Previous preclinical and clinical studies have demonstrated the efficacy of group II metabotropic glutamate receptor (mGluR) agonists as potential antipsychotics. Recent studies utilizing mGluR2-, mGluR3-, and double knockout mice support that the antipsychotic effects of those compounds are mediated by mGluR2. Indeed, biphenyl indanone-A (BINA), an allosteric potentiator of mGluR2, is effective in experimental models of psychosis, blocking phencyclidine (PCP)-induced hyperlocomotion and prepulse inhibition deficits in mice. In this study, we administered the NMDA receptor antagonist PCP (5.6 mg/kg i.p.) to rats, an established animal model predictive of schizophrenia. Here, we show that BINA (32 mg/kg i.p.) attenuated PCP-induced locomotor activity in rats. Using behaviorally relevant doses of BINA and PCP, we performed pharmacological magnetic resonance imaging (phMRI) to assess the specific brain regions that underlie the psychotomimetic effects of PCP, and examined how BINA modulated the PCP-induced functional changes in vivo. In anesthetized rats, acute administration of PCP produced robust, sustained blood oxygenation level-dependent (BOLD) activation in specific cortical, limbic, thalamic, and striatal regions. Pretreatment with BINA suppressed the amplitude of the BOLD response to PCP in the prefrontal cortex, caudaute–putamen, nucleus accumbens, and mediodorsal thalamus. Our results show key brain structures underlying PCP-induced behaviors in a preclinical model of schizophrenia, and, importantly, its reversal by potentiation of mGluR2 by BINA, revealing specific brain regions functionally involved in its pharmacological action. Finally, our findings bolster the growing body of evidence that mGluR2 is a viable target for the treatment of schizophrenia.

Fumonisin B1 (FB1) is often a co-contaminant with aflatoxin (AF) in grains and may enhance AF’s carcinogenicity by acting as a cancer promoter. Calcium montmorillonite (i.e. NovaSil, NS) is a possible dietary intervention to help decrease chronic aflatoxin exposure where populations are at risk. Previous studies show that an oral dose of NS clay was able to reduce AF exposure in a Ghanaian population. In vitro analyses from our laboratory indicated that FB1 (like aflatoxin) could also be sorbed onto the surfaces of NS. Hence, our objectives were to evaluate the efficacy of NS clay to reduce urinary FB1 in a rodent model and then in a human population highly exposed to AF. In the rodent model, male Fisher rats were randomly assigned to either, FB1 control, FB1 + 2% NS or absolute control group. FB1 alone or with clay was given as a single dose by gavage. For the human trial, participants received NS (1.5 or 3 g day−1) or placebo (1.5 g day−1) for 3 months. Urines from weeks 8 and 10 were collected from the study participants for analysis. In rats, NS significantly reduced urinary FB1 biomarker by 20% in 24 h and 50% after 48 h compared to controls. In the humans, 56% of the urine samples analyzed (n = 186) had detectable levels of FB1. Median urinary FB1 levels were significantly (p < 0.05) decreased by > 90% in the high dose NS group (3 g day−1) compared to the placebo. This work indicates that our study participants in Ghana were exposed to FB1 (in addition to AFs) from the diet. Moreover, earlier studies have shown conclusively that NS reduces the bioavailability of AF and the findings from this study suggest that NS clay also reduces the bioavailability FB1. This is important since AF is a proven dietary risk factor for hepatocellular carcinoma (HCC) in humans and FB1 is suspected to be a dietary risk factor for HCC and esophageal cancer in humans.

Human milk oligosaccharides (HMO), which constitute a major component of human milk, promote the growth of particular bacterial species in the infant's gastrointestinal tract. We hypothesized that HMO also interact with the bacterial communities present in human milk. To test this hypothesis, two experiments were conducted. First, milk samples were collected from healthy women (n = 16); culture-independent analysis of the bacterial communities was performed, HMO content was analyzed, and the relation between these factors was investigated. A positive correlation was observed between the relative abundance of Staphylococcus and total HMO content (r = 0.66). In a follow-up study, we conducted a series of in vitro growth curve experiments utilizing Staphylococcus aureus or Staphylococcus epidermidis and HMO isolated from human milk. HMO exhibited stimulatory effects on bacterial growth under various nutritional conditions. Analysis of culture supernatants from these experiments revealed that HMO did not measurably disappear from the culture medium, indicating that the growth-enhancing effects were not a result of bacterial metabolism of the HMO. Instead, stimulation of growth caused greater utilization of amino acids in minimal medium. Collectively, the data provide evidence that HMO may promote the growth of Staphylococcus species in the lactating mammary gland.

Low 25-hydroxyvitamin D (25[OH]D) and adiponectin levels are both associated with obesity and cardiovascular disease. Cross-sectional studies have suggested that 25(OH)D concentrations are positively associated with adiponectin, and that this relation may strengthen with increasing BMI. However, these studies had small samples sizes and did not account for many known confounders of adiponectin levels. We evaluated whether 25(OH)D was independently associated with circulating adiponectin in two large populations, and whether BMI modified this relationship. Cross-sectional analyses were performed on 1206 women from the Nurses’ Health Study I and 439 men from the Health Professionals Follow-Up Study. Multivariable linear regression was used to analyze the independent association between 25(OH)D and adiponectin after controlling for potential confounders. Effect modification by BMI was examined by creating interaction terms between vitamin D and BMI. 25(OH)D concentrations were positively associated with circulating adiponectin in univariate analyses, and also independently associated with adiponectin after multivariable adjustments in both populations (women: β=0.06, P<0.001; men: β=0.07, P<0.05). BMI did not significantly modify the relation between 25(OH)D and adiponectin in either population. Higher 25(OH)D concentrations were independently associated with higher adiponectin concentrations in large populations of women and men. Since lower levels of 25(OH)D and adiponectin are associated with higher cardio-metabolic risk, assessing the effect of vitamin D supplementation on adiponectin levels is warranted.

Objectives

To report real-time ophthalmoscopic findings during super-selective intra-ophthalmic artery chemotherapy (SSIOAC) in a non-human primate (NHP) model.

Methods

Six adult male Rhesus macaques (Macacca mulatta) were randomly assigned into one of two treatment cohorts; MEL treated with 5 mg/30 mL melphalan, and CBP treated with 30 mg/30 mL carboplatin. Each animal underwent three separate SSIOAC procedures at three-week intervals. Digital retinal images were obtained during each infusion. Intravenous fluorescein angiography was performed immediately after each procedure.

Results

All SSIOAC procedures were successfully completed. Toxicities were equally distributed between drug cohorts. Systemic toxicities included mild bone marrow suppression in all animals and anorexia in one. One animal had greater than 50% narrowing of the treated ophthalmic artery after its second infusion. All 18 procedures (100%) resulted in pulsatile optic nerve and choroid blanching, retinal artery narrowing, and retinal edema. Retinal artery sheathing was found during 17 (of 18, 94%) procedures, and retinal artery precipitates were seen in 10 (of 18, 56%). Choroidal hypoperfusion (18 of 18, 100%) was seen by fluorescein angiogram.

Conclusions

Real-time ophthalmic investigations are useful and, in our NHP model, indicate prevalent, acute ocular vascular toxicities during SSIOAC.

Clinical Relevance

Real-time retinal imaging is feasible in an NHP model of SSIOAC. Application to SSIOAC in children may shed insight into reported vascular toxicities.

Objective:

Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.

Methods:

We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis.

Results:

In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD.

Conclusion:

The current evidence linking common mtDNA variations with AD is not compelling.

Selective leukocyte trafficking and recruitment is primarily regulated by a specific family of small proteins called “chemokines”. This extended family shepherds and guides leukocytes through their lives, facilitating their development, regulating their interactions with other leukocyte types, and guiding their recruitment to sites of inflammation.

Through the actions of chemokines, allergen sensitization is regulated in atopic asthma, through the controlled migration of dendritic cells, T- and B-lymphocytes, mast cells and basophils. Subsequently, atopic inflammation is driven by chemokine-directed recruitment of eosinophils, basophils and lymphocytes. Diseases from cancer to chronic obstructive pulmonary disease to interstitial fibrosis are all potential targets for chemokine receptor antagonism.

Innate immunity (the early pattern-recognition responses to stimuli such as lipopolysaccharide, viral proteins and bacterial DNA) needs to bridge the gap to specific immunity and antibody production and immunological memory. Again, chemokines are likely to be fundamental mediators of these responses.

Chemokines are fundamental regulators of leukocyte homeostasis and inflammation, and their antagonism by small molecule chemokine receptor antagonists may be of enormous importance in the future treatment of human respiratory disease.

Background

Kangaroo mother care (KMC) is a safe and effective method of caring for low birth weight infants and is promoted for its potential to improve newborn survival. Many countries find it difficult to take KMC to scale in healthcare facilities providing newborn care. KMC Ghana was an initiative to scale up KMC in four regions in Ghana. Research findings from two outreach trials in South Africa informed the design of the initiative. Two key points of departure were to equip healthcare facilities that conduct deliveries with the necessary skills for KMC practice and to single out KMC for special attention instead of embedding it in other newborn care initiatives. This paper describes the contextualisation and practical application of previous research findings and the results of monitoring the progress of the implementation of KMC in Ghana.

Methods

A three-phase outreach intervention was adapted from previous research findings to suit the local setting. A more structured system of KMC regional steering committees was introduced to drive the process and take the initiative forward. During Phase I, health workers in regions and districts were oriented in KMC and received basic support for the management of the outreach. Phase II entailed the strengthening of the regional steering committees. Phase III comprised a more formal assessment, utilising a previously validated KMC progress-monitoring instrument.

Results

Twenty-six out of 38 hospitals (68 %) scored over 10 out of 30 and had reached the level of ‘evidence of practice’ by the end of Phase III. Seven hospitals exceeded expected performance by scoring at the level of ‘evidence of routine and institutionalised practice.’ The collective mean score for all participating hospitals was 12.07. Hospitals that had attained baby-friendly status or had been re-accredited in the five years before the intervention scored significantly better than the rest, with a mean score of 14.64.

Conclusion

The KMC Ghana initiative demonstrated how research findings regarding successful outreach for the implementation of KMC could be transferred to a different context by making context-appropriate adaptations to the model.

Purpose

There is evidence for complement dysfunction in age-related macular degeneration (AMD). Complement activation leads to formation of the membrane attack complex (MAC), known to assemble on retinal pigment epithelial (RPE) cells. Therefore, the effect of sub-lytic MAC on RPE cells was examined with regard to pro-inflammatory or pro-angiogenic mediators relevant in AMD.

Methods

For sub-lytic MAC induction, RPE cells were incubated with an antiserum to complement regulatory protein CD59, followed by normal human serum (NHS) to induce 5% cell death, measured by a viability assay. MAC formation was evaluated by immunofluorescence and FACS analysis. Interleukin (IL)-6, -8, monocytic chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were quantified by enzyme-linked immunosorbent assay (ELISA). Intracellular MCP-1 was analysed by immunofluorescence, vitronectin by western blotting, and gelatinolytic matrix metalloproteinases (MMPs) by zymography.

Results

Incubation of RPE cells with the CD59 antiserum followed by 5% NHS induced sub-lytic amounts of MAC, verified by FACS and immunofluorescence. This treatment stimulated the cells to release IL-6, -8, MCP-1, and VEGF. MCP-1 staining, production of vitronectin, and gelatinolytic MMPs were also elevated in response to sub-lytic MAC.

Conclusions

MAC assembly on RPE cells increases the IL-6, -8, and MCP-1 production. Therefore, sub-lytic MAC might have a significant role in generating a pro-inflammatory microenvironment, contributing to the development of AMD. Enhanced vitronectin might be a protective mechanism against MAC deposition. In addition, the increased expression of gelatinolytic MMPs and pro-angiogenic VEGF may be associated with neovascular processes and late AMD.

We examined the association between certain clinical factors and aflatoxin B1–albumin adduct (AF-ALB) levels in HIV-positive people. Plasma samples collected from 314 (155 HIV-positive and 159 HIV-negative) people were tested for AF-ALB levels, viral load, CD4+ T-cell count, liver function profile, malaria parasitaemia, and hepatitis B and C virus infections. HIV-positive participants were divided into high and low groups based on their median AF-ALB of 0.93 pmol mg−1 albumin and multivariable logistic and linear regression methods used to assess relationships between clinical conditions and AF-ALB levels. Multivariable logistic regression showed statistically significant increased odds of having higher HIV viral loads (OR=2.84; 95% CI=1.17–7.78) and higher direct bilirubin levels (OR=5.47; 95% CI=1.03–22.85) among HIV-positive participants in the high AF-ALB group. There were also higher levels of total bilirubin and lower levels of albumin in association with high AF-ALB. Thus, aflatoxin exposure may contribute to high viral loads and abnormal liver function in HIV-positive people and so promote disease progression.

Although the Autobiographical Memory Test (AMT) is widely used its psychometric properties have rarely been investigated. This paper utilises data gathered from a 10-item written version of the AMT, completed by 5792 adolescents participating in the Avon Longitudinal Study of Parents and Children, to examine the psychometric properties of the measure. The results show that the scale derived from responses to the AMT operates well over a wide range of scores, consistent with the aim of deriving a continuous measure of over-general memory. There was strong evidence of group differences in terms of gender, low negative mood, and IQ, and these were in agreement when comparing an item response theory (IRT) approach with that based on a sum score. One advantage of the IRT model is the ability to assess and consequently allow for differential item functioning. This additional analysis showed evidence of response bias for both gender and mood, resulting in attenuation in the mean differences in AMT across these groups. Implications of the findings for the use of the AMT measure in different samples are discussed.

Objectives

Stress has been shown to have a number of negative effects on health over time. Mindfulness interventions have been shown to decrease perceived stress but access to interventions is limited. Therefore, the effectiveness of an online mindfulness course for perceived stress was investigated.

Design

A preliminary evaluation of an online mindfulness course.

Participants

This sample consisted of 100 self-referrals to the online course. The average age of participants was 48 years and 74% were women.

Interventions

The online programme consisted of modules taken from Mindfulness Based Stress Reduction and Mindfulness Based Cognitive Therapy and lasted for approximately 6 weeks.

Primary and secondary outcome measures

Participants completed the Perceived Stress Scale (PSS) before the course, after the course and at 1-month follow-up. Completion of formal (eg, body scan, mindful movement) and informal (eg, mindful meal, noticing) mindfulness activities was self-reported each week.

Results

Participation in the online mindfulness course significantly reduced perceived stress upon completion and remained stable at follow-up. The pre-post effect size was equivalent to levels found in other class-based mindfulness programmes. Furthermore, people who had higher PSS scores before the course reported engaging in significantly more mindfulness practice, which was in turn associated with greater decreases in PSS.

Conclusions

Because perceived stress significantly decreased with such limited exposure to mindfulness, there are implications for the accessibility of mindfulness therapies online. Future research needs to evaluate other health outcomes for which face-to-face mindfulness therapies have been shown to help, such as anxiety and depressive symptoms.

Article summary

Article focus

Stress maintained over time can cause a number of negative effects, both physically and psychologically.

Mindfulness interventions have been shown to have significant beneficial effects to health including significantly decreasing stress.

Research question: is an online mindfulness course a feasible way to provide an intervention and decrease perceived stress?

Key messages

An online mindfulness course can significantly decrease perceived stress.

The decrease in stress is maintained at 1 month follow-up and is comparable to other interventions.

The online mindfulness course is an accessible and acceptable way for people to receive an intervention that can offer a way to decrease levels of perceived stress.

Strengths and limitations of this study

The sample consisted of people who had signed up to and paid for the online course that limits the extent to which we can extrapolate to those who might use it because referred by others (such as a health professional).

The effect of practice on mindfulness was not examined, so it is unclear what mediates the change in perceived stress. Other factors contributing to a decrease in stress were not included in this preliminary evaluation.

Objective

To inform the design of future informatics systems that support the chronic care model.

Study Design

We describe the development and functionality of a decision support system for the chronic care model of depression treatment, known as collaborative care. Dissemination of evidence-based collaborative care models has been slow, and fidelity to the evidence base has been poor during implementation initiatives. Implementation could be facilitated by a decision support system for depression care managers, the cornerstone of the collaborative care model. The Net Decision Support System (https://www.netdss.net/) is a free Web-based system that was developed to support depression care manager activities and to facilitate the dissemination of collaborative care models that maintain high fidelity to the evidence base.

Methods

The NetDSS was based on intervention materials used for a randomized trial of depression care management that improved clinical outcomes compared with usual care. The NetDSS was developed jointly by a cross-functional design team of psychiatrists, depression care managers, information technology specialists, technical writers, and researchers.

Results

The NetDSS has the following functional capabilities: patient registry, patient encounter scheduler, trial management, clinical decision support, progress note generator, and workload and outcomes report generator. The NetDSS guides the care manager through a self-documenting patient encounter using evidence-based scripts and self-scoring instruments. The NetDSS has been used to provide evidence-based depression care management to more than 1700 primary care patients.

Conclusion

Intervention protocols can be successfully converted to Web-based decision support systems that facilitate the implementation of evidence-based chronic care models into routine care with high fidelity.

Wild poliovirus has remained endemic in northern Nigeria because of low coverage achieved in the routine immunization program and in supplementary immunization activities (SIAs). An outbreak of infection involving 315 cases of type 2 circulating vaccine-derived poliovirus (cVDPV2; >1% divergent from Sabin 2) occurred during July 2005–June 2010, a period when 23 of 34 SIAs used monovalent or bivalent oral poliovirus vaccine (OPV) lacking Sabin 2. In addition, 21 “pre-VDPV2” (0.5%–1.0% divergent) cases occurred during this period. Both cVDPV and pre-VDPV cases were clinically indistinguishable from cases due to wild poliovirus. The monthly incidence of cases increased sharply in early 2009, as more children aged without trivalent OPV SIAs. Cumulative state incidence of pre-VDPV2/cVDPV2 was correlated with low childhood immunization against poliovirus type 2 assessed by various means. Strengthened routine immunization programs in countries with suboptimal coverage and balanced use of OPV formulations in SIAs are necessary to minimize risks of VDPV emergence and circulation.

Background

This report assesses the association between age of onset of major depression and later suicidality in a sample of 276 recurrently depressed patients recruited for the Oxford/Bangor Staying Well after Depression (SWAD) Trial, and interviewed when in remission.

Methods

The study enrolled adult patients with a history of at least three episodes of non-psychotic major depressive disorder from primary care and psychiatric care practices and through community advertisements. At study entry, all participants estimated the age of their first onset of a major depressive episode and completed both self-report and interview-based assessments of past and current suicidal ideation and behavior. Participants were divided into pre-adult and adult onset groups using a cut-off age of 18.

Results

Forty-eight percent of the sample reported a pre-adult age of onset. Pre-adult age of onset was significantly associated with suicidality, both from self-report and from interviewer assessment even when adjusting for differences in age, gender, employment status, length of the disorder and early adversity.

Limitations

Relevant variables were all assessed through retrospective reports.

Conclusions

Pre-adult age of onset is closely associated with risk for and severity of later suicidality, replicating, in a sample of patients assessed when in remission, findings from studies that assessed patients when currently depressed. The association of pre-adult age of onset with suicidality is not due to differences in sociodemographic variables, length of the disorder and early adversity.

Summary

Background

Motorcycles are the most popular means of transportation in northern Ghana, and their accidents are major causes of out-patient attendance and admissions in the Bolgatanga Municipality.

Objective

This paper estimates the economic burden of motorcycle accidents in the Bolgatanga Municipality in Northern Ghana.

Design

Retrospective cross-sectional cost study.

Methods

Data were collected from Drivers and Vehicle Licensing Authority, the Police, health facilities and motorcycle accident victims. Both quantitative and qualitative approaches were used for data collection. Cost analysis was based on the standard road accident cost conceptual framework.

Results

Ninety-eight percent of vehicles registered in the municipality in 2004 – 2008 were motorcycles. The motorcycles were significantly more than the cars registered. The economic burden of motorcycle accidents was estimated to be about US$1.2 million, of which, 52% were accident-related costs (i.e. property damage and administration) and 48% casualty-related costs (i.e. medical costs, out-of-pocket expenses, lost labour outputs, intangible costs and funeral expenses). Most motorcycle accident victims were in their productive ages and were males. Only a third of the motorcycles were insured. Majority of the riders (71%) did not possess valid driving license and would want to avoid the police. Main motorcycle injuries were head injuries, fractures, lacerations and contusions. Majority of the accidents were caused by lack of formal motorcycle riding training, abuse of alcohol, unrestrained animals and donkey carts.

Conclusion

Motorcycle accidents could be reduced through law enforcement, continuous mass education and helmet use.

The purpose of this work is to provide guidelines for the routine use of portal dosimetry and in vivo diode measurements to verify intensity-modulated radiotherapy (IMRT) treatments. To achieve tolerance levels that are sensitive enough to intercept problems, both the portal dosimetry and the in vivo procedure must be optimised. Portal dosimetry was improved by the introduction of an optimised two-dimensional (2D) profile correction, which also accounted for the effect of backscatter from the R-arm. The scaled score, indicating the fraction of points not meeting the desired gamma evaluation criteria within the field opening, was determined as the parameter of interest. Using gamma criteria of a 3% dose difference and 3 mm distance to agreement, a “scaled score” threshold value of 1.5% was chosen to indicate excessive tongue and groove and other problems. The pre-treatment portal dosimetry quality assurance (QA) does not encompass verification of the patient dose calculation or position, and so it is complemented by in vivo diode measurements. Diode positioning is crucial in IMRT, and so we describe a method for diode positioning at any suitable point. We achieved 95% of IMRT field measurements within ±5% and 99% within ±8%, with improved accuracy being achieved over time owing to better positioning. Although the careful preparation and setup of the diode measurements can be time-consuming, this is compensated for by the time efficiency of the optimised procedure. Both methods are now easily absorbed into the routine work of the department.

Previous research suggests distinct modes of self-focus, each with distinct functional properties: Analytical self-focus appears maladaptive, with experiential self-focus having more adaptive effects on indices of cognitive-affective functioning (e.g., Watkins, Moberly, & Moulds, 2008). The authors applied this framework to eating disorder (ED) psychopathology and manipulated the mode of self-focus prior to exposure to a stressor (imagining eating a large meal; Shafran, Teachman, Kerry, & Rachman, 1999). Study 1 showed that students high in ED psychopathology reported lower post-stressor feelings of weight or shape change and less subsequent attempts to neutralise (e.g., imagining exercising) after experiential relative to analytical self-focus. Study 2 found that partially weight restored patients with anorexia nervosa had lower post-stressor estimates of their own weight and reported lower urge to cancel stressor effects following experiential compared to analytical self-focus. Experiential self-focus was also followed by less neutralisation than analytical self-focus. Results suggest that the mode of self-focus affects cognitive reactivity following a stressor in individuals with ED psychopathology. Examining the mode within which individuals with ED psychopathology focus on self and body may raise important implications for understanding of psychopathology and open new possibilities for augmenting current treatments.

Highlights

► The way individuals with eating disorders focus on self/body may maintain pathology. ► Two experiments to examine self-focus effects on reactions to an eating stressor. ► Analytic and experiential self-focus had distinct influences on stress reactivity. ► Analytic focus increases weight/shape distortions and elicits compensatory thoughts. ► Shifting focus to experiencing vs. thinking about self/body may improve outcome.

Background

Pre-existing polyps, especially large polyps, are known to be the major source for colorectal cancer, but there is limited available information about factors that are associated with polyp size and polyp growth. We aim to determine factors associated with polyp size in different age groups.

Methods

Colonoscopy data were prospectively collected from 67 adult gastrointestinal practice sites in the United States between 2002 and 2007 using a computer-generated endoscopic report form. Data were transmitted to and stored in a central data repository, where all asymptomatic white (n = 78352) and black (n = 4289) patients who had a polyp finding on screening colonoscopy were identified. Univariate and multivariate analysis of age, gender, performance site, race, polyp location, number of polyps, and family history as risk factors associated with the size of the largest polyp detected at colonoscopy.

Results

In both genders, size of the largest polyp increased progressively with age in all age groups (P < .0001). In subjects ≥ 80 years the relative risk was 1.55 (95% CI, 1.35-1.79) compared to subjects in the youngest age group. With the exception of family history, all study variables were significantly associated with polyp size (P < .0001), with multiple polyps (≥ 2 versus 1) having the strongest risk: 3.41 (95% CI, 3.29-3.54).

Conclusions

In both genders there is a significant increase in polyp size detected during screening colonoscopy with increasing age. Important additional risk factors associated with increasing polyp size are gender, race, polyp location, and number of polyps, with polyp multiplicity being the strongest risk factor. Previous family history of bowel cancer was not a risk factor.

There has been a groundswell of interest in the UK in Mindfulness-Based Stress Reduction (MBSR) and its derivatives, particularly Mindfulness-Based Cognitive Therapy (MBCT). Many health, education and social work practitioners have sought ways to develop their competencies as mindfulness-based teachers, and increasing numbers of organisations are developing mindfulness-based training programmes. However, the rapid expansion of interest in mindfulness-based approaches has meant that those people offering training for MBSR and MBCT teachers have had to consider some quite fundamental questions about training processes, standards and competence. They also need to consider how to develop a robust professional context for the next generation of mindfulness-based teachers. The ways in which competencies are addressed in the secular mainstream contexts in which MBSR and MBCT are taught are examined to enable a consideration of the particularities of mindfulness-based teaching competence. A framework suggesting how competencies develop in trainees is presented. The current status of methodologies for assessing competencies used in mindfulness-based training and research programmes is reviewed. We argue that the time is ripe to continue to develop these dialogues across the international community of mindfulness-based trainers and teachers.

Granzyme B (GZMB) is a proapoptotic serine protease that is released by cytotoxic lymphocytes. However, GZMB can also be produced by other cell types and is capable of cleaving extracellular matrix (ECM) proteins. GZMB contributes to abdominal aortic aneurysm (AAA) through an extracellular, perforin-independent mechanism involving ECM cleavage. The murine serine protease inhibitor, Serpina3n (SA3N), is an extracellular inhibitor of GZMB. In the present study, administration of SA3N was assessed using a mouse Angiotensin II-induced AAA model. Mice were injected with SA3N (0–120 μg/kg) before pump implantation. A significant dose-dependent reduction in the frequency of aortic rupture and death was observed in mice that received SA3N treatment compared with controls. Reduced degradation of the proteoglycan decorin was observed while collagen density was increased in the aortas of mice receiving SA3N treatment compared with controls. In vitro studies confirmed that decorin, which regulates collagen spacing and fibrillogenesis, is cleaved by GZMB and that its cleavage can be prevented by SA3N. In conclusion, SA3N inhibits GZMB-mediated decorin degradation leading to enhanced collagen remodelling and reinforcement of the adventitia, thereby reducing the overall rate of rupture and death in a mouse model of AAA.

Alzheimer's disease (AD) is a complex disease that is likely influenced by many genetic and environmental factors. Citing evidence that iron may play a role in AD pathology, Robson et al. (2004) reported that epistatic interaction between rs1049296 (P589S) and rs1800562 (C282Y) in the hemochromatosis gene (HFE) results in significant association with risk for AD. In this study we attempted to replicate their findings in a total of 1166 cases and 1404 controls from three European and European American populations. Allele and genotype frequencies were consistent across the three populations. Using Synergy Factor Analysis and Logistic Regression analysis we tested each population and the combined sample for interactions between these two SNPs and risk for AD. We observed significant association between bi-carriers of the minor alleles of rs1049296 and rs1800562 in the combined sample using Synergy Factor Analysis (p=0.0016, synergy factor=2.71) and adjusted Synergy Factor Analysis adjusting for age and presence of the APOE epsilon 4 allele (p=0.002, OR=2.4). These results validate those of the previous report and support the hypothesis that iron transport and regulation play a role in AD pathology.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-L-iduronidase and attendant accumulation of the glycosaminoglycans dermatan and heparan sulfates. Current treatments are suboptimal and leave residual disease including corneal clouding, skeletal deformities, valvular heart disease and cognitive impairment. We treated neonatal mucopolysaccharidosis I dogs with intravenous recombinant α-L-iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 65–81 weeks. In contrast to previous results in animals and patients treated at a later age, all animals failed to mount an antibody response to enzyme therapy, consistent with neonatal tolerization. The higher dose of enzyme led to complete normalization of lysosomal storage in liver, spleen, lung, kidney, synovium and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and function were restored, and there were improvements in clinical and radiographic signs of skeletal disease. Glycosaminoglycan levels in the brain were normalized after intravenous enzyme therapy, with or without intrathecal treatment with recombinant α-L-iduronidase. Histopathologic evidence of glycosaminoglycan storage in the brain was ameliorated with the higher dose intravenous therapy and further improved by combined intravenous and intrathecal therapy. These findings argue that neonatal testing and early treatment of patients with mucopolysaccharidosis I may more effectively treat the disease.

Summary

This work documents from birth ERT therapy in a large animal model of MPS I, and details substantial clinical response in this model in what were previously intractable and difficult to treat tissues, all of which argues for neonatal testing and evaluation of neonatal initiated therapy in MPS I.