Impulsive choices in mice lacking imprinted Nesp55.

Genomic imprinting is the process whereby germline epigenetic events lead to parent-of-origin specific monallelic expression of a number of key mammalian genes. The imprinted gene Nesp is expressed from the maternal allele only and encodes for Nesp55 protein. In the brain, Nesp55 is found predominately in discrete areas of the hypothalamus and midbrain. Previously, we have shown that loss of Nesp55 gives rise to alterations in novelty-related behaviour. Here, we extend these findings and demonstrate, using the Nespm/+ mouse model, that loss of Nesp55 leads to impulsive choices as measured by a delayed-reinforcement task, whereby Nespm/+ mice were less willing to wait for a delayed, larger reward, preferring instead to choose an immediate, smaller reward. These effects were highly specific as performance in another component of impulsive behaviour, the ability to stop a response once started as assayed in the stop-signal reaction time task, was equivalent to controls. We also showed changes in the serotonin system, a key neurotransmitter pathway mediating impulsive behaviour. First, we demonstrated that Nesp55 is co-localized with serotonin and then went on to show that in midbrain regions there were reductions in mRNA expression of the serotonin-specific genes Tph2 and Slc6a4, but not the dopamine-specific gene Th in Nespm/+ mice; suggesting an altered serotonergic system could contribute, in part, to the changes in impulsive behaviour. These data provide a novel mode of action for genomic imprinting in the brain and may have implications for pathological conditions characterized by maladaptive response control.

Secondhand smoke exposure in Alaskan households with children.

INTRODUCTION: Secondhand smoke (SHS) exposure causes premature death and disease in children and non-smoking adults; the home is the primary source of SHS exposure. The aim of this study was to assess variance in the prevalence of children's SHS exposure in Alaskan households with an adult smoker according to rurality, race/ethnicity, income and education, household age composition, marital status, amount smoked each day, and beliefs in SHS health consequences. METHOD: Telephone interviews were conducted between 2004 and 2007 on a population-based random sample of 1119 Alaskan adult smokers with children living in the household. RESULTS: Respondents living with children over 5 years of age reported a significantly (p <0.05) higher prevalence of home SHS exposure, compared with those living with younger children. Respondents 40 years and older reported significantly more exposure than others. Alaska Native smokers reported significantly lower SHS exposure in their homes than those of other races, as did those living in very rural areas. Respondents' heavier smoking was significantly associated with more SHS exposure. The sub-population of adults living without other adults was approximately 1.5 times more likely to report SHS exposure than those living with other adults. As expected, having a no-smoking rule in the home greatly lowered the risk of SHS exposure in the home. CONCLUSIONS: Although most smokers with children believed that SHS is harmful, some need to convert those beliefs into actions. The results from this study suggest that those with school-aged children, and moderate to heavy smokers should be targeted for intervention, given their high prevalence of home SHS exposure. Future work should examine reasons for low exposure levels among Alaska Native people to inform programmatic efforts in other communities.

Outcome of a tobacco use cessation randomized trial with high-school students.

This study analyzed quantitative data on tobacco use and dependency for 3,589 high-school students, qualitative data for 448 students, and outcome data for a randomized trial comparing the efficacy of two cessation interventions and a control condition for 337 students. Data were collected from 1988 through 1992 in California and Illinois as part of a larger longitudinal study. Smokeless tobacco users, but not smokers, were more likely than controls to maintain cessation for 4 months: biochemically validated cessation at 4 months was 6.5% versus 3.2% for smokers and 14.3% versus 0.0% for smokeless tobacco users. Implications and limitations are discussed.

Metabolism of proteoglycans in tendon.

Tendons are dense, fibrous connective tissues that are responsible for transmitting mechanical forces from skeletal muscle to bone. From a clinical perspective, tendinopathy (defined as a syndrome of tendon pain, tenderness and swelling that affects function) is very common, both within the sporting arena and in the workplace. Importantly, proteoglycans are essential components of the tendon extracellular matrix (ECM) and changes in their expression and metabolism/turnover have been associated with tendinopathy. Within tendons, the small leucine-rich proteoglycans (SLPRs), decorin, fibromodulin, lumican and keratocan predominate within tensional regions, while in tendon fibrocartilage, increased concentrations of proteoglycans common to the articular cartilage phenotype are present, including aggrecan, biglycan and proteoglycan 4. However, the rate of proteoglycan turnover within tendon is markedly higher than that of cartilage, mediated via the "aggrecanases," which are constitutively active in the tendon matrix. Data suggest that this increased proteoglycan turnover is likely to be required to maintain normal tendon homeostasis, with perturbations in proteoglycan metabolism contributing to tissue dysfunction. Thus, future studies aimed at furthering our fundamental knowledge of tendon proteoglycan metabolism in health and disease are important in the development of improved treatments for tendon disorders.

Does tobacco industry marketing excessively impact lesbian, gay and bisexual communities?

BACKGROUND: Tobacco industry documents have revealed marketing plans specifically to reach lesbian, gay and bisexual (LGB) populations. Research supports a causal linkage between receptivity and exposure to tobacco industry marketing and tobacco use uptake among adolescents. Pro-tobacco messages may diminish the effectiveness of tobacco control activities and contribute to the high smoking prevalence among LGB populations. OBJECTIVE: To compare receptivity and exposure to tobacco industry marketing between LGB and heterosexual populations. METHODS: Nearly 400 gay or bisexual men and more than 600 lesbian or bisexual women were identified in the 2003-2006 Washington State Behavioral Risk Factor Surveillance System (BRFSS), a state-wide, population-based telephone survey of adults. The BRFSS included questions measuring receptivity and exposure to tobacco industry marketing. Multiple logistic regression models stratified by gender were used to assess differences for lesbians, gays and bisexuals separately, in comparison to their heterosexual counterparts. RESULTS: As expected, smoking prevalence was higher among LGB populations than among heterosexuals. After adjustment for demographic differences and smoking status, gay and bisexual men reported more exposure to tobacco industry marketing (free sample distribution) than straight men, but were equally receptive to it. Lesbian and bisexual women were more receptive to and reported more exposure to tobacco industry marketing than straight women. CONCLUSION: LGB communities, especially lesbian and bisexual women, appear to be effectively targeted by tobacco industry marketing activities. Strategies to limit tobacco industry marketing, and increase individuals' resistance to marketing, may be critical to reducing smoking among LGB populations.

Outcome of total elbow replacement for distal humeral fractures in the elderly: a comparison of primary surgery and surgery after failed internal fixation or conservative treatment.

We analysed the outcome of the Coonrad-Morrey total elbow replacement used for fracture of the distal humerus in elderly patients with no evidence of inflammatory arthritis and compared the results for early versus delayed treatment. We studied a total of 32 patients with 15 in the early treatment group and 17 in the delayed treatment group. The mean follow-up was 56.1 months (18 to 88). The percentage of excellent to good results based on the Mayo elbow performance score was not significantly different, 84% in the early group and 79% in the delayed group. Subjective satisfaction was 92% in both the groups. One patient in the early group developed chronic regional pain syndrome and another type 4 aseptic loosening. Two elbows in the early group also showed type 1 radiological loosening. Two patients in the delayed group had an infection, two an ulnar nerve palsy, one developed heterotopic ossification and one type 4 aseptic loosening. Two elbows in this group also showed type 1 radiological loosening. The Kaplan-Meier survivorship analysis for the early and delayed treatment groups was 93% at 88 months and 76% at 84 months, respectively. No significant difference was found between the two groups.

Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) is a major complication of cardiac bypass surgery. We examined whether levels of liver fatty acid-binding protein (L-FABP) can be an early biomarker for ischemic injury by measuring this protein in the urine of 40 pediatric patients prior to and following cardiopulmonary bypass surgery. AKI was defined as a 50% increase in the serum creatinine from baseline, which was normally not seen until 24-72 h after surgery. Enzyme-linked immunosorbent assay analysis showed increased L-FABP levels (factored for creatinine excretion) of about 94- and 45-fold at 4 and 12 h, respectively, following surgery in the 21 patients who developed AKI with western blot analysis, confirming L-FABP identity. Univariate logistic regression analyses showed that both bypass time and urinary L-FABP were significant independent risk indicators for AKI. After excluding bypass time from the model and using a stepwise multivariate logistic regression analysis, urinary L-FABP levels at 4 h after surgery were an independent risk indicator with the area under the receiver-operating characteristic curve 0.810, sensitivity 0.714, and specificity 0.684 for a 24-fold increase in urinary L-FABP. Our study shows that urinary L-FABP levels represent a sensitive and predictive early biomarker of AKI after cardiac surgery.

Urinary biomarkers in the early diagnosis of acute kidney injury.

A change in the serum creatinine is not sensitive for an early diagnosis of acute kidney injury. We evaluated urinary levels of matrix metalloproteinase-9 (MMP-9), N-acetyl-beta-D-glucosaminidase (NAG), and kidney injury molecule-1 (KIM-1) as biomarkers for the detection of acute kidney injury. Urine samples were collected from 44 patients with various acute and chronic kidney diseases, and from 30 normal subjects in a cross-sectional study. A case-control study of children undergoing cardio-pulmonary bypass surgery included urine specimens from each of 20 patients without and with acute kidney injury. Injury was defined as a greater than 50% increase in the serum creatinine within the first 48 h after surgery. The biomarkers were normalized to the urinary creatinine concentration at 12, 24, and 36 h after surgery with the areas under the receiver-operating characteristic curve compared for performance. In the cross-sectional study, the area under the curve for MMP-9 was least sensitive followed by KIM-1 and NAG. Combining all three biomarkers achieved a perfect score diagnosing acute kidney injury. In the case-control study, KIM-1 was better than NAG at all time points, but combining both was no better than KIM-1 alone. Urinary MMP-9 was not a sensitive marker in the case-control study. Our results suggest that urinary biomarkers allow diagnosis of acute kidney injury earlier than a rise in serum creatinine.

Regulation of endogenous gene expression using small molecule-controlled engineered zinc-finger protein transcription factors.

Small-molecule-regulated gene expression offers the promise of titrating the dose and duration of action of DNA-based therapies. To this end, we show that engineered zinc-finger protein transcription factors (ZFP TFs) can be coupled with a drug-inducible regulatory domain to permit small-molecule control of endogenous gene transcription. We constructed a drug-responsive ZFP TF via the fusion of a ZFP DNA-binding domain (DBD) targeting the human VEGF-A gene and an effector domain containing a truncated progesterone receptor ligand-binding domain linked to the NFkappaB p65 activation domain. Introduction of this engineered ZFP TF into human or murine cells allowed expression of the chromosomal VEGF-A gene to be induced upon addition of mifepristone, a synthetic steroid analog. Mifepristone-dependent VEGF-A induction was rapid, dose-dependent and reversible. Moreover, stable lines expressing the drug-responsive ZFP TF could be maintained in a state of continuous induction for at least 30 days without loss of viability. Potent VEGF-A induction was demonstrated using different engineered ZFP DBDs, thus this approach may represent a general solution to small-molecule regulation of targeted endogenous genes.

Lubrication regime of the contact between fat and bone in bovine tissue.

Fat pads are masses of encapsulated adipose tissue located throughout the human body. Whilst a number of studies describe these soft tissues anatomically little is known about their biomechanics, and surgeons may excise them arthroscopically if they hinder visual inspection of the joint or bursa. By measuring the coefficient of friction between, and performing Sommerfeld analysis of, the surfaces approximating the in vivo conjuncture, this contact has been shown to have a coefficient of friction of the order of 0.01. The system appears to be lubricated hydrodynamically, thus possibly promoting low levels of wear. It is suggested that one of the functions of fat pads associated with subtendinous bursae and synovial joints is to generate a hydrodynamic lubricating layer between the opposing surfaces.

Reconstruction of disruptions of the deep transverse metacarpal ligament of the ring finger using the A1 pulleys.

There is little information in the literature regarding the clinical features, investigation, diagnosis and treatment of closed rupture of the deep transverse metacarpal ligament. We demonstrate a case with previously undescribed features and describe the surgical management.

Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). The lack of early biomarkers for AKI has impaired our ability to intervene in a timely manner. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is recently demonstrated as an early biomarker of AKI after CPB, increasing 25-fold within 2 h and declining 6 h after surgery. In the present study, we tested whether interleukin-18 (IL-18) is a predictive biomarker for AKI in the same group of patients following CPB. Exclusion criteria included pre-existing renal insufficiency and nephrotoxin use. Serial urine samples were analyzed by enzyme-linked immunosorbent assay for IL-18 in 20 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 35 controls (age, race, and gender-matched patients who did not develop AKI after CPB). Using serum creatinine, AKI was detected only 48-72 h after CPB. In contrast, urine IL-18 increased at 4-6 h after CPB, peaked at over 25-fold at 12 h, and remained markedly elevated up to 48 h after CPB. The performance of IL-18 as demonstrated by area under the receiver operating characteristics curve for diagnosis of AKI at 4, 12, and 24 h after CPB was 61, 75, and 73% respectively. Also, on multivariate analysis, both IL-18 and NGAL were independently associated with number of days in AKI among cases. Our results indicate that IL-18 is an early, predictive biomarker of AKI after CPB, and that NGAL and IL-18 are increased in tandem after CPB. The combination of these two biomarkers may allow for the reliable early diagnosis and prognosis of AKI at all times after CPB, much before the rise in serum creatinine.

The functional anatomy of Kager's fat pad in relation to retrocalcaneal problems and other hindfoot disorders.

Kager's fat pad is a mass of adipose tissue occupying Kager's triangle. By means of a combined magnetic resonance imaging, ultrasound, gross anatomical and histological study, we show that it has three regions that are closely related to the sides of the triangle. Thus, it has parts related to the Achilles and flexor hallucis longus (FHL) tendons and a wedge of fat adjacent to the calcaneus. The calcaneal wedge moves into the bursa during plantarflexion, as a consequence of both an upward displacement of the calcaneus relative to the wedge and a downward displacement of the wedge relative to the calcaneus. During dorsiflexion, the bursal wedge is retracted. The movements are promoted by the tapering shape of the bursal wedge and by its deep synovial infolds. Fibrous connections linking the fat to the Achilles tendon anchor and stabilize it proximally and thus contribute to the motility of its tip. We conclude that the three regions of Kager's fat pad have specialized functions: an FHL part which contributes to moving the bursal wedge during plantarflexion, an Achilles part which protects blood vessels entering this tendon, and a bursal wedge which we suggest minimizes pressure changes in the bursa. All three regions contribute to reducing the risk of tendon kinking and each may be implicated in heel pain syndromes.

Implicit cognition and dissocative experiences as predictors of adolescent substance use.

The present study evaluated the mediating role of implicit cognitive processes in the prediction of alcohol and marijuana use and examined the relationships between dissociative experiences, implicit processes, and sensation seeking in models of drug use and problem experiences. Participants were 467 diverse at-risk adolescents in California. Results from latent variable models revealed that implicit cognition independently predicted alcohol and marijuana use and mediated the predictive effects of sensation seeking on drug use. Dissociative experiences did not predict implicit cognition or drug use in this sample, though this factor was a significant predictor of problem experiences and was positively correlated with sensation seeking. This research provides further evidence suggesting that implicit, associative memory processes are influential in drug-use motivation.

Relation between access to tobacco and adolescent smoking.

OBJECTIVE: To examine the relation between rates of sales of tobacco to minors and youth smoking prevalence. DESIGN: Repeated annual cross sectional surveys. SETTING: Seventy five communities in Oregon. PARTICIPANTS: A random sample of students in grades 8 and 11 (ages 13 and 17 years) and retail outlets in each participating community. MAIN OUTCOME MEASURES: Thirty day and daily smoking prevalence. RESULTS: The rate of illegal merchant sales in the communities was related to the smoking rate for 11th graders in those communities, but not for 8th graders. For every 10% increase in illegal sales rates there was an estimated 0.8% increase in 11th grade 30 day smoking prevalence and a 0.4% increase in daily smoking. Communities with lower illegal merchant sales rates had expanded use of social sources and reduced use of commercial sources by 11th graders, with the opposite pattern seen in 8th graders. CONCLUSIONS: There appears to be a relatively small positive linear relation between the community rate of sales to minors and 11th grade youth smoking prevalence in those communities. Youth adjust their tobacco sources depending on the level of commercial availability.

AICRG, Part III: The influence of antibiotic use on the survival of a new implant design.

PURPOSE: The American College of Surgeons guidelines suggest that complex oral surgery may benefit from prophylactic antibiotic coverage. The use of preoperative antibiotics, postoperative antibiotics, or both during implant placement is a widely accepted practice in the United States, whereas dentists in other countries rarely use antibiotics. PURPOSE: The purpose of this study was to determine if antibiotic coverage at the time of implant placement improves the survival of the Ankylos implant. METHODS: As part of a comprehensive, multicentered, multidisciplinary, prospective, independent, international clinical study, designed and coordinated in the United States by the Ankylos Implant Clinical Research Group (AICRG), the use of preoperative (several regimens) and postoperative antibiotics (yes/no) were carefully documented to assess their influence on improving survival. A total of 1500 Ankylos implants were placed and followed for a period of 3 to 5 years. The decision to use antibiotics and the regimen to be employed was made by the treating surgeon. Failure was defined as removal of the implant for any reason. All data were entered into a computerized database for analysis. RESULTS: The use of preoperative antibiotics produced no significant improvement (P = .21, Fisher's exact test) in survival compared with those placed without antibiotic coverage. There was no significant difference between the regimens defined as AHA-1990, AHA-1997, and Peterson's recommendations. CONCLUSIONS: The results of this study suggest that there was little or no advantage to providing antibiotic coverage when placing this implant. These findings also suggest that the use of antibiotics for implant placement may not be as beneficial as once believed. If validated by other studies, the elimination of this practice for routine implant placement would represent a small but significant step forward in the reduction of unnecessary antibiotic use.

How accurate is partial weightbearing?

The accuracy of partial weightbearing was assessed in six healthy volunteers and 23 patients who had sustained either a fracture of a lower limb or surgery. They were trained to weightbear partially using the conventional bathroom scale method and were assessed in a gait laboratory using force platforms. The amount of weight exerted on the involved limb during three-point crutch walking was determined. Four of six volunteers exerted a mean of 27% of body weight more than required. The remaining two volunteers exerted a mean of 8.5% of body weight less than required. Of the 23 patients, 21 exerted a mean of 35.3% of body weight more than that prescribed and two patients exerted a mean of 11.97% of body weight less than that prescribed. In both groups there was little relationship between the weightbearing prescribed and actual weightbearing. None of the patients or volunteers was able to reproduce the extent of partial weightbearing for which they were trained using the bathroom scale method, confirming that this technique of instructing patients in partial weightbearing is inaccurate.

Merging aquatic and terrestrial perspectives of nutrient biogeochemistry.

Although biogeochemistry is an integrative discipline, terrestrial and aquatic subdisciplines have developed somewhat independently of each other. Physical and biological differences between aquatic and terrestrial ecosystems explain this history. In both aquatic and terrestrial biogeochemistry, key questions and concepts arise from a focus on nutrient limitation, ecosystem nutrient retention, and controls of nutrient transformations. Current understanding is captured in conceptual models for different ecosystem types, which share some features and diverge in other ways. Distinctiveness of subdisciplines has been appropriate in some respects and has fostered important advances in theory. On the other hand, lack of integration between aquatic and terrestrial biogeochemistry limits our ability to deal with biogeochemical phenomena across large landscapes in which connections between terrestrial and aquatic elements are important. Separation of the two approaches also has not served attempts to scale up or to estimate fluxes from large areas based on plot measurements. Understanding connectivity between the two system types and scaling up biogeochemical information will rely on coupled hydrologic and ecological models, and may be critical for addressing environmental problems associated with locally, regionally, and globally altered biogeochemical cycles.

Multiple states in river and lake ecosystems.

Nonlinear models of ecosystem dynamics that incorporate positive feedbacks and multiple, internally reinforced states have considerable explanatory power. However, linear models may be adequate, particularly if ecosystem behaviour is primarily controlled by external processes. In lake ecosystems, internal (mainly biotic) processes are thought to have major impacts on system behaviour, whereas in rivers, external (mainly physical) factors have traditionally been emphasized. We consider the hypothesis that models that exhibit multiple states are useful for understanding the behaviour of lake ecosystems, but not as useful for understanding stream ecosystems. Some of the best-known examples of multiple states come from lake ecosystems. We review some of these examples, and we also describe examples of multiple states in rivers. We conclude that the hypothesis is an oversimplification; the importance of physical forcing in rivers does not eliminate the possibility of internal feedbacks that create multiple states, although in rivers these feedbacks are likely to include physical as well as biotic processes. Nonlinear behaviour in aquatic ecosystems may be more common than current theory indicates.