Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in CSF of healthy volunteers

BACKGROUND: Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. CSF monoamine metabolite concentrations are partly determined by genetic influences. METHODS: We investigated possible relationships between DNA polymorphisms in the serotonin 2C receptor (HTR2C), the serotonin 3A receptor (HTR3A), the dopamine D(4 )receptor (DRD4), and the dopamine β-hydroxylase (DBH) genes and CSF concentrations of 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 90). RESULTS: The HTR3A 178 C/T variant was associated with 5-HIAA levels (p = 0.02). The DBH-1021 heterozygote genotype was associated with 5-HIAA (p = 0.0005) and HVA (p = 0.009) concentrations. Neither the HTR2C Cys23Ser variant, nor the DRD4 -521 C/T variant were significantly associated with any of the monoamine metabolites. CONCLUSIONS: The present results suggest that the HTR3A and DBH genes may participate in the regulation of dopamine and serotonin turnover rates in the central nervous system

Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns

Introduction: Five different molecular subtypes of breast cancer have been identified through gene expression profiling. Each subtype has a characteristic expression pattern suggested to partly depend on cellular origin. We aimed to investigate whether the molecular subtypes also display distinct methylation profiles. Methods: We analysed methylation status of 807 cancer-related genes in 189 fresh frozen primary breast tumours and four normal breast tissue samples using an array-based methylation assay. Results: Unsupervised analysis revealed three groups of breast cancer with characteristic methylation patterns. The three groups were associated with the luminal A, luminal B and basal-like molecular subtypes of breast cancer, respectively, whereas cancers of the HER2-enriched and normal-like subtypes were distributed among the three groups. The methylation frequencies were significantly different between subtypes, with luminal B and basal-like tumours being most and least frequently methylated, respectively. Moreover, targets of the polycomb repressor complex in breast cancer and embryonic stem cells were more methylated in luminal B tumours than in other tumours. BRCA2-mutated tumours had a particularly high degree of methylation. Finally, by utilizing gene expression data, we observed that a large fraction of genes reported as having subtype-specific expression patterns might be regulated through methylation. Conclusions: We have found that breast cancers of the basal-like, luminal A and luminal B molecular subtypes harbour specific methylation profiles. Our results suggest that methylation may play an important role in the development of breast cancers

Health systems research in Lao PDR: capacity development for getting research into policy and practice

<p>Abstract</p> <p>Background</p> <p>Lao PDR is a low-income country with an urgent need for evidence-informed policymaking in the healthcare sector. During the last decade a number of Health Systems Research (HSR) projects have been conducted in order to meet this need. However, although knowledge about research is increasing among policymakers, the use of research in policymaking is still limited.</p> <p>Methods</p> <p>This article investigates the relationship between research and policymaking from the perspective of those participating in HSR projects. The study is based on 28 interviews, two group discussions and the responses from 56 questionnaires.</p> <p>Results</p> <p>The interviewees and questionnaire respondents were aware of the barriers to getting research into policy and practice. But while some were optimistic, claiming that there had been a change of attitudes among policymakers in the last two years, others were more pessimistic and did not expect any real changes until years from now. The major barriers to feeding research results into policy and practice included an inability to influence the policy process and to get policymakers and practitioners interested in research results. Another barrier was the lack of continuous capacity development and high-quality research, both of which are related to funding and international support. Many of the interviewees and questionnaire respondents also pointed out that communication between those conducting research and policymakers must be improved.</p> <p>Conclusion</p> <p>The results show that in the case of Lao PDR, research capacity development is at a crucial stage for implementing research into policy and practice. If research is going to make a consistent impact on policymaking in the Lao health care sector, the attitude towards research will need to be changed in order to get research prioritised, both among those conducting research, and among policymakers and practitioners. Our findings indicate that there is awareness about the barriers in this process.</p

Morphological correlates to cognitive dysfunction in schizophrenia as studied with Bayesian regression

BACKGROUND: Relationships between cognitive deficits and brain morphological changes observed in schizophrenia are alternately explained by less gray matter in the brain cerebral cortex, by alterations in neural circuitry involving the basal ganglia, and by alteration in cerebellar structures and related neural circuitry. This work explored a model encompassing all of these possibilities to identify the strongest morphological relationships to cognitive skill in schizophrenia. METHODS: Seventy-one patients with schizophrenia and sixty-five healthy control subjects were characterized by neuropsychological tests covering six functional domains. Measures of sixteen brain morphological structures were taken using semi-automatic and fully manual tracing of MRI images, with the full set of measures completed on thirty of the patients and twenty controls. Group differences were calculated. A Bayesian decision-theoretic method identified those morphological features, which best explained neuropsychological test scores in the context of a multivariate response linear model with interactions. RESULTS: Patients performed significantly worse on all neuropsychological tests except some regarding executive function. The most prominent morphological observations were enlarged ventricles, reduced posterior superior vermis gray matter volumes, and increased putamen gray matter volumes in the patients. The Bayesian method associated putamen volumes with verbal learning, vigilance, and (to a lesser extent) executive function, while caudate volumes were associated with working memory. Vermis regions were associated with vigilance, executive function, and, less strongly, visuo-motor speed. Ventricular volume was strongly associated with visuo-motor speed, vocabulary, and executive function. Those neuropsychological tests, which were strongly associated to ventricular volume, showed only weak association to diagnosis, possibly because ventricular volume was regarded a proxy for diagnosis. Diagnosis was strongly associated with the other neuropsychological tests, implying that the morphological associations for these tasks reflected morphological effects and not merely group volumetric differences. Interaction effects were rarely associated, indicating that volumetric relationships to neuropsychological performance were similar for both patients and controls. CONCLUSION: The association of subcortical and cerebellar structures to verbal learning, vigilance, and working memory supports the importance of neural connectivity to these functions. The finding that a morphological indicator of diagnosis (ventricular volume) provided more explanatory power than diagnosis itself for visuo-motor speed, vocabulary, and executive function suggests that volumetric abnormalities in the disease are more important for cognition than non-morphological features

Theory and practice – a case study of coordination and ownership in the Bangladesh health SWAp

BACKGROUND: In the past decade the sector-wide approach (SWAp) model has been promoted by donors and adopted by governments in several countries. The purpose of this study is to look at how partners involved in the health SWAp in Bangladesh define ownership and coordination, in their daily work and to analyse the possible implications of these definitions. METHODOLOGY: The study object was a process of decision-making in the Government of Bangladesh in 2003. Information was collected through participant observations, interviews and document review. RESULTS: During the study period the Government of Bangladesh decided to reverse a decision to unify the two wings of the Ministry of Health and Family Welfare. The decision led to disagreements with development partners, which had serious implications for cooperation between key actors in the Bangladesh health sector leading to deteriorated relationships and suspension of donor funds. The donor community in itself was also in disagreement which led to inconsistencies in the dialogue between the development partners and the Government of Bangladesh. CONCLUSION: The case shows that main actors in the Bangladesh health SWAp interpret ownership and coordination, fundamental aspects of SWAp, differently. As long as work ran smoothly, the different definitions did not create any problems, but when disagreements arose they became an obstacle. It is concluded that partners in development should devote more effort to their working relationships and that responsibilities within a SWAp need to be more clearly delineated

The Paris Declaration in practice: challenges of health sector aid coordination at the district level in Zambia

<p>Abstract</p> <p>Background</p> <p>The increasing resources available for and number of partners providing health sector aid have stimulated innovations, notably, the Paris Declaration on Aid Effectiveness, which aim to improve aid coordination. In this, one of the first studies to analyse implementation of aid coordination below national level, the aim was to investigate the effect of the Paris Declaration on coordination of health sector aid at the district level in Zambia.</p> <p>Methods</p> <p>The study was carried out in three districts of Zambia. Data were collected via interviews with health centre staff, district managers and officials from the Ministry of Health, and from district action plans, financial reports and accounts, and health centre ledger cards. Four indicators of coordination related to external-partner activity, common arrangements used by external partners and predictability of funding were analysed and assessed in relation to the 2010 targets set by the Paris Declaration.</p> <p>Findings</p> <p>While the activity of external partners at the district level has increased, funding and activities provided by these partners are often not included in local plans. HIV/AIDS support show better integration in planning and implementation at the district level than other support. Regarding common arrangements used for fund disbursement, the share of resources provided as programme-based support is not increasing. The predictability of funds coming from outside the government financing mechanism is low.</p> <p>Conclusion</p> <p>Greater efforts to integrate partners in district level planning and implementation are needed. External partners must improve the predictability of their support and be more proactive in informing the districts about their intended contributions. With the deadline for achieving the targets set by the Paris Declaration fast approaching, it is time for the signatories to accelerate its implementation.</p

Esophageal perforation in South of Sweden: Results of surgical treatment in 125 consecutive patients

<p>Abstract</p> <p>Background</p> <p>For many years there has been a debate as to which is the method of choice in treating patients with esophageal perforation. The literature consists mainly of small case series. Strategies for aiding patients struck with this disease is changing as new and less traumatic treatment options are developing. We studied a relatively large consecutive material of esophageal perforations in an effort to evaluate prognostic factors, diagnostic efforts and treatment strategy in these patients.</p> <p>Methods</p> <p>125 consecutive patients treated at the University Hospital of Lund from 1970 to 2006 were studied retrospectively. Prognostic factors were evaluated using the Cox proportional hazards model.</p> <p>Results</p> <p>Pre-operative ASA score was the only factor that significantly influenced outcome. Neck incision for cervical perforation (n = 8) and treatment with a covered stent with or without open drainage for a thoracic perforation (n = 6) had the lowest mortality. Esophageal resection (n = 8) had the highest mortality. A CAT scan or an oesophageal X-ray with oral contrast were the most efficient diagnostic tools. The preferred treatment strategy changed over the course of the study period, from a more aggressive surgical approach towards using covered stents to seal the perforation.</p> <p>Conclusion</p> <p>Pre-operative ASA score was the only factor that significantly influenced outcome in this study. Treatment strategies are changing as less traumatic options have become available. Sealing an esophageal perforation with a covered stent, in combination with open or closed drainage when necessary, is a promising treatment strategy.</p

CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers

<p>Abstract</p> <p>Background</p> <p>The CD44 cell adhesion molecule is aberrantly expressed in many breast tumors and has been implicated in the metastatic process as well as in the putative cancer stem cell (CSC) compartment. We aimed to investigate potential associations between alternatively spliced isoforms of CD44 and CSCs as well as to various breast cancer biomarkers and molecular subtypes.</p> <p>Methods</p> <p>We used q-RT-PCR and exon-exon spanning assays to analyze the expression of four alternatively spliced CD44 isoforms as well as the total expression of CD44 in 187 breast tumors and 13 cell lines. ALDH1 protein expression was determined by IHC on TMA.</p> <p>Results</p> <p>Breast cancer cell lines showed a heterogeneous expression pattern of the CD44 isoforms, which shifted considerably when cells were grown as mammospheres. Tumors characterized as positive for the CD44⁺/CD24<it>^-</it>phenotype by immunohistochemistry were associated to all isoforms except the CD44 standard (CD44S) isoform, which lacks all variant exons. Conversely, tumors with strong expression of the CSC marker ALDH1 had elevated expression of CD44S. A high expression of the CD44v2-v10 isoform, which retain all variant exons, was correlated to positive steroid receptor status, low proliferation and luminal A subtype. The CD44v3-v10 isoform showed similar correlations, while high expression of CD44v8-v10 was correlated to positive EGFR, negative/low HER2 status and basal-like subtype. High expression of CD44S was associated with strong HER2 staining and also a subgroup of basal-like tumors. Unsupervised hierarchical cluster analysis of CD44 isoform expression data divided tumors into four main clusters, which showed significant correlations to molecular subtypes and differences in 10-year overall survival.</p> <p>Conclusions</p> <p>We demonstrate that individual CD44 isoforms can be associated to different breast cancer subtypes and clinical markers such as HER2, ER and PgR, which suggests involvement of CD44 splice variants in specific oncogenic signaling pathways. Efforts to link CD44 to CSCs and tumor progression should consider the expression of various CD44 isoforms.</p