Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence.

The neurotransmitter serotonin (5-HT) has been shown to regulate alcohol consumption in both animals and humans. Since activity of the 5-HT transporter protein (5-HTT) regulates 5-HT levels, the gene encoding this protein may contribute to the risk of alcohol dependence (AD). Studies of the association to AD of a functional insertion-deletion polymorphism in the 5-HTT-linked promoter region (5-HTTLPR) have yielded inconsistent results. We conducted a meta-analysis of data from 17 published studies (including 3,489 alcoholics and 2,325 controls) investigating the association between 5-HTTLPR alleles and AD. The frequency of the short (S) allele at 5-HTTLPR was significantly associated with AD [odds ratio (OR) = 1.18, 95% CI = 1.03-1.33). Moreover, a greater association with the S allele was seen among individuals with AD complicated by either a co-morbid psychiatric condition or an early-onset or more severe AD subtype [OR = 1.34 (95% CI = 1.11-1.63)]. Allelic variation at 5-HTTLPR contributes to risk for AD, with the greatest effect observed among individuals with a co-occurring clinical feature.     

Oral and rectal immunization of adult female volunteers with a recombinant attenuated Salmonella typhi vaccine strain.

An attenuated strain of Salmonella typhi delta(cya) delta(crp-cdt) delta(asd) expressing a gene encoding a hepatitis B virus core-pre-S protein was tested in female adult volunteers for its ability to elicit a systemic and a mucosal immune response. Specifically, our purpose was to evaluate the potential of such a vaccine strain to induce specific secretory immunoglobulin A (sIgA) at genital and rectal surfaces. Oral and rectal routes of immunization were compared: oral immunization induced seroconversion against the bacterial lipopolysaccharide (LPS) in six out of seven volunteers, while after rectal immunization only one out of six volunteers seroconverted against LPS. To our disappointment, the latter volunteer was also the only one who seroconverted against the carried antigen (pre-S1), demonstrating the poor ability of this live vaccine to induce an immune response against the carried antigen. Anti-LPS sIgA was found in both the vaginal and cervical secretions of a volunteer who presented a strong seroconversion after oral immunization (16-fold increase in anti-LPS IgG). Smaller amounts of anti-LPS sIgA were found in the rectal secretions of one orally and one rectally immunized volunteer and in the saliva of three orally and one rectally immunized woman. Our data show for the first time that it is possible to induce specific sIgA in the genital and rectal tracts of women by using an S. typhi vaccine strain.     

Decisions to use complementary and alternative medicine (CAM) by male cancer patients: information-seeking roles and types of evidence used

Background  

Complementary and Alternative Medicine (CAM) is increasingly popular with cancer patients and yet information provision or discussion about CAM by health professionals remains low. Previous research suggests that patients may fear clinicians' 'disapproval' if they raise the subject of CAM, and turn to other sources to acquire information about CAM. However, little empirical research has been conducted into how cancer patients acquire, and, more importantly evaluate CAM information before deciding which CAM therapies to try.     

Evaluation of filter paper transfer of whole-blood and plasma samples for quantifying HIV RNA in subjects on antiretroviral therapy in Uganda

BACKGROUND: Most HIV-infected subjects on antiretroviral therapy (ART) in resource-limited settings do not undergo virologic monitoring. There is an urgent need for cheap, accessible HIV RNA assays for early diagnosis of virologic failure. We investigated filter paper transfer (FPT) of whole blood and plasma as an alternative to standard plasma-based assays for virologic monitoring in Uganda. METHODS: Whole blood (n = 306) and plasma (n = 218) from 402 subjects established on ART were spotted onto filter paper and transported to Europe for HIV RNA extraction and quantification. These results were compared to a gold standard plasma assay in Kampala. RESULTS: Of 402 ART-treated subjects, 39 (9.7%) had viremia detectable (>500 copies/mL) by local methods. Plasma FPT showed excellent agreement with gold standard, whereas whole blood yielded a large number of false-positive viral loads. CONCLUSIONS: This is the first study to investigate the use of FPT in ART-treated subjects and demonstrates that it may provide a practical, reliable method for virologic monitoring in resource-poor settings. Plasma FPT was accurate but requires centrifuge; whole blood produced a high number of false-positive results, but these were low-level. Whole blood may be sufficiently accurate if higher HIV RNA cut-offs were used to define virologic failure.     

The promotion of osteoblastic differentiation of rat bone marrow stromal cells by a polyvalent plant mosaic virus

To investigate the role that the micro/nano-environment plays on the differentiation pathway of bone marrow stromal cells (BMSCs) into osteoblasts, we employed a 2D substrate coated with turnip yellow mosaic virus (TYMV) particles. TYMV is a non-enveloped icosahedral plant virus which has an average diameter 28nm and the protein cage structure consists of 180 identical subunits. The temporal effect of TYMV coated substrate on the adhesion and differentiation capacity of the BMSCs was monitored for selected time periods of 7, 14 and 21 days. We examined the gene expression profile of BMSCs cultured in primary media (undifferentiated cells) and cells induced to osteoblast lineage by real time PCR analysis. To further corroborate our findings, we investigated the expression of osteogenic markers using immunohistochemistry and cytochemical staining. As expected, the genes involved in the process of osteogenic differentiation were activated more during the growth of cells under osteogenic media. In addition, we found that the BMSCs induced to undergo osteogenic differentiation on TYMV coated substrates formed fully mineralized nodules comprising of osteoblast-like cells around day 14. Comparing the gene expression pattern of BMSCs induced to osteogenic differentiation under standard culture conditions with the cells induced on TYMV substrates, we found significant differences in the temporal expression and level of expression of several key genes. Our findings indicate that TYMV, as a biogenic nanoparticle, can be employed as a model to modulate the nano-environment of the substrates in order to gain an insight into the role that the micro/nano-environment has in regulating adhesion, growth and differentiation of BMSCs towards osteogenic lineage, which will be vital for designing compatible biomaterials for tissue engineering purposes.     

Developing a model of decision-making about complementary therapy use for patients with cancer: A qualitative study

Objective

To improve our understanding of patient participation in health care consultations and decision-making by exploring a consultation that lies at the interface between mainstream care and complementary therapies.

Methods

Thirty-four holistic consultations were observed at centres offering complementary therapies for cancer, followed by interviews with patients and focus groups with professionals.

Results

A model of decision-making about complementary therapy use emerged from the data: ‘Advice: Assessor led decision’, ‘Confirmation: Joint decision’, ‘Access: Patient-led decision’ and ‘Informed: Patient-led decision’. Decision-making style was contingent on identifiable communication strategies in the preceding information-sharing and discussion phases of the consultation.

Conclusion

This study confirms the importance of gauging patients’ preferences for level of participation in decision-making. Models of consultations are generally based on the assumption that a greater degree of patient participation is a good thing that access to information and decision-making power is sought by all patients. Data from this study suggest that, in this context at least, this is not necessarily the case. The study also stresses the dynamic nature of the consultation, in which roles are fluid rather than fixed.

Practice implications

Insight were gained into professionals’ communication strategies and patients’ role preferences in decision-making, which may be applicable more widely.     

Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24

Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10(-34)), rs1867277A (p=5.90×10(-24)), rs944289T (p=6.95×10(-7)), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (P(GG vs GT + TT)=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10(-13)) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (～11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).     

The combination of high cyclin E and Skp2 expression in breast cancer is associated with a poor prognosis and the basal phenotype

Gene expression studies have identified a basal phenotype of breast cancer; these are hormone receptor and HER2-negative cancers with poor prognosis. High levels of cyclin E and Skp2, and low levels of p27 have previously been individually associated with both basal-like breast cancer and a poor outcome after diagnosis. The goal of this study was to first confirm the prognostic value of these biomolecular markers using a breast cancer tissue microarray. Second, we also test the hypothesis that the combined phenotype of high cyclin E, low p27, and high Skp2 would be a strong predictor of outcome and would be closely associated with the basal phenotype of breast cancer. Our cohort consisted of 438 cases of breast cancer and the median follow-up was 15.4 years. The tissue microarray was constructed from archival tumor blocks and we used commercially available antibodies for biomarker immunostaining. Cyclin E was positive in 46% of cases, p27 was negative in 62%, and Skp2 was positive in 35%. We found cyclin E and Skp2 to be prognostic for breast cancer-specific survival in univariate analyses, but p27 was not prognostic. The strongest predictor of outcome was the combination of cyclin E positive and Skp2 positive (difference in survival of 19% at 10 years, P = .0009). This combination was present in 78 (27%) of 288 cases for which data on both biomarkers were available. This combination was also highly associated with young age at diagnosis, grade 3 tumors, ER-negative status, HER2-negative status, and the basal biomarkers epidermal growth factor receptor and cytokeratin 5/6. However, in a multivariate model including standard clinicopathologic variables, this combination was not found to have independent prognostic significance. In conclusion, the combination of high cyclin E and Skp2 expression predicts for poor prognosis in breast cancer in univariate analysis only, it is associated with high risk features, and it is associated with the basal phenotype.     

Postural preparation prior to stepping in patients with Parkinson's disease

People with Parkinson's disease (PD) frequently have difficulties with generating anticipatory postural adjustments (APAs) for forward propulsion and lateral weight transfer when initiating gait. This impairment has been attributed to deficits in motor planning and preparation. This study examined the preparation of APAs prior to an imperative cue to initiate forward stepping. A startling acoustic stimulus (SAS) was used to probe the state of preparation of the APA in eight PD (off medication) and seven matched control subjects. Subjects performed visually cued trials involving a pre-cue light instructing them to prepare to step, followed 3.5 s later by a go-cue light to rapidly initiate stepping. In random trials, a SAS (124 dB) was presented at -1,500, -1,000, -500, -250, -100, or 0 ms before the go-cue. Subjects also performed self-initiated steps. Ground reaction forces (GRFs), center of pressure (CoP) changes, and electromyographic (EMG) signals were recorded. The SAS triggered APAs in 94 ± 11% (PD) and 96 ± 8% (control) of trials at latencies 89 ± 4 ms (PD) and 97 ± 3 ms (control) earlier than Control trials. The temporal profile of APA preparation was similar between groups. However, peak EMG, GRF, and mediolateral CoP amplitudes were reduced in PD. SAS-evoked APAs at 0 ms matched Control trial APAs and were enhanced compared with self-initiated stepping. These results demonstrate that people with mild to moderate PD can plan and prepare the appropriate APA sequence prior to the expected cue to initiate gait; however, the prepared APAs are underscaled in magnitude.