Circadian blood pressure during the early course of type 1 diabetes. Analysis of 1,011 ambulatory blood pressure recordings in 354 adolescents and young adults

OBJECTIVE Little information is available on the early course of hypertension in type 1 diabetes. The aim of our study, therefore, was to document circadian blood pressure profiles in patients with a diabetes duration of up to 20 years and relate daytime and nighttime blood pressure to duration of diabetes, BMI, insulin therapy, and HbA1c. RESEARCH DESIGN AND METHODS Ambulatory profiles of 24-h blood pressure were recorded in 354 pediatric patients with type 1 diabetes (age 14.6 +/- 4.2 years, duration of diabetes 5.6 +/- 5.0 years, follow-up for up to 9 years). A total of 1,011 profiles were available for analysis from patients not receiving antihypertensive medication. RESULTS Although daytime mean systolic pressure was significantly elevated in diabetic subjects (+3.1 mmHg; P < 0.0001), daytime diastolic pressure was not different from from the height- and sex-adjusted normal range (+0.1 mmHg, NS). In contrast, both systolic and diastolic nighttime values were clearly elevated (+7.2 and +4.2 mmHg; P < 0.0001), and nocturnal dipping was reduced (P < 0.0001). Systolic blood pressure was related to overweight in all patients, while diastolic blood pressure was related to metabolic control in young adults. Blood pressure variability was significantly lower in girls compared with boys (P < 0.01). During follow-up, no increase of blood pressure was noted; however, diastolic nocturnal dipping decreased significantly (P < 0.03). Mean daytime blood pressure was significantly related to office blood pressure (r = +0.54 for systolic and r = +0.40 for diastolic pressure); however, hypertension was confirmed by ambulatory blood pressure measurement in only 32% of patients with elevated office blood pressure. CONCLUSIONS During the early course of type 1 diabetes, daytime blood pressure is higher compared with that of healthy control subjects. The elevation of nocturnal values is even more pronounced and nocturnal dipping is reduced. The frequency of white-coat hypertension is high among adolescents with diabetes, and ambulatory blood pressure monitoring avoids unnecessary antihypertensive treatment.

Change in suicide rates in Switzerland before and after firearm restriction resulting from the 2003 “Army XXI” reform

Objective: Firearms are the most common method of suicide among young men in Switzerland. From March 2003 through February 2004, the number of Swiss soldiers was halved as a result of an army reform (Army XXI), leading to a decrease in the availability of guns nationwide. The authors investigated the patterns of the overall suicide rate and the firearm suicide rate before and after the reform. Method: Using a naturalistic study design, the authors compared suicide rates before (1995–2003) and after the intervention (2004–2008) in the affected population (men ages 18–43) and in two comparison groups (women ages 18–44 and men ages 44–53). Data were received from the Swiss Federal Statistical Office. Interrupted time series analysis was used to control for preexisting temporal trends. Alternative methods (Poisson regression, autocorrelation analysis, and surrogate data tests) were used to check validity. Results: The authors found a reduction in both the overall suicide rate and the firearm suicide rate after the Army XXI reform. No significant increases were found for other suicide methods overall. An increase in railway suicides was observed. It was estimated that 22% of the reduction in firearm suicides was substituted by other suicide methods. The attenuation of the suicide rate was not compensated for during the follow-up years. Neither of the comparison groups showed statistically significant changes in firearm suicide rate and overall suicide rate. Conclusions: The restriction of firearm availability in Switzerland resulting from the Army XXI reform was followed by an enduring decrease in the general suicide rate.

Smoking behaviour, former quit attempts and intention to quit in urban adolescents and young adults: A five-year longitudinal study

OBJECTIVES: To examine smoking behaviour, former quit attempts and intention to quit among Swiss adolescents and young adults over five year's time. STUDY DESIGN: five-year longitudinal study (2003, 2005 and 2008) based on a random urban community sample (N = 1345 complete cases). METHODS: Data were collected by computer-assisted telephone interviews with adolescents (16-17) and young adults (18-24). Main outcome measures included self-reported smoking behaviour, former quit attempts, smoking cessation methods and current intentions to quit smoking. RESULTS: Adolescents were more often non-smokers and less often daily smokers when compared to young adults at baseline (χ(2)(4) = 28.68, P < .001). Their smoking behaviour increased significantly from baseline to follow-up (T = 1445.50, r = .20, P < .001) in contrast to the stable smoking behaviour in young adults (χ(2)(2) = .12, n.s.). In longitudinal analyses young adults were also more stable in their smoking status at the later measurement points. In comparison adolescents changed their smoking status more often being non-smokers at baseline and smokers later on. Independently of the age group, the majority of smokers already had previously attempted to quit (65%) or intended to give up smoking at some point (72%). However only 17% were motivated to make the quit attempt within the next 6 months. Self-quitting was the preferred method, and 25% of the self-quitters had been successful. CONCLUSION: This study illustrates that different developments in smoking behaviour exist in adolescents and young adults. Our study reveals that a majority of smokers are willing to quit but often fail. Furthermore, the data indicates that for adolescents the focus should lie on primary prevention.

Expression and Regulation of Human Cytochrome P450 4F Isoforms in Tissue Samples and Under TNF-Alpha Challenges

CYP4F (Cytochrome P4504F) enzymes metabolize endogenous molecules including leukotrienes, prostaglandins and arachidonic acid. The involvement of these endogenous compounds in inflammation has led to the hypothesis that changes in the inflamed tissue environment may affect the expression of CYP4Fs during the pro-inflammatory state, which in turn may modulate inflammatory conditions during the anti-inflammatory state. We demonstrated that inflamed tissues have different levels of CYP4F isoform expression profiles in a number of human samples when compared to the average population. The CYP4F isoform expression levels change with the degree of inflammation present in tissue. Further investigation in cell culture studies revealed that inflammatory cytokines, in particular TNF-α, play a role in regulating the expression of the CYP4F family. One of the isoforms, CYP4F11, had different characteristics than that of the other five CYP4F family members. CYP4F11 metabolizes xenobiotics while the other isoforms metabolize endogenous compounds with higher affinity. CYP4F11 also was expressed at high quantities in the brain, and was up-regulated by TNF-α, while the other isoforms were not expressed at high quantities in the brain and were down-regulated by TNF-α. We identified the AP-1 protein of the JNK pathway as the signaling protein that causes significant increase in CYP4F11 expression. Since TNF-α stimulation causes a simultaneous activation of both JNK pathway and NF-κB signaling, we investigated further the role that NF-κB plays on expression of the CYP4F11 gene. We concluded that although there is a significant increase in CYP4F11 expression in the presence of TNF-α, the activation of NF-κB signaling inhibits CYP4F11 expression in a time dependent manner. The expression of CYP4F11 is only significantly increased after 24 hours of treatment with TNF-α; at shorter time points NF-κB signaling overpowers the JNK pathway activation. We believe that these findings may in the future lead to improved drug design for modulating inflammation.

Functional analysis of histones H3 and H4 in Tup1 repression and in GCN5 activation

Tup1 forms a complex with Ssn6 in yeast. Ssn6-Tup1 complex is recruited via direct interactions with specific DNA binding proteins to a specific promoter region and mediates repression of several sets of genes including a-cell specific genes (asg) in $\alpha$ cells. It has been shown that repression of asgs also requires histone H4 and that Tup1 can directly interact with H3 and H4 in vitro. To address whether histone H3 is required for the repression of asgs, I have examined the effect of H3 and H4 mutations on the expression of a $\alpha$2-controlled LacZ reporter. Assay of $\beta$-glactosidase shows that mutations in either H3 or H4 cause a weak derepression of the reporter gene. Some double mutations result in a stronger derepression, while others do not. The H3 N-terminal deletion also leads to a slightly decreased expression of the reporter gene in $\alpha$ cells. Our data suggest that the N-termini of both H3 and H4 are cooperatively involved in the repression of a-cell specific genes in $\alpha$ cells, possibly through their interaction with Tup1.^ GCN5 was originally identified as a transcriptional regulator required to activate a subset of genes in yeast. Recently, it has been shown that GCN5 encodes the catalytic subunit of a nuclear histone acetyltransferase, providing the first direct link between histone acetylation and gene transcription. Recombinant Gcn5p (rGcn5p) exhibits a limited substrate specificity in vitro. However, neither the specificity of this enzyme in vivo nor the importance of particular acetylated residues to transcription or cell growth are well defined. In order to define the sites of histone acetylation mediated by Gcn5p in vivo and assess the significance of histone acetylation, more than 30 yeast strains have been constructed to bear specific H3 and/or H4 mutations in the presence or absence of GCN5 function. Our genetic data suggest that Gcn5p may have additional targets in vivo that are not identified as the targets of rGcn5p by previous studies. Western analysis using antibodies specifically recognizing particular acetylated isoforms of H3 and H4 led us to conclude that Gcn5p is necessary for full acetylation of multiple sites in both H3 and H4 in vivo. Consistent with these observations, rGcn5p still acetylates histones H3 and H4 bearing mutations either in H3 K14 or H4 K8,16, sites previously identified as the targets of acetylation by rGcn5p in H3 and H4. Our data also demonstrated that Gcn5p-mediated acetylation events are important for normal progression of the cell cycle and for transcriptional activation. Furthermore, a critical overall level of acetylation is essential for cell viability. ^

User Created Content in Virtual Worlds and Cultural Diversity

User created content (UCC) has often been celebrated as a grassroots cultural revolution that as a genuine expression of creativity, localism and non-commercialism can arguably also cater for a sustainable culturally diverse environment. The present article puts these claims under scrutiny and in a more differentiated manner seeks to identify the value of UCC within digital game environments considering the constraints upon players and upon creative play that these impose. The article subsequently tests whether UCC in its dynamic sense of a creative and communicative process can be seen as a channel for the promotion of cultural diversity and if so, what the State should (and could) do about this.

Early adolescents' enjoyment experienced in learning situations and its relation to student achievement

While many studies confirm that positive emotions, including enjoyment, lead to better student achievement, less empirical evidence exists about possible mediator variables that link achievement to enjoyment. It is proposed that achievement and enjoyment form a circular dependency; enjoyment in learning leads to higher achievement but a degree of achievement is required to enjoy learning. This study provides insight into the reverse of the much studied enjoyment to achievement link and provides practical recommendations on how to use these findings. Founded in Control-value theory, which suggests that control and value cognitions are important variables that mediate the connection between enjoyment and achievement, this study explores the reciprocal achievement-cognition-enjoyment link. The reciprocal link was investigated by applying a one year longitudinal design to students of grade 6 and 7 (N = 356). This age group was chosen because early adolescence represents a critical period during which a strong decrease in positive learning emotions is observed. Part of the work involved identifying factors that might be responsible for this negative development. Results of cross-lagged path analysis identified reciprocal effects between student achievement and enjoyment with control and value cognitions functioning as partial mediators. High achievement goes with high control and value cognitions, which in turn positively affect enjoyment. However, cross-lagged correlations could only be partly confirmed. The results are discussed in terms of theoretical and practical implications.

Randomized comparison of biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents for percutaneous coronary revascularization: Rationale and design of the BIOSCIENCE trial

Background Biodegradable polymers for release of antiproliferative drugs from metallic drug-eluting stents (DES) aim to improve long-term vascular healing and efficacy. We designed a large scale clinical trial to compare a novel thin strut, cobalt chromium DES with silicon carbide coating releasing sirolimus from a biodegradable polymer (Orsiro, O-SES) with the durable polymer-based Xience Prime everolimus-eluting stent (X-EES) in an all-comers patient population. Design The multicenter BIOSCIENCE trial (NCT01443104) randomly assigned 2,119 patients to treatment with biodegradable polymer SES or durable polymer EES at 9 sites in Switzerland. Patients with chronic stable coronary artery disease or acute coronary syndromes, including non-ST-elevation and ST-elevation myocardial infarction, were eligible for the trial if they had at least one lesion with a diameter stenosis >50% appropriate for coronary stent implantation. The primary endpoint target lesion failure (TLF) is a composite of cardiac death, target-vessel myocardial infarction, and clinically-driven target lesion revascularization within 12 months. Assuming a TLF rate of 8% at 12 months in both treatment arms and accepting 3.5% as a margin for non-inferiority, inclusion of 2,060 patients would provide 80% power to detect non-inferiority of the biodegradable polymer SES compared with the durable polymer EES at a one-sided type I error of 0.05. Clinical follow-up will be continued through five years. Conclusion The BIOSCIENCE trial will determine whether the biodegradable polymer SES is non-inferior to the durable polymer EES with respect to TLF.

Endogenous nitric oxide production in canine osteoarthritis: Detection in urine, serum, and synovial fluid specimens

OBJECTIVE To measure nitric oxide (NO) concentrations in serum, urine, and synovial fluid (SF) of dogs with naturally occurring cranial cruciate ligament (CCL) rupture and normal dogs, and to compare these with clinical and histologic changes of osteoarthritis (OA). STUDY DESIGN Prospective clinical study including 2 groups of animals selected from the hospital population. ANIMALS Forty-three dogs (CCL group) with OA secondary to CCL rupture; 30 healthy dogs (control group) without CCL rupture. METHODS Serum, urine, and SF were collected before and during surgery in the CCL group or immediately after euthanasia in the control group. Articular cartilage and synovial membrane tissue specimens were prepared for routine histologic examination. The stable end products of NO, total nitrite and nitrate (NOt) activity, were measured in body fluids and compared with macroscopic and histologic degrees of OA. Urinary NOt concentration was compared with urinary creatinine concentration and stated as urinary NOt:creatinine ratio (UNCR). RESULTS-SF NOt concentrations were not significantly different between the 2 groups. Serum NOt concentrations (45.6 vs 28.9 micromol/L; P =.042) and the UNCR (0.007 vs 0.004; P =.035) were significantly higher in dogs of the CCL group compared with the control population. An association between UNCR and histologic and macroscopical OA grades could be demonstrated. CONCLUSION UNCR might be a useful indicator of nitrite and nitrate production and, therefore, osteoarthritic changes in joints. CLINICAL RELEVANCE UNCR could be used as a tool to evaluate the NOt production by joint tissues over time and might therefore provide a method of evaluating the effects of drugs in the control of osteoarthritis.

Self-esteem, coping styles, and quality of life in polish adolescents and young adults with unilateral cleft lip and palate.

Objectives : To evaluate self-esteem, coping styles, and health-related quality of life and their relationships in Polish adolescents and young adults with unilateral complete cleft lip and palate and related sex differences. Design and Participants : Self-report questionnaires measuring self-esteem (Multidimensional Self-Esteem Inventory), coping styles (Coping Inventory for Stressful Situations), and health-related quality of life (WHOQOL-BREF) were completed by 48 participants with cleft lip and palate (age, 16 to 23 years; 31 males, 17 females) and 48 controls without cleft lip and palate (age, 16 to 23 years; 28 males, 20 females) matched for age, place of residence, and socioeconomic status. Results : Regarding self-esteem, individuals with cleft lip and palate scored higher on body functioning (P < .01) and defensive self-enhancement (P < .05). Self-control showed an interaction effect: Females with cleft lip and palate scored higher than controls, but males did not differ between groups (P < .05). Males with cleft lip and palate scored lower than controls in personal power but higher in body functioning (P < .05); females showed no differences between groups. The groups did not differ with regard to coping styles or quality of life, but several correlations were found between self-esteem and coping styles, and quality of life (P < .01). Conclusions : Late adolescents and young adults with and without cleft lip and palate differed little in terms of psychological adjustment measures. The higher scores in defensive self-enhancement of individuals with cleft lip and palate suggest the need for instruments measuring social approval in psychosocial adjustment research involving this group.

Individual differences in inhibitory control - relationship between baseline activation in lateral PFC and an electrophysiological index of response inhibition

The capacity to inhibit inappropriate responses is crucial for goal-directed behavior. Inhibiting such responses seems to come more easily to some of us than others, however. From where do these individual differences originate? Here, we measured 263 participants' neural baseline activation using resting electroencephalogram. Then, we used this stable neural marker to predict a reliable electrophysiological index of response inhibition capacity in the cued Continuous Performance Test, the NoGo-Anteriorization (NGA). Using a source-localization technique, we found that resting delta, theta, and alpha1 activity in the left middle frontal gyrus and resting alpha1 activity in the right inferior frontal gyrus were negatively correlated with the NGA. As a larger NGA is thought to represent better response inhibition capacity, our findings demonstrate that lower levels of resting slow-wave oscillations in the lateral prefrontal cortex, bilaterally, are associated with a better response inhibition capacity.

Influence of screw augmentation in posterior dynamic and rigid stabilization systems in osteoporotic lumbar vertebrae: a biomechanical cadaveric study.

STUDY DESIGN Biomechanical cadaveric study. OBJECTIVE To determine whether augmentation positively influence screw stability or not. SUMMARY OF BACKGROUND DATA Implantation of pedicle screws is a common procedure in spine surgery to provide an anchorage of posterior internal fixation into vertebrae. Screw performance is highly correlated to bone quality. Therefore, polymeric cement is often injected through specifically designed perforated pedicle screws into osteoporotic bone to potentially enhance screw stability. METHODS Caudocephalic dynamic loading was applied as quasi-physiological alternative to classical pull-out tests on 16 screws implanted in osteoporotic lumbar vertebrae and 20 screws in nonosteoporotic specimen. Load was applied using 2 different configurations simulating standard and dynamic posterior stabilization devices. Screw performance was quantified by measurement of screwhead displacement during the loading cycles. To reduce the impact of bone quality and morphology, screw performance was compared for each vertebra and averaged afterward. RESULTS All screws (with or without cement) implanted in osteoporotic vertebrae showed lower performances than the ones implanted into nonosteoporotic specimen. Augmentation was negligible for screws implanted into nonosteoporotic specimen, whereas in osteoporotic vertebrae pedicle screw stability was significantly increased. For dynamic posterior stabilization system an increase of screwhead displacement was observed in comparison with standard fixation devices in both setups. CONCLUSION Augmentation enhances screw performance in patients with poor bone stock, whereas no difference is observed for patients without osteoporosis. Furthermore, dynamic stabilization systems have the possibility to fail when implanted in osteoporotic bone.

Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis.

Idiopathic pulmonary fibrosis (IPF) and bleomycin-induced pulmonary fibrosis are associated with surfactant system dysfunction, alveolar collapse (derecruitment), and collapse induration (irreversible collapse). These events play undefined roles in the loss of lung function. The purpose of this study was to quantify how surfactant inactivation, alveolar collapse, and collapse induration lead to degradation of lung function. Design-based stereology and invasive pulmonary function tests were performed 1, 3, 7, and 14 days after intratracheal bleomycin-instillation in rats. The number and size of open alveoli was correlated to mechanical properties. Active surfactant subtypes declined by Day 1, associated with a progressive alveolar derecruitment and a decrease in compliance. Alveolar epithelial damage was more pronounced in closed alveoli compared with ventilated alveoli. Collapse induration occurred on Day 7 and Day 14 as indicated by collapsed alveoli overgrown by a hyperplastic alveolar epithelium. This pathophysiology was also observed for the first time in human IPF lung explants. Before the onset of collapse induration, distal airspaces were easily recruited, and lung elastance could be kept low after recruitment by positive end-expiratory pressure (PEEP). At later time points, the recruitable fraction of the lung was reduced by collapse induration, causing elastance to be elevated at high levels of PEEP. Surfactant inactivation leading to alveolar collapse and subsequent collapse induration might be the primary pathway for the loss of alveoli in this animal model. Loss of alveoli is highly correlated with the degradation of lung function. Our ultrastructural observations suggest that collapse induration is important in human IPF.

The Beach in Anglophone Literatures and Cultures: Reading Littoral Space

From early colonial encounters to the ecological disasters of the twenty-first century, the performativity of contact has been a crucial element in the political significance of the beach. Conceptualising the beach as a creative trope and as a socio-cultural site, as well as an aesthetically productive topography, this collection examines its multiplicity of meanings and functions as a natural environment engendering both desire and fear in the human imagination from the Victorian period to the present. The contributors examine literature, film, and art, in addition to moments of encounter and environmental crisis, to highlight the beach as a social space inspiring particular codes of behaviour and specific discourses, as a geographical frontier between land and water, as an historical site of contact and conflict, and as a vacationscape promising regeneration and withdrawal from everyday life. The diversity of the beach is reflected in the geographical range, with essays on locales and texts from Britain, Ireland, the Caribbean, South Africa, the United States, Polynesia, and New Zealand. Focusing on the changed function of the beach as a result of processes of industrialisation and the rise of a modern leisure and health culture, this interdisciplinary volume theorises the beach as a demarcater of the precarious boundary between land and the sea, as well as between nature and culture.

Evaluating an e-mental health program (“deprexis”) as adjunctive treatment tool in psychotherapy for depression: design of a pragmatic randomized controlled trial

Background Major depressive disorder (MDD) places a significant disease burden on individuals as well as on societies. Several web-based interventions for MDD have shown to be effective in reducing depressive symptoms. However, it is not known whether web-based interventions, when used as adjunctive treatment tools to regular psychotherapy, have an additional effect compared to regular psychotherapy for depression. Methods/design This study is a currently recruiting pragmatic randomized controlled trial (RCT) that compares regular psychotherapy plus a web-based depression program (¿deprexis¿) with a control condition exclusively receiving regular psychotherapy. Adults with a depressive disorder (N?=?800) will be recruited in routine secondary care from therapists over the course of their initial sessions and will then be randomized within therapists to one of the two conditions. The primary outcome is depressive symptoms measured with the Beck Depression Inventory (BDI-II) at three months post randomization. Secondary outcomes include changes on various indicators such as anxiety, somatic symptoms and quality of life. All outcomes are again assessed at the secondary endpoint six months post randomization. In addition, the working alliance and feasibility/acceptability of the treatment condition will be explored. Discussion This is the first randomized controlled trial to examine the feasibility/acceptability and the effectiveness of a combination of traditional face-to-face psychotherapy and web-based depression program compared to regular psychotherapeutic treatment in depressed outpatients in routine care.