Pharmaceutical care of patients with congestive heart failure: Interventions and outcomes

We evaluated a structured pharmaceutical care program for elderly patients (> 65 yrs) with congestive heart failure (CHF) based on objective measures of disease control, quality of life, and use of health care facilities in a randomized, controlled, longitudinal, prospective clinical trial. The 42 patients in group A received education from a pharmacist on the disease and its treatment, and lifestyle changes that could help control symptoms. Patients also were encouraged to monitor their symptoms and comply with prescribed drug therapy. If necessary, dosage regimens were simplified in liaison with hospital physicians. The 41 control patients (group B) received standard care. The following outcome measures were assessed in all patients at baseline (before the start of the trial) and at 3, 6, 9, and 12 months: 2-minute walk test, blood pressure, body weight, pulse, forced vital capacity, quality of life [disease-specific (Minnesota Living with Heart Failure questionnaire) and generic (SF-36)], knowledge of symptoms and drugs, compliance with therapy, and use of health care facilities (hospital admissions, visits to emergency room, emergency calls). Patients in group A showed improved compliance with drug therapy, which in turn improved their exercise capacity compared with those in group B; education on management of symptoms, lifestyle changes, and dietary recommendations were also of benefit. Group A patients significantly improved knowledge of their drug therapy over the 12-month study and had fewer hospital admissions compared with group B patients. They also had improved outcomes compared with group B, despite the small samples. An extension of this trial to other sites with pooling of results would provide additional evidence of the value of this structured program in elderly patients with CHF.

Intravenous tolerance effectively overcomes enhanced pro-inflammatory responses and EAE severity in the absence of IL-12 receptor signaling

Intravenous (i.v.) administration of autoantigen effectively induces Ag-specific tolerance against experimental autoimmune encephalomyelitis (EAE). We and others have shown enhanced EAE severity in mice lacking IL-12 or its receptor, strongly suggesting an immunoregulatory effect of IL-12 signaling. To examine the role of IL-12 responsiveness in autoantigen-induced tolerance in EAE, we administered autoantigen i.v. in two distinct treatment regimes to wildtype and IL-12Rβ2(-/-) mice, immunized to develop EAE. Administration at the induction phase suppressed EAE in wildtype and IL-12Rβ2(-/-) mice however the effect was somewhat less potent in the absence of IL-12Rβ2. Expression of pro-inflammatory cytokines such as IFN-γ, IL-17 and IL-2, was inhibited in wild-type tolerized mice but less so in IL-12Rβ2(-/-) mice. I.v. antigen was also effective in suppressing disease in both genotypes when given during the clinical phase of disease with similar CNS inflammation, demyelination and peripheral inflammatory cytokine profiles observed in both genotypes. There was however a mild impact of a lack of IL-12 signaling on Treg induction during tolerance induction compared to WT mice in this treatment regime. These findings show that the enhanced severity of EAE that occurs in the absence of IL-12 signaling can be effectively overcome by i.v. autoantigen, indicating that this therapeutic effect is not primarily mediated by IL-12 and that i.v. tolerance could be a powerful approach in suppressing severe and aggressive MS.

Determining the role of mononuclear phagocytes in prion neuroinvasion from the skin

Many prion diseases are acquired by peripheral exposure, and skin lesions are an effective route of transmission. Following exposure, early prion replication, upon FDCs in the draining LN is obligatory for the spread of disease to the brain. However, the mechanism by which prions are conveyed to the draining LN is uncertain. Here, transgenic mice were used, in which langerin(+) cells, including epidermal LCs and langerin(+) classical DCs, were specifically depleted. These were used in parallel with transgenic mice, in which nonepidermal CD11c(+) cells were specifically depleted. Our data show that prion pathogenesis, following exposure via skin scarification, occurred independently of LC and other langerin(+) cells. However, the depletion of nonepidermal CD11c(+) cells impaired the early accumulation of prions in the draining LN, implying a role for these cells in the propagation of prions from the skin. Therefore, together, these data suggest that the propagation of prions from the skin to the draining LN occurs via dermal classical DCs, independently of langerin(+) cells.

Cigarette Smoking Increases Risk of Barrett’s Esophagus:An Analysis of the Barrett’s and Esophageal Adenocarcinoma Consortium

Background & Aims: Cigarette smoking has been implicated in the etiology of esophageal adenocarcinoma, but it is not clear if smoking is a risk factor for Barrett's esophagus. We investigated whether tobacco smoking and other factors increase risk for Barrett's esophagus.

Methods: We analyzed data from 5 case-control studies included in the international Barrett's and Esophageal Adenocarcinoma Consortium. We compared data from subjects with Barrett's esophagus (n = 1059) with those from subjects with gastroesophageal reflux disease (gastroesophageal reflux disease controls, n = 1332), and population-based controls (n = 1143), using multivariable logistic regression models to test associations with cigarette smoking. We also tested whether cigarette smoking has synergistic effects with other exposures, which might further increase risk for Barrett's esophagus.

Results: Subjects with Barrett's esophagus were significantly more likely to have ever smoked cigarettes than the population-based controls (odds ratio [OR] = 1.67; 95% confidence interval [CI]: 1.042.67) or gastroesophageal reflux disease controls (OR = 1.61; 95% CI: 1.331.96). Increasing pack-years of smoking increased the risk for Barrett's esophagus. There was evidence of a synergy between ever-smoking and heartburn or regurgitation; the attributable proportion of disease among individuals who ever smoked and had heartburn or regurgitation was estimated to be 0.39 (95% CI: 0.250.52).

Conclusions: Cigarette smoking is a risk factor for Barrett's esophagus. The association was strengthened with increased exposure to smoking until ~20 pack-years, when it began to plateau. Smoking has synergistic effects with heartburn or regurgitation, indicating that there are various pathways by which tobacco smoking might contribute to development of Barrett's esophagus.

Improved prognosis for congenital nephrotic syndrome of the Finnish type in Irish families

Congenital nephrotic syndrome of the Finnish type is a rare autosomal recessive disease with a high infant mortality without aggressive treatment. The biochemical basis of the disease is not understood fully but the disease locus has been mapped recently to chromosome 19q12-q13.1 in Finnish families. This paper describes the clinical features and outcome of 20 patients in Ireland with congenital nephrotic syndrome of the Finnish type who have presented since 1980. Before 1987, all infants died by the age of 3 years. After the introduction of daily intravenous albumin infusion, nutritional support, elective bilateral nephrectomy, and renal transplantation, mortality in the past decade has fallen to 30%, with no deaths in the past five years. Genetic linkage analysis was performed in six families in whom DNA was available and the locus responsible was mapped to the same region on chromosome 19 as in Finnish families, suggesting that Irish families share the same disease locus.

Analysis of alteration of p75NTR processing and signalling by PS2 mutation and gamma-secretase inhibition

The presenilins (PSs) were identified as causative genes in cases of early-onset familial Alzheimer's disease (AD) and current evidence indicates that PSs are part of the gamma-secretase complex responsible for proteolytic processing of type I membrane proteins. p75NTR, a common neurotrophin receptor, was shown to be subject to gamma-secretase processing. However, it is not clear if the p75NTR downstream signal is altered in response to gamma-secretase cleavage, and further there is a possibility that AD-related PS mutations may affect this cleavage, resulting in pathogenic alterations in signal transduction. In this study, we confirmed that p75NTR downstream signalling is altered by PS2 mutation or gamma-secretase inhibition in SHSY-5Y cells. The activity of the small GTPase RhoA is strongly affected by these treatments. This study demonstrates that gamma-secretase and PS2 play an important role in regulating neurotrophin signal transduction and either mutation of PS2 or inhibition of gamma-secretase disturbs this function.

ARMS2 Increases the Risk of Early and Late Age-Related Macular Degeneration in the European Eye Study

OBJECTIVE:
To study associations between severity stages of early and late age-related macular degeneration (AMD) and genetic variations in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and to investigate potential interactions between smoking and ARMS2.
DESIGN:
Population-based, cross-sectional European Eye Study in 7 countries in Europe.
PARTICIPANTS:
Four thousand seven hundred fifty participants, 65 years of age and older, recruited through random sampling.
METHODS:
Participants were classified on the basis of the more severely affected eye into 5 mutually exclusive AMD severity stages ranging from no AMD, 3 categories of early AMD, and late AMD. History of cigarette smoking was available and allowed classification into never, former, and current smokers, with the latter 2 groups combined into a single category of ever smokers for analysis. Genotyping was performed for single nucleotide polymorphisms rs10490924 and rs4146894 in ARMS2 and rs1061170 in CFH. Associations were analyzed by logistic regression.
MAIN OUTCOME MEASURES:
Odds ratios (ORs) for stage of AMD associated with genetic variations in ARMS2 and CFH and interactions between ARMS2 and smoking status.
RESULTS:
Early AMD was present in 36.4% and late AMD was present in 3.3% of participants. Data on both genotype and AMD were available for 4276 people. The ORs for associations between AMD stage and ARMS2 increased monotonically with more severe stages of early AMD and were altered little by adjustment for potential confounders. Compared with persons with no AMD, carriers of the TT genotype for rs10490924 in ARMS2 had a 10-fold increase in risk of late AMD (P<3 × 10(-20)). The ORs for associations with CFH were similar for stage 3 early AMD and late AMD. Interactions between rs10490924 in ARMS2 and smoking status were significant in both unadjusted and adjusted models (P = 0.001). The highest risk was observed in those doubly homozygous for rs10490924 and rs1061170 in CFH (OR, 62.3; 95% confidence interval, 16-242), with P values for trend ranging from 0.03 (early AMD, stage 1) to 1 × 10(-26) (late AMD).
CONCLUSIONS:
A strong association was demonstrated between all stages of AMD and genetic variation in ARMS2, and a significant gene-environment interaction with cigarette smoking was confirmed.

The neurodevelopmental progress of infants less than 33 weeks into adolescence

Background: Several studies have shown an increased incidence of neurodevelopmental impairment in very preterm survivors at school age compared with controls.

Aim: To compare findings in the same cohort at 8 years and 15 years.

Methods: A total of 151 of the 224 eligible infants born before 33 weeks of gestation from 1979 to 1982, and who were living in the UK, were assessed at 8 and 15 years. Items common to both assessments were compared to evaluate changes in neurodevelopmental function. The assessment included a structured neurological examination, psychometric tests using the WISC-R (in subjects born in 1981-82), a test of visuomotor integration (Beery), and a school questionnaire.

Results: There was a significant increase in the proportion of subjects classified as impaired with disability from 11% at 8 to 22% at 14-15 years of age. The proportion of subjects classified as impaired without disability increased from 16% at 8 to 26% at 14-15 years of age. Full scale IQ decreased from 104 to 95 from childhood to adolescence, and more adolescents (24%) were requiring extra educational provision than they had at the age of 8 years (15%).

Conclusion: Results indicate that between the ages of 8 and 15 years in this cohort of very preterm survivors there is an apparent deterioration in neurodevelopmental outcome category, cognitive function, and extra educational support. It is not clear whether this represents a genuine deterioration in neurocognitive function or whether it represents the expression of pre-existing cerebral pathology in an increasingly complex environment.

Lateralisation of language function in young adults born very preterm

Objective: To explore, using functional magnetic resonance imaging (MRI), the functional organisation of phonological processing in young adults born very preterm.

Subjects: Six right handed male subjects with radiological evidence of thinning of the corpus callosum were selected from a cohort of very preterm subjects. Six normal right handed male volunteers acted as controls.

Method: Blood oxygenation level dependent contrast echoplanar images were acquired over five minutes at 1.5 T while subjects performed the tasks. During the ON condition, subjects were visually presented with pairs of non-words and asked to press a key when a pair of words rhymed (phonological processing). This task alternated with the OFF condition, which required subjects to make letter case judgments of visually presented pairs of consonant letter strings (orthographic processing). Generic brain activation maps were constructed from individual images by sinusoidal regression and non-parametric testing. Between group differences in the mean power of experimental response were identified on a voxel wise basis by analysis of variance.

Results: Compared with controls, the subjects with thinning of the corpus callosum showed significantly reduced power of response in the left hemisphere, including the peristriate cortex and the cerebellum, as well as in the right parietal association area. Significantly increased power of response was observed in the right precentral gyrus and the right supplementary motor area.

Conclusions: The data show evidence of increased frontal and decreased occipital activation in male subjects with neurodevelopmental thinning of the corpus callosum, which may be due to the operation of developmental compensatory mechanisms.

The effect of a healthy lifestyle programme on 8-9 year olds from social disadvantage

Aims: This study assessed the efficacy of a school-based healthy lifestyle intervention (Sport for LIFE) for increasing physical activity, decreasing sedentary behaviour, reducing screen time behaviour, encouraging healthy attitudes and behaviour to nutrition, and reducing body mass index (BMI) in 8–9-year-old primary school children from lower socioeconomic backgrounds in Northern Ireland.

Methods: A non-randomised controlled trial of 416 children from 24 schools took part. Schools were randomly assigned to one of two groups, an intervention or control group with 12 schools in each group. The intervention group received a 12-week school-based programme based on social cognitive theory. At baseline and follow-up, groups completed questionnaires assessing physical activity, screen time behaviour and dietary patterns. On each occasion anthropometric assessments of height and weight were taken. Physical activity and sedentary behaviour were measured by accelerometry.

Results Significant effects were observed for vigorous, moderate and light activity for the intervention group at follow-up. Sedentary behaviour was significantly reduced for the intervention group but not for the control group. No significant effects of the intervention on BMI, screen time behaviour or attitudes to nutrition, with the exception of non-core foods, were shown.

Conclusions: The programme was effective in increasing physical activity and reducing sedentary behaviour, however no significant changes in screen time behaviour and attitude to nutrition, with the exception of non-core foods, were observed. Future research ideas are offered for tackling low levels of physical activity in children.

A mirage of genes

This paper examines the structure of popular conceptions of the new genetics, and assesses why genetics has been so readily accepted in medicine and in the public discourse. Adapting Rene Dubos' classic analysis, Mirage of Health, we examine the new genetics by comparing it to Dubos' analysis of the structure and limits of germ theory. Germ theory focuses on the internal rather than the external environment, emphasises a doctrine of specific aetiology, and adopts the metaphor of the body as a machine. The germ theory model narrowed our vision about disease aetiology, proved misleading in some cases, yet remained the basis for clinical medical models of disease. In recent years, genetics has moved to the cutting edge of medical research and thinking about disease and behaviour. The structure of popular conceptions of the new genetics shows remarkable parallels with germ theory. This has eased the acceptance of genetics but simultaneously raises questions about these genetic explanations. An appearance and allure of specificity privileges genetic explanations in the public discourse; on examination, this specificity may prove to be a mirage.

Pathobiology of rabies virus and the European bat lyssaviruses in experimentally infected mice

A comparison of the clinicopathology of European bat lyssavirus (EBLV) types-1 and -2 and of rabies virus was undertaken. Following inoculation of mice at a peripheral site with these viruses, clinical signs of rabies and distribution of virus antigen in the mouse brain were examined. The appearance of clinical signs of disease varied both within and across the different virus species, with variation in incubation periods and weight loss throughout disease progression. The distribution of viral antigen throughout the regions of the brain examined was similar for each of the isolates during the different stages of disease progression, suggesting that antigen distribution was not associated with clinical presentation. However, specific regions of the brain including the cerebellum, caudal medulla, hypothalamus and thalamus, showed notable differences in the proportion of virus antigen positive cells present in comparison to other brain regions suggesting that these areas are important in disease development irrespective of virus species.

Analysis of Betaine and Choline Contents of Aleurone, Bran, and Flour Fractions of Wheat (Triticum aestivum L.) Using 1H Nuclear Magnetic Resonance (NMR) Spectroscopy

In conventional milling, the aleurone layer is combined with the bran fraction. Studies indicate that the bran fraction of wheat contains the majority of the phytonutrients betaine and choline, with relatively minor concentrations in the refined flour. This present study suggests that the wheat aleurone layer (Triticum aestivum L. cv. Tiger) contains the greatest concentration of both betaine and choline (1553.44 and 209.80 mg/100 g of sample, respectively). The bran fraction contained 866.94 and 101.95 mg/100 g of sample of betaine and choline, respectively, while the flour fraction contained 23.30 mg/100 g of sample (betaine) and 28.0 mg/100 g of sample (choline). The betaine content for
the bran was lower, and the choline content was higher compared to previous studies, although it is known that there is large variation in betaine and choline contents between wheat cultivars. The ratio of betaine/choline in the aleurone fraction was approximately 7:1; in the bran, the ratio was approximately 8:1; and in the flour fraction, the ratio was approximately 1:1. The study further
emphasizes the superior phytonutrient composition of the aleurone layer.
INTRODUCTION
Wheat is a valuable source of betaine, choline (1, 2), B
vitamins, vitamin E, and a number of minerals, including iron,
zinc, magnesium, and phosphorus (3). Epidemiological studies
indicate that whole-grain consumption is protective against
several chronic diseases (4-12). It has not been fully elucidated
how whole-grain cereals or specific fractions (13) exert their
protective effect, but it is thought to be due to their content of
several nutrients associated with the reduced risk of disease.
Conventionally, whole grain is separated during milling into
bran, germ, and flour (14). The nutrient composition of these
fractions differ markedly; refined wheat flour contains approximately
50% less vitamins and minerals than whole-grain
flour (

Extremely premature (<or = 800 g) schoolchildren:multiple areas of hidden disability

To examine the functional abilities of extremely low birthweight (ELBW, <or = 800 g) children at school age compared with full term children.

The Interlaboratory Robustness Of Next-Generation Sequencing (IRON) Study Phase II: Deep-Sequencing Analyses Of Hematological Malignancies Performed In 8,867 Cases By An International Network Involving 27 Laboratories

Introduction: Amplicon deep-sequencing using second-generation sequencing technology is an innovative molecular diagnostic technique and enables a highly-sensitive detection of mutations. As an international consortium we had investigated previously the robustness, precision, and reproducibility of 454 amplicon next-generation sequencing (NGS) across 10 laboratories from 8 countries (Leukemia, 2011;25:1840-8).

Aims: In Phase II of the study, we established distinct working groups for various hematological malignancies, i.e. acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and multiple myeloma. Currently, 27 laboratories from 13 countries are part of this research consortium. In total, 74 gene targets were selected by the working groups and amplicons were developed for a NGS deep-sequencing assay (454 Life Sciences, Branford, CT). A data analysis pipeline was developed to standardize mutation interpretation both for accessing raw data (Roche Amplicon Variant Analyzer, 454 Life Sciences) and variant interpretation (Sequence Pilot, JSI Medical Systems, Kippenheim, Germany).

Results: We will report on the design, standardization, quality control aspects, landscape of mutations, as well as the prognostic and predictive utility of this assay in a cohort of 8,867 cases. Overall, 1,146 primer sequences were designed and tested. In detail, for example in AML, 924 cases had been screened for CEBPA mutations. RUNX1 mutations were analyzed in 1,888 cases applying the deep-sequencing read counts to study the stability of such mutations at relapse and their utility as a biomarker to detect residual disease. Analyses of DNMT3A (n=1,041) were focused to perform landscape investigations and to address the prognostic relevance. Additionally, this working group is focusing on TET2, ASXL1, and TP53 analyses. A novel prognostic model is being developed allowing stratification of AML into prognostic subgroups based on molecular markers only. In ALL, 1,124 pediatric and adult cases have been screened, including 763 assays for TP53 mutations both at diagnosis and relapse of ALL. Pediatric and adult leukemia expert labs developed additional content to study the mutation incidence of other B and T lineage markers such as IKZF1, JAK2, IL7R, PAX5, EP300, LEF1, CRLF2, PHF6, WT1, JAK1, PTEN, AKT1, IL7R, NOTCH1, CREBBP, or FBXW7. Further, the molecular landscape of CLL is changing rapidly. As such, a separate working group focused on analyses including NOTCH1, SF3B1, MYD88, XPO1, FBXW7 and BIRC3. Currently, 922 cases were screened to investigate the range of mutational burden of NOTCH1 mutations for their prognostic relevance. In MDS, RUNX1 mutation analyses were performed in 977 cases. The prognostic relevance of TP53 mutations in MDS was assessed in additional 327 cases, including isolated deletions of chromosome 5q. Next, content was developed targeting genes of the cellular splicing component, e.g. SF3B1, SRSF2, U2AF1, and ZRSR2. In BCR-ABL1-negative MPN, nine genes of interest (JAK2, MPL, TET2, CBL, KRAS, EZH2, IDH1, IDH2, ASXL1) have been analyzed in a cohort of 155 primary myelofibrosis cases searching for novel somatic mutations and addressing their relevance for disease progression and leukemia transformation. Moreover, an assay was developed and applied to CMML cases allowing the simultaneous analysis of 25 leukemia-associated target genes in a single sequencing run using just 20 ng of starting DNA. Finally, nine laboratories are studying CML, applying ultra-deep sequencing of the BCR-ABL1 tyrosine kinase domain. Analyses were performed on 615 cases investigating the dynamics of expansion of mutated clones under various tyrosine kinase inhibitor therapies.

Conclusion: Molecular characterization of hematological malignancies today requires high diagnostic sensitivity and specificity. As part of the IRON-II study, a network of laboratories analyzed a variety of disease entities applying amplicon-based NGS assays. Importantly, the consortium not only standardized assay design for disease-specific panels, but also achieved consensus on a common data analysis pipeline for mutation interpretation. Distinct working groups have been forged to address scientific tasks and in total 8,867 cases had been analyzed thus far.