OBJECTIVE--To study efficacy of treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone. DESIGN--Randomised, double blind, placebo controlled study with matching for grade and duration of disease, age, and sex. Treatment was given for 367 days, and subjects were followed up for another year. SETTING--A town in Shandong Province, China. SUBJECTS--104 men and women with chronic unilateral filarial lymphoedema or elephantiasis of the leg: 64 were randomised to benzopyrone and 40 to placebo. By the end of the study 19 patients had dropped out of the treatment group and two out of the placebo group. INTERVENTIONS--Two 200 mg tablets of 5,6-benzo-alpha-pyrone or two placebo tablets given daily. MAIN OUTCOME MEASURES--Volumes of the affected and normal legs estimated every three months, and daily listing of any side effects. RESULTS--Benzopyrone reduced oedema for all grades of lymphoedema during the year of treatment (pW0.001) and the follow up year (p = 0.026). During treatment the mean monthly reductions in leg volume were 0.62% (95% confidence intervals 0.4% to 0.85%), 1.1% (0.71% to 1.6%), and 1.6% (0.89% to 2.3%) of the volume of the normal leg for grades 1, 2, and 3-5 (elephantiasis) of lymphoedema respectively. During follow up the mean monthly reductions were 0.18% (0.01% to 0.35%), 0.54% (0.27% to 0.82%), and 0.87% (0.51% to 1.2%). At the end of the trial the total reduction in oedema was 100%, 95%, and 45% for grades 1, 2, and 3-5. Symptoms and complications were considerably reduced, including attacks of secondary acute inflammation, while side effects were minor and disappeared after one month. In the placebo group there were no changes in the severity of lymphoedema. CONCLUSIONS--5,6-benzo-alpha-pyrone reduces the oedema and many symptoms of filarial lymphoedema and elephantiasis. It has few side effects, and its relatively slow action makes it ideal for use without compression garments.
Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death (SCD) and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.
Methods and Results
First, individual estimates of African and European ancestry were inferred from genome-wide single nucleotide polymorphism (SNP) data in seven population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from electrocardiograms. Second, imputation was performed for 2.8 million SNPs and a genome-wide association (GWA) study of QT interval performed in ten cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval (p=0.94). Genome-wide significant associations (p<2.5×10−8) were identified with SNPs at two loci, upstream of the genes NOS1AP (rs12143842, p=2×10−15) and ATP1B1 (rs1320976, p=2×10−10). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low p-values (p<10−5) were observed for SNPs at several other loci previously identified in GWA studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF and PLN.
We observed no difference in duration of cardiac repolarization with global genetic indices of African ancestry. In addition, our GWA study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include African Americans.
electrocardiography; electrophysiology; genome-wide association studies; ion channels; repolarization
Kidney transplant and liver transplant are the treatments of choice for patients with end-stage renal disease and end-stage liver disease, respectively. Pancreas transplant is most commonly performed along with kidney transplant in diabetic end-stage renal disease patients. Despite a steady increase in the numbers of kidney and liver transplants performed each year in the United States, a significant shortage of kidneys and livers available for transplant remains. Organ allocation is the process the Organ Procurement and Transplantation Network (OPTN) uses to determine which candidates are offered which deceased donor organs. OPTN is charged with ensuring the effectiveness, efficiency and equity of organ sharing in the national system of organ allocation. The policy has changed incrementally over time in efforts to optimize allocation to meet these often competing goals. This review describes the history, current status and future direction of policies regarding the allocation of abdominal organs for transplant, namely the kidney, liver and pancreas, in the United States.
Kidney allograft; liver allograft; organ allocation; pancreas allograft; transplant waiting list; transplantation
Categorization is essential for survival, and it is a widely studied cognitive adaptation in humans and animals. An influential neuroscience perspective differentiates in humans an explicit, rule-based categorization system from an implicit system that slowly associates response outputs to different regions of perceptual space. This perspective is being extended to study categorization in other vertebrate species, using category tasks that have a one-dimensional, rule-based solution or a two-dimensional, information-integration solution. Humans, macaques, and capuchin monkeys strongly dimensionalize perceptual stimuli and learn rule-based tasks more quickly. In sharp contrast, pigeons learn these two tasks equally quickly. Pigeons represent a cognitive system in which the commitment to dimensional analysis and category rules was not strongly made. Their results may reveal the character of the ancestral vertebrate categorization system from which that of primates emerged. The primate results establish continuity with human cognition, suggesting that nonhuman primates share aspects of humans' capacity for explicit cognition. The emergence of dimensional analysis and rule learning could have been an important step in primates' cognitive evolution.
category learning; cognitive neuroscience; implicit/explicit cognition; primate cognition; comparative cognition
Semantic memory impairment is common in both Mild Cognitive Impairment (MCI) and early Alzheimer’s disease (AD), and the ability to recognize familiar people is particularly vulnerable. A time-limited temporal gradient (TG) in which well known people from decades earlier are better recalled than those learned recently is also reported in both AD and MCI. In this study, we hypothesized that the TG pattern on a famous name recognition task (FNRT) administered to cognitively intact elders would predict future episodic memory decline, and would also show a significant correlation with hippocampal volume.
78 healthy elders (ages 65-90) with normal cognition and episodic memory at baseline were administered a FNRT. Follow-up episodic memory testing 18 months later produced two groups: Declining (≥ 1 SD reduction in episodic memory) and Stable (< 1 SD).
The Declining group (N=27) recognized fewer recent famous names than the Stable group (N=51), while recognition for remote names was comparable. Baseline MRI volumes for both the left and right hippocampus was significantly smaller in the Declining group than the Stable group. Smaller baseline hippocampal volume was also significantly correlated with poorer performance for recent, but not remote famous names. Logistic regression analyses indicated that baseline TG performance was a significant predictor of group status (Declining versus Stable) independent of chronological age and APOE ε4 inheritance.
Famous name recognition may serve as an early pre-clinical cognitive marker of episodic memory decline in older individuals.
Famous names; episodic memory; hippocampus; semantic memory; temporal gradient
Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
We determined genomewide associations with the presence of aorticvalve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aorticvalve calcification (odds ratio per allele, 2.05; P = 9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aorticvalve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10−8 and P = 1.8×10−8, respectively), but the findings were not replicated consistently.
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
Genome-wide association studies have recently identified genetic polymorphisms associated with common, etiologically complex diseases, for which direct-to-consumer genetic testing with provision of absolute genetic risk estimates is marketed by commercial companies. Polymorphisms associated with atrial fibrillation (AF) have shown relatively large risk estimates but the robustness of such estimates across populations and study designs has not been studied.
A systematic literature review with meta-analysis and assessment of between-study heterogeneity was performed for single nucleotide polymorphisms (SNPs) in the six genetic regions associated with AF in genome-wide or candidate gene studies.
Data from 18 samples of European ancestry (n=12,100 cases; 115,702 controls) were identified for the SNP on chromosome 4q25 (rs220733), 16 samples (n=12,694 cases; 132,602 controls) for the SNP on 16q22 (rs2106261) and 4 samples (n=5,272 cases; 59,725 controls) for the SNP in KCNH2 (rs1805123). Only the discovery studies were identified for SNPs on 1q21 and in GJA5 and IL6R, why no meta-analyses were performed for those SNPs. In overall random-effects meta-analyses, association with AF was observed for both SNPs from genome-wide studies on 4q25 (OR 1.67, 95% CI=1.50–1.86, p=2×10−21) and 16q22 (OR 1.21, 95% CI=1.13–1.29, p=1×10−8), but not the SNP in KCNH2 from candidate gene studies (p=0.15). There was substantial effect heterogeneity across case-control and cross-sectional studies for both polymorphisms (I2=0.50–0.78, p<0.05), but not across prospective cohort studies (I2=0.39, p=0.15). Both polymorphisms were robustly associated with AF for each study design individually (p<0.05).
In meta-analyses including up to 150,000 individuals, polymorphisms in two genetic regions were robustly associated with AF across all study designs but with substantial context-dependency of risk estimates.
atrial fibrillation; genetics; genome-wide; prediction; SNP; meta-analysis
It has been hypothesized that radiation-induced oxidative stress is the mechanism for a wide range of negative impacts on biota living in radioactively contaminated areas around Chernobyl. The present study tests this hypothesis mechanistically, for the first time, by modelling the impacts of radiolysis products within the cell resulting from radiations (low linear energy transfer β and γ), and dose rates appropriate to current contamination types and densities in the Chernobyl exclusion zone and at Fukushima. At 417 µGy h−1 (illustrative of the most contaminated areas at Chernobyl), generation of radiolysis products did not significantly impact cellular concentrations of reactive oxygen species, or cellular redox potential. This study does not support the hypothesis that direct oxidizing stress is a mechanism for damage to organisms exposed to chronic radiation at dose rates typical of contaminated environments.
Chernobyl; Fukushima; radiation; oxidative stress; biota; cell
To investigate perceived differences in the ability of current software to simulate the actual outcome of orthognathic surgery, we chose 10 difficult test cases with vertical discrepancies and “retreated” them using the actual surgical changes. Five programs—Dentofacial Planner Plus, Dolphin Imaging, Orthoplan, Quick Ceph Image, and Vistadent—were evaluated, by using both the default result and a refined result created with each program’s enhancement tools. Three panels (orthodontists, oral-maxillofacial surgeons, and laypersons) judged the default images and the retouched simulations by ranking the simulations in side-by-side comparisons and by rating each simulation relative to the actual outcome on a 6-point scale. For the default and retouched images, Dentofacial Planner Plus was judged the best default simulation 79% and 59% of the time, respectively, and its default images received the best (lowest) mean score (2.46) on the 6-point scale. It also scored best (2.26) when the retouched images were compared, but the scores for Dolphin Imaging (2.83) and Quick Ceph (3.03) improved. Retouching had little impact on the scores for the other programs. Although the results show differences in simulation ability, selecting a software package depends on many factors. Performance and ease of use, cost, compatibility, and other features such as image and practice management tools are all important considerations. Users concerned with operating system compatibility and practice management integration might want to consider Dolphin Imaging and Quick Ceph, the programs comprising the second tier.
Systemic aciclovir and its prodrug valaciclovir are effective in treating and reducing recurrences of genital herpes simplex virus (HSV) and reducing transmission. Local aciclovir delivery, if it can achieve and maintain comparable intracellular genital tract levels, may be equally effective in the treatment and suppression of genital HSV. Intravaginal ring (IVR) delivery of aciclovir may provide pre-exposure prophylaxis against HSV acquisition.
Tolerability and pharmacokinetics were evaluated in six HIV-negative women with recurrent genital HSV who switched their daily oral valaciclovir suppression to an aciclovir IVR for 7 days (n = 3) or 14 days (n = 3). Blood and cervicovaginal lavage (CVL) were collected after oral and IVR dosing to measure aciclovir concentrations and genital swabs were obtained to quantify HSV shedding by PCR.
The rings were well tolerated. Median plasma aciclovir concentrations were 110.2 ng/mL (IQR, 85.9–233.5) 12–18 h after oral valaciclovir. Little or no drug was detected in plasma following IVR dosing. Median (IQR) CVL aciclovir levels were 127.3 ng/mL (21–660.8) 2 h after oral valaciclovir, 154.4 ng/mL (60.7–327.5) 12–18 h after oral valaciclovir and 438 ng/mL (178.5–618.5) after 7 days and 393 ng/mL (31.6–1615) after 14 days of aciclovir ring use. Median CVL aciclovir levels 2 h after oral dosing were similar to levels observed 7 (P = 0.99) and 14 (P = 0.75) days after ring use. HSV DNA was not detected in genital swabs and there was no significant change in inflammatory mediators.
This first-in-human study demonstrated that an IVR could safely deliver mucosal levels of aciclovir similar to oral valaciclovir without systemic absorption. More intensive site-specific pharmacokinetic studies are needed to determine whether higher local concentrations are needed to achieve optimal drug distribution within the genital tract.
herpes simplex virus; vaginal microbicides; genital herpes
Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. WWE on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and 12-months-old, but normalized by age 24-months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 minute, but scores were near normal in all groups at 5 minutes. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks amongst the AEDs can help inform decisions about AED selection for women during childbearing years.
Epilepsy; seizures; Antiepileptic drugs; Pregnancy; Neonatal; microcephaly; Small for Gestational Age (SGA); Apgar; Observational cohort study
Current theories of human categorization differentiate an explicit, rule-based system of category learning from an implicit system that slowly associates regions of perceptual space with response outputs. The researchers extended this theoretical differentiation to the category learning of New World primates. Four capuchins learned categories of circular sine-wave gratings that varied in bar spatial frequency and orientation. The rule-based and information-integration tasks, respectively, had one-dimensional and two-dimensional solutions. Capuchins, like humans, strongly dimensionalized the stimuli and learned the rule-based task more easily. The results strengthen the suggestion that nonhuman primates have some structural components of humans’ capacity for explicit categorization, which in humans is linked to declarative cognition and consciousness. The results also strengthen the primate contrast to other vertebrate species that may lack the explicit system. Therefore, the results raise important questions about the origins of the explicit categorization system during cognitive evolution and about its overall phylogenetic distribution.
explicit categorization; primate cognition; comparative cognition; category learning; capuchin monkeys
Previous reports have shown ambiguous findings regarding the possible associations between ischaemic stroke (IS) and single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) gene region. The SNP rs12188950 (or SNP45) has often been studied in this context. We performed a multi-centre study involving a large sample of 2599 IS patients and 2093 control subjects from the south and west regions of Sweden to replicate previous studies regarding IS risk and rs12188950. Subjects from Lund Stroke Register (LSR), Malmö Diet and Cancer Study (MDC) and Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) were enroled. Subgroups of participants with hypertension and participants <55 years of age, as well as the TOAST subgroups large vessel disease, small vessel disease and cardioembolism, were also assessed. Univariate odds ratios (ORs) and ORs controlling for hypertension, diabetes and current smoking were calculated. We additionally performed a meta-analysis including 10 500 patients and 10 102 control subjects from 17 publications (including the present study). When assessing pooled data from LSR, MDC and SAHLSIS we obtained no association between IS and rs12188950 for all participants (OR=0.93; 95% confidence interval (CI): 0.83–1.05). Significant associations were not found for hypertensive participants or participants with age <55, or when separately evaluating patients from the three different TOAST subgroups. The meta-analysis showed no significant overall estimate (OR=0.96; 95% CI: 0.89–1.04) with significant heterogeneity for random effect (P=0.042). No effect from rs12188950 on IS was found from either our pooled multi-centre data or the performed meta-analysis. We did not find any association between the examined subgroups and rs12188950 either.
stroke; polymorphism; PDE4D; rs12188950; meta-analysis
Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.
Background and aims
Common non-coding variations within the TCF7L2 locus have a strong influence on type 2 diabetes (T2D) susceptibility through uncharacterised mechanisms. An islet-specific functional polymorphism has been identified, although this does not explain the association between genotype and gene expression in other cell types. This study sought to identify these other functional TCF7L2 variants.
Methods and results
Alternative splicing and gene expression from TCF7L2 was examined from peripheral blood mononuclear cells from 100 healthy Caucasians using two T2D-associated SNPs, rs7903146 and rs12255372. Electrophoretic mobility shift assays and luciferase reporter assays were performed with these SNPs and those in strong LD to determine potential SNP functionality.
Individuals homozygous for rs7903146 and rs12255372 T2D risk alleles (TT/TT) expressed 2.6-fold greater levels of TCF7L2 mRNA compared to individuals homozygous for the non-risk alleles (CC/GG, p = 0.006), although differentially spliced TCF7L2 transcripts did not differ by T2D risk-associated genotype. From SNPs identified to be in strong LD with the T2D-associated SNPs, rs7903146 and rs12255372, five (rs4132670, rs4506565, rs7903146, rs7901695, rs17747324) demonstrated allele-specific binding in electrophoretic mobility shift assays (EMSA). In luciferase reporter assays, rs4132670 exhibited 1.3-fold higher levels of enhancer activity in the Huh7 cell line (p = 3.8 × 10−5) and 2-fold higher levels in a WiDr colon carcinoma cell line (p = 0.008).
These results suggest that rs4132670, located in a region of chromatin accessibility, is a non-tissue-specific candidate functional SNP that has the potential to play a role in TCF7L2 gene expression and T2D risk.
TCF7L2; Diabetes; Polymorphism; Gene expression; Splicing; EMSA, Electrophoretic mobility shift assay; FAIRE, Formaldehyde-assisted isolation of regulatory elements; GWAS, Genome-wide association study; MC-EMSA, Multiplexed competitor-electrophoretic mobility shift assay; PBMC, Peripheral blood mononuclear cell; SIE, cis-inducible element; SNP, Single nucleotide polymorphism; T2D, Type 2 diabetes mellitus
Patent foramen ovale (PFO) is present in approximately 25% of the general population. PFO is characterized by intermittent shunting of blood from the right to the left atrium, especially in the context of increased right-sided filling pressures, with risk of paradoxical embolism. We describe a 69-year-old woman presenting with acute chest pain, severe dyspnoea, and acute inferolateral ST-segment elevation on the electrocardiogram. The patient was diagnosed with myocardial infarction and failure of the right cardiac ventricle, which was considered to be secondary to extensive pulmonary embolism leading to increased filling pressures and paradoxical coronary embolism. The patient underwent emergent percutaneous interventions with coronary thrombus extraction and pulmonary thrombus fragmentation and local thrombolysis. The patient was free of symptoms at follow up 6 months later and echocardiography showed substantially improved right ventricular function. We discuss issues related to the diagnosis, treatment, and secondary prevention for patients with concomitant pulmonary and coronary arterial thrombosis.
Myocardial infarction; patent foramen ovale; percutaneous coronary intervention; pulmonary artery intervention; pulmonary embolism; right heart failure
Humans feel uncertain. They know when they do not know. These feelings and the responses to them ground the research literature on metacognition. It is a natural question whether animals share this cognitive capacity, and thus animal metacognition has become an influential research area within comparative psychology. Researchers have explored this question by testing many species using perception and memory paradigms. There is an emerging consensus that animals share functional parallels with humans’ conscious metacognition. Of course, this research area poses difficult issues of scientific inference. How firmly should we hold the line in insisting that animals’ performances are low-level and associative? How high should we set the bar for concluding that animals share metacognitive capacities with humans? This area offers a constructive case study for considering theoretical problems that often confront comparative psychologists. The authors present this case study and address diverse issues of scientific judgement and interpretation within comparative psychology.
metacognition; uncertainty monitoring; metamemory; comparative cognition; decision-making
To establish whether hypothalmic-pituitary-adrenal axis suppression is possible secondary to long-term topical ophthalmic corticosteroid use in patients who have undergone penetrating keratoplasty (PKP).
Patients who had undergone a PKP and had been using corticosteroid-based eye drops continuously for more than 6 months, with no history of concomitant steroid (oral, inhaled, or cutaneous) use, were included within the study. A low-dose short Synacthen (LDSST) test was performed in each patient followed later by a short Synacthen test (SST). The mean SST and LDSST after 30 min were calculated along with their corresponding 95% confidence intervals (CIs). Correlation between both baseline SST and baseline LDSST with duration of treatment was determined using Spearman's correlation.
In all, 20 patients were included within the study. The mean duration treatment was 28.2 months (range 11–96 months). All patients had normal baseline cortisol levels in both SST and LDSST tests. The mean 30 min SST was 753.8 nmol/l (95%CI: 696.6 nmol/l, 811.0 nmol/l) and no patients displayed inadequate adrenal response. The mean 30 min LDSST was 709.8 nmol/l (95%CI: 665.1 nmol/l, 754.5 nmol/l) and only one patient had an inadequate adrenal response. There was no correlation between baseline SST or LDSST and duration of treatment.
This study found no evidence that patients using continuous long-term corticosteroid eye drops after PKP experienced inadequate adrenal response. We did not find any evidence of a negative correlation between length of treatment and SST or LDSST measurements at baseline.
penetrating keratoplasty; adrenal insufficiency; topical corticosteroids
To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure.
The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999–2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5).
Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102–109), lamotrigine 106 (102–109), phenytoin 105 (102–109), valproate 96 (91–100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills.
Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.
Colorectal cancers are often chemoresistant toward antitumour drugs that are substrates for ABCB1-mediated multidrug resistance (MDR). Activation of the Wnt/β-catenin pathway is frequently observed in colorectal cancers. This study investigates the impact of activated, gain-of-function β-catenin on the chemoresistant phenotype.
The effect of mutant (mut) β-catenin on ABCB1 expression and promoter activity was examined using HCT116 human colon cancer cells and isogenic sublines harbouring gain-of-function or wild-type β-catenin, and patients' tumours. Chemosensitivity towards 24 anticancer drugs was determined by high throughput screening.
Cell lines with mut β-catenin showed high ABCB1 promoter activity and expression. Transfection and siRNA studies demonstrated a dominant role for the mutant allele in activating ABCB1 expression. Patients' primary colon cancer tumours shown to express the same mut β-catenin allele also expressed high ABCB1 levels. However, cell line chemosensitivities towards 24 MDR-related and non-related antitumour drugs did not differ despite different β-catenin genotypes.
Although ABCB1 is dominantly regulated by mut β-catenin, this did not lead to drug resistance in the isogenic cell line model studied. In patient samples, the same β-catenin mutation was detected. The functional significance of the mutation for predicting patients' therapy response or for individualisation of chemotherapy regimens remains to be established.
colon cancer; β-catenin; multidrug resistance; ABCB1; therapy response
The data are relatively clear cut that palliative care improves quality of life and symptom control, improves quality of care by reducing aggressive but unsuccessful end of life care, and reduces costs. That should be an easy message to deliver to the public, health care administrators, payers, and governments. In fact, the arguments to develop palliative care services must be clear and concise, and make the clinical and financial case for the services that the palliative care team wants to deliver. Here, we discuss some of the types of models including consult services, outpatient programs, and inpatient units; the important components; some easy to use screening tools; components of the consultation team; a model medical record that increases “prompts” to do best palliative care; and data to report to supervisors.
palliative care; clinical and financial case; screening tools; medical record
This research examined the psychophysiology of emotional arousal anticipatory to potentially aversive and highly pleasant outcomes. Human brain reactions (event-related potentials) and body reactions (heart rate, skin conductance, the probe startle reflex) were assessed along motivational gradients determined by apparent distance from sites of potential punishment or reward. A predator-prey survival context was simulated using cues that signaled possible money rewards or possible losses; the cues appeared to loom progressively closer to the viewer, until a final step when a rapid key response could ensure reward or avoid a punishing loss. The observed anticipatory response patterns of heightened vigilance and physiological mobilization are consistent with the view that the physiology of emotion is founded on action dispositions that evolved in mammals to facilitate survival by dealing with threats or capturing life-sustaining rewards.