Aim Many patients who are eligible for acute reperfusion therapy receive it after substantial delays or not at all. We wanted to determine whether over the years more patients are receiving ...reperfusion therapy. Methods and results This analysis is based on 10 954 patients with ST elevation or left bundle-branch block presenting within 12 h of symptom onset and enrolled in the GRACE registry between April 1999 and June 2006. Over this time, there was an increasing trend in use of primary percutaneous coronary intervention (PCI) from 15% to 44% (P < 0.001), while use of fibrinolytic therapy decreased (from 41 to 16%; P < 0.01). No trend in median time to primary PCI was seen but that for fibrinolysis declined significantly (from 40 to 34%; P < 0.0001). Hospital mortality declined (6.9–5.4%; P < 0.01); the relationship between observed and expected mortality improved over time (P = 0.06). Nevertheless, 33% of patients still received no reperfusion therapy. Factors associated with reperfusion use included age; prior myocardial infarction, heart failure or coronary artery bypass graft surgery; history of diabetes; female sex; and delay from symptom onset to hospital arrival. In 2006, 52% of patients receiving fibrinolysis had door-to-needle times >30 min and 42% of those undergoing primary PCI had door-to-balloon times >90 min. Conclusion Primary PCI is now used much more than fibrinolysis. Although hospital mortality and delays to fibrinolytic reperfusion have improved, over 40% of patients reperfused still receive it outside the time window recommended, and one-third of potentially eligible patients receive no reperfusion.
Neurospora crassa ARG13 and Saccharomyces cerevisiae ARG11 encode mitochondrial carrier family (MCF) proteins that transport ornithine across the mitochondrial inner membrane. We used their sequences ...to identify EST candidates that partially encode orthologous mammalian transporters. We thereby identified such a gene (ORNT1) that maps to 13q14 and whose expression, similar to that of other urea cycle (UC) components, was high in liver and varied with changes in dietary protein. ORNT1 expression restores ornithine metabolism in fibroblasts from patients with hyperammonaemia-hyperornithinaemia-homocitrullinuria (HHH) syndrome. In a survey of 11 HHH probands, we identified 3 ORNT1 mutant alleles that account for 21 of 22 possible mutant ORNT1 genes in our patients: F188delta, which is common in French-Canadian HHH patients and encodes an unstable protein; E180K, which encodes a stable, properly targeted protein that is inactive; and a 13q14 microdeletion. Our results show that ORNT1 encodes the mitochondrial ornithine transporter involved in UC function and is defective in HHH syndrome.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objectives: In patients with glutaric acidemia type 1 (GAI), biochemical and molecular markers fail to predict the course of individual patients; therefore we sought to identify nonbiochemical ...variables that correlate with severity of motor deficits or overall clinical outcome. Study design: Archival data was collected from 42 published articles describing 115 patients with GA1. A forward, stepwise, multiple regression analysis was used to find predictors for outcome. Results: Analyses show that in patients who did not have a precipitating illness before the first appearance of motor symptoms, the age at onset was significantly associated with the severity of motor impairments and overall clinical outcome. In patients who had a precipitating illness, the age at onset did not predict the outcome. In both groups of patients, basal ganglia degeneration, enlargement of spaces containing cerebrospinal fluid, and white matter abnormalities were indicative of a poorer prognosis. Treatment given after the appearance of symptoms was not associated with a better clinical outcome or fewer motor deficits. Conclusion: Because the age at symptom onset can significantly predict the severity of motor deficits and the overall outcome, it is important to identify patients with GA1 as early as possible. Several studies suggest that presymptomatic treatment may prevent or postpone the onset of symptoms. (J Pediatr 2000;137:681-6)
BACKGROUND AND PURPOSE Recently identified antagonists of the urotensin–II (U‐II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U‐II due to poor potency and ...limited selectivity and/or intrinsic activity.
EXPERIMENTAL APPROACH The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.
KEY RESULTS GSK1440115 (pKi= 7.34–8.64 across species) and GSK1562590 (pKi= 9.14–9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100‐fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA2= 5.59–7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pKb= 8.93–10.12 across species), but a competitive antagonist in monkey arteries (pKb= 8.87–8.93). Likewise, GSK1562590 inhibited the hU‐II‐induced systemic pressor response in anaesthetized cats at a dose 10‐fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU‐II‐induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT.
CONCLUSIONS AND IMPLICATIONS Whereas both GSK1440115 and GSK1562590 represent high‐affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U‐II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo.
Although digoxin is one of the most commonly prescribed drugs for the treatment of heart failure, there is uncertainty about its long-term efficacy and safety.
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Several recent short-term, ...randomized trials indicated that withdrawing digoxin worsens functional status, exercise capacity, and the left ventricular ejection fraction in patients with heart failure.
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However, the long-term effect of digoxin on mortality and hospitalization for heart failure or other causes is unknown. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the effects of digoxin (Lanoxin, Glaxo Wellcome) on mortality from any cause (the primary end point) and on hospitalization for heart . . .
A full‐term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations ...between other pregnancy‐related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case‐control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one‐ and two‐stage meta‐analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full‐term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full‐term pregnancy (OR = 0.59, 95% confidence interval CI 0.56‐0.63). The risk reduction appeared the greatest for the first full‐term pregnancy (OR = 0.78, 95% CI 0.72‐0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14‐0.28) that was independent of age at last full‐term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%‐9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full‐term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full‐term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
What's new?
Having a full‐term pregnancy reduces a woman's risk of endometrial cancer, perhaps due to a protective effect from high levels of progesterone in the third trimester. Here, the authors conducted a pooled analysis of 11 cohort studies and 19 case‐control studies to learn more about the effect of multiple pregnancies on endometrial cancer risk. They found that up to eight full‐term pregnancies each reduced endometrial cancer risk, independent of maternal age and oral contraceptive use. Interestingly, incomplete pregnancies were associated with a smaller reduction in risk, suggesting that high third trimester progesterone levels are not the only contributing factor.
A new species of shrew tenrec (Microgale) is described from the central western and southwestern portion of Madagascar. Based on pelage, morphology, and DNA sequence data, this new species can be ...readily distinguished from its sister taxon, M. brevicaudata. Mitochondrial DNA (mtDNA) divergences between the 2 species are on par with those observed in other closely related shrew tenrecs, and both taxa are recovered as reciprocally monophyletic haplotype clades. Furthermore, mtDNA sequence obtained from the holotype of Paramicrogale occidentalis confirms that the name occidentalis cannot be assigned to the new taxon and is a junior synonym of M. brevicaudata. Microgale new species and M. brevicaudata have latitudinally overlapping distributions, and although they are not known to occur in direct sympatry, specimens of both species have recently been collected at sites within 50 km of each other on opposite sides of the Soahany River in central western Madagascar. However, the respective distributions of these 2 species, among the most diminutive of Madagascar's endemic terrestrial mammal fauna, suggest that rivers do not serve as significant barriers to dispersal. Historical demographic analysis under a coalescence framework suggests that the northerly distributed M. brevicaudata has experienced a recent population expansion, whereas the new species described herein has undergone a population decline. Little is known about the ecology of Microgale new species, but it lives in dry forest formations. This species is known from sites within several protected areas (Bemaraha and Namoroka), as well as forest parcels currently proposed as new conservation zones. However, toward the southern limit of its known distribution, at the north bank of the Onilahy River, there is continued extensive anthropogenic habitat loss that may warrant future monitoring.
We carried out extensive field surveys in the dry forest portions of Madagascar to document the species of bats occurring in these regions. These data combined with information in the literature and ...museum specimen records indicate that 28 species of Chiroptera occur in this region of the island, of which we documented 27 during our inventories. The community composition at sites occurring in areas of water-eroded sedimentary rock is notably different from sites on alluvial substrates. In contrast to the majority of native land mammal species on Madagascar, much of the microchiropteran fauna is not dependent on large tracts of intact forest and anthropogenic perturbations of forests may have less direct impact on their long-term survival. Conservation strategies for Chiroptera in the dry regions of the island should focus on reducing various types of human disturbance of cave environments.
Ammonia adsorption has been studied on an Ir(100) surface in the temperature range 100−410 K. In contrast to previous studies on Ir(111), approximately 12% of the chemisorbed ammonia undergoes ...stepwise decomposition at 200 K. However, decomposition has been found to be an activated process wherein a difference in the activation energy of dissociation and desorption is estimated to be 21 kJ/mol. Recombinative nitrogen desorption, occurring at temperature as low as 500 K, has been found to be the crucial step for having continuous and efficient ammonia decomposition with an activation energy of 64 kJ/mol. Coadsorption of hydrogen and ammonia have been carried out to understand the partial pressure dependences for ammonia decomposition---0.9 ± 0.1 with respect to ammonia and −0.7 ± 0.1 with respect to hydrogen. Coadsorption data indicate that the negative order with respect to hydrogen is due to enhancement of the reverse reaction (NH x + H → NH x +1, x = 0−2) as well as reduction in the desorption temperature of ammonia in the presence of excess H-atoms on the surface. In contrast, coadsorbed oxygen acts as a promoter for the ammonia dissociation and leads to 100% ammonia conversion. The differences in the decomposition behavior with respect to the previous results for Ir(111) are indicative of the structure sensitivity of the reaction.
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