Adeno-associated viral vector 9 (AAV9) has recently been shown to penetrate the blood-brain barrier via intravascular administration, making it a good candidate for diffuse gene delivery. However, ...the potential side effects of systemic delivery are unknown. Intrathecal viral vector administration may be more invasive than intravenous injections, but it requires far less vector and it can be performed on an outpatient basis, making it an ideal route of delivery for clinical translation. A total of 12 domestic farm pigs (<20 kg) underwent a single-level lumbar laminectomy with intrathecal catheter placement for AAV9 delivery. Animals were perfused and the tissue was harvested 30 days after treatment. Gene expression was assessed by anti-green fluorescent protein immunohistochemistry. Although a single lumbar injection resulted in gene expression limited to the lumbar segment of the spinal cord, three consecutive boluses via a temporary catheter resulted in diffuse transduction of motor neurons (MNs) throughout the cervical, thoracic and lumbar spinal cords. We now present the first successful robust transduction of MNs in the spinal cord of a large animal via intrathecal gene delivery using a self-complementary AAV9. These promising results can be translated to many MN diseases requiring diffuse gene delivery.
Aims/hypothesis
The aim of this study was to determine the frequency of undiagnosed glucose abnormalities and the burden of cardiovascular disease (CVD) risk among south Asians and white Europeans ...attending a systematic screening programme for type 2 diabetes (ADDITION-Leicester) and to estimate the achievable risk reduction in individuals identified with glucose disorders.
Methods
Random samples of individuals (
n
= 66,320) from 20 general practices were invited for a 75 g OGTT and CVD risk assessment. Ten-year CVD risk among screen-detected people with diabetes or impaired glucose regulation (IGR) (impaired fasting glycaemia and/or impaired glucose tolerance IGT) was computed using the Framingham-based ETHRISK engine and achievable risk reduction was predicted using relative reductions for treatments extracted from published trials.
Results
A total of 6,041 participants (48% male, 22% south Asian) aged 40–75 years inclusive were included. Undiagnosed glucose disorders occurred more frequently in south Asians than white Europeans; age and sex adjusted odds ratios were 1.74 (95% CI 1.42–2.13) and 2.30 (95% CI 1.68–3.16) for IGT and diabetes respectively. Prevalence of any undetected glucose disorder was 17.5% in the whole cohort. Adjusted 10-year risk was similar in screen-detected people with IGR and diabetes (18.3% vs 21.6%), and was higher in south Asians across the glucose spectrum. Absolute CVD risk reductions of up to 13% in those with screen-detected type 2 diabetes and 6% in IGR are achievable using existing cardioprotective therapies.
Conclusions/interpretation
Population screening with an OGTT identifies a significant burden of modifiable CVD risk, especially within south Asian groups. Strategies enticing this population to consider screening programmes are urgently needed as significant risk reduction is possible once a glucose abnormality is identified.
Trial registration:
ClinicalTrials.gov NCT00318032
Funding:
The project is funded for support and treatment costs by NHS Department of Health Support for Science and project grants.
Earlier diagnosis followed by multi-factorial cardiovascular risk intervention may improve outcomes in type 2 diabetes mellitus (T2DM). Latent phase identification through screening requires ...structured, appropriately targeted population-based approaches. Providers responsible for implementing screening policy await evidence of clinical and cost effectiveness from randomised intervention trials in screen-detected T2DM cases. UK South Asians are at particularly high risk of abnormal glucose tolerance and T2DM. To be effective national screening programmes must achieve good coverage across the population by identifying barriers to the detection of disease and adapting to the delivery of earlier care. Here we describe the rationale and methods of a systematic community screening programme and randomised controlled trial of cardiovascular risk management within a UK multiethnic setting (ADDITION-Leicester).
A single-blind cluster randomised, parallel group trial among people with screen-detected T2DM comparing a protocol driven intensive multi-factorial treatment with conventional care.
ADDITION-Leicester consists of community-based screening and intervention phases within 20 general practices coordinated from a single academic research centre. Screening adopts a universal diagnostic approach via repeated 75g-oral glucose tolerance tests within an eligible non-diabetic population of 66,320 individuals aged 40-75 years (25-75 years South Asian). Volunteers also provide detailed medical and family histories; complete health questionnaires, undergo anthropometric measures, lipid profiling and a proteinuria assessment. Primary outcome is reduction in modelled Coronary Heart Disease (UKPDS CHD) risk at five years. Seven thousand (30% of South Asian ethnic origin) volunteers over three years will be recruited to identify a screen-detected T2DM cohort (n = 285) powered to detected a 6% relative difference (80% power, alpha 0.05) between treatment groups at one year. Randomisation will occur at practice-level with newly diagnosed T2DM cases receiving either conventional (according to current national guidelines) or intensive (algorithmic target-driven multi-factorial cardiovascular risk intervention) treatments.
ADDITION-Leicester is the largest multiethnic (targeting >30% South Asian recruitment) community T2DM and vascular risk screening programme in the UK. By assessing feasibility and efficacy of T2DM screening, it will inform national disease prevention policy and contribute significantly to our understanding of the health care needs of UK South Asians.
Clinicaltrial.gov (NCT00318032).
Diabet. Med. 29, 404–409 (2012)
Aims To investigate validity of waist circumference measurements obtained by self‐report and self‐measurement with non‐verbal pictorial instructions among a ...multi‐ethnic population.
Methods Five hundred and twenty‐six individuals aged 40–75 years (91 South Asian, 430 White European and five other), who attended a screening programme for Type 2 diabetes, estimated their waist circumference and measured their waist with a paper tape measure. Participants were also provided with simple pictorial instructions for measurement of waist circumference in their preferred language and remeasured their waist circumference. We calculated 95% limits of agreement with measures undertaken by a healthcare professional unaware of prior measures.
Results Mean age was 56.8 years (sd 9.0), mean BMI 30.0 kg/m2 (sd 5.6) and mean waist circumference 98.4 cm (sd 14.1). Seventy‐nine per cent had high waist circumference according to International Diabetes Federation criteria. The mean of participants’ self‐reported value was 6.8 cm lower than the healthcare professional measure (sd 8.8; 95% limits of agreement −10.4 to 24.0 cm), with significant differences by sex and ethnicity (South Asian men 7.5 cm, South Asian women 0.1 cm, White European men 7.8 cm, White European women 7.0 cm, P < 0.001). Compared with healthcare professional measures, mean self‐measured waist circumference was very similar, both with instructions (0.4 cm higher; sd 5.5 cm; −11.1 to 10.4 cm) and without instructions (0.5 cm lower; sd 5.6; −10.4 to 11.4 cm), but with significant differences by sex and ethnicity (P < 0.001).
Conclusions There was systematic underestimation of self‐reported waist circumference in this multi‐ethnic UK population. The magnitude of underestimation might reduce the performance of risk scores; however, this can be corrected through self‐measurement with pictorial instructions.
Objective: Comprehensive information about access and patterns of use of mental health services in Europe is lacking. We present the first results of the use of health services for mental disorders ...in six European countries as part of the ESEMeD project.
Method: The study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. Individuals aged 18 years and over who were not institutionalized were eligible for an computer‐assisted interview done at home. The 21 425 participants were asked to report how frequently they consulted formal health services due to their emotions or mental health, the type of professional they consulted and the treatment they received as a result of their consultation in the previous year.
Results: An average of 6.4% of the total sample had consulted formal health services in the previous 12 months. Of the participants with a 12‐month mental disorder, 25.7% had consulted a formal health service during that period. This proportion was higher for individuals with a mood disorder (36.5%, 95% CI 32.5–40.5) than for those with anxiety disorders (26.1%, 95% CI 23.1–29.1). Among individuals with a 12‐month mental disorder who had contacted the health services 12 months previously, approximately two‐thirds had contacted a mental health professional. Among those with a 12‐month mental disorder consulting formal health services, 21.2% received no treatment.
Conclusion: The ESEMeD results suggest that the use of health services is limited among individuals with mental disorders in the European countries studied. The factors associated with this limited access and their implications deserve further research.
We studied the potential roles of testosterone and serotonin in various forms of aggressive and violent behaviors by measuring each biochemical and behavior in free-ranging adolescent male nonhuman ...primates. Our results showed that (1) CSF free testosterone concentrations were positively correlated with overall aggressiveness, but not with measures of impulsivity. (2) CSF 5-HIAA concentrations were negatively correlated with impulsive behavior, and severe, unrestrained aggression, but not with overall rates of aggression. High rates of impulsive behavior were positively correlated with severe, unrestrained aggression, but not overall rates of aggression. (3) Dimensional analyses showed that while subjects with low CSF 5-HIAA exhibited high rates of aggression, high CSF testosterone further augmented rates and intensity of aggression in subjects with low CSF 5-HIAA. We conclude that high CSF free testosterone concentrations are associated with competitive aggression, while low CSF 5-HIAA concentrations are associated with severe aggression which results from impaired impulse control, and perseverance.
Kinins exert multiple pathophysiological functions, including vascular permeability and mitogenesis, by activating their cognate receptors, bradykinin subtype 1 receptor (B1R) and bradykinin subtype ...2 receptor (B2R), which belong to the superfamily of G protein-coupled receptors. Tissue-specific expression pattern or contribution of the individual kinin receptors to pathological prostate cell growth is not known. We report here the differential expression of B1R and B2R in human benign and malignant prostate specimens. Whereas B2R is ubiquitously expressed, the B1R is detected only in prostatic intraepithelial neoplasia and malignant lesions and not in benign prostate tissues. Using androgen-insensitive prostate cancer PC3 cells, we show that specific stimulation of endogenous B1R promotes cell growth, migration, and invasion. These findings identify B1R as an early marker for pathological growth of the prostate and suggest its potential utility as a drug target effective for the treatment of prostate cancer.
Summary Ultraclean air (UCA) in operating theatres is defined as <10 colony-forming units (cfu)/m3 . The current European standards for surgical gowns are contained in EN13795 but these do not ...include containment of bacterial dispersal as a standard test. A trial in 2003 found that there were bacterial air counts of 1 cfu/m3 with Rotecno gowns and 0.5 cfu/m3 with body exhaust suits in total knee arthroplasty (TKA). This study compared bacterial air counts using Rotecno gowns with a new type of occlusive gown made from Gore liquid-proof fabric, which were superior to the Rotecno gowns on standard EN13795 laboratory testing. Fifty-six joint replacements were allocated randomly either to Rotecno or to Gore gowns with stratification into TKA, total hip arthroplasty (THA) or revision THA. Airborne bacteria were collected from within 30 cm of the wound for the first 10 min of surgery using a Casella slit sampler. The new gowns were associated with higher air counts (3.7 cfu/m3 ) than the Rotecno gowns (1.2 cfu/m3 ) ( P < 0.001). Three of the Gore samples exceeded the clean air standard of 10 cfu/m3 . In TKA patients, the existing Rotecno gowns, now many years old, had higher air counts (2.0 cfu/m3 ) than in the 2003 trial (0.8 cfu/m3 ) ( P < 0.001). The new gowns were superior in standard laboratory tests but not superior at preventing airborne bacterial dispersal. Rotecno gowns, although many years old, were still effective. This study highlights the importance of testing new materials in a clinical environment with UCA; in-vitro testing alone is probably not an adequate assessment.
The purpose of this study was to examine the relationship between behavior and serotonin by using a nonhuman primate model of aggression and impulse control.
During a routine capture and medical ...examination, 26 adolescent male rhesus macaques (Macaca mulatta) were selected as subjects from a free-ranging population of 4,500 rhesus monkeys inhabiting a 475-acre sea island. Physiological data were obtained from 22-23 of the subjects. Blood and CSF samples were obtained, and each subject was fitted with a radio transmitter collar for rapid location. The subjects were released into their social groups, and quantitative behavioral observations were made over a 3-month period.
CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations were inversely correlated with "escalated" aggression, i.e., a measure of more intense or severe aggression as defined by the ratio of chases and physical assaults to all aggressive acts. CSF 5-HIAA concentrations were significantly lower in those subjects who showed evidence of physical wounding than in subjects with no wounds. Low CSF 5-HIAA concentrations were also correlated with greater risk-taking as determined by an analysis of leaping behaviors in the forest canopy. The ratio of long leaps (leaps that traversed the longest distances at dangerous heights) to all leaps was negatively correlated with CSF 5-HIAA concentrations.
Adolescent male rhesus macaques with low CSF 5-HIAA concentrations are at risk for 1) exhibiting more violent forms of aggressive behavior and 2) loss of impulse control as evidenced by greater risk taking during movement through the forest canopy.
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