Safety and clinical outcome of thrombolysis in ischaemic stroke using a perfusion CT mismatch between 3 and 6 hours

Objective

It may be possible to thrombolyse ischaemic stroke (IS) patients up to 6 h by using penumbral imaging. We investigated whether a perfusion CT (CTP) mismatch can help to select patients for thrombolysis up to 6 h.

Methods

A cohort of 254 thrombolysed IS patients was studied. 174 (69%) were thrombolysed at 0–3 h by using non-contrast CT (NCCT), and 80 (31%) at 3–6 h (35 at 3–4.5 h and 45 at 4.5–6 h) by using CTP mismatch criteria. Symptomatic intracerebral haemorrhage (SICH), the mortality and the modified Rankin Score (mRS) were assessed at 3 months. Independent determinants of outcome in patients thrombolysed between 3 and 6 h were identified.

Results

The baseline characteristics were comparable in the two groups. There were no differences in SICH (3% v 4%, p = 0.71), any ICH (7% v 9%, p = 0.61), or mortality (16% v 9%, p = 0.15) or mRS 0–2 at 3 months (55% v 54%, p = 0.96) between patients thrombolysed at 0–3 h (NCCT only) or at 3–6 h (CTP mismatch). There were no significant differences in outcome between patients thrombolysed at 3–4.5 h or 4.5–6 h. The NIHSS score was the only independent determinant of a mRS of 0–2 at 3 months (OR 0.89, 95% CI 0.82–0.97, p = 0.007) in patients treated using CTP mismatch criteria beyond 3 h.

Conclusions

The use of a CTP mismatch model may help to guide thrombolysis decisions up to 6 h after IS onset.     

A model for the study of diffusion and perfusion limitation

On the basis of a very simple model for the association of diffusion and perfusion, an association common to many respiratory gas transfers, a simple equation is described that defines gas partial pressure equilibration in diffusion-perfusion-limited systems as a function of the ratio of D to beta bQ(D = diffusing capacity, beta b = blood capacitance coefficient, Q = perfusion). The equation applies to steady-state conditions and assumes D, beta b, and Q to be independent of gas partial pressures. In spite of the fact that this assumption may represent a gross simplification, the equation can be regarded as a powerful conceptual tool in the analysis of most gas exchange systems.     

The interaction of diffusion and perfusion in homogeneous tissue

A mathematical model is proposed to examine the interaction between blood perfusion and gas diffusion in the uptake of inert gases in tissue. The standard Haldane perfusion model is contrasted with the Hills radial bulk diffusion model in a variety of homogeneous tissue types used in decompression theory. It is the intention of the present analysis to fix ideas on the role of diffusion, perfusion and axial concentration and quantitative studies are given and seem to show that Haldane's perfusion theory is at best a poor approximation even at asymptotic times. It is shown that a strong interaction exists between diffusion and perfusion in muscle tissue and neither approach adequately describes the actual uptake half-time of an inert gas.     

Stability and dynamics of G-actin: back-door water diffusion and behavior of a subdomain 3/4 loop.

Molecular dynamics simulations have been performed on solvated G-actin bound to ADP and ATP, starting with the crystal structure of the actin-DNase 1 complex, including a Ca2+ or Mg2+ ion at the high-affinity divalent cation-binding site. Water molecules have been found to enter the nucleotide-binding site (phosphate vicinity) along two pathways, from the side where the nucleotide base is exposed to water, as well as from the opposite side. The water channels suggest a "back-door" mechanism for ATP hydrolysis in which the phosphate is released to a side opposite that of nucleotide binding and unbinding. The simulations also reveal a propensity of G-actin to alter its crystallographic structure toward the filamentous structure. Domain movement closes the nucleotide cleft, the movement being more pronounced for bound Mg2+. The conformational change is interpreted as a response of the system to missing water molecules in the crystal structure. The structures arising in the simulations, classified according to nucleotide cleft separation and radius of gyration of the protein, fall into two distinct clusters: a cluster of states that are similar to the G-actin crystal structure, and a cluster of states with small cleft separation and with the subdomain 3/4 loop 264-273 detached from the protein. The latter states resemble the putative filamentous structure of actin, in which the loop connects the two strands of the actin filament.     

Enterohepatic circulation of N-acetyl-leukotriene E4

N-Acetyl-leukotriene E₄, the end product of leukotriene C₄ metabolism in the mercapturic acid pathway, was rapidly eliminated from the blood circulation into the bile of rats. Part of the N-acethyl-leukotriene E₄ secreted from bile into the intestine undewent enterohepatic circulation. Leukotriene absorption occurred from the small intestine and from the colon. Biliary and urinary excretion within 5.5 h amounted to 15 and 2%, respectively, of the intraduodenally administered N-acetyl- H leukotriene E₄ in animals anesthetized with ketamine. HPLC analyses indicated that 35% of the biliary radioactivity corresponded to unchanged N-acetyl- H leukotriene E₄, while 65% in bile and 100% in urine were polar metabolites. Enterohepatic circulation extends the biological half-life of N-acetyl-leukotriene E₄.     

Warming, plant phenology and the spatial dimension of trophic mismatch for large herbivores

Temporal advancement of resource availability by warming in seasonal environments can reduce reproductive success of vertebrates if their own reproductive phenology does not also advance with warming. Indirect evidence from large-scale analyses suggests, however, that migratory vertebrates might compensate for this by tracking phenological variation across landscapes. Results from our two-year warming experiment combined with seven years of observations of plant phenology and offspring production by caribou (Rangifer tarandus) in Greenland, however, contradict evidence from large-scale analyses. At spatial scales relevant to the foraging horizon of individual herbivores, spatial variability in plant phenology was reduced--not increased--by both experimental and observed warming. Concurrently, offspring production by female caribou declined with reductions in spatial variability in plant phenology. By highlighting the spatial dimension of trophic mismatch, these results reveal heretofore unexpected adverse consequences of climatic warming for herbivore population ecology.     

Partitioning and diffusion of large molecules in fibrous structures

This paper consists of three parts. In the first part we present diffusion and partition coefficients of proteins in agarose that were measured with gel permeation chromatography. In the second part we present a partition model which includes the effects of solute concentration and of cosolutes. In the third part we modify and extend Ogston’s diffusion equation to account for the effects of solute and fiber flexibility, solute concentration and cosolutes. We find good agreement between the proposed models and data from the literature.     

Survival of ovine embryos stored at 4 degrees C for 24 hours

This study was conducted to ascertain if sheep embryos collected for transfer can be stored for short periods without freezing to allow for international transport. Of twelve Finnish Landrace ewes treated with equine follicle stimulating hormone (FSH), eleven ewes ovulated with a mean of 9.1 +/- 4.3 (SD) corpora lutea. Recovery rate from the nine ewes with normal corpora lutea was 68 +/- 27%, providing 61 morulae which were then cooled to 4 C and stored for 24 h while transporting them from Scotland to France. Romanov recipients received either 4 (n = 14) or 5 (n = 1) of these morulae. Fourteen of the recipients lambed, with a mean lambing rate of 2.1 +/- 0.8, representing 48.3% of embryos transferred. Cooling of embryos to 4 C and storing them in ovum culture medium for 24 h at 4 C may be a valuable technique for the handling and short-term storage of embryos.     

Lack of signaling by IL-4 or by IL-4/IL-13 has more attenuating effects on Leishmania amazonensis dorsal skin--than on footpad-infected mice

Lesion development in tegumentary leishmaniasis is markedly influenced by the inoculation site and the type and number of injected infective forms. This and the yet unclear contribution of Th2 cytokines as susceptibility factors to Leishmania amazonensis infection prompted us to investigate the roles of IL-4, IL-13 and IL-10 on C57BL/6 and BALB/c mice infected in the footpad (paw) or rump with low-dose L. amazonensis purified-metacyclics. Wild-type (WT) mice of either strain developed, in the rump, a single large ulcerated lesion whereas paw lesions never ulcerated and were much smaller in C57BL/6 than in BALB/c mice. However, rump-inoculated IL-4-deficient (IL-4(-/-)) C57BL/6 mice did not develop any visible lesions although parasites remained in the dermis and lymph nodes, even after systemic IL-10-receptor blocking. By comparison, all IL-4(-/-) BALB/c mice developed rump ulcers. Strikingly, only 30% of rump-infected IL-4Rα(-/-) BALB/c mice developed lesions. IL-4(-/-) mice had higher IFN-γ and lower IL-10 and IL-13 levels than WT mice. Paw-infected IL-4Rα(-/-) BALB/c mice developed minimal paw lesions. While other factors contributing to L. amazonensis susceptibility cannot be discounted, our results indicate that absent signalling by IL-4 or by IL-4/IL-13 have more intense attenuating effects on rump than on paw lesions but do not eradicate parasitism.     

A method for in vivo diffusion tracer studies combining perfusion fixation with intravenous tracer injection

Summary A method permitting exact time studies in diffusion tracer experiments in vivo is described. The method consist in application of perfusion fixation via the aorta abdominalis after the injection of the tracer substance. As the animal can be prepared for perfusion before the tracer is injected, time accuracy is in the order of a few seconds. Some applications of the method are demonstrated. A further advantage of the method is good tissue preservation. This perfusion technique is also recommended for study when exact timing is necessary, for example in autoradiography.Supported by grants from the Fonds national suisse de la Recherche scientifique, Berne, Switzerland. We wish to thank M. P. Detraz for technical assistance.     

Otx2 expression in anterior neuroectoderm and forebrain/midbrain is directed by more than six enhancers

Otx2 plays essential roles in each site at each step of head development. We previously identified the AN1 enhancer at 91 kb 5' upstream for the Otx2 expressions in anterior neuroectoderm (AN) at neural plate stage before E8.5, and the FM1 enhancer at 75 kb 5' upstream and the FM2 enhancer at 122 kb 3' downstream for the expression in forebrain/midbrain (FM) at brain vesicle stage after E8.5. The present study identified a second AN enhancer (AN2) at 88 kb 5' upstream; the AN2 enhancer also recapitulates the endogenous Otx2 expression in choroid plexus, cortical hem and choroidal roof. However, the enhancer mutants indicated the presence of another AN enhancer. The study also identified a third FM enhancer (FM3) at 153 kb 5' upstream. Thus, the Otx2 expressions in anterior neuroectoderm and forebrain/midbrain are regulated by more than six enhancers located far from the coding region. The enhancers identified are differentially conserved among vertebrates; none of the AN enhancers has activities in caudal forebrain and midbrain at brain vesicle stage after E8.5, nor do any of the FM enhancers in anterior neuroectoderm at neural plate stage before E8.5.     

Digitonin-collagenase perfusion for efficient separation of periportal or perivenous hepatocytes.

Intact rat liver cells from the perivenous region were isolated by collagenase perfusion after first destroying the periportal region by a brief portal infusion of digitonin. Periportal cells were isolated after retrograde digitonin infusion. Significantly higher alanine aminotransferase, gamma-glutamyltransferase and lactate dehydrogenase activities and lower glutamate dehydrogenase and pyruvate kinase activities in periportal than in perivenous cells demonstrate marked separation. The high yield allows further characterization in vitro of the cell populations.     

Multitracer study in Heidenhain variant of Creutzfeldt-Jakob disease: mismatch pattern of cerebral hypometabolism and perfusion imaging

Creutzfeldt-Jakob disease (CJD) is a subacute spongiform encephalopathy. This fatal prion disease is characterized by rapidly progressive dementia with a variety of neurological disorders. Diagnostic methods provided by nuclear medicine might be helpful for evaluation of patients with probable CJD as additional diagnostic tools to MRI and cerebro-spinal fluid evaluation. The experience with FDG-PET and brain perfusion SPECT is presented.     

Stability of large segmental duplications in the yeast genome

The high level of gene redundancy that characterizes eukaryotic genomes results in part from segmental duplications. Spontaneous duplications of large chromosomal segments have been experimentally demonstrated in yeast. However, the dynamics of inheritance of such structures and their eventual fixation in populations remain largely unsolved. We analyzed the stability of a vast panel of large segmental duplications in Saccharomyces cerevisiae (from 41 kb for the smallest to 268 kb for the largest). We monitored the stability of three different types of interchromosomal duplications as well as that of three intrachromosomal direct tandem duplications. In the absence of any selective advantage associated with the presence of the duplication, we show that a duplicated segment internally translocated within a natural chromosome is stably inherited both mitotically and meiotically. By contrast, large duplications carried by a supernumerary chromosome are highly unstable. Duplications translocated into subtelomeric regions are lost at variable rates depending on the location of the insertion sites. Direct tandem duplications are lost by unequal crossing over, both mitotically and meiotically, at a frequency proportional to their sizes. These results show that most of the duplicated structures present an intrinsic level of instability. However, translocation within another chromosome significantly stabilizes a duplicated segment, increasing its chance to get fixed in a population even in the absence of any immediate selective advantage conferred by the duplicated genes.