Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice.

Macular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3-/- mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.

Optimizing OCT acquisition parameters for assessments of vitreous haze for application in uveitis.

Detection and evaluation of inflammatory activity in uveitis is essential to the management of the condition, and yet continues to be largely dependent on subjective clinical measures. Optical coherence tomography (OCT) measurement of vitreous activity is an alternative to clinical vitreous haze scoring and has passed a number of early validation studies. In this study we aimed to evaluate the impact of 'operator factors' on the variability of the technique as part of the validation process, and to help evaluate its suitability for 'real world' use. Vitreous haze index was calculated as a ratio between the reflectivity of the vitreous and of the outer retina in each scan. Different scanning conditions were tested and their effect on the measurement is reported. Our results show that the 'quantitative imaging' technique of OCT-measured vitreous activity had good reliability in normal subjects under a range of 'real world' conditions, such as when the operator changes the averaging value. The technique was however vulnerable to highly inaccurate focussing or abnormal downward displacement of the image. OCT-based quantification of vitreous activity is a promising alternative to current subjective clinical estimates, with sufficient 'tolerance' to be used in routine clinical practice as well as clinical trials.

Association of availability of tobacco products with socio-economic and racial/ethnic characteristics of neighbourhoods.

OBJECTIVE: To examine the association of neighbourhood median income and racial/ethnic composition with the availability of tobacco products in Omaha Metropolitan Area, Nebraska, USA. METHODS: A total of 94 census tracts were selected at random. The outcome measures were the percentage of stores that sold tobacco and the number of stores that sold tobacco per square mile in each census tract. RESULTS: Median household income was negatively associated (P<0.001), and percentage African American population (P<0.001) and percentage Hispanic population (P=0.049) were positively associated with the percentage of stores that sold tobacco. Median household income was negatively associated (P<0.001) and percentage Hispanic population (P=0.012) was positively associated with the number of stores that sold tobacco per square mile. CONCLUSION: Policies that reduce the number of tobacco outlets might reduce social disparities in tobacco use.

Effectiveness of web-based interventions in achieving weight loss and weight loss maintenance in overweight and obese adults: a systematic review with meta-analysis.

The objectives of this systematic review are to evaluate the effectiveness of web-based interventions on weight loss and maintenance and identify which components of web-based interventions are associated with greater weight change and low attrition rates. A literature search from 1995 to April 2008 was conducted. Studies were eligible for inclusion if: participants were aged >or=18 years with a body mass index >or=25, at least one study arm involved a web-based intervention with the primary aim of weight loss or maintenance, and reported weight-related outcomes. Eighteen studies met the inclusion criteria. Thirteen studies aimed to achieve weight loss, and five focused on weight maintenance. Heterogeneity was evident among the studies with seven research questions examined across interventions of varying intensity. Seven studies were assessed for effectiveness based on percentage weight change, with four studies deemed effective. Although the four meta-analyses suggest meaningful weight change, it is not possible to determine the effectiveness of web-based interventions in achieving weight loss or maintenance due to heterogeneity of designs and thus the small number of comparable studies. Higher usage of website features may be associated with positive weight change, but we do not know what features improve this effect or reduce attrition.

Racial/ethnic and socioeconomic variations in duration of smoking: results from 2003, 2006 and 2007 Tobacco Use Supplement of the Current Population Survey.

BACKGROUND: Little is known about racial/ethnic and socioeconomic variations in the duration of smoking. The goal of this research was to examine these variations. METHODS: Data came from the 2003, 2006 and 2007 Tobacco Use Supplement of the Current Population Survey. The analysis was limited to ever-smokers (n = 117,168). The outcome was number of years of daily smoking. Survival analysis was employed to predict smoking duration. RESULTS: American Indians with 32 years had the highest median duration of smoking, followed by Blacks and 'other' races with 30 years, Whites with 28 years and Hispanics with 24 years. The difference in the duration of smoking between Blacks and Whites disappeared after adjusting for poverty. Individuals in poverty had a median duration of smoking of 40 years, while those with a family income of at least three times that of the poverty threshold had a median duration of 22 years. Median duration of smoking was 40 years among individuals without a high-school diploma and 18 years among those with a bachelors or higher degree. CONCLUSION: This research revealed large variations in smoking duration between racial/ethnic and socioeconomic groups. Longer exposure to tobacco among groups that are already disadvantaged is likely to exacerbate existing health disparities.

Comparison of the fate and toxicity of chlorpyrifos--laboratory versus a coastal mesocosm system.

The widespread use of chlorpyrifos for pest control in urban and rural environments poses a risk of contamination to aquatic environments via runoff, spray drift or spillage. The aim of this study was to assess the fate of chlorpyrifos and its toxicity to common freshwater invertebrates in the laboratory and in stream mesocosms. Chlorpyrifos was rapidly lost from the test systems but the rates of loss varied considerably, such that losses in the mesocosms could not be reliably predicted from the static laboratory studies. This was likely due to the mass transport of chlorpyrifos from the mesocosm via stream flow. Chlorpyrifos was acutely toxic to all invertebrates tested with the cladoceran species (laboratory 48h LC(50) values 0.07-0.10 microg L(-1)) being most sensitive. Despite the differences in the dynamics of chlorpyrifos in the laboratory and mesocosm systems, the sensitivities of the mayfly Atalophlebia australis and the cladoceran Simocephalus vetulus were similar in the 2 systems.

A novel method for rapidly diagnosing the causes of diarrhoea.

BACKGROUND: The microbiological diagnosis of infectious diarrhoea may take several days using conventional techniques. In order to determine whether flatus can be used to make a rapid diagnosis, the volatile organic compounds associated with diarrhoea were analysed. METHODS: Stool samples were collected from 35 patients with infectious diarrhoea and from six healthy controls. Gaseous compounds were extracted from a headspace using solid phase microextraction and analysed using gas chromatography and mass spectroscopy. RESULTS: Characteristic patterns of volatile gases were found for the main causes of infectious diarrhoea in hospitals. Furan species without indoles indicated Clostridium difficile, ethyl dodecanoate indicated rotavirus, ammonia without ethyl dodecanoate suggested other enteric viruses, and the absence of hydrocarbons and terpenes indicated Campylobacter infection. CONCLUSION: These results could be the basis of rapid near patient diagnosis of infectious diarrhoea.

Commencing, continuing and stopping brisk walking: effects on bone mineral density, quantitative ultrasound of bone and markers of bone metabolism in postmenopausal women.

Regular walking is associated with reduced risk of fracture and, in our recent randomized trial, reduced calcaneal bone loss relative to controls. The present follow-up study compared the effects on dual-energy X-ray absorptiometry, ultrasound and biochemical indices of bone density and metabolism of (i) taking up (ii) continuing with and (iii) ceasing brisk walking for exercise. Subjects were 68 postmenopausal women aged 60-70 years. Twenty previously sedentary women remained sedentary (Sed/Sed) whilst 17 took up brisk walking (Sed/Walk). Fifteen women who had been walking regularly for 1 year returned to their former sedentary lifestyle (Walk/Sed), whilst 16 continued brisk walking over a second year (Walk/Walk). Bone mineral density (BMD), broadband ultrasonic attenuation (BUA), and biochemical markers of bone formation (serum osteocalcin, C-terminal propeptide of type I collagen and bone alkaline phosphatase) and resorption (urinary deoxypyridinoline) were assessed at baseline and 12 months. Women in the Sed/Walk and Walk/Walk groups completed a mean (SEM) of 16.9 (0.7) and 20.8 (1.2) min of brisk walking per day, respectively. Changes in BMD did not differ significantly between groups. Calcaneal BMD decreased significantly in Walk/Sed women [by 2.7 (1.4)%; p = 0.01] whilst changes in other groups were not significant. Calcaneal BUA increased significantly (p = 0.02) in Sed/Walk women [by 7.4 (3.3)%] relative to other groups. Urinary deoxypyridinoline increased over the year in the Sed/Sed group but there were no significant changes in biochemical markers in other groups. Women taking up brisk walking for exercise showed no change in BMD but a significant increase in calcaneal BUA. There was no significant effect on BMD or BUA of continuing brisk walking but calcaneal BMD declined on ceasing brisk walking. Bone resorption increased in sedentary women but not exercisers, suggesting the effect on exercise on bone in postmenopausal women could be through amelioration of this increased turnover.

Resistance to an herbivore through engineered cyanogenic glucoside synthesis.

The entire pathway for synthesis of the tyrosine-derived cyanogenic glucoside dhurrin has been transferred from Sorghum bicolor to Arabidopsis thaliana. Here, we document that genetically engineered plants are able to synthesize and store large amounts of new natural products. The presence of dhurrin in the transgenic A. thaliana plants confers resistance to the flea beetle Phyllotreta nemorum, which is a natural pest of other members of the crucifer group, demonstrating the potential utility of cyanogenic glucosides in plant defense.

Activation of diacetyldapsone and a preliminary evaluation of a cyclodextrin-diacetyldapsone complex in cultured lung cells.

A diacetyldapsone-2-hydroxypropyl-beta-cyclodextrin complex (DADDS-CD) was evaluated with regard to the ability of cultured lung cells to activate DADDS to the active metabolite dapsone. The same system was used to assess the effect of the complex on cell growth. The complex was incubated with cells for periods of 24 to 72 h, followed by extraction of metabolites from the incubation medium and analysis by HPLC. In addition, the Trypan Blue exclusion technique was used to assess cell viability during this time period. Results indicated that lung cells could activate DADDS to dapsone and that, while the complex appeared to delay cell growth in the first 24 h period, no significant difference was seen between cells incubated in the presence and absence of the complex at 72 h. These results indicate that DADDS-CD has significant potential as a drug-delivery system for DADDS in the lung based upon the ability of the cells to activate DADDS. The mixed effects of the complex on cell growth may have important implications when considering the frequency of administration of the complex to the lung.

Reliability of Allen's test in selection of patients for radial artery harvest.

BACKGROUND: Allen's test is widely used to assess the ulnar collateral blood supply of the hand before radial artery harvest for coronary bypass surgery. This study was performed to determine the optimum cut-off point for a positive Allen's test and the clinical reliability of Allen's test in this role. METHODS: Patients undergoing coronary artery bypass surgery were examined by independent observers using both Allen's test and a Doppler ultrasound test of the ulnar collateral circulation. RESULTS: We examined 93 hands in 47 patients; mean age was 63.6 years. Receiver operating characteristic analysis found that at a conventional cut-off of 6 seconds on Allen's test had a sensitivity of 54.5%, specificity of 91.7%, and diagnostic accuracy of 78.5%. At a cut-off of 5 seconds diagnostic accuracy was maximal (79.6%), with sensitivity of 75.8% and specificity of 81.7%; 100% sensitivity occurred at a cut-off of 3 seconds, with specificity of 27% and diagnostic accuracy of 52%. CONCLUSIONS: At no cut-off point does Allen's test perform satisfactorily as a discriminatory test. It should be replaced by more objective tests, such as Doppler ultrasound.

Prior exercise and postprandial substrate extraction across the human leg.

Prior exercise decreases postprandial plasma triacylglycerol (TG) concentrations, possibly through changes to skeletal muscle TG extraction. We measured postprandial substrate extraction across the leg in eight normolipidemic men aged 21-46 yr. On the afternoon preceding one trial, subjects ran for 2 h at 64 +/- 1% of maximal oxygen uptake (exercise); before the control trial, subjects had refrained from exercise. Samples of femoral arterial and venous blood were obtained, and leg blood flow was measured in the fasting state and for 6 h after a meal (1.2 g fat, 1.2 g carbohydrate/kg body mass). Prior exercise increased time averaged postprandial TG clearance across the leg (total TG: control, 0.079 +/- 0.014 ml.100 ml tissue(-1).min(-1) ; exercise, 0.158 +/- 0.023 ml.100 ml tissue(-1).min(-1), P <0.01), particularly in the chylomicron fraction, so that absolute TG uptake was maintained despite lower plasma TG concentrations (control, 1.53 +/- 0.13 mmol/l; exercise, 1.01 +/- 0.16 mmol/l, P < 0.001). Prior exercise increased postprandial leg blood flow and glucose uptake (both P < 0.05). Mechanisms other than increased leg TG uptake must account for the effect of prior exercise on postprandial lipemia.

Nitric oxide delivery to the lung: a model.

Dedicated nitric oxide equipped ventilators are now available commercially but are not yet common in clinical practice. With other ventilators, there is no standardized procedure for the administration or monitoring of nitric oxide. We describe the use of nitric oxide in conjunction with a simple time-cycled, pressure regulated, flow generating ventilator attached to a model infant-sized lung. The measured nitric oxide concentrations were always less than calculated. Infusion site, minute ventilation and sampling port all affected nitric oxide concentration (P < 0.05). Increasing minute ventilation lowered measured nitric oxide concentration exponentially. Mixing of gases improved when nitric oxide was infused closer to the ventilator. Acid contamination was found in water samples from humidifier, water trap and ventilator gas outlet. Acidification was reduced, without change in measured nitric oxide delivery, when infused prehumidifier. We recommend, when used as therapy, nitric oxide levels in inspired gases should always be measured.

The significance of definitions of success in program evaluation.

In program evaluation, determining whether a program is reaching its goals is key to evaluating program success. Having an understanding of the stated goals of each organization within a system rather than simply knowing the formal system goals can aid in program development and inform policy making. Evaluability assessments were used initially as a means of learning how Philadelphia delinquency prevention programs define success. Subsequent surveys of programs were conducted to ascertain whether any changes in definitions of success had occurred. Examination of programs' definitions of success over time has facilitated program development and policy making.

Pharmacokinetics of midazolam in critically ill pediatric patients.

Midazolam is frequently used to produce sedation in critically ill pediatric patients. We studied the pharmacokinetics of midazolam in 22 patients (age 8 days to 16 years). The intravenous infusion rate to produce sedation ranged from 49-385 mcg/kg/hr. The blood samples were obtained at steady-state and midazolam was measured by gas chromatography with electron capture. The steady-state plasma concentrations of midazolam ranged from 49-385 ng/mL. The total clearance, apparent volume of distribution, and elimination half-life ranged from 0.1-3.1 L/kg/hr, 0.2-3.5 L/kg, and 0.3-10.9 hours, respectively. The marked interpatient variability in pharmacokinetics explains in part, the substantial variation in dosage requirements of midazolam to produce sedation in critically ill pediatric patients.

The UDP-glucose:p-hydroxymandelonitrile-O-glucosyltransferase that catalyzes the last step in synthesis of the cyanogenic glucoside dhurrin in Sorghum bicolor. Isolation, cloning, heterologous expression, and substrate specificity.

The final step in the biosynthesis of the cyanogenic glucoside dhurrin in Sorghum bicolor is the transformation of the labile cyanohydrin into a stable storage form by O-glucosylation of (S)-p-hydroxymandelonitrile at the cyanohydrin function. The UDP-glucose:p-hydroxymandelonitrile-O-glucosyltransferase was isolated from etiolated seedlings of S. bicolor employing Reactive Yellow 3 chromatography with UDP-glucose elution as the critical step. Amino acid sequencing allowed the cloning of a full-length cDNA encoding the glucosyltransferase. Among the few characterized glucosyltransferases, the deduced translation product showed highest overall identity to Zea mays flavonoid-glucosyltransferase (Bz-Mc-2 allele). The substrate specificity of the enzyme was established using isolated recombinant protein. Compared with endogenous p-hydroxymandelonitrile, mandelonitrile, benzyl alcohol, and benzoic acid were utilized at maximum rates of 78, 13, and 4%, respectively. Surprisingly, the monoterpenoid geraniol was glucosylated at a maximum rate of 11% compared with p-hydroxymandelonitrile. The picture that is emerging regarding plant glucosyltransferase substrate specificity is one of limited but extended plasticity toward metabolites of related structure. This in turn ensures that a relatively high, but finite, number of glucosyltransferases can give rise to the large number of glucosides found in plants.

The effect of childhood spinal cord injury on skeletal development: a retrospective study.

STUDY DESIGN: Cross-sectional clinical review. OBJECTIVES: To assess the relationship between late spinal deformity in childhood onset spinal cord injury (SCI) and level of spinal cord lesion, severity of lesion, age at onset, duration of paralysis and pelvic deformities. SETTING: People with spinal cord injury (onset in childhood) treated and followed up at the National Spinal Injuries Center (identified from case notes review, contacted and agreed to participate). METHOD: One hundred and eighty-nine subjects satisfying study inclusion criteria (acute onset SCI before the 16th birthday) were identified by case note review of 8200 records. Eighty formed the group attending for clinical review including whole spine radiographs (AP and lateral). Clinical examination included neurological status and joint range of movements. Demographic data was recorded. RESULTS: Scoliosis occurred more frequently and was more severe in those injured at a younger age, 38 degrees, compared with 24 degrees in those injured later (P<0.05), in paraplegia, 33 degrees, versus tetraplegia, 17 degrees, (P<0.01) and in complete, 36 degrees, versus incomplete lesions, 18 degrees, (P<0.001). Lordosis angulation in paraplegic subjects was significantly greater than in tetraplegic subjects in both seated, 50 degrees versus 25 degrees (P<0.014) and standing subjects 78 degrees versus 59 degrees (P<0.017) respectively and for kyphosis in standing subjects, 52 degrees versus 31 degrees (P<0.01). Sagittal measurements were influenced by habitual posture (which also corresponded to the severity of the lesion). CONCLUSION: Younger age at onset was shown to be associated with more severe scoliosis, as has been reported by others. Subjects with paraplegia and complete lesions demonstrated a greater and more frequently occurring scoliosis than those with tetraplegia and incomplete lesions respectively. Lordosis was greater in those with paraplegia than with tetraplegia and in those with very incomplete lesions compared with complete lesions. However the influence of the severity of the lesion cannot be separated from the postural position when analyzing spinal deformity.

Areas of fat loss in overweight young females following an 8-week period of energy intake reduction.

In order to investigate the main areas of fat loss after an 8-week period of energy intake reduction, the distribution of body fat was assessed on 14 females (BMI 27.3+/-0.83 kgm(-2)) (mean +/- SEM), aged 18-22 years. Total body fat was determined by hydrostatic weighing and subcutaneous fat mass and distribution were assessed using ultrasound and waist-hip circumference ratios prior to, and following, an 8-week period during which subjects attempted to reduce their energy intake by about 4.2 MJ day(-1). Subjects lost an average of 2.99+/-0.34 kg (p < 0.001), with greater loss (p < 0.001) of internal fat (1.5+/-0.2 kg) than of subcutaneous fat (0.7+/-0.1). Subjects reduced their waist-hip ratio from 0.771+/-0.01 to 0.762+/-0.01 (p < 0.01), their waist circumference from 807+/-24 to 790+/-23 mm (p < 0.001) and their hip circumference from 1047+/-29 to 1037+/-29 mm (p < 0.001). Those with an android distribution of fat (n = 5) lost more weight than those with gynoid distribution (n = 9) (3.80+/-0.38 kg vs 2.54+/-0.14 kg, p < 0.05); they also showed a greater decrease in waist circumference (27+/-5 vs 14+/-4 mm, p < 0.05) and a greater loss from internal fat stores (2.1+/-0.3 kg vs 1.1+/-0.2 kg, p < 0.05). The findings suggest that individuals are prone to lose internal fat during a short period of reduced energy intake. As the visceral fat store is the largest internal fat depot in the body, this suggests that individuals are indeed losing fat that could predispose to upper body obesity.

Brisk walking and postural stability: A cross-sectional study in postmenopausal women.

This study compared body sway, a measure of postural stability, between regular brisk walkers and control subjects. Furthermore, the relationship between body sway and physical activity duration in postmenopausal women was examined. Subjects were 31 healthy postmenopausal women, aged 61-71 years. They were recruited from a randomized controlled study of the influence of brisk walking on bone: 16 women had been completing 20 min d-1 brisk walking, whilst 15 controls had been completing habitual activities only. Body sway was measured using a swaymeter that measured displacement at the waist whilst subjects stood on a compliant surface, with eyes closed, for 1 min. The activity was measured using activity monitors which were worn at the waist for 3 consecutive days. Body sway (eyes closed, standing on a compliant surface) was lower in walkers than in controls: 2,958 +/- (SE) 270 versus 5,225+/-371 mm2 min-1, respectively (p < 0.05). A negative correlation was found between body sway and minutes of physical activity (r = -0.47, p < 0.01). Analysis of variance revealed that body sway differed significantly (p < 0.05) between groups of differing physical activity participation, being 4,839 +/- 499, 4,167 +/- 516, and 2,877 +/- 362 mm2 min-1, respectively, in women completing <20, 20-40, and >40 min d-1 of physical activity. Body sway was significantly lower in the most active group than in the least active (p < 0.01). These data suggest that postural stability is better in regular walkers than in control subjects. Furthermore, a dose-response relationship was observed between physical activity and postural stability in postmenopausal women. These findings provide a preliminary indication that brisk walking, a low-cost and acceptable form of physical activity for the elderly, could be incorporated into strategies for improving balance in the elderly.

Anti-calculus activity of a toothpaste with microgranules.

OBJECTIVE: The objective of the trial was to determine the efficacy of the proven anticalculus active system (zinc citrate trihydrate [ZCT] and triclosan), when the ZCT is delivered from microgranules incorporated in a silica-based toothpaste containing 1450 ppm F as sodium fluoride. DESIGN: A monadic, single-blind, two phase design clinical trial was used to compare the effect of the test and a negative control fluoridated toothpaste on the formation of supragingival calculus. SUBJECTS AND METHODS: Male and female calculus-forming volunteers, aged 18 or over, were recruited for the study following a 2-week screening phase. All subjects were given a scale and polish of their eight lower anterior teeth at the start of both the pre-test and test phases. Subjects were supplied with a silica-based 1450 F ppm fluoridated toothpaste with no anti-calculus active for use during an 8-week pre-test phase. Calculus was assessed at the end of the pre-test and test phases using the Volpe-Manhold index (VMI). Subjects were stratified according to their pre-test VMI score (8-10, 10.5-12, > 12) and gender and then allocated at random to test or negative control toothpaste groups. Subjects with < 8 mm of calculus were excluded from further participation. MAIN OUTCOME MEASURE: The outcome variable was the mean VMI score for the test and negative control groups. RESULTS: The test toothpaste caused a statistically significant 30% reduction in calculus compared with the control paste after a 13-week use. No adverse events were reported during the study. CONCLUSION: The incorporation of the ZCT in microgranules did not adversely affect the anticalculus activity of the new formulation.