OVPSYCH2: A randomized controlled trial of psychological support versus standard of care following chemotherapy for ovarian cancer.

BACKGROUND: Fear of disease progression (FOP) is a rational concern for women with Ovarian Cancer (OC) and depression is also common. To date there have been no randomized trials assessing the impact of psychological intervention on depression and FOP in this patient group. PATIENTS AND METHODS: Patients with primary or recurrent OC who had recently completed chemotherapy were eligible if they scored between 5 and 19 on the PHQ-9 depression and were randomized 1:1 to Intervention (3 standardized CBT-based sessions in the 6-12 weeks post-chemotherapy) or Control (standard of care). PHQ-9, FOP-Q-SF, EORTC QLQ C30 and OV28 questionnaires were then completed every 3 months for up to 2 years. The primary endpoint was change in PHQ-9 at 3 months. Secondary endpoints were change in other scores at 3 months and all scores at later timepoints. RESULTS: 182 patients registered; 107 were randomized; 54 to Intervention and 53 to Control; mean age 59 years; 75 (70%) had completed chemotherapy for primary and 32 (30%) for relapsed OC and 67 patients completed both baseline and 3-month questionnaires. Improvement in PHQ-9 was observed for patients in both study arms at three months compared to baseline but there was no significant difference in change between Intervention and Control. A significant improvement on FOP-Q-SF scores was seen in the Intervention arm, whereas for those in the Control arm FOP-Q-SF scores deteriorated at 3 months (intervention effect = -4.4 (-7.57, -1.22), p-value = 0.008). CONCLUSIONS: CBT-based psychological support provided after chemotherapy did not significantly alter the spontaneously improving trajectory of depression scores at three months but caused a significant improvement in FOP. Our findings call for the routine implementation of FOP support for ovarian cancer patients.

Fulminant corticobasal degeneration: a distinct variant with predominant neuronal tau aggregates.

Corticobasal degeneration typically progresses gradually over 5-7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson's syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate (p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.

Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial.

BACKGROUND: Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised and open-label trial. PATIENTS AND METHODS: Patients were randomised (1 : 1 : 1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR). RESULTS: Participants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08-2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96-1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms. CONCLUSION: In this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS.This study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.

Exploring the putative role of kallikrein-6, calpain-1 and cathepsin-D in the proteolytic degradation of α-synuclein in multiple system atrophy.

AIMS: There is evidence that accumulation of α-synuclein (α-syn) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) results from impaired removal of α-syn rather than its overproduction. Kallikrein-6 (KLK6), calpain-1 (CAPN1) and cathepsin-D (CTSD) are among a small number of proteases that cleave α-syn and are dysregulated in PD and DLB. Our aim in this study was to determine whether protease activity is altered in another α-synucleinopathy, multiple system atrophy (MSA), and might thereby modulate the regional distribution of α-syn accumulation. METHODS: mRNA and protein level and/or activity of KLK6, CAPN1 and CTSD were measured and assessed in relation to α-syn load in multiple brain regions (posterior frontal cortex, caudate nucleus, putamen, occipital cortex, pontine base and cerebellar white matter), in MSA (n = 20) and age-matched postmortem control tissue (n = 20). RESULTS: CTSD activity was elevated in MSA in the pontine base and cerebellar white matter. KLK6 and CAPN1 levels were elevated in MSA in the putamen and cerebellar white matter. However, the activity or level of these proteolytic enzymes did not correlate with the regional distribution of α-syn. CONCLUSIONS: Accumulation of α-syn in MSA is not due to reduced activity of the proteases we have studied. We suggest that their upregulation is likely to be a compensatory response to increased α-syn in MSA.

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

A novel Alzheimer disease locus located near the gene encoding tau protein.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma.

BACKGROUND: Treatment options for wild-type BRAF melanoma patients remain limited. Selumetinib, a MEK 1/2 inhibitor, suppresses pERK levels independent of BRAF and NRAS mutation status, and combination with docetaxel has demonstrated synergy in xenograft models. The aim of this study was to assess the efficacy and safety of selumetinib plus docetaxel as first-line treatment in patients with wild-type BRAF advanced melanoma. PATIENTS AND METHODS: In this double-blind multicentre phase II trial patients with wild-type BRAF melanoma were randomized (1:1) to docetaxel with selumetinib or placebo. Docetaxel 75 mg/m(2) was administered intravenously every 3 weeks up to six cycles. Selumetinib 75 mg or placebo was given orally twice daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Tumour NRAS mutation status was analysed retrospectively and correlated with treatment outcomes. RESULTS: Eighty-three patients were randomized to docetaxel plus selumetinib (n = 41) or docetaxel plus placebo (n = 42). The PFS hazard ratio (HR) (selumetinib:placebo) was 0.75 [90% confidence interval (CI) 0.50-1.14; P = 0.130], with a median PFS of 4.23 months (90% CI 3.63-6.90) for docetaxel plus selumetinib and 3.93 months (90% CI 2.07-4.16) for docetaxel alone. There was no significant difference in overall survival. The objective response rate was 32% with selumetinib versus 14% with placebo (P = 0.059). In a retrospective subset analysis, NRAS mutation status did not affect significantly upon clinical outcomes in either arm. The combination of docetaxel and selumetinib could be administered effectively to patients with metastatic melanoma, although the combination was less well tolerated than docetaxel alone. CONCLUSIONS: The combination of docetaxel with selumetinib showed no significant improvement in PFS compared with docetaxel alone, although more patients showed a response to combination therapy. We found no evidence to support using tumour NRAS mutation as a basis for selecting patients for combined MEK inhibitor and chemotherapy. CLINICAL TRIAL: DOC-MEK (EudraCT no: 2009-018153-23).

Field efficacy of praziquantel oral paste against naturally acquired equine cestodes in Ethiopia.

The efficacy of an oral formulation of praziquantel (Equitape, Horse paste, Fort Dodge) in the reduction of cestode egg counts and serum antibody level against Anoplocephala perfoliata was assessed in 44 donkeys under field conditions. The donkeys were confirmed both by faecal examination and serum antibody assessed by an enzyme-linked immunosorbent assay to have natural infection with tapeworms. The donkeys were randomly allocated into treatment (n = 22) and control (n = 22) groups. The treatment group was treated with both praziquantel and ivermectin (Ivomec, Merial) at a dose rate of 1 mg/kg and 200 µg/kg, respectively while the control group was treated only with ivermectin. Faecal samples were collected before treatment (day-0) and 2, 6, 8, 12, and 16 weeks post-treatment while blood samples were collected before treatment and 8 and 16 weeks after treatment and analysed. The results of the study demonstrated that praziquantel paste was highly effective in reducing cestode eggs in donkeys and had an efficacy of more than 99 % until week 16 (day 112). No cestode egg reappearance by 16 weeks post-treatment in any animal in the treatment group was observed while donkeys in the control group continued shedding cestode eggs. The immunological assay also showed a significant reduction in serum antibody level against A. perfoliata in treated donkeys compared to the control group (p = 0.0001). This marked decrease in serum antibody level indicates reduced risk of cestode-associated colic and other gastrointestinal disorders and clinical diseases. No adverse reactions or clinical effects were encountered in any animal within either group throughout the trial period.

Climate-driven convergent evolution in riparian ecosystems on sky islands.

Climate-induced evolution will determine population persistence in a changing world. However, finding natural systems in which to study these responses has been a barrier to estimating the impact of global change on a broad scale. We propose that isolated sky islands (SI) and adjacent mountain chains (MC) are natural laboratories for studying long-term and contemporary climatic pressures on natural populations. We used greenhouse common garden trees to test whether populations on SI exposed to hot and dry climates since the end of the Pleistocene have phenotypically diverged from populations on MC, and if SI populations have converged in these traits. We show: (1) populations of Populus angustifolia from SI have diverged from MC, and converged across SI, in reproductive and productivity traits, (2) these traits (cloning and aboveground biomass, respectively) are significantly correlated, suggesting a genetic linkage between them, and (3) the trait variation is driven by both natural selection and genetic drift. These shifts represent potentially beneficial phenotypes for population persistence in a changing world. These results suggest that the SI-MC comparison is a natural laboratory, as well as a predictive framework, for studying long-term responses to climate change across the globe.

e-Consent in UK academic-led clinical trials: current practice, challenges and the need for more evidence.

BACKGROUND: During the COVID-19 pandemic, in-person healthcare visits were reduced. Consequently, trial teams needed to consider implementing remote methods for conducting clinical trials, including e-Consent. Although some clinical trials may have implemented e-Consent prior to the pandemic, anecdotes of uptake for this method increased within academic-led trials. When the increased use of this process emerged, representatives from several large academic clinical trial groups within the UK collaborated to discuss ways in which trialists can learn from one another when implementing e-Consent. METHODS: A survey of UKCRC-registered Clinical Trials Units (CTUs) was undertaken in April-June 2021 to understand the implementation of and their views on the use of e-Consent and experiences from the perspectives of systems programmers and quality assurance staff on the use of e-Consent. CTUs not using e-Consent were asked to provide any reasons/barriers (including no suitable trials) and any plans for implementing it in the future. Two events for trialists and patient and public involvement (PPI) representatives were then held to disseminate findings, foster discussion, share experiences and aid in the identification of areas that the academic CTU community felt required more research. RESULTS: Thirty-four (64%) of 53 CTUs responded to the survey, with good geographical representation across the UK. Twenty-one (62%) of the responding CTUs had implemented e-Consent in at least one of their trials, across different types of trials, including CTIMPs (Clinical Trial of Investigational Medicinal Product), ATIMPs (Advanced Therapy Medicinal Products) and non-CTIMPs. One hundred ninety-seven participants attended the two workshops for wide-ranging discussions. CONCLUSION: e-Consent is increasingly used in academic-led trials, yet uncertainties remain amongst trialists, patients and members of the public. Uncertainties include a lack of formal, practical guidance and a lack of evidence to demonstrate optimal or appropriate methods to use. We strongly encourage trialists to continue to share their own experiences of the implementation of e-Consent.

Effect of polymer deposition method on thermoresponsive polymer films and resulting cellular behavior.

Poly(N-isopropyl acrylamide) or pNIPAM is a thermoresponsive polymer that is widely studied for use in bioengineering applications. The interest in this polymer lies in the polymer's unique capability to undergo a sharp property change near physiological temperature, which aids in the spontaneous release of biological cells from substrates. Currently, there are many methods for depositing pNIPAM onto substrates, including atom-transfer radical polymerization (ATRP) and electron beam ionization. Each method yields pNIPAM-coated substrates with different surface characteristics that can influence cell behavior. In this work, we compare two methods of pNIPAM deposition: plasma deposition and codeposition with a sol-gel. The resulting pNIPAM films were analyzed for use as substrates for mammalian cell culture based on surface characterization (XPS, ToF-SIMS, AFM, contact angles), cell attachment/detachment studies, and an analysis of exocytosis function using carbon-fiber microelectrode amperometry (CFMA). We find that although both methods are useful for the deposition of functional pNIPAM films, plasma deposition is much preferred for cell-sheet engineering applications because of the films' thermoresponse, minimal change in cell density, and maintenance of supported cell exocytosis function.

Neonatal rat model of intraventricular haemorrhage and post-haemorrhagic ventricular dilatation with long-term survival into adulthood.

AIMS: post-haemorrhagic ventricular dilatation (PHVD) is a significant problem in neonatal care, with sequelae extending beyond childhood. Its management is important in determining outcome. Although rodent hydrocephalus models have been developed, PHVD, as a specific entity with a distinct pathophysiology, has not been studied in a small animal model surviving to adulthood. Our objective is to evaluate survival, to adulthood, in our immature (7-day-old, P7) neonatal rat model, and to analyse early motor reflexes and fine motor and cognitive function, and neuropathology, at 8-12 weeks. METHODS: sixty-six rats underwent sequential bilateral stereotactic intraventricular haemorrhage (IVH); 36 more acted as controls. Staircase and radial maze evaluations were carried out at 7-11 weeks; animals were sacrificed at 12 weeks. Post mortem ventricular size and corpus callosum thickness were determined. RESULTS: seventy-six per cent of IVH animals developed PHVD; median (interquartile range) composite ventricular area was 3.46 mm(2) (2.32-5.24). Sixteen (24%) animals demonstrated severe ventricular dilatation (area > 5 mm(2) ). IVH animals failed to improve on the negative geotaxis test at 2 weeks. The staircase test did not identify any significant difference. On the radial maze, animals with severe PHVD made more reference errors. Histopathology confirmed PHVD, ependymal disruption and periventricular white matter injury. Median anterior corpus callosum thickness was significantly lower in IVH animals (0.35 mm) than in those not undergoing IVH (0.43 mm). CONCLUSION: our P7 neonatal rat IVH model is suitable for long-term survival and replicates many of the morphological and some of the behavioural features seen in human PHVD.

Stable high-sensitivity cardiac troponin T levels and the association with frailty and prognosis in patients with chest pain.

Background: Chronic myocardial injury is defined by stable high-sensitivity cardiac troponin (hs-cTn) levels above the 99th percentile value, which may be a sign of a biologically aged heart. This study investigated the association between frailty and chronic myocardial injury. Methods: In a cohort of patients with chest pain and stable hs-cTnT levels measured 2011-2014, we included all patients who were assessed by two scoring systems measuring frailty. Adjusted odds ratios (ORs) were calculated to estimate the risk of frailty at different hs-cTnT levels (referent: hs-cTnT ≤ 14 ng/l). Cox regression was used to estimate risks of death and cardiovascular events in relation to frailty status and hs-cTnT levels (referent: non-frail and hs-cTnT ≤ 14 ng/l). Results: A total of 979 patients were included, of whom 269 (27%) had chronic myocardial injury. The risk of being frail was almost four times higher in patients with chronic myocardial injury, compared with patients in the reference group (hs-cTnT ≥ 30 ng/l: OR: 3.69, 95% CI: 2.02-6.76). During a follow-up of 4.3 years, 275 (28%) patients died. Mortality risks increased with increasing hs-cTnT levels and degree of frailty, being increased four-fold in frail patients with hs-cTnT levels ≥ 30 ng/l (HR: 4.07, 95% CI: 2.42-6.86). Conclusions: Stable hs-cTnT levels are associated with the degree of frailty, and frailty measurements could help to identify patients with stable hs-cTnT levels who are at a high risk of death. The findings support the hypothesis that chronic myocardial injury could be a marker of a biologically aged heart.

Endothelin-converting enzyme-1 in Alzheimer's disease and vascular dementia.

AIMS: Alzheimer's disease (AD) is believed to be caused by the accumulation of amyloid beta (Aß) peptide within the brain. Endothelin-converting enzyme-1 and 2 (ECE-1 and ECE-2) are expressed in endothelial cells and neurones, respectively, and both cleave 'big endothelin' to produce the vasoconstrictor endothelin-1 (ET-1). ECE-1 and ECE-2 also degrade Aß. AD patients have regionally reduced microvascular blood flow in the brain, with impaired endothelium-dependent relaxation and cerebrovascular autoregulation, and abnormal production of ET-1 has been demonstrated in mice overexpressing amyloid precursor protein. We recently found ECE-2 mRNA and protein to be elevated in the brain in AD. In vitro, expression of ECE-2 was upregulated by Aß. Our aims for this study were to examine expression of ECE-1 (which has 57% homology with ECE-2) in temporal cortex from patients with AD, vascular dementia (VaD) and controls. METHODS: We examined the distribution of ECE-1 with immunohistochemistry, and measured ECE-1 mRNA by real-time polymerase chain reaction (PCR). ECE-1 protein levels were measured by western blot, and results analysed before and after adjustment for factor VIII-related antigen. RESULTS: We showed ECE-1 to be in vascular endothelial cells. We did not find significant differences in ECE-1 mRNA or protein levels (either full-length ECE-1 or the soluble spliced variant, ECE-1sv) in AD or VaD compared with controls. CONCLUSIONS: Our findings suggest that any disease-specific contribution of ECE-1 to the accumulation of Aß or reduction in local microvascular blood flow in AD or VaD is probably small, with abnormal production of ET-1 being more likely to reflect Aß-mediated upregulation of ECE-2.

Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia.

SUMMARY: All UK patients with bleeding disorders treated with any UK-sourced pooled factor concentrates between 1980 and 2001 have been informed that they may be at an increased risk of infection with variant Creutzfeldt-Jakob disease (vCJD). We describe a study to detect disease-associated, protease-resistant prion protein (PrP(res)) in 17 neurologically aymptomatic patients with haemophilia considered to be at increased risk of vCJD. Materials from 11 autopsy and seven biopsy cases were analysed for PrP(res). The tissues available from each case were variable, ranging from a single biopsy sample to a wide range of autopsy tissues. A single specimen from the spleen of one autopsy case gave a strong positive result on repeated testing for PrP(res) by Western blot analysis. This tissue came from a 73-year-old male patient with no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 in the prion protein gene. He had received over 9000 units of factor VIII concentrate prepared from plasma pools known to include donations from a vCJD-infected donor, and some 400,000 units not known to include donations from vCJD-infected donors. He had also received 14 units of red blood cells and had undergone several surgical and invasive endoscopic procedures. Estimates of the relative risks of exposure through diet, surgery, endoscopy, blood transfusion and receipt of UK-sourced plasma products suggest that by far the most likely route of infection in this patient was receipt of UK plasma products.

Botulinum toxin assessment, intervention and after-care for lower limb spasticity in children with cerebral palsy: international consensus statement.

Botulinum neurotoxin type-A (BoNT-A) has been used in association with other interventions in the management of spasticity in children with cerebral palsy (CP) for almost two decades. This consensus statement is based on an extensive review of the literature by an invited international committee. The use of BoNT-A in the lower limbs of children with spasticity caused by CP is reported using the American Academy of Neurology Classification of Evidence for therapeutic intervention. Randomized clinical trials have been grouped into five areas of management, and the outcomes are presented as treatment recommendations. The assessment of children with CP and evaluation of outcomes following injection of BoNT-A are complex, and therefore, a range of measures and the involvement of a multidisciplinary team is recommended. The committee concludes that injection of BoNT-A in children with CP is generally safe although systemic adverse events may occur, especially in children with more physical limitations (GMFCS V). The recommended dose levels are intermediate between previous consensus statements. The committee further concludes that injection of BoNT-A is effective in the management of lower limb spasticity in children with CP, and when combined with physiotherapy and the use of orthoses, these interventions may improve gait and goal attainment.

Hypogammaglobulinemia in racing Alaskan sled dogs.

BACKGROUND: Serum immunoglobulin dynamics have not been studied in racing sled dogs, despite hypoglobulinemia having been reported during racing events. HYPOTHESIS/OBJECTIVES: Hypoglobulinemia in racing sled dogs is associated with decreases in serum IgA, IgE, IgG, and IgM concentrations during prolonged exercise. ANIMALS: One hundred and fifty-seven Alaskan sled dogs that successfully completed a 1,000 mile race. METHODS: Serum was obtained from 118 sled dogs within 1 month before the race and within 12 hours after completing the race. Serum also was obtained after 4 months of rest from 51 dogs that successfully completed the race, including 12 previously sampled dogs. Serum total protein ([TP]), albumin, and globulin ([Gl]) were measured, and serum IgA, IgE, IgG, and IgM were quantified by ELISA. RESULTS: The proportion of dogs with [Gl] < or = 2.2 g/dL was significantly greater immediately after racing (38 of 118 dogs, 32.2%) than before racing (21 of 118 dogs, 17.8%, P = .005). Four months after racing, [Gl] was < or = 2.2 g/dL in 23.5% (12 of 51) of dogs. [IgG] was significantly lower before (8.21 +/- 4.95 mg/mL) and immediately after (7.97 +/- 5.62) racing compared with 4 months after racing (18.88 +/- 5.76). Serum [IgM] and [IgE] were higher and [IgA] was lower before racing compared with immediately after racing. CONCLUSIONS AND CLINICAL IMPORTANCE: Sled dogs participating in long-distance racing have substantial decreases in [IgG] in addition to decreases in [IgM] and [IgE]. The pronounced hypogammaglobulinemia observed in a large proportion of racing sled dogs might predispose them to infectious disease.

A direct measurement of the terrestrial mass accretion rate of cosmic dust.

The mass of extraterrestrial material accreted by the Earth as submillimeter particles has not previously been measured with a single direct and precise technique that samples the particle sizes representing most of that mass. The flux of meteoroids in the mass range 10(-9) to 10(-4) grams has now been determined from an examination of hypervelocity impact craters on the space-facing end of the Long Duration Exposure Facility satellite. The meteoroid mass distribution peaks near 1.5 x 10(-5) grams (200 micrometers in diameter), and the small particle mass accretion rate is (40 +/- 20) x 106 kilograms per year, higher than previous estimates but in good agreement with total terrestrial mass accretion rates found by geochemical methods. This mass input is comparable with or greater than the average contribution from extraterrestrial bodies in the 1-centimeter to 10-kilometer size range.

Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain.

A major feature of Alzheimer's disease is the accumulation of amyloid-beta peptide (Abeta) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Abeta plaques can be reversed by immunotherapy. In this study, we hypothesized that Abeta in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Abeta. We have performed a follow up study of Alzheimer's disease patients immunized against Abeta42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Abeta40 and Abeta42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Abeta42 in the cerebral cortex (P<0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Abeta40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Abeta load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Abeta is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Abeta immunization results in solubilization of plaque Abeta42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Abeta immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined.

Stabling causes a significant increase in the pH of the equine airway.

Regulation of pH homeostasis in the equine lung is poorly understood. Measurement of exhaled breath condensate (EBC) pH provided a simple, highly repeatable and noninvasive method for the longitudinal investigation of changes in airway pH in response to environmental changes. Stabling of horses was found to lead to a small (approximately 100-200 parts/billion) but significant (P < 0.001) increase in ambient ammonia concentration when compared to pasture. This increase in exposure to ambient ammonia concentration was associated with significant (P = 0.002) increases in EBC pH and exhaled ammonia (P = 0.013). Stable feed/bedding management type had no effect on EBC pH or exhaled ammonia concentration, while ambient ammonia concentration was influenced by stable management type.