Evolution of precopulatory and post-copulatory strategies of inbreeding avoidance and associated polyandry.

Inbreeding depression is widely hypothesized to drive adaptive evolution of precopulatory and post-copulatory mechanisms of inbreeding avoidance, which in turn are hypothesized to affect evolution of polyandry (i.e. female multiple mating). However, surprisingly little theory or modelling critically examines selection for precopulatory or post-copulatory inbreeding avoidance, or both strategies, given evolutionary constraints and direct costs, or examines how evolution of inbreeding avoidance strategies might feed back to affect evolution of polyandry. Selection for post-copulatory inbreeding avoidance, but not for precopulatory inbreeding avoidance, requires polyandry, whereas interactions between precopulatory and post-copulatory inbreeding avoidance might cause functional redundancy (i.e. 'degeneracy') potentially generating complex evolutionary dynamics among inbreeding strategies and polyandry. We used individual-based modelling to quantify evolution of interacting precopulatory and post-copulatory inbreeding avoidance and associated polyandry given strong inbreeding depression and different evolutionary constraints and direct costs. We found that evolution of post-copulatory inbreeding avoidance increased selection for initially rare polyandry and that evolution of a costly inbreeding avoidance strategy became negligible over time given a lower-cost alternative strategy. Further, fixed precopulatory inbreeding avoidance often completely precluded evolution of polyandry and hence post-copulatory inbreeding avoidance, but fixed post-copulatory inbreeding avoidance did not preclude evolution of precopulatory inbreeding avoidance. Evolution of inbreeding avoidance phenotypes and associated polyandry is therefore affected by evolutionary feedbacks and degeneracy. All else being equal, evolution of precopulatory inbreeding avoidance and resulting low polyandry is more likely when post-copulatory inbreeding avoidance is precluded or costly, and evolution of post-copulatory inbreeding avoidance greatly facilitates evolution of costly polyandry.

Demographic consequences of invasion by a native, controphic competitor to an insular bird population.

Species invasions and range shifts can lead to novel competitive interactions between historically resident and colonizing species, but the demographic consequences of such interactions remain controversial. We present results from field experiments and 45 years of demographic monitoring to test the hypothesis that the colonization of Mandarte Is., BC, Canada, by fox sparrows (Passerella iliaca) caused the long-term decline of the resident population of song sparrows (Melospiza melodia). Several lines of evidence indicate that competition with fox sparrows for winter food reduced over-winter survival in juvenile song sparrows by 48% from 1960 to 2015, enforcing population decline despite an increase in annual reproductive rate in song sparrows over the same period. Preference for locally abundant seeds presented at experimental arenas suggested complete overlap in diet in song and fox sparrows, and observations at arenas baited with commercial seed showed that fox sparrows displaced song sparrows in 91-100% of interactions in two periods during winter. In contrast, we found no evidence of interspecific competition for resources during the breeding season. Our results indicate that in the absence of marked shifts in niche dimension, range expansions by dominant competitors have the potential to cause the extirpation of historically resident species when competitive interactions between them are strong and resources not equitably partitioned.

Inbreeding depression in male gametic performance.

One key objective in evolutionary ecology is to understand the magnitude of inbreeding depression expressed across sex-specific components of fitness. One major component of male fitness is fertilization success, which depends on male gametic performance (sperm and pollen performance in animals and plants, respectively). Inbreeding depression in male gametic performance could create sex-specific inbreeding depression in fitness, increase the benefit of inbreeding avoidance and reduce the efficacy of artificial insemination and pollination. However, there has been no assessment of the degree to which inbreeding generally depresses male gametic performance and hence post-copulatory or post-pollination fertilization success. Because inbreeding depression is understood to be a property of diploid entities, it is not clear what degree of inbreeding depression in haploid gametic performance should be expected. Here, we first summarize how inbreeding depression in male gametic performance could potentially arise through gene expression in associated diploid cells and/or reduced genetic diversity among haploid gametes. We then review published studies that estimate the magnitude of inbreeding depression in traits measuring components of sperm or pollen quantity, quality and competitiveness. Across 51 published studies covering 183 study traits, the grand mean inbreeding load was approximately one haploid lethal equivalent, suggesting that inbreeding depresses male gametic performance across diverse systems and traits. However, there was an almost complete lack of explicit estimates from wild populations. Future studies should quantify inbreeding depression in systematic sets of gametic traits under naturally competitive and noncompetitive conditions and quantify the degree to which gamete phenotypes and performance reflect haploid vs. diploid gene expression.

Genetic covariance between components of male reproductive success: within-pair vs. extra-pair paternity in song sparrows.

The evolutionary trajectories of reproductive systems, including both male and female multiple mating and hence polygyny and polyandry, are expected to depend on the additive genetic variances and covariances in and among components of male reproductive success achieved through different reproductive tactics. However, genetic covariances among key components of male reproductive success have not been estimated in wild populations. We used comprehensive paternity data from socially monogamous but genetically polygynandrous song sparrows (Melospiza melodia) to estimate additive genetic variance and covariance in the total number of offspring a male sired per year outside his social pairings (i.e. his total extra-pair reproductive success achieved through multiple mating) and his liability to sire offspring produced by his socially paired female (i.e. his success in defending within-pair paternity). Both components of male fitness showed nonzero additive genetic variance, and the estimated genetic covariance was positive, implying that males with high additive genetic value for extra-pair reproduction also have high additive genetic propensity to sire their socially paired female's offspring. There was consequently no evidence of a genetic or phenotypic trade-off between male within-pair paternity success and extra-pair reproductive success. Such positive genetic covariance might be expected to facilitate ongoing evolution of polygyny and could also shape the ongoing evolution of polyandry through indirect selection.

Feasibility study of analgesia via epidural versus continuous wound infusion after laparoscopic colorectal resection.

BACKGROUND: With the adoption of enhanced recovery and emerging new modalities of analgesia after laparoscopic colorectal resection (LCR), the role of epidural analgesia has been questioned. This pilot trial assessed the feasibility of a randomized controlled trial (RCT) comparing epidural analgesia and use of a local anaesthetic wound infusion catheter (WIC) following LCR. METHODS: Between April 2010 and May 2011, patients undergoing elective LCR in two centres were randomized to analgesia via epidural or WIC. Sham procedures were used to blind surgeons, patients and outcome assessors. The primary outcome was the feasibility of a large RCT, and all outcomes for a definitive trial were tested. The success of blinding was assessed using a mixed-methods approach. RESULTS: Forty-five patients were eligible, of whom 34 were randomized (mean(s.d.) age 70(11·8) years). Patients were followed up per-protocol; there were no deaths, and five patients had a total of six complications. Challenges with capturing pain data were identified and resolved. Mean(s.d.) pain scores on the day of discharge were 1·9(3·1) in the epidural group and 0·7(0·7) in the WIC group. Median length of stay was 4 (range 2-35, interquartile range 3-5) days. Mean use of additional analgesia (intravenous morphine equivalents) was 12 mg in the WIC arm and 9 mg in the epidural arm. Patient blinding was successful in both arms. Qualitative interviews suggested that patients found participation in the trial acceptable and that they would consider participating in a future trial. CONCLUSION: A blinded RCT investigating the role of epidural and WIC administration for postoperative analgesia following LCR is feasible. Rigorous standard operating procedures for data collection are required.

Neurosarcoidosis-related intracranial haemorrhage: three new cases and a systematic review of the literature.

BACKGROUND AND PURPOSE: Intracranial haemorrhage in neurosarcoidosis (NS-ICH) is rare, poorly understood and the diagnosis of NS may not be immediately apparent. METHODS: The clinical features of three new NS-ICH cases are described including new neuropathological findings and collated with cases from a systematic literature review. CASES: (i) A 41-year-old man with headaches, hypoandrogenism and encephalopathy developed a cerebellar haemorrhage. He had neuropathological confirmation of NS with biopsy-proven angiocentric granulomata and venous disruption. He responded to immunosuppressive therapy. (ii) A 41-year-old man with no history of hypertension was found unconscious. A subsequently fatal pontine haemorrhage was diagnosed. Liver biopsy revealed sarcoid granulomas. (iii) A 36-year-old man with raised intracranial pressure headaches presented with a seizure and a frontal haemorrhage. Hilar lymph node biopsy confirmed sarcoidosis, and he was treated successfully. Systematic review: Twelve other published cases were identified and collated with our cases. Average age was 36 years and M:F = 2.3:1; 46% presented with neurological symptoms and 31% had CNS-isolated disease. Immediate symptoms of ICH were acute/worsening headache or seizures (60%). ICH was supratentorial (62%), infratentorial (31%) or subarachnoid (7%). Forty percent had definite NS, 53% probable NS and 7% possible NS (Zajicek criteria). Antigranulomatous/immunosuppressive therapy regimens varied and 31% died. CONCLUSIONS: This series expands our knowledge of the pathology of NS-ICH, which may be of arterial or venous origin. One-third have isolated NS. Clinicians should consider NS in young-onset ICH because early aggressive antigranulomatous therapy may improve outcome.

Non-stroke admissions to a hyperacute stroke unit.

A significant proportion of patients presenting to hyperacute stroke units (HSUs) are diagnosed with non-stroke (NS). This study aimed to assess the rate and diagnoses of NS patients admitted to a HSU and the implications for clinical service provision. Admissions to the HSU at the Southern General Hospital, Glasgow, were retrospectively assessed (March 2007-September 2007). NS patients were identified by two parallel ascertainment methods and NS diagnosis was confirmed by case-note and discharge letter review. Of 375 presentations, 116 (31%) were due to NS. NS diagnosis was more likely for local referrals than from regional hospitals (41% versus 19%; P = 0.0002). Compared with stroke/transient ischaemic attack patients, NS patients were significantly younger, more likely to have an magnetic resonance imaging (MRI) scan and had a shorter length of hospital stay. Common NS diagnoses were migraine (22%), functional neurological disorder (14%), syncope (12%) and seizure (6%). NS patients who had an MRI scan were more likely to have a length of stay ≥2 days (75% versus 53%; P = 0.03). NS makes up one-third of acute stroke-like presentations with a high frequency of neurological conditions. NS patients tend to be younger and require significant investigation. The increased use of MRI and neurological services has implications for providing a hyperacute stroke service.

Chondrocytic and pharmacokinetic properties of Phlpp inhibitors.

Objective: The pleckstrin homology domain leucine-rich repeat protein phosphatases (Phlpp1/2) were recently identified as potential therapeutic targets for cartilage regeneration in osteoarthritic joints. Phlpp inhibitors NSC 117079 and NSC 45586 increase chondrocyte proliferation and matrix production, but the pharmacodynamics and pharmacokinetics of these compounds are not known. Design: Chondrocytic effects of Phlpp inhibitors, NSC 117079 and NSC 45586, were measured by western blotting of Phlpp substrates, glycosaminoglycan (GAG) assays, and transcriptomic assays. Liquid chromatography/mass spectroscopy assays were established to measure NSC 117079 and NSC 45586 in vitro and in vivo. The effects of NSC 117079 and NSC 45586 on articular cartilage structure in vivo after intra-articular injection were determined by histology. Results: The Phlpp inhibitors NSC 117079 and NSC 45586 were highly stable in vitro and stimulated GAG, Sox9, proteoglycan 4 and collagen 2 production in maturing but not more differentiated chondrocytes in vitro. Both molecules reduced Phlpp1/2 levels and suppressed matrix degradation to functionally extend their inhibitory effect on these phosphatases. In vivo, NSC 117079 was eliminated from the bloodstream within 4 â€‹h after intravenous injection, while NSC 45586 was eliminated in 8 â€‹h and had a higher volume distribution. Both molecules increased articular cartilage area on lateral and medial tibial plateaus and femoral condyles by 15% in C57Bl/6 mice between four and five weeks of age. Conclusion: These data advance our understanding of how Phlpp inhibitors promote and preserve cartilage formation and provide a basis for understanding their safety and activity in vivo.

Ultrasonic Doppler technique for imaging blood vessels.

Present ultrasonic Doppler flow detectors that use the Doppler effect on waves scattered from moving blood have provided useful information when directed by hand to trace the circulation of animals and man. By scanning with a highly directive flow detector, the areas of flow can be localized. Images can be formed of the interior of blood vessels. These images have the appearance of arteriograms and venograms made by dye contrast radiography, but have none of its hazards. The resolution appears adequate for useful images.

Voltage-gated potassium channel-associated limbic encephalitis in the West of Scotland: case reports and literature review.

BACKGROUND AND AIMS: The syndrome of limbic encephalitis (LE) associated with antibodies against voltage-gated potassium channels (VGKC-LE) has recently been described. The number of published cases is however small. We therefore aimed to review all cases seen at our centre and compare with published cases. METHODS: Retrospective cases of VGKC-LE were identified using a questionnaire to Neurologists at the Southern General hospital, Glasgow, and by reviewing patients with a positive VGKC antibody test (2002-2007). Case-note review of identified cases and a literature review of all published cases of VGKC-LE were performed. RESULTS: Seven cases were identified (four female, age range 51-81). Patients presented sub-acutely with seizures and anterograde memory loss. Five patients had medial temporal lobe change on cranial imaging. No paraneoplastic cases were identified. 5/7 patients made some improvement with immunotherapy. In 2006, 3/18 (17%) patients with a coded discharge of encephalitis were diagnosed with VGKC-LE. The literature review revealed 40 patients with VGKC-LE. Age, gender or VGKC level did not predict likelihood for a significant recovery. Patients treated < or =5 months of symptom onset with immunotherapy were more likely to make a significant recovery (83% vs. 45%, p=0.04). CONCLUSION: VGKC-LE is being increasingly diagnosed and is best identified early and treated with immunotherapy to offer the greatest chance of recovery. This series and literature review expands the current published evidence in VGKC-LE.

Testing evolutionary models of senescence in a natural population: age and inbreeding effects on fitness components in song sparrows.

Mutation accumulation (MA) and antagonistic pleiotropy (AP) have each been hypothesized to explain the evolution of 'senescence' or deteriorating fitness in old age. These hypotheses make contrasting predictions concerning age dependence in inbreeding depression in traits that show senescence. Inbreeding depression is predicted to increase with age under MA but not under AP, suggesting one empirical means by which the two can be distinguished. We use pedigree and life-history data from free-living song sparrows (Melospiza melodia) to test for additive and interactive effects of age and individual inbreeding coefficient (f) on fitness components, and thereby assess the evidence for MA. Annual reproductive success (ARS) and survival (and therefore reproductive value) declined in old age in both sexes, indicating senescence in this short-lived bird. ARS declined with f in both sexes and survival declined with f in males, indicating inbreeding depression in fitness. We observed a significant agexf interaction for male ARS (reflecting increased inbreeding depression as males aged), but not for female ARS or survival in either sex. These analyses therefore provide mixed support for MA. We discuss the strengths and limitations of such analyses and therefore the value of natural pedigreed populations in testing evolutionary models of senescence.

Investigating patterns and processes of demographic variation: environmental correlates of pre-breeding survival in red-billed choughs Pyrrhocorax pyrrhocorax.

1. Quantifying the pattern of temporal and spatial variation in demography, and identifying the factors that cause this variation, are essential steps towards understanding the structure and dynamics of any population. 2. One critical but understudied demographic rate is pre-breeding survival. We used long-term colour-ringing data to quantify temporal (among-year) and spatial (among-nest site) variation in pre-breeding survival in red-billed choughs (Pyrrhocorax pyrrhocorax) inhabiting Islay, Scotland, and identified environmental correlates of this variation. 3. Random-effects capture-mark-recapture models demonstrated substantial temporal and spatial process variance in first-year survival; survival from fledging to age 1 year varied markedly among choughs fledged in different years and fledged from different nest sites. Spatial variance exceeded temporal variance across choughs fledged from well-studied nest sites. 4. The best-supported models of temporal variation suggested that first-year survival was higher in years following high tipulid larvae abundance and when weather conditions favoured increased invertebrate productivity and/or availability to foraging choughs. These variables explained up to 80% of estimated temporal process variance. 5. The best-supported models of spatial variation suggested that first-year survival was higher in choughs fledged from nest sites that were further from exposed coasts and closer to flocking areas, and surrounded by better habitat and higher chough density. These variables explained up to 40% of estimated spatial process variance. 6. Importantly, spatio-temporal models indicated interactive effects of weather, tipulid abundance, local habitat and local chough density on first-year survival, suggesting that detrimental effects of poor weather and low tipulid abundance may be reduced in choughs fledged from nest sites surrounded by better foraging habitat and lower chough density. 7. These analyses demonstrate substantial temporal and small-scale spatial variation in pre-breeding survival, a key demographic rate, and indicate that this variation may reflect interactive effects of weather, prey abundance, habitat and geography. These patterns illustrate the value of holistic models of demographic variation, and indicate environmental factors that may limit the growth rate of Islay's protected chough population.

An atypical case of neuralgic amyotrophy with respiratory muscle weakness: case report and review of literature.

This report is of an atypical case of neuralgic amyotrophy with a Horner's syndrome, bilateral brachial plexus, lumbar plexus and phrenic nerve involvement. The diagnosis isconfirmed based on a classical history and examination findings with typical neurophysiological investigations for this condition. This report also highlights the novel use of positional magnetic resonance imaging to investigate patients with respiratory muscle weakness. This case report expands the recognised clinical features of neuralgicamyotrophy and the literature concerning atypical features of this condition is reviewed.

External validation of a six simple variable model of stroke outcome and verification in hyper-acute stroke.

We aimed to validate a previously described six simple variable (SSV) model that was developed from acute and sub-acute stroke patients in our population that included hyper-acute stroke patients. A Stroke Outcome Study enrolled patients from 2001 to 2002. Functional status was assessed at 6 months using the modified Rankin Scale (mRS). SSV model performance was tested in our cohort. 538 acute ischaemic (87%) and haemorrhagic stroke patients were enrolled, 51% of whom presented to hospital within 6 h of symptom recognition. At 6 months post-stroke, 42% of patients had a good outcome (mRS < or = 2). Stroke patients presenting within 6 h of symptom recognition were significantly older with higher stroke severity. In our Stroke Outcome Study dataset, the SSV model had an area under the curve of 0.792 for 6 month outcomes and performed well for hyper-acute or post-acute stroke, age < or > or = 75 years, haemorrhagic or ischaemic stroke, men or women, moderate and severe stroke, but poorly for mild stroke. This study confirms the external validity of the SSV model in our hospital stroke population. This model can therefore be utilised for stratification in acute and hyper-acute stroke trials.

A case-control study of tissue plasminogen activator for acute ischemic stroke.

BACKGROUND: Randomized trials demonstrate that intravenous tissue plasminogen activator (tPA) improves outcome in acute ischemic stroke (AIS). To assess translation of this efficacy into effectiveness in routine clinical practice we performed a case-control study of tPA treatment for AIS in a single hospital. METHODS: 151 tPA-treated AIS patients (1996-2005) were matched 1:1 with blinding to outcome to controls from a prospective registry based on age, gender, pre-stroke Oxford handicap scale (OHS), stroke severity, and subtype. The outcomes were in-hospital death, symptomatic intracranial hemorrhage (SICH), length-of-stay (LOS), discharge OHS and long-term survival. RESULTS: In-hospital mortality (23% vs. 24%) or long-term survival (median follow-up of 2 years) was not different between cases and controls (p = 0.83). SICH occurred in 7.8% (95% CI 4.2-13.5%) of tPA-treated patients. Median LOS was non-significantly shorter for cases (13 [7-29] vs. 16 [8-32] days, p = 0.14) but significantly shorter in tPA-treated vs. non-treated women (14 [7-28] vs. 20 [11-34] days, p = 0.04). At discharge 6.6% (95% CI 1.1-12.0%) more tPA-treated patients than controls had no disability (OHS < or = 1, p = 0.02). However, there was no difference in discharge independence rates or proportion discharged home. CONCLUSION: We demonstrate minor improvements in early recovery after stroke with tPA but the impact is less dramatic than that reported in randomized trials. This may relate to timing of treatment and the type of patients treated.

Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Childrens Cancer Study Group report.

Idarubicin (4-demethoxydaunomycin) is an anthracycline analogue with striking in vitro and in vivo activity against murine leukemias. Based on activity in adults with acute lymphoblastic leukemia, the Childrens Cancer Study Group initiated studies to evaluate idarubicin in children with leukemia in second or subsequent relapses. As part of those studies, we have characterized the plasma pharmacokinetics of idarubicin and the major circulating metabolite idarubicinol in 21 patients. Idarubicin plasma elimination was described by a three-compartment open model following i.v. infusion (10-15 mg/m2) on a schedule of weekly for 3 weeks and on a schedule of daily for 3 days every 3 weeks (total dose, 30-45 mg/m2). There was substantial variability in idarubicin elimination among patients, but no indication of dose-dependent or of schedule-dependent changes in pharmacokinetic parameters. The mean terminal half-life, total body clearance, and steady state volume of distribution were 17.6 h, 679 ml/min/m2, and 562 l/m2, respectively. Idarubicinol elimination was prolonged compared to that of the parent drug with a terminal half-life of 56.8 h. This metabolite clearly accumulated in plasma during the 3 days of treatment on the schedule of daily for 3 days. Urinary recoveries (48 h) of idarubicin and idarubicinol after a single dose of idarubicin were 2.4 and 10.1%, respectively. Idarubicin was detected in 2 of 21 cerebrospinal fluid samples obtained 18-30 h after administration. In marked contrast, idarubicinol was detected in 20 of those 21 samples. Concentrations in the 20 samples varied from 0.22-1.05 ng/ml with a mean value of 0.51 ng/ml.

Murine pharmacokinetics and metabolism of penclomedine [3,5-dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine, NSC 338720].

Penclomedine, a highly substituted pyridine derivative, has been selected by the National Cancer Institute for evaluation as a potential anticancer agent based on antitumor activity observed in murine tumor models following i.v., p.o., and i.p. administration. We have developed a reverse-phase high performance liquid chromatography assay for PEN, and subsequently investigated murine pharmacokinetics and metabolism. Following rapid i.v. injection of PEN (300 mg/m2) to mice, plasma elimination was best described by a 2-compartment open model with an elimination phase half-life, total body clearance, and steady-state distribution volume of 69 min, 114 ml/min/m2, and 4800 ml/m2, respectively. While PEN displayed good p.o. absorption, bioavailability of PEN after p.o. administration was approximately 2% of that observed following i.v. administration. Metabolism contributed substantially to drug clearance, and total metabolites were slowly eliminated from plasma. After i.v. and p.o. administration of radiolabeled PEN, less than 0.2% of the parent drug was excreted in the 48-h urine, and 25-30% of the total radioactivity was recovered in urine. NADPH-dependent oxidative and reductive metabolism was observed when penclomedine was incubated with mouse microsomal preparations. Microsomal reductive metabolism of PEN led to formation of a metabolite tentatively identified as a molecule formed by dimerization of the radical species produced by cleavage of chlorine from the trichloromethyl moiety of penclomedine.

Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion.

Topotecan, a water-soluble semisynthetic analogue of camptothecin, is the first topoisomerase I inhibitor to undergo evaluation in pediatric patients with refractory malignancies. A phase I and pharmacokinetic study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities, the incidence and severity of other toxicities, and the pharmacokinetics of topotecan in children. Twenty-nine patients received 42 courses of i.v. topotecan administered as a 24-h continuous infusion every 21 days at doses ranging from 2.0 to 7.5 mg/m2. Dose-related hematological toxicity was the dose-limiting toxicity. Leukopenia, neutropenia, and thrombocytopenia occurred sporadically at the 3.0- to 5.5-mg/m2 dose levels, but at 7.5 mg/m2 4 of 5 patients experienced dose-limiting thrombocytopenia (grade 4) and 2 of 5 had dose-limiting neutropenia (grade 4). No other dose-limiting toxicities were observed. Nausea and vomiting were mild and occurred in < 20 and 10% of patients, respectively. Grade 2 hematuria occurred in one patient. No objective responses were observed. Pharmacokinetic studies revealed a linear relationship between the steady-state topotecan concentration and dose. The mean steady-state concentration at the MTD was 18.2 +/- 3.7 nmol/liter and the total body clearance was 28.3 +/- 6.5 liters/h/m2. Elimination was biexponential with a t1/2 alpha of 14.4 +/- 1.8 min and a t1/2 beta of 2.9 +/- 1.1 h. The recommended starting dose for phase II pediatric trials is 5.5 mg/m2. Although this dose exceeds the MTD identified in heavily pretreated adult patients receiving topotecan on the same schedule, it is less than the MTD for minimally pretreated adult patients. Therefore, dose escalation to 7.5 mg/m2 in phase II pediatric trials should be considered for patients who tolerate treatment well at the 5.5-mg/m2 dose.

Disappearance of the hyperdense MCA sign after stroke thrombolysis: implications for prognosis and early patient selection for clot retrieval.

Disappearance of the hyperdense middle cerebral artery sign (HMCAS) following intravenous thrombolysis for ischaemic stroke is associated with improved outcome. Debate exists over which radiological thrombus characteristics can predict disappearance of the HMCAS after thrombolysis such as vessel attenuation or extent of thrombus length. Methods Ischaemic stroke patients treated with intravenous thrombolysis from our hospital were entered into a European registry. Patient demographics, stroke severity pre- and 24 hours post-thrombolysis were recorded. Patients with HMCAS were identified from the registry using records from 2010-2013. Images from the pre and post-thrombolysis computed tomography scan were measured. Thrombus characteristics (length and attenuation), extent of ischaemic change and clinical outcome (stroke severity and 3 month survival) were compared between patients with and without HMCAS disappearance. Logistic regression analysis was performed to identify predictors of HMCAS disappearance. Results HMCAS was present in 88/315 (28%) of thrombolysed ischaemic stroke patients. 36/88 (41%) of patients had thrombus disappearance 24 hours after thrombolysis. HMCAS disappearance was associated with reduced stroke severity, less radiological ischaemic change, and higher 3 month survival (87% vs 56%). Median thrombus length was shorter in the HMCAS disappearance group (11 vs 17 mm, p = 0.0004), but no significant difference in vessel attenuation was observed (48 vs 51 Hounsfield Units, p = 0.25). HMCAS disappearance occurred in 73% of cases where HMCAS length was > 10 mm, 38% when length was 10-20 mm, and 21% if < 20 mm. Thrombus length was the only independent predictor of HMCAS disappearance (odds ratio 0.90 per mm; 95% CI 0.84-0.96, p = 0.01). Conclusion Disappearance of HMCAS is associated with better clinical and radiological outcomes. A shorter thrombus is more likely to disappear postthrombolysis. The data highlight the limitation of intravenous thrombolysis in patients with longer hyperattenuated vessels, and the potential role for clot retrieval in such patients.

Flavone-8-acetic acid (Flavonoid) profoundly reduces platelet-dependent thrombosis and vasoconstriction after deep arterial injury In vivo.

BACKGROUND: Flavone-8-acetic acid (FAA; [Flavonoid]), an adjuvant antitumor drug, inhibits ristocetin-induced aggregation of human platelets. The effect of FAA on platelet-dependent thrombosis was studied in vivo in the porcine carotid artery after deep arterial injury by balloon angioplasty. METHODS AND RESULTS: (111)In-labeled autologous platelet and (125)I-labeled porcine fibrin(ogen) deposition, and the incidence of macroscopic mural thrombosis onto deeply injured artery (tunica media) were compared in 20 pigs (40+/-1 kg [mean+/-SEM], body surface area=1.0+/-0.1 m(2)), randomized to FAA bolus (n=10) of 5.5g/m(2), followed by an infusion at 0.14g. m(-2). min(-1) or placebo (n=10). Vasoconstriction was measured immediately beyond the dilated segment using quantitative angiography. Platelet deposition (x10(6)/cm(2) of carotid artery) was reduced over 12-fold in pigs treated with FAA (13+/-3 versus 164+/-51, P=0.001) compared with placebo. Fibrin(ogen) deposition (x10(12) molecules/cm(2) of carotid artery) did not significantly differ in FAA-treated pigs versus placebo (40+/-8 versus 140+/-69, P=0.08). Large mural thrombi were present in 100% of placebo-treated pigs versus very small thrombi in 40% of FAA-treated pigs (P=0.005). Vasoconstriction was reduced from 46+/-6% in the placebo group to 15+/-3% in the FAA group (P<0.001). Plasma level of FAA before angioplasty was 515+/-23 microgram/mL. The activated partial thromboplastin time was unchanged. The bleeding time was >2SD above the normal mean in 4 of 5 treated pigs (increased from 157+/-29 to 522+/-123 s). CONCLUSIONS: FAA markedly reduced platelet deposition, mural thrombi, and injury-induced vasoconstriction after deep arterial injury, suggesting that a major inhibition of platelet glycoprotein Ibalpha may be beneficial therapy.