patients with AD compared to healthy controls. Treatment with either 0.1% tacrolimus ointment or a corticosteroid regimen for one year enhanced recall antigen reactivity. Transepidermal water loss (TEWL), an indicator of skin barrier function, decreased at months 6 and 12 in both tacrolimus- and corticosteroid-treated patients; TEWL for the head and neck was significantly lower in tacrolimus-treated patients. Patients in the 10-year open follow-up study showed a decrease in affected body surface area from a baseline 19.0% to a 10-year 1.6% and those with bronchial hyper-responsiveness at baseline showed an increase in the provocative dose of inhaled histamine producing a 15% decrease in FEV1, indicating less hyper-responsiveness. Respiratory symptoms (asthma and rhinitis) reported by the patient decreased in those with active symptoms at baseline. A good treatment response after one year of tacrolimus treatment predicted a good treatment response throughout the 10-year follow-up and a decrease in total serum IgE levels at the 10-year follow-up visit. The 2-week pharmacokinetic and the long-term study with 0.03% tacrolimus ointment showed good and continuous improvement of AD in the infants. Tacrolimus blood levels were throughout the study low and treatment well tolerated. This thesis underlines the importance of effective long-term topical treatment of AD. When the active skin inflammation decreases, cell-mediated immunity of the skin improves and a secondary marker for Th2 cell reactivity, total serum IgE, decreases. Respiratory symptoms seem to improve when the eczema area decreases. All these effects can be attributed to improvement of skin barrier function. One potential method to prevent a progression from AD to asthma and allergic rhinitis may be avoidance of early sensitisation through the skin, so early treatment of AD in infants is crucial. Long-term treatment with 0.03% tacrolimus ointment was effective and safe in infants over age 3 months.

Catalytic cyclopropanation of olefins using copper(I) diphosphinoamines

Catalytic cyclopropanation reactions of olefins with ethyl diazoacetate were carried out using copper(I) diphosphinoamine (PPh2)(2)N(R) (R = Pr-i, H, Ph and -CH2-C6H4-CH=CH2) complexes at 40 degrees C in chloroform. High yields of the cyclopropanes were obtained in all cases. The rate of the reaction was influenced by the nuclearity of the complex and the binding mode of the ligand which was either bridging or chelating. Comparison of isostructural complexes shows that the rate follows the order R = Pr-i > H > Ph, where R is the substituent on the N. However, cyclopropane formation versus dimerization of the carbene, and trans to cis ratios of cyclopropane was similar in all cases. The nearly identical selectivity for different products formed was indicative of a common catalytic intermediate. A labile "copper-olefin" complex which does not involve the phosphine or the counterion is the most likely candidate. The differences in the reaction rates for different complexes are attributed to differences in the concentration of the catalytically active species which are in equilibrium with the catalytically inactive copper-phosphinoamine complex. To test the hypothesis a diphosphinoamine polymer complexed to copper(I) was used as a heterogeneous catalyst. Leaching of copper(I) and deactivation of the catalyst confirmed the proposed mechanism. (C) 2008 Elsevier B. V. All rights reserved.

Chelating and bridging diphosphinoamine (PPh2)(2)N(Pr-i) complexes of copper(I)

The ligand bis(diphenylphosphino) isopropylamine (dppipa) has been shown to be a versatile ligand sporting different coordination modes and geometries dictated by copper(I). Most of the molecular structures were confirmed by X-ray crystallography. It is found in a chelating mode, in a monomeric complex when the ligand to copper ratio is 2:1. A tetrameric complex is formed when low ratios of ligand to metal (1: 2) were used. But with increasing ratios of ligand to metal (1: 1 and 2: 1), a trimer or a dimer was obtained depending on the crystallization conditions. Variable temperature P-31{H-1} NMR spectra of these complexes in solution showed that the Cu-P bond was labile and the highly strained 4-membered structure chelate found in the solid state readily converted to a bridged structures. On the other hand, complexes with the ligand in a bridging mode in the solid state did not form chelated structures in solution. The effect of adding tetra-alkylammonium salts to solutions of various complexes of dppipa were probed by P-31{H-1} NMR and revealed the effect of counter ions on the stability of complexes in solution. (C) 2008 Elsevier B.V. All rights reserved.

Individual variation in in vitro efficacy of antiplatelet medication - aspirin and clopidogrel

Antiplatelet medication is known to decrease adverse effects in patients with atherothrombotic disease. However, despite ongoing antiplatelet medication considerable number of patients suffer from atherothrombotic events. The aims of the study were 1) to evaluate the individual variability in platelet functions and compare the usability of different methods in detecting it, 2) to assess variability in efficacy of antiplatelet medication with aspirin (acetylsalicylic acid) or the combination of aspirin and clopidogrel and 3) to investigate the main genetic and clinical variables as well as potential underlying mechanisms of variability in efficacy of antiplatelet medication. In comparisons of different platelet function tests in 19 healthy individuals PFA-100® correlated with traditional methods of measuring platelet function and was thus considered appropriate for testing individual variability in platelet activity. Efficacy of ongoing 100mg aspirin daily was studied in 101 patients with coronary artery disease (CAD). Aspirin response was measured with arachidonic acid (AA)-induced platelet aggregation, which reflects cyclo-oxygenase (COX)-1 dependent thromboxane (Tx) A2 formation, and PFA-100®, which evaluates platelet activation under high shear stress in the presence of collagen and epinephrine. Five percent of patients failed to show inhibition of AA-aggregation and 21% of patients had normal PFA-100® results despite aspirin and were thus considered non-responders to aspirin. Interestingly, the two methods of assessing aspirin efficacy, platelet aggregation and PFA-100®, detected different populations as being aspirin non-responders. It could be postulated that PFA-100® actually measures enhanced platelet function, which is not directly associated with TxA2 inhibition exerted by aspirin. Clopidogrel efficacy was assessed in 50 patients who received a 300mg loading dose of clopidogrel 2.5 h prior to percutaneous coronary intervention (PCI) and in 51 patients who were given a loading dose of 300mg combined with a five day treatment of 75mg clopidogrel daily mimicking ongoing treatment. Clopidogrel response was assessed with ADP-induced aggregations, due to its mechanism of action as an inhibitor of ADP-induced activation. When patients received only a loading dose of clopidogrel prior to PCI, 40% did not gain measurable inhibition of their ADP-induced platelet activity (inhibition of 10% or less). Prolongation of treatment so that all patients had reached a plateau of inhibition exerted by clopidogrel, decreased the incidence of non-responders to 20%. Polymorphisms of COX-1 and GP VI, as well as diabetes and female gender, were associated with decreased in vitro aspirin efficacy. Diabetes also impaired the in vitro efficacy of short-term clopidogrel. Decreased response to clopidogrel was associated with limited inhibition by ARMX, an antagonist of P2Y12-receptor, suggesting the reason for clopidogrel resistance to be receptor-dependent. Conclusions: Considerable numbers of CAD patients were non-responders either to aspirin, clopidogrel or both. In the future, platelet function tests may be helpful to individually select effective and safe antiplatelet medication for these patients.