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.

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.

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.

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.

Pre-hospital notification is associated with improved stroke thrombolysis timing.

Intravenous thrombolysis increases disability-free survival after acute ischaemic stroke in a time-dependent fashion. We aimed to determine whether pre-hospital notification, introduction of a CT scanner near to assessment site and introduction of out-of-hours thrombolysis services affect thrombolysis timing. Methods Timings related to thrombolysis were collected between May 2012 and June 2014 at a single hospital site; these included time to stroke physician assessment, time to cranial CT imaging and door to needle time. All thrombolysed ischaemic stroke patients admitted via the emergency department were included. Ambulance services were asked to pre-notify the emergency department of any suspected stroke patient during this period. Results We studied 182 patients (48% female; mean age 74 years; 59% pre-notified). Pre-hospital notification was associated with a significantly higher rate of CT scanning within 25 minutes (60% vs 24%, odds ratio [OR] 4.7, 95% confidence interval [CI] 2.4-9.0; p<0.001), earlier stroke physician assessment (median 6 vs 32 minutes; p<0.001) and receiving thrombolysis within 60 minutes (89% vs 49%, OR 8.0, 95% CI 3.8-16.9; p<0.001). Being treated outside normal working hours did not alter thrombolysis timing. Logistic regression identified the introduction of a near-site CT scanner (OR 4.6 [95% CI 1.7-12.5]) and pre-hospital notification (OR 4.7, [95% CI 2.3-9.6]) as independent predictors of door to CT time less than or equal to 25 minutes, and pre-hospital notification (OR 11.6, [95% CI 4.9-30.3]) and stroke severity (OR 1.15 per point of NIHSS scale, [95% CI 1.08-1.23]) as predictors of door to thrombolysis time less than or equal to 60 minutes. The most common perceived timing delays were radiology-related (33%), the need to acutely lower blood pressure (15%) and obtaining consent (12%). Conclusion Pre-hospital notification is associated with earlier stroke physician review, CT imaging and delivery of thrombolysis. Referral to an out of hours thrombolysis service was not associated with additional delay.

Comparison of predictive scores of symptomatic intracerebral haemorrhage after stroke thrombolysis in a single centre.

UNLABELLED: Symptomatic intracerebral haemorrhage following thrombolysis for ischaemic stroke causes significant morbidity and mortality. This study assessed which of four risk scores (SEDAN, HAT, GRASPS and SITS) best predicts symptomatic intracerebral haemorrhage. METHODS: Data from 431 patients treated at Aberdeen Royal Infirmary (2003-2013) were extracted from a thrombolysis database. Score performance was compared using area under the curve. RESULTS: Any intracerebral haemorrhage occurred in 12% of patients (53/413); 11% fulfilling the SITS-MOST symptomatic intracerebral haemorrhage definition (6/53), 34% the ECASS II definition (18/53), and 43% the National Institute of Neurological Disorder and Stroke definition (23/53). Stroke severity, as defined by the National Institutes of Health Stroke Scale, significantly improved after 24 hours in patients without intracerebral haemorrhage, but not in those with. Significant symptomatic intracerebral haemorrhage predictors were age, glucose, stroke severity, hyperdense middle cerebral artery on CT scan, ASPECTS score and anti-platelet therapy. The haemorrhage after thrombolysis score performed best at predicting symptomatic intracerebral haemorrhage (area under the curve 0.67-0.78, p < 0.001). CONCLUSION: The haemorrhage after thrombolysis score uses the least variables and has the best predictive value for symptomatic intracerebral haemorrhage. Using predictive scores for clinical decision making depends on estimation of overall benefits as well as risk.

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.

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.

Panda sign due to severe coughing.

We present the case of a patient who developed periorbital ecchymosis (panda sign) following an exacerbation of asthma with severe coughing. There was no history of cranial trauma. Investigations for a structural or haematological cause were negative. The panda sign is typically seen following a base of skull fracture, but rarely reported due to severe coughing.

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.

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.

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.

Maternal history of autoimmune disease in children presenting with tics and/or obsessive-compulsive disorder.

OBJECTIVES: A commonality across a number of pediatric neuropsychiatric disorders is a higher than typical rate of familial - and especially maternal - autoimmune disease. Of recent interest, a subtype of obsessive-compulsive disorder (OCD) and tic disorders known collectively as Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) is believed to be secondary to central nervous system (CNS) autoimmunity that occurs in relation to group A streptococcal infection. Thus, we hypothesized that a sample of children with OCD and/or tics would have an increased maternal risk for an autoimmune response relative to population norms. We also expected maternal prevalence of various autoimmune diseases to be higher among those participants that met the putative criteria for PANDAS. METHODS: We examined, via structured interview, the medical history of the biological mothers of 107 children with OCD and/or tics. RESULTS: Autoimmune disorders were reported in 17.8% of study mothers, which is significantly greater than the general prevalence among women in the United States (approximately 5%). Further, study mothers were more likely to report having an autoimmune disease if their children were considered "likely PANDAS" cases versus "unlikely PANDAS" cases. CONCLUSIONS: The results offer preliminary support for hypothesized links between maternal autoimmune disease and both OCD/tics and PANDAS in youth. Further research is necessary to clarify these general associations; links to specific autoimmune disease; and relevance of autoimmune disease in other family members (e.g., fathers).

Phase I trial of autologous hematopoietic SCT with escalating doses of topotecan combined with CY and carboplatin in patients with relapsed or persistent ovarian or primary peritoneal carcinoma.

We designed a phase I clinical trial of escalating doses of topotecan with CY and carboplatin in combination with autologous hematopoietic SCT (AHSCT) for the treatment of relapsed or persistent platinum sensitive ovarian or primary peritoneal carcinoma. After stem cell collection, 16 patients received topotecan at 1.5, 2.5, 3.5, 4.5 or 6.0 mg/m(2)/d combined with CY 1.5 g/m(2)/d and carboplatin 200 mg/m(2)/d, all by 4-day continuous infusion. Steady state pharmacokinetics of topotecan and carboplatin were examined. Pre-treatment biopsies were examined for the expression of topoisomerase (topo) I, Ki67 and Bcl-2 family members by immunohistochemistry. One of six patients at a topotecan dose of 4.5 mg/m(2)/d and two of three patients at 6.0 mg/m(2)/d had dose-limiting toxicity of grade 3 stomatitis lasting >2 weeks. There was no treatment-related mortality. As topotecan clearance was constant over the dose range examined, topotecan steady state plasma concentrations increased with dose. Median progression-free survival and overall survival were 6.5 months and 2.7 years, respectively. Shorter progression-free survival was observed in tumors with low topo expression (P=0.04). Topotecan can safely be dose escalated to 4.5 mg/m(2)/d in combination with CY, carboplatin and AHSCT. This trial is registered at ClinicalTrials.gov as NCT00652691.

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.

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.

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.

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.